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I
RF_DR_16_SUDHA
G.P.O. Box 134
Baroda 390 00'’
C' ‘ ■'M'TTED TO THE
MEDiClNE
K
MINUTES OF THE MEETING OF RATIONAL THERAPY CELL HELD
ON 5/10/1986 AT
BOMBAY
Those who were present t the meeting were - Y.K. Amdekar,
Satish Tibrewala, Anita Srivastava, Ashwin Patel, Anil
Pilgaonkar, Raj Anand, Satish Abhyankar, Arun Bal, Nimitta,
Srinivasan, Ravindra Pathak,T.R. Krishnaswamy and Arvind Jha
(for part of the meeting)..
1)
Agenda s
The proposed agenda for the meeting was - a) Quality Control
for LOCOST, b) Rationality of Multivitamin preparations
c) Ravindra Pathak’s suggestion about Female foeticide issue
and the studies conducted by his students d) Reporting about
research projects of LOCOST and e) Next meeting - date and
topics for discussion.
2)
Next Meeting g
The meeting started with a brief discussion on the theme for
next meeting. Agenda decided are s
a) Rationality of M.v. Preparations, Part II
In Adults and
Part III - The Pharmacological Aspects - papers to be pre
pared by Jitendra Lakhani and Sagun Desai respectively.*
b)
Irrationality in the uses of Oestrogen and Progesterone
drugs - paper to be prepared by Catish Tibrewala.
THS~ NEXT MEETING OF RTC IS SCHEDULED TO BE HELD ON DECEMBER 7TH
AT BARODA.
---- 3)
Quality Control of Drugs g
A background paper on the subject was prepared by .
Mr. T.R. Krishnaswamy (Retd. All India Quality Control Director,
Wyeth Labs Bbmbay) ,, and was circulated in advance.
It was pointed out that in case of drugs, quality control has
to be exercised at every level ; the raw material used, the
excipients used, the equipment, the packing, personal hygiene
of the workers and finally the product. Certain problems like
disintegration time and other physical defects of the final
product can be corrected by redoing the product only in case
the excipients etc., are upto the standard, otherwise the
final product will have to be destroyed totally which means
lot of wastage.
The person who weighs the ingradients should have enough
training and should also know the physical and chemical impli
cations of mixing them in certain order. However, it was not
clear whether it is mandatory to employ a formally trained
person for this purposeo
Certain benefits- of LOCOST having its own quality control
laboratory were expressed by the group. It adds credibility to
our product; costs of the tests may be reduced; this will serve
as a neutral laboratory for various levels of organisations and
consumers as well as some honest manufacturers; etc^
However, a need was expressed that before going for our own
laboratory, we need to establish the case for a quality lab
more systematically and also think of possible clientele. If
we would start giving independent and true results, not many
contd.•o a.2
4
/2/
■
4
manufacturers will come forward to use our services. The
laboratory may lose its viability if it has to depend only on
the requirements of the consumer and other social organisations.
If necessary LOCOST should take up a small study in this regard
and generate original’data.
It was pointed out by one member of the group that the results
of the Italab are also often not very reliable. In such circum
stances a need for a neutral and competent laboratory outside
the alternative of LOCOST having its own laboratory was also
realised. We may need to compare and see also whether quality
of our results are reliable technically. One member suggested
that the laboratory of Nagpur Pharmacy College is approved by
F.D.A. and we may use it in some cases at least.
Some other practical issues like space and equipment specifi
cations were also discussed.. However a need to find out the
mandatory requirements laid down by the Govt, was also expressed.
A suggestion was also made that the Quality Control Laboratory
project could also be made independent of LOCOST.
4)
Rationality of
Preparations s
Part I of this paper about myths of M.V. in children prepared
by Anita was discussed in detail.
Th© group recognised the need for vitamins in the life of a
human being. The issue at hand was whether we need to supple
ment the diets of children by giving mixture of all vitamins
or improve the dietary habits ? If at all we need the M.V.
preparations what should be the exact dosage and ideal preparations?
It was pointed out that generally the infants do not require
any vitamin supplementation during the first four months of their
life, After that the best strategy would be to give supplements
to the lactating mother and not to the child 'directly. However,
in case of very malnourished child or mother we may have to have
a different strategy<. i.e, the child may be given some vitamins
as supplements.
One member pointed out that in general clinical practice we do
not give M.V. to the children and treat only those with frank
deficiencies by individual vitamin supplements. It was felt
by the group that this was the correct strategy.
Most MV preparations available in the market are not appropriate
for giving us supplements because they contain too high quanti
ties of vitamins, which is not required, and results into wastage.
It must be considered that the child on normal dietary habits does receive certain amount of the re juirements from the diet.
So the supplement must contain little lower concentrations
than the R.D.A.
A study was also quoted where a periodical prophylactic supplement of MV is recommended. Howeverz the group could not resolve
how the periodical supplements of water soluble vitamins could
help the daily requirements.
It was also suggested that more information must ^e obtained from
WHO or other sources on whether the use of MV is indicated at all.
The WHO essential drug list does not recommend the MV preparations
zAlso, the WHO literature does not recommend
any specific use of
such mixtures either in pediatric or geriatric population.,
contd.o.o o 3
/3/
♦
4
Soma discussions on rationale of giving individual vitamins
in case of multi deficiency states also took place. The
group felt that this may prove even cost beneficial because
the cost of preparing a mixture of vitamins could be higher
because of some complex manufacturing processes. Also by
adopting this method one can save the patient from what he/she
is being given but actually does not require.
5)
Vitamin A s
Among all vitamins. Vitamin A needs special attention. A
UNICBF study was quoted wherein they have shown that Vitamin A
prophylaxis to a malnourished child is able to reduce the infant
mortality and morbidity by lowering the incidence of gastric
infections. Same study also shows its value in prevention of
illness related to eyes like xerophthalmia. The UNICEF reco
mmendations for mass prophylaxis of xerophthalmia programme
were found to be ideal by the group. However, it was pointed
out by one member that giving massive doses of the vitamin
results into more wastage than giving supplements every day.
This is because the vitamin gets oxidised in the body and the
degradation is faster in the oxidised state. However, exact
quantification of how much wastage is involved in such a stra
tegy is not known. Even if this was true, in a country like oi..rs,
it is more practicable to give the mass prophylaxis with massive
doses than to give individual supplements every day. There
is enough epidemiological evidence to show that the mass prophy
laxis programme is able to protect the particular population
from developing deficiency.
6)
Vitamin B-Complex s
It was agreed upon that there are some clinical situations when
there is deficiency of the whole group of B - vitamins. In
such cases one may need to use B-Complex as a combination
However, the group unanimously rejected the use of popular
combination of
, and Bj_2 vitamins as this is not indi
cated in any conditionThe group examined the rationality
of giving pyridoxin with'INH therapy in Tuberculosis. While
some members said this was not necessary at all, it was also
pointed out that the combination is not only allowed, but.
widely recommended in some of the literature. This requires
further discussion and the group felt that the question of
bioavailability in presence and absence of pyridoxin may be
examined by Sagun in Part III of this paper.
Other issues like absorption of Vit. B2.2 uss of folic acid
in management of threatened abortion etc., will, also be
covered in the other part of the paper by Lakhani and Sagun
Little mention of the sprouted pulses, vegetables and other
seasonal foods as ideal and natural sources of vitamins was
also made. The wheat grass therapy and its scientificity as
a natural source of vitamin could not be ascertained due to
lack of enough information.
7)
i
Female foeticide ;
Ravindra Pathak reported the magnitude of this problem in
Bombay city. It is estimated that at least 40000 to 50000
female foeticides per year takes place in Bombay itself,. with
the help of the sexpredetermination technology. He reported
that womens* activist groups in Bombay have been organising
mass campaigns against this. A ban on this technology is also
being adovocated. However, the campaign to restrict the use of
contdo o
.4
f
>
/4/
this technology for detecting congenital deformities in
suspect cases only
is also being held, There is also a
demand to -- ’,oan on abortions ---put a
after such a
a test.
test. Various
forums are <organising public debates in this regard.
regard. Recently
& young doctors
_ors group in Bombay has also become
’’
—e active
in this
campaign, r
He explored the possibilities whether
LOCOST
whether LOCOST as a
group may participate in this <campaign or initiate similar
campaign in Gujarat. There are- it
many such clinics for sexpredetermination in Gujarat also, Vasu Pharma of Baroda is
manufacturing a drug which claims a promise treatment
to
have male progeney.
Can we expose these claims ?
expectations
• a) Will LOCOST collect
sionatur^iC e
*pecytions were
we^e on this issue from lay
‘ ‘‘L-t as much information
/ advertisements,
interest litigation in this
responded
Dy say
is not
not v
y^-oup
-x
j-7■*. mg that
-- - LOCOST
'-'‘-'i is
very close network
t-n
--‘
campaign
in
such
issues!
T.
other oraani-att^ camp^i9n ln
issues. However there are
other organisations mi Gujarat
GVHA which
could do so
Gujarat like
like GVHA
which could
JnWZt^S2?eld -^
1?-such
SUCh an action
acti-ch as it^uld
help
manner.
9?j-- xs-- pro^
Ravindra also said that: in his capacity of a teacher in
Pharmacy College he has guided some students to take up the
rationality studies of ■anticough preparations, anticold preparations, ORS, etc, from the pharmaceutical
------ point of view,
He would appreciate if the group can give
their detailed
comments in this regard, It was decided that the three
studies he has <already
sent to LOCOST is seen by some of us
and they will be further
circulated to other members of the
group at Baroda,
Detailed comments will
_1_ be given to him in
due course.
ofhfocoS^a^o1^?0^ StatUS °f VarioUS res^rch projects
or uocotT also took place at the meeting.
,**.**********,**i*******l******
A CORRECTION
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One of our earlier communications
communications quoted
quoted that
that the
the
cost of visit by a medical representative —
ini rBombay
’
to a n?
doctor
Josh
C^°^works
WOrk- °Ut
be
30/“ excluding the'
of gifts ano samples. Please
note that
that this
this
Please note
estimate includes the cost of samples and not that
of gifts.
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ng
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■- i s---’86 to Feb. 28.,
9 A.M. to 4-30 P.M«
)urs ■
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RATIONALITY OF
MULTIVITAMIN
PREPARATIONS
Part-l-.r. The Myths...of Multivitamins of children
Dr. Anifa Srivastava
The word "VITAMIN" refers to organic compounds which are required
in minute amounts to catalyse cellular metabolism essential for
They must be supplied
maintenance or growth of the organism
wholly or in part exogenously.
Recommendstions for daily intake of Vitamins
(1)
mgo
Ascorbic
Acid
mg.
D
IU
mg.
0.6
8
35
400
0.4
0.7
0.8
9
45
400
0.8
-i 5 1650
0.8
400
1.2
1.3
1.5
11
16
40
6 - 9 2300
10 -12 3300
13 -15 3300
0.8
1.4
400
1.6
1.7
18
18
45
50
60
0.8
1.0
400
400
1.2
1.4
Age
A
Thiamine
Ribof laviin
Year
IU
mg.
mg.
1 year 1300
2 - 3 1300
0.5
4
Niacin
(Recommended Dietary Allowances, Revised 1980, National Research
Council, National Academy of Sciences).
Properties and Food Sources of the Vitamins (1)
Vitamin A
Provitamin A
; Retinol
Plant pigments. Alpha, Beta
and cryptoxanthines.
and Gama carotenes
Characteristics s Fat soluble
Effects of deficiency s
Nyctalopia, Xerophthimia-,. Keratomalacia,
leading to blindness faulty epiphyseal bone formation defective
tooth enamel, Keratinisation of mucous membranes and skiq retarded
growth.
Effects of Excess s Dietary excess of Vitamin A-unlikely. Excessive
carotene intake may produce carotenemia with xanthosis cutis, There
is individual variation in sensitivity to high intakes of Vit. A
concentrates.
50,000 I.U. taken daily for prolonged period may be toxic and cause
Anorexia, slow growth, drying and crackling of skin, enlargement of
liver and spleen, swelling and pain of long bones, bone rragility,
increased intracranial pressure.
Recommended allowances s Upto 1 year-1500 lU/day; 1-2 years 2000 lU/day, increasing to 4500 IU with age^over 12 years-5000
lU/day. These amounts assume that 2/3 comes from the provitamins,
which are less efficiently utilised than the vitamin.
If only
Vitamin A is taken,then 900 to 3000 lU/day would suffice.
contd.... 2
/2/
Sources §
Liver, fish liver oils, whole milk, milk fat products,
egg yolk, carotenoids from plants - green vegetables, yellow fruits
and vegetables.
VITAMIN B COMPLEX
COBALAMIN s Group of complex coordination compounds of Cobalt
Vitamin B12"
Characteristics s
Slightly soluble in water
destroyed by light.
Effects of deficiency : Jufenile pernecious anemia.
Effects of excess s
Unknown
Recommended allowances s Infants s 1-2 micrograms.
Children (1-18 years) 2-5 micrograms,
muscle and organ meatst fish, eggs, milk, cheese.
Sources
86
3
3 active forms -pyridoxin, pyridoxal and
pyridoxamin
Characteristics s Water solublem,destroyed by ultraviolet light
and
by heat.
Effects of deficiency
Infants - irritability, convulsions,
hypochromic anemia, perepherel neuritis in patients receiving INH.
Effects of excess s
Unknown.
Recommended allowances s Infants - 0.2 to 0.4 mg.
Children - 1 to 10 years s 0.5 to 1.2 mg, 10 - 18 ye.rss 1.4 to 1.8 mg.
If abnormal
Bg metabolic state exists 5 - 10 mg.
Sources s Meat, liver, kidney, whole grains, peanuts, soyabeans.
FQLACIN
Characteristics s Slightly soluble in water, labile to heat and light
Effects of deficiency 33
Megaloblastic anemia particularly in
infancy and pregnancy.
Effects of excess s Unknown
20-50
Recommended allowances s
microgram/day
Sources :
Liver, green vegetables, nuts. cereals, cheese.
.NIACIN s
Nicotinamide, nicotinic acid.
Characteristics s
Water soluble, heat and light stable
Effects of deficiency s Pellagra
Effects of excess 3 Nicotinic acid (not the amide) is vasodilator,
reactions include skin flushing and itching, circulatory disturbances
increased peristalsis.
Recommended allowances s 6.6 mg/1000 calories
Sources s Meat, fish, paultry, liver, whole grain and enriched
cereals, green vegetables, peanuts, protein food in general, from
conversion of tryptophone (60 mg from 1 mg of niacin)
contd.....3
/3/
Vitamin B2
‘ RIBOFLAVIN, s
Characteristics :
Sparingly soluble in water/ sensitive to light/
stable to heat
Effects of deficiency s Ariboflavinosis; early symptoms are
photophobia/ blurred vision, burning and itching of eyes, cprneal
vascularisation poor growth. One of the most common dietary
inadequacies often accompanying other B vitamin deficiencies.
Effects of excess s Not harmful
Recommended allowances s 0.025 mg/gm of dietary protein
Milk, cheese, liver and other organs, meats, eggs, fish,
Sources s
green leafy vegetables, whole or enriched grains.
s Vitamin Bi
THIAMIN
Characteristics s Water soluble/ heat labile
Effects of deficiency s
Effects of excess s
Beriberi
None from oral
intake
Recommended allowances s 0.4 mg/1000 Kcal
Sources s Liver, meats, esp. pork, milk, whole grain or enriched
legumes, pests.
cereal. wheat germ,
*
BIOTIN 2
(Please refer page No. 14)
Characteristics s Water soluble, crystallised from yeast
Effects of deficiency s Dermatitis/ Seborrhoea
Effects of excess s Not known
Recommended allowance ;
Source s Yesst/ animal products/ synthesised in intestines.
VITAMIN C
Ascorbic Acid
Characteristics s
Water soluble/ easily oxidised
Effects of deficiency s
Effects of excess s
Scurvy and poor wound healing
Notj harmful
Recommended allowances s 35 to 60 mg depending on age and sex
Sources s Citrus fruits. Tomatoes, berries, cabbage, green vege
tables, cooking has deleteriaes effects.
Group of sterols having similar physiological activity.
VITAMIN-
02
- Calciferol is activated ergosterol
D3
- is activated 7 dehydrocholesterol
Characteristics ;
Fat soluble/ stable to heat and oxidation *
contd
4
/4/
Effects of deficiency ?
Rickets, infantile tetany poor growth.
osteomalacia.
Effects of excess 2 Vide variation in tolerance.
In general
20,000 to 50,000 lU/day is toxic when continued for weeks (prolonged
administration of 1800 lU/day may be toxic).
Manifestations are nausea, diarrhoea, weight loss, polyuria,
nocturia, eventually ccalcification of soft tissues, including
heart, renal tubules, blood vessels, bronchi, stomach.
Recommended allowances 2
400 lU/day
Sources s Vitamin D fortified ’ . milk and margarine, fish liver
oils, exposure to sun light or other ultraviolet sources.
VITAMIN E s Group of related chemical compounds tocopherols - having
similar biological activity.
Characteristics s Fat soluble, heat stable in absence of oxygen.
Effects of deficiency 2 Anti-oxidant important to cell membrane
integrity, endoplasmic reticulum and mitochondrial oxidative
function.
May be involved in red blood cell
hemolysis in premature
infants
Effects of excess ? Unknown
Recommended allowances 2 Requirements related to polyunsaturated
fats intake.
Infants - 5 IU, Children - 1-6 years s 10 IU
6-10 years 2 15 IU, 10-14 years 2 20 IU, 14-18 years 2 25 IU.
Sources s Germ oils of various seeds, green leafy vegetables.
nuts, legumes.
? Group of compounds, napthoquinones with similar
VITAMIN K
f
biological activity
is phylioquinone
Characteristics s Natural compounds are fat soluble but several water
soluble products have been developed (menadione) stable to heat.
Effects of deficiency s Hemorrhagic manifestations are result of
faulty intestinal synthesis of Vitamin K (new born, prolonged use
of antibiotics)
faulty intestinal absorption or inability to
synthesise prothrombin (hepatic damage) .
Dicumarol and salicy
lates act as .Vitamin K antimetabdlites.
Effects of excess 2 Not established medicinally, may produce
hyperbilirubenemia -in prematures.
Recommended allowances s Not a dietary problem.
appear
to
be adequate.
4
1
1 to 2 mg/day
Sources 2 Green leafy vegetables, pork liver, widely distributed.
contd
5
/^/
The U.S. Food and Drug Administration (FDA)
has estimated that
40% of adults in USA take Vitamin suppiemtns
on a daily basis,
(FDA Drug Buu. 13:27, 1983) most of these
people do not need
vitamins (but multivitamin preparations
can be useful for patients
on highly restricted diets or those with increased nutritional
requirements). Healthy adults on varied diets that maintain
their
body weight ordinarily do not need vitamin supplementations.
PREGNANCY s
Requirements for vitamins, particularly folic acid.
are increased during pregnancy and lactation,
Supplemental vitamins
with iron are often prescribed to
ensure that these requirements
are met, but except for 0.4
mg of folic acid daily throughout gestation (Medical letter 14:50, 1972) there is
no well established need
to take supplements of other vitamins during pregnancy and vitamin
overdosage may be harmful to the fetus. A diet that includes green
or yellow vegetables contain sufficient amounts of Vitamin A and
more than 25,000 IU per day can cause congenital malformation.
Enough Vitamin D to meet requirements can be obtained from seasonal
exposure to sunshine or from four cups daily of vitamin D forti
fied whole or skin milk. Overdose
Overdose of vitamin D in pregnancy can
cause aortic stenosis, hypoparathyroidsu and other
caugenital
malformations in the new born infant. One hundred mg daily of
vitamin C available in one cup of orange juice, i
meets the requirements of pregnant women, more than 1 gram per day
may condition
the ,etus to a high Vitamin C environment and cause scurvy in the
new born (Medical letter 20s65, 1978)
It has been suggested that vitamin mineral supplements may help
prevent several tube defects in the new born (RW Smitheils it al
Lancet, 121027
1983).
.JiiiarrArKILpHOOp 3. All new
Dorn inrants
new born
infants should
should receive
receive Vitamin
K once (0.5 to 1 mg or 1-2 mg orally) to prevent lhemoranagic di se-uso
Premature
infants weighing
less than
Premature infants
weighing less
than 1.5 kg should
receive vitamin E (SOO/t^Ag daily) to prevent hemolytic anemia.
of the new born.
Exclusively breast fed infants may need supplemental vitamin D
(400 lU/day) if they have limited exposure to sunlight. Breast fed
infants whose mothers have been strict vegetarians for several
years may need vitamin B12
66:1015, 1980).
(Committee on Nutritian, Pediotrics
Empirical experience suggests that fully breast fed infants nursed
by reasonably nourished mothers will receive adequate amounts of
nutrients with the possible exception of vitamin D for the first 4
months or sol
in the northern U.S. and Canada there is evidence
to suggest that breast milk may not contain adequate amount of
Vit. D, a supplement approximating the recommended intake level is
contd..0.6
/&/
Most, if not all, infant formulae contain added
.for the
. Supplementation should not be necessary
often suggested.
Vitamin D.
formulated infant except in the case of very law birth weight
or premature infant who consumes much less formula and hence less
Vitamin D and who may have a higher requirement for the vitamin (2).
Table-1
Computed Nutrient Density
Criteria by Level of Coverage
for infants
NUTRIENT
(Units)
ADEQUATE TO'COVER ALL
BUT
50% 25%
10%
2.5%
0
‘ADEQUATE TO COVER ALL
BUT
10%
2.5%
5 0% 25%
15
3
17
5.9 months
19
29
Protein g/1000
kcal
16
18
2.9 months
20
25
Thiamin mg/1000
kcal
0.3
0.34
0.37
0.4
0.3
0.34
0.37
0.4
Riboflavin mg/
1000 kcal
0.38 0.42
0.45
0.5J
0.38 0.42
0.45
0.5
Niacin
Niacin equiv./
1000/kcal
5.5
6.1
6.6
7.1
5.5
6.1
6.6
7.1
Folacin><g/1000
kcal
42
48
55
64
47
54
62
73
Vitamin B12MU/
kcal
0.46 0.55
0.67
0.85
0. 33 0.4
0.48
0.61
Vitamin C mg/
1000/kcal
30
36
44
56
21
26
31
40
Vitamin A
600
Retinol equiv./
1000 kcal
750
900
1150
450
525
650 - 800
Vitamin DHq/1000 15
kcal
19
22
28-
11
13
16
20
Vitamin E mg/1000 4.6
kcal
5.5
6.7
8.5
3.3
4
4.8
6.1
Calcium mg/1000
kcal
540
650
780
990
38
46 0
560
710
Iron mg/lOOOkcal
0.6
1.1
76
47
6.5
54
7.9
49
0.87
65
5.4
Magnesium mg/
1000 kcal
0.72
57
62
10
73
Zinc mg/lOOOkcal
3
3.6
4.4
5.6
3.3
4
4.8
6.1
Vitamin Be>/<g/gm
protein
11.5 12.7
13.8
15
11.5 12.7
13.8
15
6
8 months
11.9 months
9
Protein gm/1000
kcal
16
17
19
22
15
17
19
21
Thiamin mg/1000
kcal
0.3
0.34
0.37
0.4
0.3
0.34
0.37
0.4
Riboflavin mg/
1000/kcal
0.38 0.42
0.45
0.5
0.38 0.42
0.45
0.5
Niacin Niacin
equiv./lOOOkcal
5.5
6.6
7.1
5.5
6.6
7.1
6.1
6.1
contd.... 7
/V
Table
ADEQUATE TO COVER ALL
BUT
5 0% 25%
10%
2.5%
NUTRIENT
(Units)
ADEQUATE TO COVER ALL
BUT
5 0% 25%
10%
2.5%
6 8 months
Folacin
g/1000
kcal
48
55
9
54
63
74
47
0. 29 0. 35
0.42
0.53
0. 24 0. 29
19
23
27
35
16
Vitamin A Retinol 400
eguiv./lOOO kcal
45 0
550
700
Vitamin D/hg/
1000 kcal
9.6
12
14
Vitamin E mg/
1000 kcal
2.9
3.5
Calcium mg/1000
kcal
385
Iron mg/1000 kcal 6.8
Magnesium mg/
48
1000 kcal
Vitamin B12AU/
Zinc mg/lOOOkcal
Vitamin B5 />. g/
gm protein
11.9 months
62
72
0.35
0.45
19
23
29
3 25
400
450
600
18
3.1
9.8
12
15
4.2
5.3
2.4
2.9
3.5
4.5
465
560
710
325
390
470
600
8.1
55
9.8
63
12
74
5.7
41
6.9
8.3
54
11
63
3.5
11,5 12.7
4.2
5.3
15
2.4
3.5
4.5
13.8
15
1000 kcal
Vitamin C mg/
1000 kcal
1 Contd.
2.9
13.8
47
2.9
11.5 12.7
Derived from Recommended Nutrient Intakes for Canadians•
Recent evidence shows that at least the first four months of life,
full breast feeding by an adequately nourished mother gives assurance
of adequate nutrient intake for almost all infants. This 'epidemio
logical evidence may suggest that there is need to reconsider some
of the current estimates of infant requirement.
(2)
If a formula or a feeding mixture falls seriously short of the
recommended criteria consideration could be given to prophylactic
supplementation.
The level of supplement indicated would be kess
than the recommended nutrient intake, since the formula or mix is
a
mot devoid of the nutrient(s). In such/situation a practical
approach might r'e to offer a supplement every other day or perhaps
twice a week, using the 'usual dose suggested on the label (assu
ming that the 'uaual dose' provided a level of nutrient approximating
the recommended nutrient intake). Judgement on whether or not such
supplementation is indicated could be based on the levels of coverage
recommended in the above Table, as estimates of the likelihood that
the formula or mix is adequate for the infant at hand a random, member
of the population of similar infants.
If the risk is relatively low
the practitioner may deem that the chances of any benefit of supple
mentation is too low to justify either the cost or effort of the
mother. (2)
contd....8
/Q/
Table
2
Approximate composition of Human milk and Coz/’s
milk
Vitamins (litre)
Human milk
Cqw1s milk
Vitamin A (IU)
1898
1025
Thiamine (/Ag)
160
440
Riboflavin (^g)
Niacin (/-<g)
36 0
1470
1750
Pyridoxin (/-fg)
Pantothenate (mg)
100
640
2
52
3
Folacin Qtg)
(1)
940
55
Vitamin C (mg)
Vitamin D (IU)
Vitamin E (mg)
43
22
2
11
14
0.4
Vitamin K
15
60
Some vitamin can interfere with the effect of commonly prescribed
drugs and some drugs may increase the dosage requirements for a
vitamin. Information in this area is still limited however, and
the absence of a listing in the table below does not necessarily
mean that no interaction will occur.,
Table
VITAMIN
Vitamin
Folic acid
DRUG
3
INTERACTIONS (3)
Drug
Interaction
Phenytoin
Decreased phenytoin effects
decreased dietary folate
absorption
Sulfasalazine
decreased dietary folate
absorption
Triamterene
Decreased utilization of
dietary folate
Zinc
Decreased zinc availability
Niacin
Isoniazid
Niacin requirement may be
increased
Pyrcbdoxine
Barbiturates
Contraceptives,
oral
Decreased barbiturate effect
May increase pyridoxine
requirement
May increase pyridoxine- 2
requirement
May increase pyridoxine
requirement
Decrease levodopa effect
(but not with carbidopa)
May increase pyridoxine
requirement
Hydralazine
Isoniazid
Levodopa
Penicillamine
Phenytoin
Decrease phenytoin effect
contd.... 9
/*/
Table
Vitamin
Drug
3 contd.
Interaction
Vitamin A
Anticoagulants,
oral
Increased anticoagulant
effect with large doses
vitamin A
Vitamin C
Anticoagulants,
oral
Occasional decreased anti
coagulant effect
Contraceptives,
oral
Increased serum concentra
tion and possibly adverse
effects of estrogen with
1 gm/day of vitamin C
Estrogens
Increased serum concentra
tion and possibly adverse
effects of estrogens with
1 gram/day of vitamin C
Phenothiazines
Decreased phenothiazine
effect after vitamin C
deficiency corrected
Phenytoin
Decreased activity of vitamin D
Phenobarbital
Decreased activity of
vitamin D
Vitamin E
Oral anticoagu
lants
Increased anticoagulant
effect
Vitamin K
Oral anticoagula
nts
Decreased anticoagulant
effect
Vitamins
Cholestyramine
Decreased vitamin absorption
Decreased vitamin absorption
decreased vitamin absorption
Vitamin D
Fat soluble
Colestipol
Neomycin
Vitamin dependency states require higher than usual dosage of vitamins.
Table
Vitamin
Disease
4
Untreated state
daily
dose
A
Darier
Bi
Leigh-pyruvic-lactic Ataxia/ retardation
acidosis
6 00 mg
Thiamine responsive
anemia
Megaloblastic andmia
20 mg
Maple syrup urine
disease
Hypotonic, seizures
10 mg
Riboflavin
Pyruvate Kinase
deficiency
Hemolysis
10 mg
Niacin
Hartnup
Ataxia, Eczema
■Cystathiaminuria
Homoc .ystinuria
Bg anemia
No symptoms
200 mg
200 mg
200 mg
10 mg
B6
Hyperkeratosis folli- 25/000 IU
aulasis
Retardation
Hypochromic Micro
cytic ar ...mia
contd..,.10
/IO/
Table
Disease
Vitamin
b6
Seizures
4authuremic aciduria
Folic acid
Gyrate atrophy of
choroid
Oxaluria
Formiminotransferece
deficiency
Untreated state
4 contdo
Daily
dose
Seizures
25 mg
retardation
Blindness
10 mg
100 mg
100 mg
Oxalate crystals
Retardation
5 mg
Folate reductase
deficiency
Megaloblastic
anemia
5 mg
Homoc ystinuria
Retardation
10 mg
Methylmalonic
acidemia
Retardation
1 mg
Propionic acidemia
Retardation
10 mg
Beta Methylcrotonyl
glycinuria
Cama
10 mg
C
Chediak-Higashi
Infections
5 0 mg
D
Dependency
Familial hypophosphateuria
Rickets
b12
Biotin
4000 IU
100000 IU
Rickets
Vitamins in Malnutrition
With an adequate therapeutic regime no specific dietary supplements
are usually needed although they may be employed if a particular
vitamin deficiency is known to be common locally. Therapeutic
doses of vitamin A should be given I.M. initially when occular signs
of vitamin A deficiency are present
because the
lesions can pro
gress very rapidly to irreparable damage. Folic acid administra
tion might be required in cases with megaloblastic anemia. (4)
According to certain surveys, the prevalance rate of B-complex
deficiency is 5% in pre school children and 17.8% in pregnant women
(assessed by the presence of angular stomatitis and glossitis) (9)
The prevalance of vitamin A deficiency is high in the eastern and
southern parts of India and the main suffer er is the underprivileg'-u
The age group most affected in our country is between
1-5 years and as many as 5 - 10 % of the toddlers have been st. ted
class.
to be suffering from clinical deficiency
(10)
Vitamin A Prophylaxis
Prophylaxis should be directed at the ’at risk' situation, Here
again the massive dose is the earliest and most efficient way of
action, ^very marginally fed child suffering from diarrhoea,
apetite reducing pyrexia, measles etc., can be protected at least
from xerophthalmia, by one single therapeutic oral or I.M. dose.
COntdoaoo11
/12/
In adults or older children, a
higher initial dose of 100 mg
could he given without toxic symptoms.
However, in seriously
ill patients, an attempt should be made to inject slowly, part of
the initial dose
. I.V. to get an immediate maximal effect.
In infantile beriberi, which almost occurs among breast fed
infants, mothers should also be treated daily with 50 mg thiamin
orally (or IM for the first few days)
«
Niacin deficiency - Pellagra
10 to 20 mg may be given thrice daily as tablets. Nicotinamide
is preferable as it produces less burning sensation in the skin.
Riboflavin deficiency
Ariboflavinosis is quickly cured by administering 2-5 mg tablets
daily, of the pure vitamin.
Folic
acid deficiency
2-5 mg/day . Treatment should be continued for 3-4 weeks. Satis
factory responses have been obtained with dose of 50/^/day (1)
Vitamin C deficiency - Scurvy
In the established case,large amounts
tablets in a single dose.
upto 1 gm may be given as
There is little to recommend the tra
ditional but cautious administration
of 50-100 mg thrice daily,
unless a loading dose has been previously given.
Vitamin D deficiency - Rickets
(1)
The administration of 1500/tgm of vitamin D in a single dose,
without further therapy for several months is advantagesuus.
This is followed by
more rapid healing
and less ddpendence on
the parents for daily a ministration of the vitamins.
If no hea
ling occurs Rickets is probably resistant to vitamin D.
After
healing is complete vitamin
(l^tg = 40 IU)
D should be lowered to lO/^ig daily,
MISUSE OF MULTIVITAMINS
’’Probably no single class of drug has been the target of as much
quackery, misunderstanding^misrepresentation and misuse as the
vitamins"
(9), Among the pharmaceutical preparations that are
indiscriminately prescribed are the vitamins, particularly those
of the B - complex group.
Patients often come with vague symptoms which can be correlated .
to no known disease. So one usually prescribes a multivitamin or
B-complex preparation because the physician may sincerely believe
that vitamins will help the patient or he may feel compelled to
prescribe something.
contd....13
/Il/
Safeguarding the newborn infant might be achieved by giving him
LUo orally or 3/00/ 000 I«Uo to the lactating mother after
delivery.(4)
d0z 000
Mass prophylaxis of xerophthelmia
has been practiced in India
and Bangladesh in child population between 1 to 4 years every
6 months. The massive dose of 2,00,000 - 3,00,000 of retinol in
oil by mouth is sufficient to maintain a satisfactory serum level
for at least 3 months (it also fills up the liver stores)
(4)
W.H.O. recommends that in areas of the world where vitamin A
deficiency occurs 1,00,000 IU of vitamin A be
given orally in a
water miscible base 4 times yearly.
The same .osa should be given
postpartum to mothers of breast fed infants (1).
THlRAPY in vitamin deficIency diseAses
(4)
Vitamin A deficiency - Xeropthelmia
The purpose of treatment is the rapid restoration of vitamin A
liver stores and its mobilisationi into the blood and lymph streams
Delay for even one day at stage X2 or X3 a when changes are still
reversible. may make all the difference in future vision capacity.
Serious corneal lesions in hospitalised children should be treated
with deep I.M. injection of 2 x 1,00,000 I U. (half in infants under
one year) of the water dispersible preparation for quickest action.
The oil solution is not suitable for parenteral use as the vitamin
is liberated extremely slowly. But the oil solution by the oral
route is next choice . Slight transient signs of toxicity (eg.
vomiting) can be disregarded. (4)
Every confirmed or Rubious corneal lesion of this kind should be
treated
within the
/
it is discovered by any cadre of medical
personnel. Improvement must be evident within 5 days, otherwise
diagnosis becomes doubtful. The nonperforating lesions are easily
reversible.
There is no sense in local application of retinol
preparationso
Thiamine deficiency - Beriberi
In seriously ill patients, 25 mg of Thiamine should be slowly
given I.V., then a further injection of 25 mg should be administered
I.M. Thereafter, 20 mg should be given orally or I.M. once or twice
a day until major symptoms have subsided
after which an oral dose
of 10 mg daily for several weeks should be maintained.
contd,t ,
12
. . Ab
/13/
The
The trouble arises with the dose that is prescribed
physician should realise that in such undefined situation.
The burden rests an him to
know whether he has prescribed the right amount. less or more.
the therapy is purely empirical,
One must differentiate between vitamins taken as nutrients to
those
ward off deficiency and/taken for therapeutic purposes, in esta
blished deficiency.
Since water soluble
vitamins are consi
dered fo be relatively innocuous, the amounts prescribed are very
high.
An argument may be put forward that since water soluble
vitamins are harmless compounds there is no need to raise a hue
and cry about the dosage prescribed. This may be true but,
'such practice is economically wasteful and in same instances,
causes financial hardship’„
Vitamin therapy is often given to patients wit£hgolyneuropathy,
although it is clear that polyneuropathy is
of vitamin
/
due to deficiency
Bi2 nor any other known vitamin. Such treatment has
only a placebo value.
(9)
Several workers have advocated large doses of water soluble group
of vitamin to improve molecular composition and function of brain
and also for schizophrenia. Except at extremely low vitamin con
centrations or very high concentrations
centrations are relative y constant.
the excretory mechanisms
the brain vitamin con
At very high concentrations,
in kidney operate and I.V. injections
are required to produce very high vitamin levels. Even <£hen, it
is still doubtful whether megavitamins help to improve cerebral
functions.
Only in certain conditions such as retarded children
folate transfer mechanism
are reduced.
Whether high folate
therapy can increase brain folate levels in such children with
affected transport mechanisms is still debatable. During menin
gitis also the transport mechanisms are suppressed. The use of
high dose vitamin therapy in such cases remains to be established.
MULTIVITAMINS AND THE DRUG INDUSTRY
In India, 126 vitamin B12 preparations are available - the cost
of a day’s treatment with multivitamins in India and Bangladesh
is equivalent to 20 to 30 per cent of the average daily wage. (5)
In India 40,000 children become blind each year because of vitamin
A deficiency, which is a leading cause of blindness in pre-school
children„ It is associated with 6-12 times higher infant instaWith 42% of India’s population below the age of 15 years
bilitya
and with children population increasing, vitamin A requirement
would necessarily increase. Unfortunately vitamin A production
has not merely NOT INCREASED BUT ACTUALLY DECREASED. (6)
contd...14
I
/14/
PRODUCT FORMULATION AT WHOSE COST ?
Sector wise shar
in Bulk drugs and formulations.
in four Anatomical Groups in 1978 (6).
Production
Therapeutic group percent contribution
Foreign
Indian
Pvt.
79.3
7„ 2
18.6
82.3
Market share
38.4
57.8
Bulk production
3. Analgesics
11.0
49.0
3.8
40. 0
Market share
46.3
51.3
2.4
Bulk production
4. Anti Parasitic
Market share
4.0
72.0
24.0
67.1
31.5
1.4
Bulk production
37.0
49.0
14.0
Public
1. Vitamins
Market share
Bulk production
2.1
10.5
2. Antibiotics
REFERENCES
1.
Nelson Text book of Pediatrics
2.
PCNA, Vol. 32 No. 2, April 1985
3.
Medical letter 27:66-68, 1935
12th Ed. 1983
4.
Disease of children in the subtropics and tropics Ed. by
D.B. Jelliffe & J.P. Stanfield, 3 Ed.
5.
Indian Express, Magazine March 23, 1986
Rational Drug Policy ? Facts and Figures
AIDAN,March 1986
6.
7.
p. 3
Nutrition Atlas of India (C. Gopalan & K.V, Raghavan
NIN Hyderabad 1971
i Eds)
8.
'Brain Tonics' by Dr. B.P. Udwadia
Handout of Academic
Society of K.G.P . Children Hospital andJajodia Research
Centre, Baroda.
9.
’Tonics s How much
an Economic Waste*
Kamala S Jayarao; MFC Bulletin, Nov. 1976.
10,
Nutritional problems in India,by P.K.Shukla, 1982.
Biotin s
(Contd.£rom Page 3)
Daily requirement of Biotin in adults has a provisional value of
100-200/<g as assigned by Committee on Dietary Allowances.
In infants : upto 6 months
35/-* g
o
6 months to 1 year
In children: 133 years
4-6 years
7-10 "
s
s
50 g
65/. g
85/\ g
120;< g
11 years onwards
nw a rd s
ii
:
100 - zOOz^g
200,.^g
(Goodman and Gilman)
It is found in adequate amounts in our diet. 7A part of it is
.
also
available from what is synthesised by bacteria in the intestines.
Biotin deficiency is not known in humans, Clinical deficiency
syndrome has not manifested so far The vitamin has no clinical
application.
K-
*
A'
■,
n
G.P.O. Box 134
Baroda-390 00'
hh
HU
COMMITTED TO THE
CORRECT MEDICINE
K;
NEWS LETTER NO. 10
OCTOBER 1986
HAVE YOU BEEN USING ANABOLIC
STEROIDS ?
Dear Partner,
More and more evidence is coming up recently that use of Anabolic
Steroids in most conditions, where it is generally used is not
justified by standard literature.
What are the Anabolic Steroids ?
They are the synthetic derivatives of the male sex hormone
testosterone. Testosterone stimulates the growth of male sex
organs and other sexual characteristics like beard growth, deep
ening of voice, etc., (called androgenic effect). It also sti
mulates protein synthesis and the growth of body tissues such as
muscles, bones and blood (called anabolic effect).
Using Anabolic Steroids s
Most anabolic steroids are claimed to have only anabolic effects
They are hypothetically administered to enhance the growth of
muscle
above normal levels and for their effects such as
increase in haemoglobin levels, skeletal growth and increased
levels of blood proteins. But its androgenic effects are much
more serious and amount to make them a non use in most conditions.
It must be remembered that "ALL ANABOLIC HORMONES TESTED TO
DATE ARE ALSO ANDROGENIC".1
The androgen therapy at present is indicated only in cases of
hypogonadism (inadequate gonadal functions as manifested by
deficiencies in formation of cva or spermatazoa and/secretion
of gondal hormones), hereditary angioneurotic oedema (an allergic
condition producing' swelling of the skin and severe itching)
and selected cases of anaemia due to bone-marrow failure.2
Its use is not justified or established by standard literature
in any other conditions like convalescence (a condition when there
is a major break down in body proteins resulting out of say, a
major surgery or a long standing debilitating disease).
Osteoporosis (loss of bony tissue resulting in bones that are
brittle and liable to fracture), breast cancer, to reverse the
negative effects of high dose glucococticoid therapy, kidney
failure, general cases of anaemia, athletic performance and its
use in children.2
Until 1982 this product was recommended for treatment of delayed
growth and development in children, specially in the malnourished
children. Whatever little immediate advantage they may exhibit,
is far little in benefit when weighed against the risk such as
"bone maturation may occur before the growth has finished and
so halt further growth'A.
Contd.o o
Loccct’s Worki^o Hours
From jv-’BB to Feb. 28, ’87:
9 A.M. to 4-3Q P.M.
. plorjc.
o .2
&
\
r
/2/
Adverse Effects of Anabolic Steroids
(1) In males
I
2
(a) Prepubertal
i) Enlargement of Penis
ii) Increased frequency of erections
(b) Post pubertal
(2)
i) Inhibition of testicular function; Oligospermia,
ii) Gynaecom:stia o
In females
(3)
(a) ^reJersibl®.hirsutism, male-pattern baldness, deepening
oice, clitoral enlargement (b)Menstrual irregularities.
In both sexes
(a) Nausea, (b) Increased or decreased libido,
(c) Inhibition
<?^.g°Ii12dotf?phins'
Premature closure of Spiphysis
1 I
of. laboratory tests like GTT, Liver functions
(q)' TheS^aS11^1011 tests, (f) Suppression of clotting factors
pellos" hepati?“
°£
carcinoma and
Safer alternative s
Nutritious food to maintain normal growth.
Testosterone to be
used for aplastic anemia and old age osteoporosis
in man. Oestrogen is as effective for <osteoporosis in women.
Some generic and brand names s
Orabolin, Trune?gicf^ntbal; ^iistroirebc^6' Durabolin' Evabolin,
Literature about Hazardous Drugs s
Very useful information
.
about the hazardous drugs etc., is
forthcoming. Following are the details of reference material
s
1.
by Health Action International
I
2. 44. Problem, drugsPublished
’ Published by Health Action
-i
International
3. Dear Doctor’ Published by All India r__
Drug
Action
Netwo’rk
4. Wrong Kind of Medicine’ by ^.Medawar/Social
Audit Published
(by Consumenrs1 Association and Hodder r
5. Ban Bannable and Hazardous Drugs’, VHAIand Stoughton.
New Delhi.
All these books are available from”
?.' 40 Institutional Area,
South of IIT, NEW DELHI - 110 016
With best festival wishes.
Sincerely^
NIMITTA BHATT
References;
n
Of TherapeuticS ■, Goodman and
a 1!?5'' 2)
Problem Drugs’, A. Chetley & D. Gilbert
MSlndaf O?982tef?^n°ne7' 19S5‘' 3) ’The Extra Pharmacopeia •
All Mia nn n L ’
Dru9 Information Packet,
^±j_ maia Drug Action Network, 1986.
i
i§t
©£3$ fcafedi
Therapeutics (Locost)
S^hity^ Sabha Hall,
Da&dla Bazar,
LOCOST NEWS LETTER NO. 11
DECEMBER 1986
DEALING WITH RESPIRATORY INFECTIONS
Dear Partner,
In this part .of the season you must be encountering many
episodes of respiratory infections, especially among children.
Upper Respiratory Tract Infections (URI) are those which involve
the structures of the respiratory tract above the larynx and those
below it are known as Lower Respiratory Tract Infections (LRI).
Timely and effective interventions to treat the URls can prevent
some of the LRIs.
THE TREATMENT 2
Many a times the URI is of nonbacterial origin and does not need
an active treatment with antibiotics. However, in case of
infections of viral origin;, like common colds and coughs, sympto
matic treatment with steam inhalations,salt water gargles,
increased fluid intake, and paracetamol may help, till it subsides.
The allergic conditions may be treated with antihistamines, or
only a symptomatic relief may be provided. URI with xever is
often of bacterial origin and may have to' be treated with anti
biotics. All the mis should be treated wikth antibiotics.
The World Health Organisation recommends the following antibio
tics for out patients with moderate Acute Respiratory Infections
(ARI).
Table
1
PROCAINE
PENICILLIN
Activity against
the bacteria
causing pneumonia
Toxicity
Administration
/
Cost for 5 days,
for a 10 kg child
Comments
AMOXYCILLIN,
AMPICILLIN
COTRIMOXAZOLS
Good
Good, but the Good, but the
number of resis
number of
resistant bac- tant bacteria is
teria is
increasing
increasing
Fatal bone
1/500 get "IS Diarrhoea and
marrow
toxicity
minute madness' rash common.
and
fatal
skin
Fatal
anaphy
1/250,000 get
rash
occur
laxis
in
less
fatal anaphy
than 1/250,000. rarely.
laxis. Skin
testing is NOT
necessary
routinely.
<Oral
Intramuscular Oral
Amoxycillin 10 Trimethoprim
50,000 /kg
mg/kg 3 times a ■4 rng/kg 2 times
once a day
day.
Ample i 11 i ni a day
15 mg/kg 4 times
a day.
Usually effe
ctive, long
acting, but_
intramuscular
administra
tion required
Rs. 9.00
Usually effec
tive, but mild
Rs. 2.9.0
Effective and
cheap, but
side effects
may cause seri
common
ous side
effects (rare)
contd
2
/
i'
/2/
I
\r
However in more severe cases, the second line antibiotics as
suggested below should be used.
Table
2
Hospitalised cases of pneumonia
Neonatal pneumonia
(age<^6 weeks)
Very severe cases of pneumonia
Severe malnutrition
(cyanosis, unable to drink)
Suspected staphylococcal
pneumonia, (empyema, abscess,
pneumatocele)
Benzylpenicillin
50.000 units/kg IM every
6 hours
Benzylpenicillin
50.000 units/kg IM every
6 hours plus
Gentamicin 2.5 mg/kg IM
every 8-12 hour's
(Kanamycin 10 mg/kg IM
every 8-12 hours when
Gentamicin is unavailable)
Chloramphenicol
25 mg/kg IM every 6 hours
(naximum 1 gram’ per dose)
Oxacillin 50 mg/kg IM
every 6 hours plus
Gentamicin 2.5 mg/kg IM
every 8-12 hours
(Kanamycin 10 mg/kg IM
every 8-12 hours when
Gentamicin is unavailable)
or
Chloramphenicol 25 mg/kg IM
every 6 hours (maximum
Igm/dose)
Note s In case of Chloramphenicol one should switch over to
oral route as soon as the child is able to drink..
Changing antibiotics and duration s
Generally children with acute respiratory infections i should
receive at least a ten days1 course of antibiotics. Children
who do not respond to the initial antibiotics within two days
may have an infection with resistant agent (bacterial or viral)
an associated meningitis, or a non-infectio us process such as
airway obstruction due to foreign body, a heart failure, etc.
In such cases efforts should be made to diagnose these condi
tions. Persistent illness should give an alert to rule out
tuberculosis or pertusiso If a child being treated with benzyl
penicillin alone becomes worse, i.e, develops cyanosis (skin
becomes blue) or is unable to drink, then change the therapy
to Chloramphenicol or oxacillin plus gentamycinM (dosage stated
in table - 2).
Important hints s
Whenever a child with stridor (a harsh noise heard each time the
child breathes IN), restlessness and rapid breathing with
in^rawing of chest (rate over 50/minute) is noticed, immediate
treatment for ARI has to be giveno
Wheeze is a soft, almost musical, whistling sound that is heard
each time the patient breathes OUT. This could also be due to
an allergic factor or asthma. Almost all children with wheeze
also have chest indrawing. In such children the important signs
to look for are very fast breathing (rate over 70/minute),
bluish colour of the tongue and inability- to drink. Such
children may be given a broncho dilator like Salbutamol.
Contd. . . o «, «3
!
/3/
«>
If the breathing rate is less than 50/minute the child may not
need antibiotics, but may be watched if the condition deteriorates
If the rate is 50 - 70/minute, antibiotic may be started. It
the rate is above 70/minute then the child requires hospitali
sation and probably oxygen with second line antibiotic therapy
as suggested above.
The children having measles should be specially watched for
ARI and must be treated immediately, ARI after an episode of
measles is a common feature among children.
c--
Supportive therapy
Fluids such as ORS must be given to the dehydrated child or
1.
child with accompanying diarrhoea. In a child who is
unable to drink, the fluid may be given through intragas
trie tubes. Intravenous administration of fluids shou d
be chosen only for patients in shock. However, care must
be taken not to give too much fluid.
Medicines such as expectorants, cough suppressants, mucoly2.
tics, antihistamins and decongestants are expensive,
• ineffective and sometimes harmful in the treatmentof ARI.
Their use should be generally discouraged because it may
give the parents a wrong belief that the child is being
treated. Often because of this the child may miss out on
the real lifesaving medicines.
The fever (temperature above 101°F) should be lowered by giving
-x- a six bouts1
a dose of paracetamol 10-15 mg/kg body weight at
interval.
Wheezing in
in children under
under 12
12 months is most likely due to bronc io
litis.
Such
children
may
not
respond well to bronchodilatorsolitis. i--- Best treatment for severe forms is oxygen and an effective antianti
biotic therapy.
The child should not be allowed to’become too hot or too cold.
Keep him/her lightly clothed’ in a warm place.. Inhalation of
warm vapours from boiling water may be soothening to the child s
airways, thus reducing the difficulty in breathing.
/If the child’s nose is too congested, warm saline water drops
(a pinch of salt in 100 ml clean water) may be put into each
nostrill. The sticky secretions can be sucked out when they are
humid enough.
Note s Most children with ARI can be successfully treated with
I.M. injections of procaine penicillin. Oral penicillin has.
no value. Ampicillin may be used in case an oral antibiotic is
required to be given. Do not use mixture of benzyl, procaine
and benzathine penicillin.
With best
X-mas wishes,
Sincere ly,
NIMITTA BHATT
(Major portions of this article have been adopted from
ARI News, August
issue)
FACTORY AND
ITS IMPLICATIONS TO
LOCOST DRUG
SUPPLY
In the previous paper we have seen present functioning
of LOCOST. Now we will try to find out the implications of
factory to LOCOST functioning -
PRODUCTION
At present, the lag between the purchase of raw materials
and the finished goods reaching LOCOST varies from 20 - 45 days.
The major portion being accounted for by manufacturing and quality
control.
With a manufacturing unit this can effectively be reduced to
to 15 - 25 days. More than the reduction
. in time what is more
important is that schedules once fixed can be met unlike at present
io ez when we inform our partners that medicines will be available
in a certain number of days then they will be available, unlike
at present.
In 1989 due to stock out we were unable to supply medicines worth Rs. 1,05,000/- to our partners. More than loss of
sale it results in a loss of goodwill among partners. We will
be able to effectively tackle their major complaint - unreliability
in drug supply.
QUALITY
The whole drug supply of LOCOST rests on the ability to
suoply good quality drugs. Our basic strength is • juality’ and
therefore all efforts shoul be directed towards attaining this
objective.
All of us agree that quality doesn’t mean, only finished
goods passing pharmacoepial standards. Quality has to be built
into every aspect of production. Ini'
the present set up there
is an inherent limitation in our ability to enforce Good Manu
facturing Practices and our efforts to control quality are limited
to testing the final product.
The testing done by commercial labs is unreliable to
say the least. ^here have been several instances when one lab
’passes’ a sample while another ’fails’ it.
In such cases who
to rely on and on whom not to? There have been instances when
glaring mistakes were found in the sports which
' ultimately
change the final result.
In short a factory would strengthen the weak foundation
of our drug supply. And an added advantage is that the time
in testing would be reduced considerably.
PRICES AND VIABILITY
At the present volume of sales the prices will not change
substantially. At the present volume of sales there would be
sufficient capacity utilisation to take care of fixed costs that
would be incurred.
In 1989 we have been able to reach 70 to 80% of the
projected sales minimum for breakeven. With a little moreeffort
and more streamlining we would be able to achieve the minimum.
The first two years we would be able to breakeven and from
then on the surplus generated would more than take care of the
loan repayment obligatories.
ooo2
i
. 2 oo
INVESTMENT REQUIRED & SOURCES OF FUNDS
The LOCOoT factory as^envisaged would mean an m investment
of around Rs. 27 lakhs. ^he proposed site is at Ankleshwar,
GIDC and land has been acquired for the same. The proposed
sources of finance are as follows -
LOCOST internal funds
6<75 lakhs
Govt, subsidy
6.75 lakhs
(Ankleshwar is a GOvt.
notified backward area)
Loans from financial insti
tutions
13.50 lakhs
The
envisaged.
ine factory as envisaged,
r the current and future volume of
sales is appropriate in terms of technology.
> .
Cable
LOCOST'
o ----------
Phone ; 63962
LOCOST
G.P.O.POX: 134
BARODA • 390001
/ # ’ a0
1JEW DRUG PRICE POLICY
NEWS LETTER NO. JL6
OCTOBER - "1987
DeaP partner.
been announced by the
1987 (DPCO). The
while
ambit of price control*
the
The DPCO is in
lise the drug lna„st^rSanSe0DpSetISi:r?:i3S pkSSgXect.
<Srug9 required tor the netionH
” base« on the
programmes for eradication of TB leprosv^mala63 Su^1? as. ~ National
programs tor the control of hilndnLe & predion
to iaenti?rtogsh?hat’SrePto S”lSiJea°” g'KeUtar Comittee)
Category II drugs.
1J 3 of essential drugs
exhaustive
enough in the'
Indian context, it identified c.„
another 166 drugs for possible inclusion. Based on certain exclusion
n , ;—1 Prxnciples drugs were identified
in the above list C
’ ‘ could
,hich
be excluded from the ambit of price'1
control and a final list of --J
139 drugs were arrived at.
Salient Features
aJ ihe" tSfS? a^X^tS^ WH0
*n
. T1?e government would fix <
classified as Category I/n. :r a maximum sale price for bulk drugs
Bulk drugs cannot be sold at a price
exceeding the maximum sale price.
kite
would be categorised
A f
£emulation
'™“
““??Sed as
•?
I formation
viduallynor"=
iyouxKorug specified in Category I either indi------ 1 other drugs.
.formulation
would be <Se^f^^
—'
if it contains
anJnbSkd±
Cate^ry II formulation
indhn’riH^h > any
• bulk
K drug
ug specified
sPecifxed in
m (Category II either
individually or in combination with
other drugs,
druas
extner
--- 1 other
If a formulation contains a bulk drugs
I and another bulk drug specified in Category specified in Category
II then it would be
classified as Category
“
j drug.
o
pJease
Accost’.
TpScpr. 87 to Feb forking JJ,oars
A.M. to 4-30 P.M '■ 23. eg*
2
/2/
L0C03T
F
For Category I drugs a maximum mark up of 75% is allowed
on the cost of production (cost of production includes only
Material Costs, Packing Material,Conversion Costs and packing
charges).
*
For Category II formulations a maximum mark up of 100% is
allowed on the cost of production.
*
Once the retail price of formulation are fixed, a manufacturer
cannot increase the price without the prior approval of the Govt.
*
Bulk drug manufacturers and manufacturers of formulations
have to keep the prices at pre DPCO level till the Govt, fixes
the prices as per the new DPCO.
-A-
Multivitamin formulations which till how have been outside
the ambit of price control have now come under price control
because of the fact that Vitamins A, B-, B?, Bfi C, D, E are
categorised as Category II drugs.
z
'
*
Single ingredient vitamin formulations containing individual
vitamins specified in the DPCO are- outside price controle
*
sj-ngle ingredient formulations based on drugs in the DPCO
and sold, under generic names" are"~~~outside price control.
PRICE RISE
The prices of medicines have gone up due to a substantial
increase in the prices of raw materials.
Prices of Ampicillin and Amoxycillin have gone up due to a
shortage of 6-APA, an intermediary in their production. Shortage of
6-AP7X is due to a shortage of Penicillin G in the country, which is
needed to manufacture 6-APA. The Govt, is allowing imports of
Penicillin G only/those companies which have lifted 40% of their /to
requirements from, the public sector companies-IDPL & HAL.
Manufacturers reluctance to lift stocks from- IDPL & HAL is, because th..
international prices of Penicillin G is ha'if that of Penicillin G
manufactured by these units, Consequently the price of Ampicillin
rose from Rs. 1775/kg on 28.2.87 to Rs. 2054/kg on and Amoxycillin
rose from Rs. 1950/kg on 28.2.87 to Rs. 21007kg on 1.8.87,
We have not been having stock of Cotrimoxazole tablets .S.S
due to shortage of raw materials - Trimethoprim and Sulphametho
xazole (SMS) - especially the later. Consequently the price of
SMS has gone up by Rs. 100/kg which is the cause for a substantial
increase in the prices of Cotri S.S., Cotri D.S. & Cotri Syrup.
With best wishes.
Sincerely,
srikriShna t
&ews Letter No. 9
STOP USING
CHLOROSTREP
Sept. *86
Dear Partner,
Have you been using the pbpular combination of Chloramphenicol
with Streptomycin ? The standard medical opinion has a different
view on this.
About Chloramphenicol
World Health Organisation says : * It is advised that it should be
administered only to treat acute attacks of typhoid and paratyphoid
fever purulent meningitis (due to H. influenzae or listeria©;
E. coli and Klebsiella©) and in life dangering infections caused by
sensitive organisms in which less dangerous antibiotics are in
effective or contraindicated*„
’It is also advised that 2 Chloramphenicol should never be used
simultaneously with other drugs having a potential to damage bone
marrow (like Analgin, Phenylbutazone, etc.,). The daily dose in
the new borne should never exceed 25 mg/kg/day*.
~Even for use as topical antibiotics in eye and ear infections.
Chloramphenicol should not be used for more than 10 days because
of its toxicity.
’ . » Even when topi&ally used, a part of it is absorbed
through the skin and danger of patient developing aplastic anaemia
is increased especially in the new born children.'
Tetracycline
is the alternative drug of choice.
This drug has been put under restricted use in several European
countries, like Netherlands, Denmark, Francd, Federal Republic of
Germany, etc.
About Streptomycin s
Streptomycin injection is the first line treatment for tuberculosis.
It has been accepted by the National Tuberculosis Programme also.
It is opined that it should not be used in any other conditions
for the fear of resistance. Especially when the drug is used in
inadequate doses the resistant strains of bacteria are likely to
appear.
The problem of development of resistance factor in bacteria is
•a threat to public health throughout the world .oQ... The conse
quences of resistance affect not only our ability to treat the
infections but also the cost and duration of treatment*.
The Combination s
Fixed ratio combination of two antibiotics other than Cotrimexazole
have few indications. The US FDA has withdrawn almost all such
contd
2
combinatiors and WHO essential drug list mentions only Cotrimexazole as fixed dose combination of two antibiotics.
It is sad that the combination is being prescribed for use in
bacillary dysentry which is not very uncommon. It is quite
irrational to use this drug in bacillary dysentry. There are
very few indications for the use of an antibiotic in dysentry
Only in certain kind of bacterial infections use of Chloramphenicol
may be justified. But in no case its combination with Strepto
mycin is justified. Antibiotics like Sulphadimidine, Tetracycline,
Cotrimexazole, Ampicillin .. can be used with success in such
infections.
—•
-.1
1
u
Some brand names which contain this combination are s
Chlorostrep, Enterostrep, Rheofin, Strepto Paraxin, etc.
Those which contain streptomycin are Imosec - S, Inseptin,
Renokab, Saril, Streptomagma, Streptotriad, Strycital, etc.
/of
So, dear partner, please destroy all the brands' containing
combinatior/Chloramphenicol and Streptomycin and never use these
antibiotics for trival infecticn.s where other antibiotics can
be used with success.
LOCOST1S NEW PRODUCTS S
LOCOST has been able to obtain Loan Licence for the following
items. Please send us your "months’ requirements for each of
them. so that we can undertake the production. They are s
Name of the drug
Strength
Shelf life
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Amoxycillin Capsules
Amoxycillin Oral Suspension
Ampicillin Oral Suspension
Clofazimine Capsules
Pyrazinamide Tablets
Pyrimethamine Tablets
Diloxamide Furoate Tablets
Ethambutol Tablets
Ethambutol Tablets
Cotrimexazole Tab. D.S.
250 mg, 500 mg
125 mg in 5 ml
125 mg in 5 ml
100 mg
5 00 mg
25 mg
5 00 mg
4 00 mg
800 mg
800 mg
16 0 mg
24 months
18 months
18 months
ANALYSIS OF LOCOST SALE OF DRUGS
We are enclosing a statement showing the analysis of drug supply
during the period January *86 to June ’86. As you will see,
more than 77% of LOCOST sale of drugs is for the rural set ups o
This would not have been possible without your active cooperation.
Thanking you.
Sincerely,
Nimitta Bhatt
1
BREAK-UP OF SALES
Month
URBAN HOSPITALS
.Total Sales <no. of
Value ;
Orders
UF3AN DISPENSARIES
Total Sales ■No. of
Value
Orders
8916
Sales vaiUe in Rupees
______________ __Percentage_in-.Brackats---RURAL DISPENSARIES
RURAL HOSPITALS
Total Sales No. of
Total Sales
No. of
Value
Orders
Orders
Value
(%)
(%)
JANUARY
1-1-86 TO 31-6-86
7
(667)')
(%)
6470
(4.8)
3
3 2618
19
84926
(63.9)
10
(24.6)
FEBRUARY
11335
(12.93)
12
9880
(11.29)
3
28316
(32.3)
16
38112
(43.48)
9
MARCH
8051
(9.9)
4
24740
(30.49)
11
3 2689
(15.56)
15
15651
(19.30)
5
APRIL
21149
(17.6)
10
15272
(12.7)
10
18699
(15.56)
14
65028
(54.14)
11
MAY
7261
(9.88)
10
8048
(10.96)
4
226 08
(30.79)
9
35508
(48.35)
5
JUNE
6912
(5.28)
5
15337
(11.72)
10
12970
(9.91)
10
95599
(73.07)
15
, TOTAL
63624
(10.18)
79747
(12.73)
39
(17.25)
147900
(23.62)
83
(36.72)
334824
(53.47)
55
(24.33)
48
(21.22)
•
TOTAL SALES s Rs, 6Z 26,125 = 00
JL
NEWS LETTER NO, 17
LOCOST
GPO BOX?134
BARODA - 390001
Phono ’ 63962
Nov./December, 1987
Dear Partner,
I
UPDATE ON DRUG USE IN MALARIA CONTROL
Mafaria remains hne of the mctjur puonc neaith problems at
major public health problems
control aim'-’ ai"
v.
general approach for malaria
control aimo at covering as much of the target population
Treat
through drugs! ZV'
chemoP^ylaxiS (prevention
drugs) are tne two rnajor prongs of the drug therapy.
enidZmhi LfeCbVe methods of vector control depending on the
of oeSnle°?nCfhp!PeCtS
the disease' socie-cultural behaviour
or popple in the area and vector ecology must accompany such
efforts, especially in endemic areas.
lc
Treatment of
?cute Malaria
a)
Chloroquine s’Th
"’^’ S-is the drug of choice for malaria
especially
P#Jvivax
and P.falciparum,
fsensitive
’’‘- - to chloroquine.
I HQ
v- rst i -J- 4 v._ T i
-i .
q
L ,
•,
The
routine
adult
dose
i.
-- o may
be given, as follows
--- S
1 gm 027 4 tcLolets
of Chloroquine PhosphateJ as a loading dose t 500 mg or 2 tablets
after six hours, <and- then 500 mg or’2 tablets
---- > on the second
and third day. cOral' dose
~
of ChloroquineJ ]base for children being
10
--- mg/kg on day 1.
1, -followed by 5 mq/kg
6 hours
.
1
j after and then
d mg/]<g each on day 2 & day 3 i e
total 25 mg/kg body weight
spread over 3 days.
The tablets.should be given with food
food or
or milk
milk to
to avoid
avoid
nauseasc and vomiting
o
~
'
-’
Chloroquine
is
-3 absolutely
run ec ess airy, except i n un c o ncious
■--’ •intolejFanceT
——
in cerebra 1 malaria
^ffS^^^-h^ntoJ^ance.
“Whe^I^n
■2£.-in seve re'gastric
-1
possibi? rhl06
2 tO swltch over
over to
oral therapy
therapy as soon every
to oral
as
possiole. Chloroquine injections in
la :routine course are neither
more effective nor can the side effects of the drug like nausea
and_vomiting be avoided. m fact, chances of
serious adverse
effects lixe cardiovascular collapse are more common with
parenteral use. The usual intramuscular
dose being
----- dose being,
200
mg
Chloroquine base given intramuscularly, half
theJ dose on each
buttock. The dose can be repeated after 6 hours' total dai ly
dose not exceeding 800 mg Chloroquine base in 24' Hourso
a Other 4 aminoquinoline group of drugs (e.g. amodioquine)
1710276 actlve than Chloroquine especially against the
-esi^tant strains of P.falciparum is used as follows : '
contd
2
•. 2 ..
tablets (200 mg) each on the first day
aay as a s^gle dose,
3 tablets each on the second and-the third c.ay
single dose,
2
used
in
place
of Chloroquine.
These drugs should not be routinely u. .
Pv rime th amine S Pyrimethamine in combination with
b)
__
^-“^SSl-for treatment of acute chloroquine resistant
diazene is The usual dose being Pyrimethamine 25 mg twice a day
malaria,
and Sulphadiazene 500 mg four times a day. £q£. 5.day o
for
3 days
Its combination
with Sulphamethopyrazine (metakelfin) of with
Sulphadoxin (Fansidar) should not be used alone, for ye^ment
pSlaaa.
«
quine. The combination is u
The drug should be used very
easily develop iresistance towards
this combination also.
' > should be' included in the regimen for
c)
Quinine : Quinine
attacks of Chloroquine resistant or rtiultidrug
treatment of acute The usual oral dose of quinine sulfate is
resistant malaria.
day for two days followed by 600 mg twice a
6 00 mg 3 times a
• with Quinine being 7 - .10 days.
bay, total duration of treatment
Sulfonamide
is used for
Whenever
Pyrimethamine
-F treat-,
'a1 ong with it.
curative
d)
Primaquine s This drug is used for radical Whenever
attacks.
treatment and other relapsing malarial
with
Chloroquine or amodionecessary, w: should always be given f base daily as a single dose
quine. Its
Its usual dosage being 15 mg ' base (i»ez 6 tablets)
for 14
14 days.
days. A single dose frx 'rS mg
parum malaria
for
should be given at the end Ou. ti^-tm^nt
mnvrial
in the community.
The radical cure with primaquine should not be used in.
1-Iowever, it may be given
e.-xo for
ft,r fear of reinfection.
■
endemic areas
with
seasonal
infections,
during
epidemicsj and to
in areas v--- where malaria
prevent the recurrence of infection from areas v.--is already eliminated.,
Chemoprophylaxis
The conventional dosage
" --- ; being two tablets of ^h|^^Xxtn
(^r" as th! Jerson is
Amodioquine or one tablet of Pyrimethamine
as !oiq
as
week
on
a
fixed
day,
(500 mg), once a.w®e^ °^T
ria infection.o Experience has shown
exposed to the risk of
of malaria' infection
|v fail to either reduce the
to
that when used on large scale t they
t - fail
33ion>
On the other hand,
of
transmission
„
level of endemicity or
rate
dtolnlshodkhe sensitivity of the parasite
such programmes have Q--2.
J
2
sco
o.
3
..
to the drug used and have resulted in drug resistance
So the
W.H 0 has suggested that th^ chemoprophylaxis h as a'malaria
control strategy on a mass seale should only"aZHTarT^ducina"t?e hiqh r±Sk ^ups such as pregnant women,
cardiac patients, non immune visitors, persons living inclosed
poTicrari^aSv 3 S5°rt 2±me SUCh aS refu9ee camPS, labour force,
ponce ano army units, etc.
. Zlg_-P£g.g_ti.ce of giving drugs for individual prophylaxis
in
prophylaxis in
a-^x22££d» The‘inadequate blood levels of
individuals
will result into malarial
developing drug such
resistance^
Suc^individSl^SerbecOTe
, Such individuals then become
voirs of drug resistant malarial parasites and in long run
harm the community.
II
MANAGEMENT COURSE FOR SENIOR HEALTH MANAGERS
The Institute of Health Management at Pachod, runs a six
week course in health rmanagement,
--for all those who -are in decision
making position at the health projects„ The course offers an
intensive training in health planning, management & evaluation.
It also gives an opportunity to observe & discuss various
processes in community organisation and participation
~ addition,
In
ba®ic skills in community diagnosis, epidemiologv“
demography and statistics. I had recently undergone this
f°und it extremely
\ helpful
\
at grassroot level.
Two courses, once in January and then in August are held every
year, r
^2?^ ofmteaching is{ English, The total course fees
is Rs. 3000/-,,
±he institute also offers part scholarship to
deserving candidates,
- . For further information please write
to me or to Ms.
Ms. Nandita
Nandita Kapadia,
Kapadia, Institute of Health Management
Pachod, Dist. Aurangabad, Maharashtra - 431 121.
III
MlW products
We are planning to introduce some new medicines shortly.
They are- s
Aminophylline - 100 mg
Premethazine
— 25 mg
Ibuprofen tabs.- 200 mg, 400 mg.
Erythromycin J
stearate tabs I - 250 mg
Pyrantel Pa1-3
moate oral
J
Suspension
!
We would like to know your
r
your response regarding these medicines.
Things like whether they would be useful/not?? Any other strengths
you would like to be introduced ? Any other medicines which
you feel are important but wx are not on L0C03T list (excluding
i'iajrotiuiijs -s-inca at pgesont wa
not-in a -pos .1-4*1 on
f-ac tu-r^Zs-t-er e—them due—^t e pra-c t ica 1—d-irf f i-e-u 1-t-i-es
contd..,
i
.4
. . 4 ..
injections since at present we are not in a position to
manufacture/store them due to practical difficulties)
With best wishes.
Sincerely,
N
NIMITTA BHATT
References :
1.
Goodman, Gilman et al s
of Therapeutics, 1985.
The Pharmacological Basis
World Health Organisation s WHO Expert Committee on
Malaria, Eighteenth Report, T,R.S. 735, 1986.
3.
I
LOCOST, RTC background paper on Malaria, Antimalarial
drugs and Chemotherapy of Malaria by Dr, Sagun Desai
Nelson - Text book of Pediatrics, 1983.
LOCOST
GPO BOX: 134
BARODA - 390001
PHONE: 63962
CABLE :
'LOCOST'
NEWS. LETTER No. 18
Dear Partner,
WE WISH YOU AND YOUR TEAM
A VERY
HAPPY
NEW
YEAR
Changing Needles But Not The Syringe ?
A dangerous practice has slipped into common use, particularly in
developing countries: changing needles but using the same syringe
for several consecutive injections. There is ample evidence that
changing needles does not eliminate the risk of cross infection.
The WHO Expanded Programme on Immunization (EPI) recommends that
a sterile needle and sterile syringe be utilized for each injection.
Hepatitis outbreak investigations beginning in the 1940s first
raised the spectre of hepatitis transmission by contaminated syringe^
These epidemics were characterized by their clear demonstration of
a distinct relationship between the time of disease onset and
exposure to re-used syringes, consistent with the presently welldefined incubation periods for viral hepatitis. In none of the
reported epidemics was evidence found of secondary spread, the
presence of which would have argued in favour of another mode of
epidemic transmission. It seems most likely today that these
outbreaks were attributable to both hepatiti.?. B, and non-A,
non-B hepatitis viruses.
The epidemiological evidence was also supported by animal data.
This evidence has been conclusive enough to convince most health
authorities to abandon the practice of changing only the needles and
using the same syringe for injections given to different individuals.
In countries which have experienced shortages of injection equip
ment^. the choice has often been one of using a non-sterile technique
or of not providing the injection. It is still possible to find
clinics with only a handful of syringes and needles with which to
carry out the work.
The best solution is to continuously sterilise by boiling or using
disposable syringe-needles. The later may not be feasible because
of the cost factor. But one has to realise the dangers involved
in providing a non-stdrile technique and of exposing the children
to the hazards of hepatitis while saving them
from other
communicable diseases.
(Reference : Weekly Epidemiological Record, WHO, No. 46, Nov.1987)
A change at LOCOST
Srinivasan (Chinu) is retiring from his responsibility as the
Coordinator of LOCOST from 31st December, 1987. A team of three,
Nimitta, Krishna and Dilip ^esai will handle all the work at LOCOST
from 1st January, 1988.
With regards.
Sincerely.
NIMITTA BHATT
2
0 R S
PACKETS
latisoducing ORS packets
- doesn
---- ’t- seem feasible at pres mt
o lu.ci.cj packet would
wouid cost about Rs. 3 to Rs. 3.50. Instead
^fft,P}TninS
various ingredients
as per
the WHO
o to packn , -the
J as
per
the
formula (i. e, Sodium
.• . .
. -------..
*Chloride,
Pottasium.
^iloride. Glucose,
Sodium
Citrate)'“ separately so that ORS solution could be made
,
as and when required by mixing the various salts in water at the
time of dispensing.
At present there afe two alternatives available 2
ALTERNATIVE I
350 gms
150 gms
3000 gms
290 gms
of
of
of
of
Sodium Chloride
Pottasium Chloride
Glucose
Sodium Citrate
1
I
(i.e, various ingredients
packed separately in suffi
cient quantities to make
100 one litre packssolutions).
-calibrated spoons 1would
' " 'be provided for measuring
the.various salts so that a one litre solution could be made by
mixing
the salts without ■che
,
-- need for weighinc. —
The kit (the four
^aits.packed separately in sufficient <quantities
’
to make hundred,
one litre , solution
- ---- of
„
ORS and the spoons) would cost aroundI Rs/
Rs. 100/-o
ilhat is. it works out to Re. 1/- for every one litre of solution.
ALTERNATIVE
II
3.5
gms of
1!.., 5
gms of
20 ■ »gms of
2oR
gms of
Sodium Chloride
Pottasium Chloride
Glucose
Sodium Citrate
I
(i.e, various ingredients
packed separately, in suffi
cient quantities to make
one litre solution)
■L^? _’this case wThen the ORS solution has •*to be prepared, the
salts could be mixed,r Without
C‘_'_
any need for weighing., In this case
the kit would cost between
- Rs.. 2.00 and Rs. 2.50.
vie would like to have your reactions regarding the two
alternatives listed out here. You could write to us regarding your
preferences., the quantities you would be able to purchase.
(The
enclosed questionnaire could help you in your reply)
OCHER DRUG/NON DRUG ITEMS
^re also in a position to supply other non drug items
i Gentian 10let. Potassium Permanganate, Glycerine, Menthojcrysta_s. Cotton, Gauze, etc. Looking to the total demand and other
1.actors
may go for stocking these items. Please send your
requirements on the questionnaire attached immediately.
(Please fill this questionnaire and return it to LOCOST latest
by the 15th of January)
NAME
Date s
:
Address
I
We prefer
a) 100 litre pack
b) 1 litre pack
II
On an average we would need
1 litre pack P. m.
(number)
Ill
We would like LOCOST to stock the following
(A-) Non^-drug items
Pack
Approximate 'Average
Item
Size
requirement per month
1.
Gentian Violet
Crystals
2.
Pottasium Per
manganate Crystals
3.
Glycerine
4.
Cotton
5.
Gauze
100 litre pack/
6.
7.
8.
(b)
Drug Items s
Item
1.
Metronidazole
Syrup
2.
Antacid Syrup
3.
Codeine Phosphate
syrup
Strength &
Pack Size
Average requirement
per month
4.
IV
Other suggestions for LOCOST Drug Supply
LOCOST
GPO BOX 134
PHONE - 65 96 0
BARODA - 390 001
News Letter No.29 December 90
CABLE : ?L OCOST’
Dear Partner,
After a long gap, we are renewing this mode of communication with
you, hoping for your indulgence at this la.pseB
D
Es s en tj.a 1 Dr up. s
The Ministry of Health of the Government of India has finally
brought out a list of essential drugs - a much awaited step that
ought to be considered an advance for the rational therapy
movement.
However, some controversial drugs like analgin (dipyrone)
hydroxyouinoline .• and oxyphenbutayone have been irolduded in this
Partners may recollect that on all these three drugs, drug
activists have been seeking a ^an/restricted use. It is to be seen
what the new governments attitude is towards this list.
For a copy of the list, you may write to LOCOST,
2)
GONOSHASTHAYA P HARMACEUTIC&LS (GPL)
An urgent message from Dro Zafrullah Chowdhury of GPL, Dhaka, says
that the GPL8s Dhaka office was destroyed by a suspected arson and
fire on October 27, 1990, Loss is estimated at one crore Taka (One
Indian rupee equals 3,00 Taka approx,) Dr.. Chowdhury and Gonoshasthaya Kendra (G0K0) have been in the forefront for the advocacy of
a new National Health Policy for Bangladesh which among otherthings, is seen to hit at private practice by medical college
teachers and junior doctors under train?ngo
It also advocates
some radical structural changes in health administration, medical
education, health manpower training and measures for a safe and
healthy environment (anti-smoking laws, shifting of polluting
factories, restriction on leaky food marketing, etc,). For a copy
of this interesting health policy, you may write to LOCOST,
You may also write to GK/GPL expressing your solidarity at the
following address (with a copy preferably to LOCOST)s
GONOSHASTHAYA PHARMACEUTICALS LTD.
P.O. NAYARHAT
(VIA) DHAMRAI, DHAKA
BANGLADESH
Telex : 65849 GK DA BJ
3)
a)
n
■1 -
LOCOST Drug?rices
We reluctantly have; had to increase drug
.prices of many'
2 -
important drugs as prices of raw-material have increased
(attributed to the Gulf Oil crisis among other reasons),. Also
it was becoming increasingly difficult for us to absorb these
increases as we have been attempting to do in the pasto Hope t
dear partner. you will continue to understand and support us o
b)
Stock levels
We have increased stock levels and reorder levels of key items
so that stock outs (out of stock a f 'not available’) are
minimised z if not completely removed by January 1991o Also we
have taken measures to increase the speed of quality control
which was proving to be a major bottleneck
o
c)
This is our new year resolution
Packing
0
o
LOCOST has decided, on popular demand, to increase the
quality of packing on all the costlier itemso This is being
done in a phased manner over the next three monthso Some of
the cost increase will also be because of this measureo We hope
we continue to have your support in thiso
d)
Erythromycin Stearate Tablets will not be available till
further notice. Partners are requested to make alternative
cirrangementso We regret the inconvenienceo
e)
T -Srikrishna
Srikrishna, who was our co ordinatior, resigned w.e*fcSeptember
01, 1990o He has been wanting to work for sometime on more
grassroots rural developmento He is in Malshiras near Puna, He
however, continues to be involved as an active resource persor
for LOCOST and drua issues.. We wish him wello
Own Formulations Unit
LOCOST has decided to go for its own formulations unit near
Baroda after considerable debate, dialogue and consultation
including a consultation of health activists at Bharuch in
February, 1990o The middle of the new year will see the
inauguration of our new factory.. The major reasons for this
venture, among others, have been that?(a) The Government of
Inaia now defininitely proposes to abolish loan licence (our
present system of production) in India by Dec»31, 1991 and (b)
Having our own unit and quality lab is expected to increase
the quality and range of services to our partnerso
5)
l}n^ST nro^Tis' watch this space,
space f as they sayo
un oenalif o. ^OCOoT, we wish you a nappy
happy new year.
Sincerely
,
For LOCOST Team
Ends Article on "PROPHYLACTIC PARACETAMOL WITH CHILDHOOD
IMMUNISATION”o
PROPHYLACTIC PAPftCETAMQl WITH CHILDHOOD IHMIJHISATION ?
Some doctors and nurses advise that infants should be given paracetamol
at and after each of their primary immunisations as prophylaxis
against febrile reactions.. However,no advisory body has recommended
such, acjne^cil prophylactic use of paracetamol; Is the advice justified?
BACKGROUND
About 5% to 7% of children have a personal or first-degree family
history of febrile or non-febrile fits’which puts them at higher than
normal risk, of febrile fitSo These children should nevertheless
receive diphtheria-pertussis (DTP)/ polio and mumps-measles-rubella
(MMR) vaccines at the usual recommended ages'; Paracetamol reduces
fever after immunisation and two American advisory bodies have therefore
fore,suggested its use in such children when they are immunised
3,
against pertussiso
; ADVERSE EFFECTS OF IHMUNTS^-.TIOh!
DTP vaccine causes fever in about 50% of children and in 6% the
temperature rises above 39°c within 48 hours of the injection."’5
The fever can be expected to cause either a fit or collapse (also
termed hypotonic hyporesponsivc episode) in equal proportion after
about one in 900 DTP INJECTIONS Calculations show that about one in
5,000 infants will happen to have a fit due to something else within
48 hours of a DTP injectioni.Such a fit or collapse is very frightening
for the family and usually leads to hospital admission.0 These are
the major adverse reactions to DTP vaccine/ but the evidence suggests
that they do not lead to long-term damrige of the brain.
If there is a risk of brain damage from DTP immunisation, it is extre^
55,99
mely smallo '
In 1985 the National Childhood Encephalopathy Study
(NCES) estimated the attributable risk of serious neurological
disorder at one year after immunisation as 1 in 3,30,000 injections
(with very wide 95% confidence limits of 1 in 50,000 to 1 in 18
million)o
The judge in Susan Loveday’s 4-month long test case in
1988 concluded that the NCES was biased towards overestimating the
risk of brain damage, and was not persuaded that pertussis vaccine
could cause permanent brain damage at all in young children "
There
has been no appealo
ROLE OF PARACETAMOL
In two randomised controlled trials'*'’
prophylactic oral pa.racotamol
halved the number of children who developed fever above 38°C after
DTP and polio immunisationo Infants under 6 months appeared to benefit
13 ...
.
mosto
in noth trials/ children received paracetamol or placebo at
the time of each of their immunisations/ and then at 4- to 6-hour
intervals for periods ranging from 12 to 72 hourSo In one trial th?
dosage was 15mg/kg/dose f in -the other lOmg/kg/doseo In both trials,
infants received their first immunisation at 2 monthSo
No febrile
fits or hypotonic hyporesponsive episodes occurred in these trials.,
Unfortunately, they were designed with insufficient power to detect
any effect of paracetamol bn the incidence of these complications ,
i
leaving that crucial question unanswered
needed to settle ite
A large trial would be
MUMPS, MEASLES AMf) RUBELLA (MMR) TMV! IN IS ATI UN
Any fever usually occurs between the 5th and 10th day after immunisa
tion., There are no data on the use of prophylactic paracetamol with
MMR vaccineo
ADVISING PARENTS ON MINOR REACTIONS
All parents should be advised on how to deal with common reactions
after immunisation, namely local redness, swelling and pain, fever
(delayed with MMR) and fretfulness* They are more common after DT-?
chan after DT vaccine. Oral paracetamol every 4 to 6 hours ( under
3 months 5~10mg/kg/dose,3 months-lyear
60-120mg/kdose; maximum of
4 doses in 24 hours),14 and physical cooling for fever, is the corr. jf
treatment for such reactions* These small doses are better measured
with an oral syringe than with a spoony such syringes are sold in
pharmacies but cannot yet be prescribed on form FP 10.,
If fever persists after the second dose, the parents should ask
first dose of DTP and polio vaccine*
Although manufacturers of
paracetamol have not yet amended their printed recommendations, there
is no reason why infants under 3 months should not safely be given
paracetamol at the reduced dose*
UPTAKE OF PERTUSSIS IMMUNISATION
In England in 1987/88 73% of infants received a complete course of
immunisation against pertussis*
The target is 90% and it is
estimated that up to 97.5’% of children have no absolute contraindica
tion and are eligibleo
The one absolute contraindication is a
personal history of a severe local or general reaction to a preceding
dose of the vaccine.^ Unjustified fear amongst doctors, nurses and
parents that children might suffer brain damage has resulted in a
quaarter of eligible children not receiving the vaccine*^7
C^CLUSIOM
The general prophylactic use of paracetamol with childhood immunisa
tions is not justified unless it can be shown to reduce the incidence
of post immunisation fits or collapse (hypotonic hyporesponsive
episodes)o
Doctors might consider offering prophylactic oral paracetamol to
c 3 o o o
3 infants at higher than normal risk of febrile fits to reduce the risk
of fever with each of the 3 primary diphtheriatetanus pertussis (DTP)
and polio immunisations (2 months lOmg/kg/dose; 3 months to 1 year
60~120mg/dose)e The first dose may be given at the time of the injec
tion , followed by only 3 further doses at 4 to 6 hourly intervals.
to treat their children with
Doctors and nurses should advise parents to
paracetamol infant suspension at the appropriate dose when common
minor reactions occur, such as fever or painful swelling at the sireo
This remains sound symptomatic treatment and should not be confused
with prophylaxis.
lo
Cherry JD, Brunell PA, Golden GS-# Karzon DT • Pediatries 1988«? 81
(suppl): 939-84,
2O
Department of Health, joint Committee on Vaccination and
immunisation, Immunisation against infectious disease, London
3o
HMSO 1990o
Advisory Committee on Immunisation Practices (ACIP) MMWR 1987;
36:281-82,
4o
5«
Committee on Infections Diseases., Pediatrics 1987;80; 743 <
Cody CL, Baraff LJ, Cherry JD, Marcy SM, Manclark CR, ibid 1981:
68;650-660,
7o
Drug Ther Bull 1987;25:9-11,
Baraff LJ, Shields DW, Beckwith L et al Pediatrics 1988; 81:789-94
8O
Griffin MR, Ray WA, Mortimer E, Fenichel GM,Schaffiner W,JAMA
9o
1990;263:1641-45,
Pollock TM Miller E, Mortimer JY, Smith Go Lancet 1984; 2 ? 1 0-49
Miller D, Wadsv’orth J.Diamond JoRoss Eo Dev Biol Stand 1935; 61.-
6o
10 o
389-94.
12 o
Dyer Co Br Med J 1988; 296: 1189-90o
Ipp MM, Gold RoGrecnborg S et aloPediatr Infect Dis J 1987;6:
13 o
721-25,
Lewis K,Cherry DG,Sachs MH et aloAm J Dis Child 1938; 142: 62-65,
11 o
15 o
British National Formulary 1990; No,20: 157 & 403,
Department of Healtho On the state of the public health for the
16 o
London f HMSO 1989; 196 a
year 1988o London,
Hewitt Mo Arch Dis Child 1989;64: 1052-63,
17 o
Drug Ther Bull 1988; 26: 31-84,
14
Drug and Therapeutics Bulletin Volc.28 No019jl7 September 1990.-,
LOCOST NEWS LfiTTER N0-29/December 90.
f
FL'XEMATINICS
Part IV : AC
_Survey of' ”
Haematinics (Iron containing formulations)
available in India
- Dr.Sagun Desai
Dr.Rajul Desai.
1.
Total No. of formulations
63
2.
Number of companies marketing37
them
Formulations
Sr.No.- Formulation type
~ %
No.
1.
2.
3.
4.
5.
Tablets
4
Capsules
29
Liquids
25
Injections
1
Special forms drops
4
spansules etc.
6.35
46. tS
39.68
1.59
6.39
4. No. of ingredients
Sr. No.
n3. of“iHgFedients“ No~f~fSrSuTations --- % “
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
-11.
12.
13.
One
Two
Three
Four
Five
Six
Seven
Eight
Nine
Ten
Eleven
Twelve
Thirteen
5.
Various ingredients present s
Sr.No.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Name of the ingredient
Folic acid
Vitamin Bl2
Vitamin C (ascorbic acia)
Other B Complex vitamins
Liver Extract
Enzymes/amino acids
Trace metals
Alcohol
Other vitamins/minerals
Haemoglobin
Miscellaneous
3
5
3
14
8
6
7
4
5
2
3
2
1
4.76
7.94
4.76
22.22
12.70
9.52
11.11
6.35
7.94
3.17
4.76
3.17
1.59
I
No.""
39
52
26
29
10
15
9
141
6
3
32
%
61.90
82.54
41.27
46.03
15.87
23.81
14.29
56.tO1
9.52
4.76
4.762
1. Expressed as percentage of liquid preparations,t
since only liquids contained alcohol.
2
ingredients like dioctyl sodium sulphosuccinate
(laxative) and calcium carbonate.
1
I
X
♦
6.
- 2 Indications (in order of frequency)
a)
b)
c)
d)
e)
f)
g)
h)
i)
7.
o
Anaemia due to nutritional deficiency )for treatment
Anaemia of varied aetiology
(and prophylaxis.
Pregnancy and lactation
Convalscence
Lack of appetite
Did age
Loss of vitality
Growth promotion
General - like bleeding disorders, threatened and
v habitual abortion, protein deficiency, post operative,
pica, adolescence, efc.
Specific contra indications and special precautions
mentioned only for four (6.35%) formulations.
8.
Form of iron used
Sr.No. Form of iron
No.
%
1.
2.
3.
4.
5.
Ferrous sulphate
Ferrous fumarate
Ferrous gluconate
Haemoglobin
Others
11
22
2
3
25
17.46
34.92
3.17
4.76
39.68
9.
Cost of the therapy per day
Sr.No, Range of cost/^y
No.
%
Loss than 20 paisa ★
21 - 25 paisa
26-50 paisa
51 - 75 paisa
76 - 100 paisa
1.01
1.50 Rs.
1.51
2.00 Rs.
More than 2 Rs.
1
3
14
13
11
10
3
5
1.59
4.76
22.22
20.63
17.46
15.87
4.76
7.94
1.
2.
3.
4.
5.
6.
7.
8.
Note : Drop formulations (3) omitted.
* 11 paisa / day.
10.
Comparative cost of Rational Therapy
Prescribed treatment s
cfeb. ferrous sulphate
200 mg x 3 times / day
Tab. Folic acid
5 mg x 2 times
day.
* cost = 2.1 paisa for ferrous sulphate
5.0 paisa for folic acid
7.1 paisa per day.
* based on availability at Sheth Khushalchand Charitable
Medical Centre as on 17-8-85.
1. Tab. ferrous sulphate
70m paise per 100
Rup Pharma/LOCOST
2. Tab. folic acid
Rs. 2.50 per 100
Mercury/LOCOST.
-3-
ys2_And_Misuse_of_Oestrogen-Pr°gestogene Forte Combination
Use as suggested in the past :
— m—!■>! M*—
——— —
IIM
IIB —mw— »
1.
2.
3.
Hormone testing for pregnancy.
To bring on a delayed period.
Abort!facient.
1.
The drug companies themselves agree it is not to be used.
A.
However, the idea has got so firmly ingrained in the minds of
the medical profession and general public that if the drug
continues to be available, its misuse will be hard to police.
B.
Simpler and simpler pregnancy tests are available, which do
not require much skill and do not require refrigeration for
storage. They are cost effective (Less Rs. I?/- per test).
C.
It is generaly believed that if the woman is given this
preparation in the event of pregnancy, she will not menstruate.
There is evidence to show that 18.9% of females who did not
menstruate were not pregnant (false positives).
D,
The drug has a potential teratogenic effect on the foetus.
In the event that the woman wishes to continue pregnancy
after taking the injection, she finds herself in a dilemma of
i) either bearing a child with the possibility of birth
defect/defect which may be manifested later in life (?) at
puberty or ii) going ahead with termination of pregnancy
with all its social, medical and psychological implications
for her.
2.
In the normal menstrual cycle, menses is brought about due
to a fall in the circulating level of the hormone progesterone. In case of a delay in menses, in a female
who otherwise menstruates regularly, she may either a) have
not produced progesterone at all or b) the level may not
Contd.e..2|
- 2 have reached the low threshold level.
In either case there
is no place to give her a drug containing both Oestrogen and
Progesterone. Moreover, the drug may further delay the fall
in her hormone level and hence delay her menses, even
further.
In the case of a woman who does not menstruate due to very
low endogenous production rate of Oestrogen, this short
course of exogenous Oestrogen is not sufficient to stimulate
endometrial growth and subsequent shedding.
3.
There is on-going research to discover an oral hormonal
abort!facxent
and the future holds promise of a drug
containing high doses of hormone(s).
However, this would
have to be taken soon after intercourse as it acts by
preventing implantation of the fertilised egg within the
uterus.
The side-effects of the drug are too severe to
recommend its use as a regular contraceptive and it may be
helpful only in occasional cases.
In any case, the drug
being tested has a hormonal concentration several times
that found in the drug Oestrogen-Progesterone forte.
RTC Meeting on 21 st June. / 87
The meeting of the Rational therapy Cell of WCOST. was
held in Bombay at J.J. Hospital on the 21.06.1987.
Drs.Sagun Desai, Ashwin Patel, Raj Anand, Y.K. Amdekar
Satish Tibrewala, Arun Bal, as well as Anil Pilgaonkar, Arvind
Jha, Padma Prakash, Nimitte Bhatt were present at the meeting.
The agenda for discussion included (l) uses and misuses
of E.P. drugs; Paper prepared by Dr.Satish Tibrewala,
(2) Strategy for the S.P. hearing in Bombay, (?) Relationship
of the consumer groups and professional bodies with the industry
(4) Reporting on hearing for category ii drug list (5) Educational
Programme for internsand residents in Baroda (6) Next Meeting.
Uses.and.Misuses of. EP Drugs:
After a brief explanation by Satish, regarding the
menstrual cycle and its relationship with the estrogen and
progesterone levels in the. body, the. following
were
brought out. EP drugs have no place at all in-any of the
conditions. The common practice regarding this drug were
listed by Satish in his paper. The group discussed the various
aspects such as the possible misuse by the general practioners,
active promotion by the manufacturer at the retail trader (who
in turn sells the drug as OIL product), availability of the
pregcolor test for pregnancy testing, etc. were discussed at
length and concluded that the ban should be continued.
Regarding the teratogenicity of the drug, it was pointed
out that the risk of developing cervicaicancer in the progerny
of the user is significantly higher than the nonusers of this
drug. Also the relationship of congenital malformations in the
foetus rejects the need to use this useless drug by the pregnant
women.
A concern was show about the physical psychological and
social anxieties and hardships that a woman would experience
on hearing that the drug she was prescribed for bringing about
a missed/delayed period was harmful to the foetus and she may
have to undergo a medical termination of pregnancy now.
It was also expressed by a member that the majority of the
doctors use this drug because of their ignorance and traditional
.practice. However, other members felt that there is a difference
between the ignorance of lay peoplet General practitioners and
Consultant gynecologists, such a practice by the experts to
...2..
2
whom all opportunities for knowledge are open cannot be easily
overlooked. One needs to make them know that they are really
ignorant as far as the truth in this case is concerned.
2.
Preparation,for EP hearing
It was decided to meet several senior Gynecologists and Obstetrians and try to seek their supporting opinion in favour of the
I^P Ban. The Bombay and Baroda groups will hold local meetings
'for the purpose -and the proceedings will be minuted. The minutes
can be submitted to the drug controller at the time of hearing.
Satish will prepare a small paper explaining the technical
aspects of the hormonal levels in relation to the menstrual
cycle of a woman, This paper can be circulated amongst all
concerned.
3.
Some pressure from the women’s groups will also be brought.
Padma will talk to the women’s groups in Bombay. The work at
Bombay will be coordinated by Arun Bal and that at Baroda will be
looked after by Nimitta and Sagun.
Sagun
the. Drug, Industry:
inis point was raised by one of the members and the group
thought that the relation with the drug industry should be either
on all or none basis. Generally we should not have any relation
with the drug industry and we should try to carry the message
even to the professional bodies/ to which we belong.
4.
Storage and drug expiry
It was opined that it is not advisable to use a drug which
has expired or is not stored at specified condition. However, the
actual changes which may have occured because of this, can be
worked out for some of the drugs.
5• gducatijongJ S££2rt.s_£9r.. intoms and residents:
Sagun reported about the plans of the Baroda group regarding
running regular courses for interris and residents to improve their
prescription-habits. However, more details will be worked out
at Baroda. Some suggestions in this regard were also made.
Moxt. Meeting;
Next meeting of the ETC will be held at Baroda on the
Suggested, agenda for discussion is - (1) Use and
misuse of I.V .fluids - Paper to be prepared by Dr.Arun Bal.
(2) Formation of Adverse Drugs Reaction Cell, More suggestions
are we 1c ome.
■cx-w—III-' ■ II I. IllMUM—■■num
L 0 C 0 S T
ur. -< -
GPO Box Nor134
Baroda 390 001
ARE YOU
PRESCRIBING THESE DRUGS ?
■tuxTjMwrr
on*'.*. MII■■■
MaiMM •
OBM «» •■»■
Dear Prescriber,
This letter is being written to warn you
against the possible hazards of four commonly used
drugs. They are Analgin, EP Forte, Chlor strep
combination and Anabolic Steroids. We have briefly
described here the possible adverse effects and the
irrationality of use, of each of them.
Please go through this and stop prescribing
these medicines, if you have not done so far. For
any queries regarding this please contact :
Low Cost Standard Therapeutics (LOCOST), 1st floor,
Premanand Sahitya Sabha Hall, Opp. Lakadi pool,
Dandia Bazar, Baroda 390 001.
Sincerely yours,
(Nimitta
Encl:
Bhatt
)
ANALGIN
All the drugs in the group of medicines called
pyrazolone derivatives may fause Agranulocytosis *
a fatal blood disorder, Out of these, the drugs
belonging to aminophanazone are already banned in
India and many other countries for their dangerous
adverse effects and relatively low medical benefits.
Analgin is a close congener of Aminophenazones. Its
other generic names are Dipyroie, Metanizol, Methampyrone,
Sulpyrine and Noremidopyrine Methane sulphonate sodium.
Drugs containing these compounds are used to get
rid of symptoms like headache, fever, bodyache, joint
pains, etc. Most of them are available as over the .
counter drugs. They are also prescribed by general
practitioners. But Looking into their adverse effects
and relatively low medical benefits should we not stop
using it ?
Though the risk of developing agranulocytosis is
1 to 10,000 other non steroidal anti inflammatory
drugs like Aspirin and Paracetamol are 2*3 times
cheaper, equally effective and much safer and easily
available in the market. They should be given
preference over Analgin.
Hi^X-dose combination of pestrogen and
proge_s_t^one~' HZl^^orte^r
No standard text book of Gynaecology or Pharmaco
logy
even mentions this combination. This drug
has been extensively used for pregnancy testing, A
series of studies have shown association betv/o-en
congenital abnormalities and administration of these
hormones during early pregnancy. There is increased
incidence of multiple abnormalities of.VACTERL type i.e.
vertebral, anal and limo abnormalities . Although
conflicting data is also available, it has been clearly
shown that ’There is no longer9^ny justification for the
use of hormone pregnancy testsz .
Exposure to any hormonal steroids like oral
contraceptives, Diethylatiberol, post coital contracep—
during early pregnancy (specially in organogeposis
stage) could be very harmful to the foetus.
It is required that the drug companies in India
mention ^the non indication of their use during pregnancy,
ine Fooc: and Drug Administration of USA has passed
for
use 2f a11 ProSestogens, (principally
dimethioterone, dydrogesterone, etynodiol, hydroxy
progesterone, lynestrenol noretynodrel, norgestrel
’
and progesterone). It is mandatory to enclose a special
-2leaflet describing the increased risk of birth defects
and other dangers if they are used for pregnancy testing.
Also the instructions to physicians must contain that
’In absence of adequate evidence of efficacy, they
should also not be used to prevent^habitual abortion
or to treat threatened abortion.’
: rWls clear from the above that use of this combina
tion for pregnancy testing is not justified at all.
ANjdBOLIC, STEROIDS
( Anapolon, ~(Txym ethol one, Stanozolol, etc,)
Until 1982, this product was recommended for,
treatment of delayed growth end development in children,
but this use is not justified. The evidence suggests
that the possible benefits of treatment are slight
and that there is serious risks of irreversible
disturbances of growth andrsexual development particu
larly in younger children • Liver disturbances,and
jaundice are common with normal doses . Other side
effects also include sodium and water retention, hyper
calcaemiar increased vascularity of skin, stoppage,of
linear growth, etc. In elderly women symptoms of virilism
are seen with high doses. In men, large doses would
suppress supermatogenesis and cause degenerative
changes in seminiferous tubules.
Looking at so many adverse effects of irreversible
kind, should it not be our scientific responsibility
not to prescribe them any more ?
Chlor _st_rep__combin_atipn
Combination of two antibiotics chloramphenicol and
streptomycin is not only unjustified but irrational too.
Color amphenicol is the drug of choice against enteric
fever (typhil and paratyphil) till today. It,should
not be used routinely because of fear of resistance.
Streptomycin is a vexy effective anti tuberculosis drug.
This^ should also not be used when other antibiotics
can be effective. Let apart the side■effects of using
thorn frequently, combining these two antibiotics in
low doses does not have any additional advantage.
The common indication for which this combination
is used is basically dysentery. Let us see what
text books say • ’Only in patients with life bhreatening
dysentery, the use of antibiotics is probably justified
and should be guided by accurate knowledge of the entero
- 3 -
bacteria involved. Drugs like streptomycin and
kanamycinggiven orally, though effective should not
be used .
In bacillary dysentery ’Chloramphenicol
used in the dose of 250 mg. 6 hourly also causes the
infection but does notyappear to have any advantage
over tetracyclines..
,
The above facts show that the use of chlor strep
combinations is not rational and justified^
References
1
D.M, Davies, Textbook of Adverse Reactions
1981, P.74-75
2 &
World Health Organisation, Drug Information
Bulletin, 77-3, p.7
3
4.
Charles Medawar, The Wrong Kind of Medicine. 1984.
P.114
5.
Martindale, The Extra Pharmacopoea, 1982. p.1430
6< &
7
Satoskar et al. Pharmacology and Pharmacotherapeutics.
Ninth Edition, 1985, p.566.
'
’
LOCOST
(Low Cost Standard Therapeutics)
1st Floor, Premanand Sahitya Sabha
Opp. Lakadi Pool, Dandia Bazar
BARODA 390 001 (GUJARAT)
Phone No: 63962
Cable
: LOCOST
Date : 11.07.198?
To
The Drug Controller of India
Nirrnan Bhavan
Nev/ Delhi 110 011
C/o.Public Hearing at
Bombay College of Pharmacy
Kalina? Bombay
Reg: High dose preparation of Oestrogen
and Progesterone.
w ■gnir-»y
•- —np-T” r—1-
r->;-.ignKTr i gr.Ji
Dear Sir,
The Rational Therapy Cell of Locost*consisting of expert
doctors (List at Appendix-A) of various diciplines of medical
science met at Bombay on the 21st June, 198? to discuss the issue
at hand.
Enclosed, please find the paper (Appendix-B) prepared
and presented by Dr.Satish Tibrewala (M.D. Ob & Gy), to which
the group agrees in toto.
Besides the points raised in the paper
we would also
like to give our submission regarding seme of the arguments as
we have come across in several professional forums and
literature regarding the ban on E.P. high dose preparations.
They ares
1.
DRUG MISUSE:
1.1
All drugs can be misused, picking on E.P
drugs is
arbitary and discriminatory:
Our Answer:
The mere argument that all drugs can be
misused, picking on these drugs being arbitary and discriminatory is baseless.
This is I’.vkin to ^situation wherein
four persons commit one murder each, and only one of them
is caught and prosecuted.
In this situation also he can not
claim that this is discriminatory as other three were not
...2..
2
caught and could escape.
At the same time, by forwarding this argument the manufa
cturers accept that E.P. drugs are being misused and thus
a natural consequence they should be banned.
Vigilant organisations and individuals have sought bans
against drugs like Analgin , anabolic steroids, etc. also in
the recent past.
Thus it is not discriminatory^they demand
ban against E.P. high dose preparations also.
1.2
Warnings as required by the drug controller , are issued in
the package inserts and the cartons.
Our answer:
■“”1
-t ■■ ■
misuse.
Mere insertion of warning does not prevent
Also it does not desist people from misusing.
This
has been amply proven by the fact that inserting statutory
warnings on ciggaratte packs 9 have not reduced ciggarette
smoking at all.
1.3 ' The E.P. drugs are not misused because they are schedule 5?L?S
drugs and rules 65 (9) and (10) ensure safe use because
rule 65(9) requires writing of prescription duly signed with
name and address.
Rule 65(10) requires that such drugs are
sold by retail through prescriptions.
Under Rule 97, cont-
arners of schedule ‘‘L” drugs should carry a warning and
should be sold only against prescription of a registered
medical practioner.
1.3.2 The drug therefore cannot and is not misused 9 but if it is
misused, it is not the responsibility of the manufacturer.
1.3.3 Adequate warnings can and do prevent drug misuse.
Our Answer:
As a proof against this, we are prepared to take
anyone right now in a medical store and get EP preparations
under the present consideration, across the counter without
prescription.
We have ourselves bought this drug without
...3..
3
prescription and without bill.
bearing in this situation.
The rule has thus lost its
Also this argument is contradi-
ctory to that of the first in the present set, wherein the
manufacturer has accepted that EP drug is misused.
The drug is not being misused for inducing abortion and for
1.4
pregnancy testing.
Our Answer:
Let us humbly but forcibly contend that in every
alternate OPD
at the Medical College 'Hospital, Baroda
■THirraH.
• atleast one patient on an average, solicits MTP because she
has taken this drug for pregnancy testing or inducing
abortion. If the authority is interested we invite them to
visit this institution and get this verified.
We are sure
this situation is prevalent in all teaching institutions
as well as other general hospitals. We reque st the D.C.I.
to communicate directly with these hospitals.
1.5
No drug has ever been banned because of associated misuse.
Our Answer:
This argument is completely incorrect and
misleading,
Let
Cr.n ra :x <|
JW—W——O”
quote the example of the famous Thalido-
mide tragedy which, took place in the Western countries
wherein this potent analges ic was sold across the counter
and it lead to the horrendous malformation of Phocomelia.
The drug had been outrightly banned,
Ever since then its
example is being quoted extensively in related Medical
literature.
Though- we may grant the argument for the sake
of arguing? knowing it very well that it is incorrect, every
act need not . j have a precedent, lest no good things would
have ever occured on this earth.
Also the drugs like
Amidopyrine and Tetracycline syrups have been banned recently.
1.6
For drug misused the prescribers and dispensers are respon
sible and not the; manufacturers.
Our Answers
If it would not have been manufactured it would
...4..
4
not have been misused.
It is not understood how can the menu-
facturer escape-from their responsibility.
Some drugs like
Morphine are not solicited for being banned though they cause
addiction states.
This is so because they are proven life-
saving and ■very effective in many situations.
The E.P. preprat- *
ions under consideration are neither life saving nor effective
Thus to prevent its misuse it should be banned.
j The EP drugs were banned under public pressure and
2.
organisations like FOGSI have strongly criticised the ban.
Our Answer:
ers.
We^ have met several FOGSI members and office bear-
One of them Dr.Pankaj Desai, who is present here person
ally also has been an active member of Baroda 0. & G. Society
for last seven to eight years which is a member body of FOGSI.
So much so that for two years he has been the Gen.Secretary y the
Vice-President for two years and he was its treasurer and an
executive member for one year each.
He has been an executive
member of The State Organisation of Obstetricians and GynecoLet us take the liberty to tell
logists of Gujarat also.
this investigating authority that if and whenever FOGSI has
opposed the ban, it is not the voice of all members of FOGSI
but a hand-full of its few
office-bearers, whose decision
does not reflect the opinion of all FOGSI members.
If such
an important decision is to be taken by Office-bearers than
it is unfortunate that each and every member of FOGSI was not
consulted for the same.
We openly challenge
c the Office
Bearers of FOGSI to hold a refrendum on the matter and take
opinion of each and every member of FOGSI as well as those
gynecologists who are not its members9 others working in 0b.&
Gyn. depts, of Medical colleges.
It will also be worth seeking
an opinion from members of the Pharmacology as well as PSM
depts, of these institutions.
We are sure there will be an
overwhelming majority to support the ban on these preparations.
...5..
5
3.
ICMR is merely a research body, its recommendation to ban has
no value, views of FOG-SI which deals with patients has not been
taken.
We are really shocked to hear this argument.
Our Answer:
In fact, arguments and results of ICMR have much more scientific
validity than FOGSI.
ICMR studies and opinions are quoted not
On the other
only in the country but also internationally.
hand, FOGSI is an association of professionals with no syste
matic plans or out-lay for research like ICMR.
We cannot und
erstand that such an argument ever exists.
4.
If drugs are banned for misuse no drug will be left for
prescription.
°ur Answer:
Banning is not the right answer.
The latest list of Essential Drugs as published
by The W.H.O. (Technical report series No,722. 1985) does not
include E.P. high dose preparations.
Thus there is no point
in retaining such an inessential drug.
More so, because their
adverse effects have come into light.
Thus banning them’-will
not bring about a situation wherein there will be no drug G/.Kfor prescribing.
But
We accept that educating people is of course important.
let us be pragmatic.
In the present situation waiting for the
education to do its work will mean waiting for a very very
long time.
In the mean time these preparations will continue
to play havocs and we shall be sitting as>nute spectators
with folded hands in a state of "Masterly Activity".
These drugs are not hazardous because no hazards have
5.
been reported in any publications in India.
Our Answer: This argument is totally wrong.
The Journal of
Indian Medical Association wherein the series of Dr.Pallani-
appan’s
study is published and is being quoted by the
manufacturers also is essentially an Indian publication.
..-.6..
6
Even if we grant the argument for the sake of argument, data
of adverse reactions, be it western does exist and we have
reprints of at least two papers which clearly show the
hazardous effect of these preparations.
Also Text book of
Pharmacology by Goodman & Gilman P.1417-1418 supports the possi
bilities of adverse effects
Also let us inform this committee
that at the Medical College at Baroda?an ongoing study
four out of 50 cases of congenital malformations are found,
■d n: *■
■
there is definite association of high dose EP prep
arations .
We are sure
similar studies must be going on in
Medical college hospitals elsewhere also, which can be obtai
ned by the hearing committee from them directly.
6.
Tn 20-30 years' usage no hazards have been reported to the
manufacturers.
Our Answers If no hazard has been reported to the manufacturer.
that does not mean that no hazard exists.
We are sorry to
deduce that those technical personnels who are dealing with
these companies are probably not well read with the existing
scientific literature.
In such a situation we have our
sympathies for the manufacturers for the mere inefficiency of
their staff.
Als o, in India, the post marketing monitoring
system is not healthy due to various reasons.
No wonder the
hazards have not been reported to the manufacturers.
7.
This drug is not hazzardous, because FOGSI members constituting
of practising Gynecologists consider S.P. drugs totally safe.
Our Answer; This is a sweeping statement and if taken in its
true spirit, many of our friends and Dr.Pankaj Desai, who is
a FOGSI member do not consider High dose E.P. preparations
to be safe.
8.
The list of 22 drugs recommended for banning by the Drug
Consultative Committee in 1979, did not include high dose E.P.
drug combination neither did the D.T.A.B.
...7..
7S
Eight years have passed since 1979>and Science
Our Answer:
today, is advancing so fast that we have to run to be at the
In this situation what was eight years back might
same pace.
be obsolete today.
An ammendment to such a list is a must.
We would only request
that these lists are amended as fast as possible.
Ban order issued on 21st June 9 1982 banned the manufacture of
9.
this formulation from 31st Dec.1982 and sales from June 1983.
There-
This shows that there was no grave urgency in the ban.
fore, the product can not be hazardous.
Our.Answer:
.
The mere fact that it requires to be banned,.a
product is in itself a proof that the drug is hazardous,
As
per the existing laws, the manufacturer is given time to
exhaust the stock of already manufactured product which was
produced when there was no ban.
In the light of the same, the
enforcement of the t h is bound to take some time.
We would
plead that the law requires to be amended in order to save
hazards to the unborn children and social tranma to their
mothers.
10.
No non-hormonal substitutes for treatment of secondary
amenorrhea, Menorrhagia, Oligomennorrhea, Menopausal Syndromes
and endometriosis are available.
10.2 Use of low dose E.P. drugs can cause confusion and treatment
could be more costly.
Our Answer:
Hormonal & non-hormonal substitutes for the
treatment of above disorders are very muoli avail ablee.g.
Danazol, low dose EP combinations 9 etc.
patently wrong.
If at all there is any indication then also
it is very very remote.
preparation far
duction.
Thus this argument is
However, the side effects of these
far out weigh; the necessity of their pro
Thus banning them is not going to cause any confusion
or rise in cost of treatment.
•••8
8
Low dose EP preparation have never caused any confusions.
This has
been proved extensively.
A pack of low dose EP prepar-
r
ation drugs cost Rs.4.50 to 5.00 whereas high dose EP preparations
cost somewhere Rs. 8 to 8.50.
8.50 !
By any arithmetic 4.50 is less than
Here we are comparing only opal preparations, in case of
injectables this difference would still be higher.
11. Use of Combining single Preparation of estrogens and progestrone
can cause confusions and misuse
Pur ..Anjwex*
(
This, argument is wrong.
Any person with slight skill
and knowledge about dosage can easily combine the two.
An average
general practitioner is much more skilled
12 Dr.Palaniappanfs study shows that 51% of the 52 mothers of congential malformed new horns had taken E.P. drugs.
It shows that
there is no association with malformations since 69% had not taken
it.
Our Answers
fit
1 .Ji-Il ■LSg»SMi,i nr,
We are sorry to note that the statistics of
•.«
Dr.Palaniappan's study have been wrongly presented.
We think J1%
of mothers giving a positive history with SP drugs means that in any
group if a woman takes EP high dose preparation, her chances of
developing a malformed child are 51% which is very high, by any
sensible standards.
In fact, this should serve as a basis for
banning the drugs.
It proves our claims that the drug is very
harmful and
we thank the manufacturers for accepting our point.
OUR RECOMMENDATIONS AND REQUEST TO THE DRUG CONTROLLER OF INDIA ARE:
1)
IMPOSE THE TOTAL BAN ON ALL EP HIGH DOSE PREPARATIONS AND
WITHDRAW THE DRUG IMMEDIATELY.
2)
CONSULT ALL MEDICAL COLLEGES AND OTHER HOSPITALS VffiETHER THE
DRUG IS HARMFUL OR NOT.
3)
INTRODUCE STRICT POST MARKETING SURVEILLANCE SYSTEM FOR ALL
DRUGS.
...9..
9
Please also note that v/e have collected more than 40 doctors’
opinion^ who are working in the Ob.
College.
Gy. deptt. of Baroda Medical
The women’s organisations like-Self Employed Women’s
Associations (SEWA), Ahmedabad,
Ahmedabad, Sahiyar, Baroda have also opined
in favour of the ban on EP high dose preparation;
Moreover,
experts fro^m Medical colleges of Ahmedabad also hold the view
that the drug should be banned and withdrawn immediately.
Dr.O.Do Gulati a Senior Pharmacologist of our country and
Medical Director of a Medical Research Centare
at Karamsad,
Gujarat has also signed in favour of the ban.
A comprehensive
list of persons who have opined in favour of the ban is enclosed
at App.’C’.
Many more signatures could have been obtained in
favour of the ban, had there been more time.
In view of all these, vze will only request once again that
a total ban and withdrawal of EP hi^h. doseions...is_made
eff^Jie„^m^d,iat^Bz.
Hoping for a favourable action.
Sincerely,
t, luc-.d.
■‘z!‘
i
(Nirnitta Bhatt ).. < ■ '
LOG OST, Bar oda
A22endix^A
List of_Rgti. OTial_JHierasc Cell Members
1.
Dr.Ashwin J Patel (M.D.Paed )
219 Nirman Society
Alkapuri
BARODA 390 005
2.
3.
4.
Dr.Son i1 R De s a i (MBBS)
5, Dhayber Col.
Near Baroda High School
Opp. Polo Ground
BARODA 390 001
6.
8.
9.
14. Dr.Anita. Srivastava (M.D. Paed)
R/2, Doctors Qtrs.
Jail Road
BARODA 390 001
15. Dr.Daxa Shah (MBBS)
ARCH, Mangrol
(Via) Rajpipla
Mr.S. Srinivasan
Behind Harikrupa Society
16. Dr.L.N. Chauhan (M.D.O^G)
M.D. Shah Medical College
7-B/A9 Medical Campus
JAMNAGAR 360 008
Ms.Nimitta Bhatt
21, Nirman Society
Alkapuri
BARODA 390 005
Dr.Abhay Bamg (M.D.Medicine)
Directors, 'SEARCH'
P.O. & Dist.Gadchiroli
MAHARASHTRA 442 605
7.
Dr.Arun Bal (M.S)
Flat No.6, 'Mallika'
Makarand Hsg.Society, ■
SVS Road
BOMBAY 400 016
Dr.Kartik Nanavati (HD, Med.)
3-D, Ravjibhai Apartments
Harihar Society, Man inagar
AHMEDABAD 380 008
Gotri Road
BARODA
5.
13
Dr.Vasfint Talwelkar
394, Bhadkamkar Marg
BOMBAY 400 004
Dr.Satish N Tibrewala (MD.O.G)
Krishna Niwas, 5th Floor
Charni Road Corner (Next to
Saif ee Hospital)
BOMBAY 400 004
Dr.R o K 8 Anand (M.D• Paed)
559 Kavi Apartments
Worli
BG-IBAY 400 01 8
10. Dr.Y.K. Amdekar (M.D. Paed)
Vora House, Bhimani Street
Matunga
BOMBAY 400 019
11. Dr.J.D. Lakhani(M.D. Medicine)
T/23, Doctor__s Qtrs.
Jail Road
BARODA 39 0 001
12. Dr.Jlayan D Swadia (M.S.)
T/20; Doctors Qtrs.
Jaillal Road
BARODA 390 001
Dist.BHARUCH 393 150
17. Mr.Akshaya Upadhyay
A-7, New Medical Boys Hostel
Jail Road
BARODA 390 001
18. Mr.Tushar A Shah
N-8? Tarabaug
Polytechnic Campus,
F'atehgunj,
BARODA 390 002
19. Dr.Arun Phatak (M.D.Paed)
Kharchikar's Lane
Behind GPO, Raopura
BARODA 390 001
20. Dr.Y. Patel (M.B.B.S.)
Professor, Community Medicine
Dept., SSG Hospital (PSM)
BARODA 390 001
21. Dr.Dilip Mavlankar (M.D.PSM
M.P.H.
17, Maharashtra Society
Near Ellis Bridge
AKlEDAB/iD 380 006
22. Dr.R.N. Hydrabadi (MBBS)
1/18, Doctors Qtrs.
V.S. General Hospital
AHMEDABAD 380 006
23. Dr.Kashyap Patel (MBBS)
7j Maneklal Park
Naranpura
Affl-IEDABAD 380 013
24. Dr.Asit G Shah (MD, Medicine)
42“B, Sthanakwasi Society
Naranpura
AHMLDABAD 3«0 013
(Contd..)
(APPENDIX-A CONTD.)
* ag.!■ in—i • .mb i—iii'mis-aaMaarvims**.r
25. Dr.Lalit Shah. (MD Medicine)
26. Dr.framesh Durvasula (M.D.P&SM)
9 6-B, Kunj S oc ie ty
Alkaptiri
BARODA 390 005
27. Dr.Divyesh Mehta (Haematologist)
83, Samnatrao Colony
BARODA 390 005
28. Ms.Padma Prakash
Economic & Political Weekly
Skylark5 284, SBS Road
BOMBAY 400 038
29. Dr.A.M. Jha
1/19, Tilak Nagar
Chembur
BOMBAY 400 018
30. Dr.Anil Pilgaonkar
34-B, Noshir Bharucha Road
BttlBAY 400 00?
i
31. Dr.Sunil Ahhyankar (MD, Paed. )
Fellow in Ped.Hematology,
Oncology
Down State Medical Centre
450, Clarks on Avenue
Brooklyn, N.Y. 11203
CV
V. • <
-
•
v■
\
t'
I
i
!
'■j
«» -
rv..-
J
/1
■
APPENDIX - 3
Use and Misuse of Oestrogen-Progestogene Forte
Combination (Dr.Satish Tibrewala (M.D.Ob.&Gyn)
ut-.
n* -ac.
Use as suggested in thg east:
1.
Hormone testing for pregnancy.
2.
To bring on a delayed period.
3.
Ab ort if ac ie nt.
1.
The drug companies themselves agree it is not to be used.
A.
However, the idea has got so firmly ingrained in the minds
of the medical profession and general public that if the drug
continues to be available, its misuse will be hard to police,.
3.
Simpler and simpler pregnancy tests are available, which do
not require much skill and do not require refrigeration for
'*
storage.
C.
They are cost effective (Less’.
c. i-
17/~ per test). J -
It is generally believed that if the woman is given this
preparation in the event of pregnancy, she will not
menstruate.
There is evidence to show that substantial number
of females who did not menstruate were not pregnant (false
positives).
D.
The drug has a potential teratogenic effect on the foetus.
In the event that the woman wishes to continue pregnancy
after taking the injection, she finds herself in a dilemma
of (i) either bearing a child with the possibility of birth
defect/defect which may be manifested later in life (?) at
puberty or (ii) going ahead, with termination of pregnancy
with all its social, medical and psychological implications
i
for her.
2.
In the normal menstrual cycle, menses is brought about due *
to a fall, in the circulating level of the hormone - progestorone.
In case of a delay in menses, in a female who
otherwise menstruates regularly, she may either a) have not
produced progesterone at all or(b) the level may not have
... Cont -' -
( APgEI® MJIONTD)
reached tue low ’threshold level.
In eifher case 'there is no
t
place to give her a drug containing both Oestrogen and
Progesterone.
Moreover, the drug may further delay the fall
in her hormone level and hence delay her menses, even further.
In the case of a woman who does not menstruate due to very
low endogenous production rate of Oestrogen, this short
course of exogenous Oestrogen is not sufficient to stimulate
endometrial growth and subsequent shedding.
3.
There is on-going research to discover an oral hormonal
abortifacient and the future holds promise of a drug containing
high doses of hormone(s).
However, this would have to be taken
soon after intercourse as it acts by preventing implantation of
the fertilised egg within the uterus.
The side-effects of the
drug are too severe to recommend its use as a regular contra
ceptive and it may be helpful only in occasional cases.
In any
case, the drug being tested has a hormonal concentration several
times that found in the drug Oestrogen-Progesterone forte.
~ Paper prepared for the Rational
Therapy Cell of LOCOST, Baroda.
Minutes of the Rational Therapy Cell Meeting on
---------------- - 21st June, 1987
The meeting of the Rational Therapy Cell of LOCOST was
held in Bombay at J.J. Hospital on the 21.06.1987, to discuss
the rationality of using the E.P. high dose preparation for
various conditions.
The group agreed with all the points brought out by Satish in
his paper regarding Uses and Misuses of EP Drugs.
Over and above
this. the following points were emphasised by the group,
At the
end,group held the strong ’opinion that the EP high dose ^^Ear^
ailSlsJiSZe.il. any of the conditions. and that
(Contd..;
(APPENPIX-B ’CQNTD< )
lihey shouM,b_ajm_ed from our country.
Regarding the teratogenicity of the drug, it was pointed
out that the risk of developing cervicalcancer in the progerny
i
of the user is significantly higher than the nonusers of this
drug.
Also the relationship of congenital malformations in the
foetus rejects the need to use this useless drug by the pregnant
women.
A concern was shown about the physical, psychological and
social anxieties and hardships that a woman would experience on
hearing that the drug
she was prescribed for bringing about a
missed/delayed period was harmful to the foetus and she may have
A
to undergo a medical termination of pregnancy now.
It was also expressed by a member that the majority of the
doctors use this drug because of their ignorance and traditional
practice.
However, other members felt that there is a difference
between the ignorance of lay people , general practitioners and
consultant gynecologists.
Such a practice by the experts to whom
all the opportunities for knowledge are open, cannot be easily
overlooked.
-APPEND IX-C
Sr.
No.
Name
. Designation/
Qua'lif ic at i on
Institution.
1o
Ms.Renana Jhabwala
Secretary
Self Employed Women’s
Association,
Opp.Victoria Garden
Ahmedabad 380 001
2.
Ms .Trupti Shah
In-Charge
’Sahiyar1 (a VZomen’s org
anisation) ,
Opp.Ahmdavadi Pole
Baroda 390 001
3.
Dr.O.Do Gulati
M.D, M.S.,F.A.M.S.
Medical Director
(Ex-He ad of de ptt.
of Pharmacology
Medical College
Baroda)
Medical Research Centre
and Charutar Arogya
Mandal, Karamsad
Distt.Kheda 388 325
4.
DraB.Pa Udwadia
M.D. Pharmacology
Ambalal Sarabhai
(Ex-Prof, of
Enterprises (D & P)
Pharmacology,
Wadi Wadi, Baroda
Med.College,Baroda)
5-
Dr.K.C. Dave
M.D., F.C.A.I.,
M.A.M.S.
Professor and Head
Dept.of Pharmaco
logy
N.H.L. Municipal
Medical College
Ahmedabad 380 006
6.
Dr.K.J. Nanavati
M.D. Medicine
Supdt.& Prof.of
Medicine
S.C.L. Municipal
General Hospital
Saraspur
Ahmedabad 380 018
7.
Dr.Nimish Pandya
Prof.& Head of
Deptt. of Ob.&Gyn.
8.
Dr.Harish M Shah
9.
Dr.Vali Sujaat J.
10. Dr.Ampara R.B.
R II O.G. Dept.
-do-
Baroda Medical. College &
SSG Hospital, Baroda.
'
O.G. Dept.
11• Dr.Sudha Pate1
12. Nandita Maitra
R III O.G. Dept.
13. Dr.Anjana Joshi
R II O.G. Dept.
14. Dr.Nayan Bax i
R II O.G. Dept.
15. Dr.Harshat B.Patel
H
16. Dr.Smita H. Shah
ft
If
ci
•17. Dr.Sanjeev A shad
it
it
18
ft
??
tt
it
Dr.Rupesh H Shah
19.
20. Dr.Dipan N Thakkar
R III O.G. Dept.
fi
Contd .
*
AgPgNDIX-C (CONIT), )
-»■
Sr.
No.
Designation/
Qualification
Name
r-——1 —
m
f•
■ ~
J..
ill Ml m.m
.i
-
11
_
Institution
r f~-i» r-
21. Dr.Gayatri C
R TV O.G
22. Dr.N.B. Sonipur a
HBBS/D.G.O.
n
23. Dr • Shah
M.D/O.G.
t?
24. Dr.Raman M Patel
R II O.G.
tt
25.
H..HW1MI, —
Dept.
'
Baroda Medical College c
SSG Hospital, Baroda.
i!
26. Dr.Preeti M Pandya
RI
27. Dr.Niranjana
G. Pate 1
R III O.G.
O.G.
28. Dr.K.K. Hepde
n
29. Dr.Sahnavi K
R II
30. Dr.J.V. Shukla
R III O.G.
31. Dr.Varsha E
K
32. Dr.Sheila
R I
O.G.
n
33. Dr.Batia
M.D.
O.G.
if
34. Dr.Bhagat
R III, O.G.
it
35 • Dr .Ghanshyam
Patel
R II, O.G.
if
36. Dr.Mehul Thakkar
M.D. ? Paed.
ti
37. Dr.Anita Thakar
R III, Paed.
ii
38. Dr. Ash it Mehta
R III, Paed.
it
39. Dr.Manoj
Ambvani
R III, Paed.
si
4o
M. 0
L * e' fc:-
O.G.
6, Unit
-
LOCOST
G.P.O.BOX i 134
BARODA - 390001
BY REGD. A.D
July 17, 1987-.
To,
The Drug Controller of India
Nirman Bhawan
NEW DELHI
Sub : Regarding Ban on EP highdose preparations
Dear Dr. Gupta,
Many thanks for giving us an opportunity of presenting our case
in favour of the ban on EP highdose combination drugs at the public
hearing at Bombay College of Pharmacy, Kalina, Bombay.
I had submitted 30 copies of our letter regarding why we want the
ban and xerox copy of a set of 40 letters from doctors demanding
the ban. Please find enclosed another set of
letters from some
more doctors and concerned citizens/organisations. Persons/orga
nisations who have signed the letters are :
Name
Qualification /
Designation
Name of
Institution
1,
Dr. Sushma Shah
M.D.Ob.& Gy., FRIPHH
Dept, of Ob.&Gy.
Med. College,Baroda o
2.
Dr. Leela Trivedi
Prof. Ob. & Gy.
3.
Dr. Meera Desai
4.
Dr. M.I. Singh
M.D. D.G.O, Const.
Obstetrician & Gy.
R.O. (HRMC ICMR Centre)
B.J. Medical College
Ahmedabad
Dandia Bazar,
Baroda.
5.
6.
7.
Dr. Bharat Rana
Dept, of Ob, & Gy.
Med.College,Baroda.
R III, Ob. & Gy.
R II, Ob. & Gy.
- do -
R IV, Ob. &■ Gy.
R IV, Ob. & Gy.
do
M.D.-*ab. & Gy.
Asst. Pfof.
10. Dr. Sadhana Gandhi R IV, Ob. & Gy.
do
. 8.
9.
Dr. Bipin Shah
Dr. Gor
Dr. Dipak Sura
Dr. H.B. Saini
11. Dr. Dasharath P.
R
12. Dr. Shaunak Shah
13. Dr. Dipak Thakkar
14. Dr. J.C. Shah
R III
15. Dr. Vijay Sheth
16. Dr. Awb. Sharma
R III
Ob. & Gy.
Surgery
R III Anaesth.
R III Anasth.
it
do
do
do
do
Med. College,Baroda
- do do
do
17. Dr. Sudhir Patel
R III Surgery
R II Medicines
do
18. Dr. Nilesh Vyas
R III
Path.
do
19. Dr. S. Vyas
20. Dr. Sushila
21. Dr. Ravi Patel
22. Dr. Mashru
R II
R II
Path.
E.N.T
do
23. Dr. Rajesh Parikh
24. Dr. B.M. Patel
25. Dr. Sunil D.S.
R III Radiology Dept.
R II Psych.
R II Paed.
R III Paed.
R II Psych.
do -
do
do
- do
do
do
do
2
Qualiflication /
Designation
Name of
Institution
26. Dr. Satish Pandya
M.D. Paed. Hon.Const.
K.G.P.Children
Hoptl. & J.Resea
rch Inst.Baroda
27. Dr.Sheela Aiyer
M.D. Paed.Chief Res.Paed.
28.
R III
- do Medical College
Baroda.
Name
\
29. Dr. Bakula Chawdhari
30. Ms. Tanushree
Ob. Gy.
R IV Ob. & Gy.
ecretary, Chingari
Nari Sangathan
- do 2, Gandhibagh Soc.
Navrangpura
Ahmedabado '
We would like to once again emphasise that since EP high dose
combinatior^s do not have any rational use and that since they are
definitely associated with adverse effects so serious as congenital
malformations, they should be banned totally and withdrawn imme
diately from the market. If still in doubt .. may
we request
you to
1)
hold a referendum of all gynecologists of India especially
those working in Govt, hospitals & medical colleges.
2)
Call for data in relation to the use of EP high dose pre
parations - its misuse and malformations reported, and
3)
establishing a post marketing surveillance system for all
the drugs circulating in the market.
Hoping for an action in favour of the millions of women and
unborn children in our country.
Sincerely,
NIMITTA BHATT
A BACKGROUND ABOUT
DRUG SUPPLY ACTIVITIES OF
LOCOST
LOCOST distributes some medicines after manufacturing on loan
licence and others after purchase from reliable small scale
manufacturers o
LOAN LICENCE
Under loan licence, LOCOST purchases the raw material, and
manufactures the tablets, capsules, syrups under our own
supervision. The machinery and the man power belong to another
entrepreneur (M/s white Way Products). For manufacturing, a
fixed charge of Rs. 5000/- per month is paid.
Costlier items were chosen for manufacture of loan licence.
This serves to purposes -
(a)
a greater ■por.ticn- of cost reduction can be passed on to
the end users.
(b)
It assures
viability of the drug supply activity.,
RESALE
In resalet drugs are mainly purchased from reliable small scale
manufacturers and then sold after testing at ITALAB - Bombay.
NOo OF DRUGS
2\t present we supply 55 drugs in 7 5 formulations 26
of them RESA-LE ITEMS in 33 formulations, and
27 of them LOAN LICENCE ITEMS in 42 formulations.
SALES BREAK UP
The break up of sales for the last three years as
follows g
(figufces in lakhs)
TABLE - 1
’86
‘88
*89
(15 ; months), (upto Jan.)
*87
———I
■»»
i
RESALE ITEMS
o
•
6.35
o
.LOAN LICENCE ITEMS
4.12
5.23
5.63
Ii
• • oI
c
7.25
12.15
16.96
13.71
J
TABLE
2
(figures in lakhs)
87
88
(15 months)
7.53
12.47
9.10
10.31
'RURAL
14.57
18. 53
URBAN
3.88
5.95
WITHIN GUJARAT
OUTSIDE GUJARAT
I
I
/2/
PARTNERS
Medicines are supplied to around 200 partners all over India.
Around 100 are within Gujarat and the rest outside. Over the
years there has been a steady growth in the number of partners
as shown in Table 3.
TABLE - 3
YEAR
1984
1985
1986
1987
1988
NO. OF INSTITUTIONS
38
102
135
141
164
PRICING AND OTHER DETAILS OF COST
*
For loan licence items, the prices of drugs are fixed after
calcul&ing all costs incured in their manufacture. (Raw
material cost, manufacturing charges, Q.C. charges, packing
material, etc.) The mark up is 10%. This mark up is inten
ded to meet administrative costs (rent, salaries, typing
and xerox, travel, etc).
*
The administrative expenses per annum
Rs. 1,34 lakhs.
->
In loan licence items, the cost of raw materials works out
to 85 % to 95% of the cost of finished goods depending on the
product. The costlier the product, the greater the percentage.
*
Manufacturing and process charges are included in the cost
of finished product. These charges are Rs. 60,000/- per
annum irrespective of the number of batches manufactured.
*
Quality control charges are included in the cost of medicines.
These include testing charges of raw material and testing
charges of finished goods at two different laboratories.
Last year these charges were Rs. 49,000/-.
*
Packing and forwarding charges of finished goods are borne
by partners themselves. Freight and forwarding charges of
raw material and resale items from
manufacturer to
LOCOST/ are borne by LOCOST.
/office
*
In the case of resale items the prices are fixed after
adding a mark up on the cost of the product.
at present are
PROBLEMS
i)
ii)
Preference is always given by the manufacturer to his own
product. This upsets our schedule and causes lots of prob
lems’ in distribution. This leads to loss of. goodwill among
partners.
There is always a limitation to the extent to which we can
force v > the. manufacturer to adopt good manufacturing
practices (GMP) and other steps to im rove quality. As long
as it does not involve any costs, he would agree to quality
oriented changes. . '
-I
iii) Canltt extend the product range,
repacking items, etc.
?or eg. ORS,powders.
o3
iv)
LOAN LICENCE IS SCHEDULED TO 3E SCRAPPED BY 1993. Infact
according to IDMA and other drug industry sources there is
a move by the govt, to scrap it by March 31, 1990 itself.
v)
The scope for research into appropriated technology
techniques in pharmaceutics is virtually non existent.
This is all the more important in the case of LOCOST because
it is not a ’BUSINESS VENTURE’
in the traditional sense .
Drug Movement in India and Locost like Organisations :
Over the last 10 years (1980-90), a drug movement of
sorts, has emerged in India, as an adjoint to the slightly
elder community health movement. This movement has rightly or
wrongly, claimed wide media attention, probably at the cost
of a primary health ^are debate, and has focussed on,
inter-alia :
(1)
(2)
(3)
(4)
Availability of essential drugs matching the
country’s disease pattern.
Rational Drug Therapy.
Advocacy for Rational Drug Policy that is people
oriented than industry oriented.
Critique of medical eatablishileht and the drug
administration.
(5)
Banning of hazardous, irrational and useless
drugs, with legal action initiuted by activists
on particular drug categories.
(6)
Critique of drug pricing structures and drug
production incentives.
Increased awareness about quality of drugs
being marketed.
(7)
There is today an active Zvll India Drug Action Netwerk
(AIDAN). The Government of India’s Hathi Committee Report
(1975) on the drug industry was in itself a land-mark as
also the more recont expose of the politician - prefessional
drug industry nexus by the Justice Lentin Commission (1987-88).
Drug Supply / Production Effects
It is therefore not unnatural- that in an era' of voluntary
initiatives on several socio-economic fronts, several groups
in India have set up of are in the process of setting up
community drug delivery systems with one or more of the following
features :
(1)
(2)
bulk purchase and supply to reduce costs
loan licence manufacture with strict quality checks
(3)
(4)
Manufacturing unit for formulations.
bulk dnmg ( basic drug) manufacture
(5)
quality control labs.
LOCOST - Baroda, CDMU
Calcutta, the more recent
voluntary CDMU- Type initiatives in Orissa and Bihar are
some of the outcomes of the eighties. Since September
1988k the Comprehensive Msdical Services, India (CMS-l) ,
Madras, a trust sponsored by the Inter Church Service
Association, has been supplying essential drugs in bulk
packs mostly southern institutions through a leased out
drug unit. It is still to stabilise its operations. There
is also the Ratnagiri Drugs Private Ltd. ^1988) seeking to
enter the presc-ription drugs market with only generics (an
activitis of the All India Drug Action Network is the
marketing director of this otherwise private limited company).
. . 2..
// 2
//
The West Bengal unit of the FMR*I (Federation of Medical
Representatives -Association of India) has sought to resuscitate,
(1986) a sick private drug formulations unit with prescription
giene-rfic-g probably the first effort of its kind by a trade
union anywhere is the world. Across the border, in Bangladesh,
we have the Gon.oshasthaya Pharmaceuticals (GPL), near Dhaka,
a trend setter ameng NGO efforts, at manufacturing and
marketing essential drug formulations in a big way (since 1982).
More recently (1989) GPL has started making basic antibiotic bulk
drugs fromdrug intermediates (Ampicillin, Amoxycillin from
6-APA). The Catholic Hospital Association and of late the
Christian Medical Association of India , with their lurge
number of constituents, have also been active participants in
these efforts as also in promoting the caus’e: of pational drug
therapy in general.
In India, the All India Mission Tablet Industry (AIMTI)
at1 Bangarpet, near Bangalore, has pioneered making drug formulat tions since the 1920,s . The AIMTI, under the umbrella of theMethodist Church, was established initially to provide medicines
at low cost to mission institutions (initially only Protestant
instititions and later expanded to include Catholic Hospitals).
The AIMTI, founded by Dr. Linn, Sr , an American Missionary,
is a fine example of the formulations industry as a smallscale entrepeneurial venture- clean and quality conscious and
befeft of the paraphernalia and technological accoutrements
that have become endemic to the present day formulations
industry, in the name of GMP, but actually not really aiding
GMP in as much as t.ie speed, and convenience of production.
The AIMTI has been apparently in some kind of doldrum
since 1980, when Dr. Linn Jr., returned back to USA. 'J ’
■
•
*
■
-
.
•
.
*
Lessions from Voluntary In tiatives
experience
experie-riofe -:‘o-f
o-f th^bove
throve efforts at production have
been mixed viewed especially is terms of financial viability
LOCOST , CDMU at Calcutta, and the AIMTI have been •successes’
with probably, LOCOST at Baroda, consistently marketing drugs
at the lowest prices among these three. These three inatitation
as also the CMS-I have the following features in common
(1)
(2)
(3)
(4)
(5)
Formulations marketed in bulk packs
Focussed and captive market.- that of voluntary
health institutions- with no medical representativeNo attempt to enter the prescription drugs market
per • se
All threuclaim to espouse in addition a value
system (be it rational therapy, community health
or the healing ministry of Christ) that has a
following/network around it that provides the
core of the captive market and that also does
the not so visible market promotion efforts on
behalf of the drug distribution agency. NGOs do
not ingoneral mind'’ promoting the cause of an
agency doing useful work that also delivers goods,
even if not on time always.
All four are essentially non-profit in nature
and started of with soft loans or grants.
e .3. . O
3
//
The financial performance of the others mentioned above has
been mixed. They all have medical detail men, and aim to
make a dent in the more diffuse prescription market. All of
them have had to develop a market for their products ab initio.
To develop a market segment for generic prescription drugs/ in a
market that is by and large wedded to patent products, is
difficult if not heroic, especially without an assured captive
sales guarantee to fall back upon as is the case with the
former four which have primarily relied on bulk pack marketing
to the captive ’hospital health agency'sector.
What then, have been the other major outcomes of these
efforts, by voluntary and /or rational drug policy oriented
groups ?
Briefly, these outcomes have been :
(1)
Demystification of formulations technology as
also commercial .business1 Operations for NGOs,
previously considered esoteric territory by NGOs
(2)
It is indeed possible to market (by way of
manufacture or bulk purchase)essential generic
drugs at prices that are comparatively lower
priced than similar packs of commercial, for
profit, institutions; and lower priced than
of course patent drugs. (The savings are due
to no commissions to wholesale and retail dealers,
no frills packing , no detailnu n expenses, no
marketing expenses and no excise duty(as in the
case of patent drugs). Given the set of conditions
described above, most such exercises at drug
supply ought to be viable, unless there is
rank herd marEngaaerit of finances, or bad product
mix and market development strategies.
(3)
Acceptable quality can be achieved in all such
drugs marks ted.
(4)
There is a rational therapy/ and rational
drug policy/ oriented market segment, especially
among NGOs and some medical college professors,
that is conscious of the need to promote
drugs only in generics and to weed out .nnecessary combinations as also harmful and
useless formulations.
(5)
For L0C03T itself. the gains have been the following:
(a)
(b)
Understanding of the generics and raw material
market in drugs
A record of clean business, something which
is considered a contradiction in terms.
(c)
A good understanding of pricing mechanisms as
well as that of costs of production.
(d^
An understanding of the limitations of the
loan licence model of production of drugs
over extended periods of time.
An understanding of the limitations of private
and government quality control agencies.
An increase in credibility for . J3C0ST in
relation to drug issues in general because
of being in the delivery of a concrete service.
(e)
(f)
..4. .
//
4
An upshot of this experience is the realisation that
loan licence system is a precarious form of existence for a
LOCOST like organisation solely dependent on loan licence or
resale items for supply. Production cannot be easily planned,
?or -quality be reliably monitored. However, the loan licence
system is a good way of building one’s market.
There is also the impending abolition, of the loan licence
system. Therefore, short of closing this segment of LOCOST1s
activitiy, the alterative is to go in for a self-owned unit.
The alternative of resale of items of other LOCOST- like
organisations is not really viable because there are major
points of departure in the outloo-k of these other organisations
and that of -LOCUST. The cost of items marketed by these others
are also higher on the average. MOre importantly, because of
its geographical Locale, LOCOST appears to have better access
to the raw material market than these others.
LOCOST also has been an important reference point on
voluntary action in the AIDAN network.’ The implications of closin
'LOCOST* s drug supply activity for the AIDAN, and AIDAN-type move
ment needs to be considered.
LOCOST like organisations without their drug supply activity,
will then be organisations promoting issues related to drug
therapy. Such
<
an activity can well be carried out by the state
voluntary health association or any
i
of the community health organisation in Gujarat/Maharashtra etc;
.; LOCOST and LOCOST - like
organisations should logically then divest their assets and
'hand-over1 whatever remain to such other organisations. Th a
existing partners of LOCOST can be helped to establish their
contacts with the remaining LOCOST like organisations.
In the event of such a happening, we will muse in learned
ways in the years to come, why a successful micro-level,
sub-sectoral enterprise could not ' '
extend its arms to new
challenges, but withdrew into quiet oblivion.
ABOUT LOCOST
LOCOST
is a voluntary initiative to reach out essential, generic drugs to those working
•rking with
with the
the poor.
poor.
LOCOST is a product of a movement to seek alternatives in health and development.
❖
is a response to promote a need-based, ethical drug industry. This means we make only those drugs
that the disease pattern of our country warrants. Drug industry should meet people’s needs and
not create artificial demands.
is an attempt to blend the best of a humane, medical and scientific culture with honest, business
ethics. Irrational prescription practices of the medical profession, with no or little social
accountability, as well as unethical promotional practices of the drug industry - both are
responsible for widespread exploitation of already impoverished families.
LOCOST’S present project
The dedication of our new formulations unit
at For, 20 km from Baroda, is a new milestone
for us. It is part of our decade-long ongoing effort to promote the idea that high quality drugs at
lowcost is not only desirable but is possible. It is also part of our collective goal to help demystify
not only medicine and medical knowledge, but also the production of medicines. We welcome
enquiries from service-minded individuals and groups for help in setting up similar efforts
elsewhere in the country. We also promote social initiatives for production of bulk drugs from the
basic and intermediate stage.
The unit at For will be manufacturing all essential drugs in the form of tablets, capsules and
liquids. The total project cost is Rs. 50 lacs. While LOCOST contribution has been 20 percent of
LOCOST studies have shown
*
$
*
$
*
86% of market formulations of cough
syrups are useless.
70% of Antacid preparations should not
be prescribed.
82% of painkillers in the market are not
justified.
87% antianaemia formulations are
irrational.
70% of ORS preparations arc
unscientific.
85% of antidiarrhoeal drugs are useless.
(Based
on survey of products listed in
Monthly Index of Medical
Specialities,
1986-87, 88)
this amount, the rest has been funded by the following international groups/funding agencies :
Action Aid (UK), Bread for the World (Germany), Misereor (Germany), Oxfam (India) and TUFF
(Sweden). LOCOST is grateful for their trust and support, even as it experienced tremendous
difficulty and resistance in raising support from leading public sector banks within the country.
2
Our service record
Approximately, 80 percent of our drug sales, during the last 10 years, have been to those working
in rural areas, with 50 percent of our sales going outside Gujarat, including to some remote areas in
Nepal.
At present LOCOST supplies 46 drugs in 65 formulations. The new manufacturing unit will make
about 100 essential drug formulations in the first phase.
On an average, our prices have been 200 to 4000 percent lower priced than comparative leading
products in the market. These prices have generated us enough surplus to meet our overheads.
LOCOST has an active Prescription Guidance and Information Service as well as a regular
Gujarati monthly, Apanu Swasthya. LOCOST promotes unbiased, scientific information on
medicines in Gujarati and other Indian languages to literate and non-literate populations.
LOCOST, the future and you
LOCOST is part of a larger struggle for promoting a just economic order, to anticipate among other
things - and prepare ourselves for - the harmful fallout of the Structural Adjustment Programme
(SAP), the Dunkel Draft and the new patent regime that arc being sought to be imposed on India.
The Indian pharmaceutical industry, and poor people especially, arc going to be hit severely if,
for instance, mindless liberalisation takes place in the name of restructuring. If production pattern
does not match needs, and if prices of drugs shoot up, as they will in the event, we would be losing
even the little gains that India has made in the battle against disease and poverty.
Worse will follow, if we do, not, as human beings, live and let live.
The battle against disease, inasmuch as for peace, begins in the minds of people.
Drug situation today
$
More than 45000 formulations are
available in India today. Most of them
are unnecessary.
$
For our country not more than 300 drugs
are required (Seventh WHO Essential
Drug List, 1992).
Only about 20 out of these 300 drugs
need to be multi-ingredient
formulations.
Brand names of drugs increase their
cost. They help in confusing people and
support false claims.
If you think, you can help us in this effort in any way, please get in touch with us at LOCOST, 1st Floor,
Premanand Sahitya Sabha Hall, Lakadipool, Dandia Bazar, Baroda 390 001. Phone : (0265) 66960
^4
LOCOST
*
tG. p. O. Box No. 13*
Baroda « 390 001.
TeL No; 58481
ANTACIDS
Prepared by:
Dr.J.D. Lakhani
Asstt.Prof.in Medicine &
Neurology
Medical College
BARODA
1.
Introduction
2.
General Information
a) Uses of Antacids
b) Classification
c) Individual Antacids : (.;
(1) Aluminium hydroxide
(2) Aluminium
phosphate
(3)
n
>-) Other Aluminium
compounds (4) Calcium carbonate (5) Magnesium
hydroxide and oxide (6) Magnesium trisillicate
(7) Magnesium carbonate (8) Magaldrate
(9) Sodium bicarbonate (10) Sodium citrate
(11) Tripotassium dicitrat@ bismuthate
(12) Miscellaneous gastric antacids (13) Antacid
combinations.
■
3r
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
f
<
d) Gastrointestinal ?rotectives and Abdosbents s
1 Simethicone (2) Kaolin (3) Activated charcoal
(4) Pectin (5) Magnesium triscillicate.
Comparison of Antacids
Choice of Antacid
Dosages of Antacid
Evaluation of available preparations
Review of promotional literature
Practices and malpractices followed by G.P.s
Other antiulcer drugs and surgery
Role of gastric antacid in management of Peptic ulcer.
Dangers of antacids
Epidemiological aspects of peptic ulcer
Clinical aspects
Preventive aspects
15.
16.
Issues - Hyperacidity - Antacid pru
Action Plan
17-r
Conclusions
18.
References
’’The desire to take medicine is perhaps the greatest
feature which distinguishes man from animals”-Sir William Osler.
The hucpan desire 'to take medicine' carriest however
a price
.
‘tag
u“'3 ’ A desire to take Antacids in any 'dyspepsia',
'flatulence', 'gas', 'belching'. 'Bosborygms'
has made
them one of the most abused drugs. Because of irresponsible
advertising it has become misused drugs and public has
started believing that man is constantly fighting a battle
against acidity and every little belch or upper gastro
intestinal upset calls for an antacid.Who is responsible
for such misuse of Antacids ? The answer is four 'P's s
(1) Power of Placebo s'" Many studies have revealed
substantial incidence of placebo responsiveness of individuals
with minor gastrointestinal upset.
/
(2) Physicians: The first weapon used by a physician
for any abdominal discomfort is 'Antacid'.
(3) Pharmaceuticals: Irresponsible advertising has
misguided physicians and public. In profit maximisation and
adoption of management principle like 'foot-in-the
door-phenomenon' has made antacids most abused drug. The
drug proved-effective for healing ulcer is promoted for
indigestion .
(4) Publics They have started believing that they have
to pay penalty in form of ulcer for their stressful life.
General Information of Gastric Antacids
Gastric antacids are agents that neutralises or remove
acid from the gastric contents. They are indicated in
following conditions s
(1) Peptic ulcer : Administration of antacids has been
the major accepted form of treatment for peptic ulcer.
(2) Reflux Oseophagitis : Reflux of gastric contents
through an incompetent lower oesophageal sphincter
can
lead to oesophageal inflammation and cause heart burn.
Hiatal hernias can be seen on radiogrpphs of patient with
fceflux oesophagitis. The medical therapy of patients with
reflux is mainly aimed at reducing the quantity and acidity
of the gastric contents available for reflux which is done
by Antacids<
(3) Use as prophylaxis for GI bleeding - The patients
who are seriously ill especially admitted in intensive
care unit are having risk of development of upper GI
haemmorhage. Many of these patients have been treated
prophylactically with either antacids or cimetidine to
prevent haemmorhage. Studies have shown that antacids are
more effective than placebo or cimetidine for this purpose
(N.Engl.J. Med.302:426, 19S0) Surg.Gynecol.Obstet. 153:214,1981)e
(4) Erosive gastritis which is also known as
haemorrhagic gastritis or multiple gastric erosions is an
important cause of upper GI bleeding. Once bleeding stops, a
regimen of hourly antacids or cimetidine is the line of
management.
2
Though these are the scientific usages of antacids,
in practice, it is used in wide variety of conditions.
Lay people use them as self medicament in almost any
GI condition.
Classification
Antacids are commonly divided into s
1) Nonsystemic antacids
2) Systemic antacids.
Nonsystemic antacids includes aluminium hydroxide,
magnesium hydroxide, magnesium oxide, magnesium trisilicate,
calcium carbonate, bismuth carbonate and calcium phosphate.
These drugs are water insoluble, generally unabsorbable
and are called nonsystemic because they do hot produce
systemic alkalosis.
Systemic antacids include compounds like sodium
bicarbonate and sodium citrate which are absorbed into the
systemic circulation and may cause metabolic alkalosis.
Individual .Antacids 2
(1) Aluminium Hydroxide z It is a weak antaqid and
generally is marketed with other antacids. Although it is
considered to be nonsystemic, some absorption from the
gastrointestinal yract occurs. The acid neutralizing
capacity has been found to differ according to the process
of manufacture, age of the product and it is varying from
batch to batch in the case of given product. Pepsin activity
is not significantly inhibited. Particles of wet aluminium
hydroxide are somewhat adhesive and the compound is demulcent.
The role that the demulcent action plays in the treatment
of peptic ulcer is controversial.
zldverse reaction g Constipation, hypophosphaemia
interfere with absorption of drugs like tetracyclines, iron
salts, antichXolinergic drugs digoxin and PAS. Aluminium
hydroxide may prevent the absorption of phosphate from
the intestine which would result in hypophosphatemias and
osteomalcia giving use to proximal myopathy. Encephalopathy
might result in patients undergoing hemodialysia.
Other uses ? It can be used to reduce intestinal
absorption of phsophate ins case with phosphatic renal
calculi and in chronic renal failure.
(2) Aluminium phosphate z It is sometimes prefered to
aluminium hydroxide as it does not interfere with phosphate
absorption. It has however no special advantages and it is an
ineffective antacid.
(3) Oth
er aluminium compounds g Basic Aluminium carbonate
Other
has its pharmacological property same as Aluminium hydroxide.
However its capacity for neutralisation is greater.
Amongst the aluminium containing Antacids it is best for
the management of phosphatic nephrolithiasis.
Dihydroxyaluminium sodium carbonate combines in a
single chemical entity, properties of both sodium bicarbonate
and aluminium hydroxide. ..The drug is partially systemic
antacid. It is claimed better than aluminium hydroxide
however lacks the confirmatory data.
3
Dihydroxyaluminium aminoacetate is a basic salt of
aluminium and glycene. Claims that the substance is less
constipating than aluminium hydroxide are not objective,
but there is less aluminium per chemical equivalent.
The capacity for neutralisation is low.
(4)
(4) Calcium carbonate ? It occurs as a white, odourless
powder with a chalky taste. It was the first gastric antacid
to be used. It has remained popular for a century and a
half. Its antacid effects are rapid in onset and relatively
prolonged in duration CaCO- has a high capacity for
neutralising acid in vivo. It is inexpensive. It was
m considered to be the most effective antacid for many years.
However today, CaCO3 is used much less frequently.
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Adverse reactions s CaC03 has long been considered to be
a nonsystemic antacid. However enough is absorbed to cause
systemic and renal effects in certain circumstances. A
slight to moderate alkalosis occurs. Hyper calamia may
result in patients having uremia.
It may cause acid rebound,
might be because of uactionof Catt on the small intestine
to stimulate release of 'gastrin.
It has tendency to produce
constipation and fecal concretions. The administration of
CaC03 promotes positive phosphate balance and lead to
hyperphosphatemia especially in patients who have developed
milk alkali syndrome. Disturbance resulting from the
liberation of carbondioxide may lead to belching in some
individuals. Nausea is also an occasional complaint..
Hypercaleiuria and alkalgria predispose to nephrolithiasis.
(5) Magnesium hydroxide and oxide s Magnesium oxide, a
on contact with water is converted to magnesium hydroxide and
then acts. Magnesium oxide is available as a light colourless
- -*
'hydroxide
_ n
" i
is
powder insoluble in water, while
Magnesium
containing
available as milk
i.. '/’ of~ magnesia
'
' ’”’
7 7 to 8.5% of magnesium
hydroxide.
It is quick acting antacid and the action is prolonged,
Mg(OH) 9 as milk of Magnesia has long been popular among the
cathartic. Acid rebound
as an antacid and a
cathartic,
laity
occurs. However it is insignificant.
f
i
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(
I
i,
Adverse reactions s It has mild cathartic action. It is
contraindicated in patients having impaired renal.function or
it might cause hypermagneSimla. Although Mg(OH)3 is
classified as nonsystemic antacids,, 5 to 10 % of the
magnesium can be absorbed.
(6) Magnesium trisilicate z It has too slow rate of reaction
with acid, to be useful for the management of peptic
ulcer. Even in a normal person it rarely elevates*the
intragastric pH above 2.7. As it becomes gelatinous in
consistency it provides a protective coating to the ulcer
• crater.
Adverse reactions — laxation by high doses. Approximately
5% is absorbed any hypermagnesemia can occur in patients witn
•renal insufficiency. Approximately 7% of silica may be
absorbed which may lead to siliceous nephroliths. Intestinal
concretions also occur. It is good absorbent which may
interfere with absorption of dietary proteins and number
of other drugs. It adsorbs pepsin also.
4
(7) Magnesium carbonate s This attacid has properties
similar to those of magnesium hydrcixide except that
carbondioxide is liberated which may cause belching. It has
been shown to be an excellent antacid in clinical practice.
(8) Mag al dr ate s It is complex hydro>ymagnesium aluminate
which reacts with acid in stages. The ay dr oxymagnesium is
relatively rapidly converted to magnesim in and the
aluminate to hydrated aluminium hydroxide. The aluminium
hydroxide then reacts slowly to give a Sustained antacid
effect. Magaldrate more consistently buffers the gastric
contents than do th§ mixtures. The PH is usually maintained
between 3.5 to 4.t Its systemic effects are those of
Mg(OH)2.
i
(9) Sodium Bicarbonate sit exerts immediate and rapid antacid
action in the stomach because of its solubility, however it
has short duration of action. It is a systemic antacid.
Eructation of the carbon dioxide liberated during the process
of acid neutralisation often gives the patient a sense of
relief from abdominal discomfort. This is the basis of its
reputed carminative action.
Adverse reactions g Chronic use of NaHCOS alone as an
antacid (taking with milk) can cause milk alkali syndrome.
Because of its sodium content it might lead to weight gain,
volume expansion, increase in BP and may promote oedema.
It may be hazardous in renal insufficiency, incipient or active
hypertensives and in CCF patients. Continuous maintenance
of raised pH by NaHC03 in stomach may lead to stimulation
of gastrin and rebound '
acidity.
(1) In metabolic acidosis
(2) In urinary tract infection to mkke
urine alkaline and to prevent precipitation of
substance like sulfonamide and uric acid, it is used.
(3) For topical application it is useds
as an antipruritic lotion, as an eyewash, motith wash,
douch to loosen wax'
in the ear and in enemata.
1
&
Other uses
(1.0) Sodium citrate g Sodium citrate has properties similar
to those of sodiumbicarbonate except that there is no
liberation of carbondioxide. Effervescent preparation that
’fizz' consist of sodium bicarbonate and citric acid which
react in solution producing carbondioxide and sodium citrate.
(11) Tripotassium dicitrate bismuthate (de-nol) s A
colloidal bismgth preparation accelerates healing of gastric
and duodenal ulcer. In a crossover trial, Lam et al found
that colloidal bismuth subcitrate headed 85% cimetidine
resistant ulcers whereas high dose of cimetidine headed only
4*% * Similar comparison was done with ranitidine and
healing. Relapse of duodenal ulcer was compared. Though
there was no statistical difference in healing at 4 wks and
8 wks with both these drugs there was difference in relapse
rates. 74% and 84% of ranitidine beated patients developed
relapse of duodenal ulcer after 4 months and 8 months
respectively. In contrast to this,~41% and .55% of the patients
treated with TBB develBped^relapse*. Similar results have
been obtained by Martin DF .
i
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I
I
1
5
Agverse reaction : It causes black discoloration of
stools . Liquid preparation is less acceptable to the
patient because of its odo^r. However TDB tablets can be
given which are effective and acceptable \
(12) Miscellaneous gastric antacids s Gaviscon is mixture
containing small amounts of NaHC03, ^l(0H)3, Mg2Si308
and ^Iginic acid. It makes foam (raft) which floats on top
of gastric juice. It is intended that in gastro oesophageal
reflux, the floating mixture is the first material to make
contact with the oesophagus. However it has negligible effect
on gastric acid below the raft.
The mineral hydrotalate (Mg^AI
oz (OH) AlZ
C0Q.4Ho
t) has
O
io
z
an acid neutralising capacity 84% of that of Mg(OH)2.
Milk as antacid has very little effect.
(13) Antacid combinations s Antacids are combined for a
variety of reasons and probably such combinations can be
considered rational. Laxative and constipating compound can
correct the disadvantage of each other, a fast acting
ingredient can be combined with a slow acting ingredient to
increase the total buffering time, the daily dose of a
single entity can be decreased to reduce the risk of toxicity,
patient compliance can be improved by combining agents,
rather than by giving multiple separate preparations.
The most common mixture of anto.cids are those of
Al(OH)3 andMg(0H)3 in gravimetric ratio of 2:1 or 1:1.
Gastrointestinal Protectives and Adsorbents : These are
discussed here because they are used in combination with
Antacids.
1. Simethicone s It is a. common ingredient in the
antacid combinations. It is included, to defoam the gastric
juice in order to decrease the tendency towaids gastrooesophageal reflux.
It is light gray, translucent liquid of greasy
consistency. It is a mixture of liquid demethylpolyolloxanes
with antifoaming and water repellent properties. It is
promoted as an adjunct in the treatment of conditions
in’, which gas is a problem, such as flatulence, functional
gastric bloating and *
s postoperative gaseous destension.
It has also been used to reduce gas shadows in radiography
of the bowel to improve visualisation in gastroscopy
clinical studies in support of these recommendations are
Abt convincing. Simethicone is used in combination with
antacids, antispasmodics, sedatives* and digestants.
A
^2. Kaolin is a native hydrated aluminium silicate
powdered and freed from gritty particles by elutrication.
It is used internally and externally for its adsorbent
properties.
.X’
6
fine blaJk^owdSr 5hilh°is reJd/3
odourless' tasteless
di still-,T wnicn is residue from the destructive
itar?asl ta? -°f V?2°US °rgGnic ^terials, treated S "
of various brands of Sti^lted^chircoll^ifCapacity
emergency ta treatment of oral drug
poisoning.
4. Pectin ? I'_
'
^t^is
a purified carbohydrate product
obtained from fruits
its aand chemicallv
<=+-3 of chiefly
chemically mncH
consists
polygalacturonic acid, It is claimed to be
an adsorbent and
demulcent.
5. Magtrisilicate s It is an effective gaaL^^
gastrointestinal
adsorbent but a weak antacid/ discussed earlier.
Comparisons of
various Antacids
The ideal antacid should have following characteristics3;
1. It should be potent in neutralising
acid
2. Inexpensive
3. Should not be adsorbed from the gastrointestinal
tract.
4. Should contain negligible amount of sodium
5. sufficiently palatable.
6. Readily tolerated arid
.free from side effects.
. A1’though the ideal antacid is yet to be developed a
number of preparations are available which can be used'for
the treatment of patients with duodenal ulcer?
-i Q h, One Of the w^ys by which we can compare the antacids
SisYbu?f^rng
e bufferin5 capacity of individual antacids
of ac?dfn?^ niGaP?C1 Y 1S exPressed in form of mulliequivaleAt
of acid neutralised per gram or per ml. of antacid Western
literatures of various proprietary brands of antacid
suspension and tablets and their buffering capacita is
available. However such data is leading for Indian brands of
antacids. Following chart of western brand antacid is given
thegVLg“eaStsOf
Antacid
“
Buffering capacity
meq/15 ml.
Sodium content
meq/15 ml.
1. AI (OH)3
Amphogel
20
0.9
2. Al(OH)3+Mg(0H)2
Maalox Therapeutic
concentrate
95
0.11
Maalox plus
40
(containing simethicone)
3. CaCO3
Turns tablet
19.5 per 2 tab. :
4. AI(OH)3+Mg(0H)2+CaCO3
Carnalox
54
*•.18
^125
• .33
(Chart from Manual of Medical Therapeutics - 24th Edition
p. 251) .
-a.
4
- 7 It is evident that maximum buffering capacity is of
Antacids containing Mg(0H)2.
Choice of Antaeid
4
1.
In general liquid antacids are more effective th?n tablets .
Tablet preparation of magnesium hydroxide and/or aluminium hydroxide
possess little acid neutralising capacity and are not recommended in
the treatment of duodenal ulcer •
2.
Magnesium hydroxide is a potent antacid but large, frequent dose
can cause severe diarrhoea. For this reason it is combined with
Al(OH)3. In most popular preparation, this antacid howevet would be
contraindicated in patients with severe renal disease.
Aluminium hydroxide has moderate buffering activity and is
3.
hardly used alone as an antacid.
4.
Calcium carbonate though effective in expensive and well tolerated
antacid, it produces a genuine acid rebound. Again it might lead
to hypercalcemia, hypercalciuria and milk alkali syndrome and
that is why not preferred.
Magnesium trisallicate which is XRdMKsd included in various
5.
antacid mixtures is a slow acting and weak antacid.
Dosage of antacids
Antacid-dosage should be based on multiequivalents of ,
9
neutralising capacity rather than on volume or number of tablets • An
80—100 mEq dose of. antacid is usually prescribed for patients with
ulcer disease. This dosage varies from 30 ml. of magnesium and
aluminium hydroxide containing antacid to 45 ml. of an aluminium
hydroxide containing antacid. As in India the neutralising capacity
of various proprietary brands of antacids is not available,
scientific recommendation about the dosage is difficult to mkke.
In Western set up where throe meals per day is taken,
recommended dose of antacid is 80 - 100 mEq of liquid antacid. 1 and
3 hours after meal and at bed time 4,9,10.. This means a person
has to take antacid 7 times in a day. If the most potent antacid
is used it means that person has to drink 210 ml. of liquid antacid.
If the stomach is empty, antacids must be taken frequently. In
treating fasting patients, for example, patients in intensive
care units it may be necessary to give antacids every 30 to 60
min. to achieve adequate reduction of acidity.
In adal Indian set up we take meals twice in a day. Thus 5
dosages logically may be sufficient* However this needs confirmation.
Evaluation of availab1e preparations
—w
rt* ~Wi ■■■
i w > ■irw ii i » M
n>w»fI *****■■■ n u -
I have triad to analyse the^ntacid preparations listed by
MIMS- India (Vol. 2 November 10)
and have come to following
conclusions.
1. 34 brands of antacids is listed.
2. Of these 34 brands 15 are marketed in the form of liquid,
and tablets both. 15 are marketed only in tablet form and 4 are marke
ted only in liquid form.
In view of less rationality of tablet preparation, to have
30 brand out of 34 in tablet form of which t® 15 are marketed in
tablet forms only seems concernable.
v»
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3. I have tried to designate a commercial preparation
’pure antacids’ for preparation having a single and/or combined
ingredient in form of antacid without having combination of
gastrointestinal adsorbents or anticholinergics,
’ * ‘
for the
evaluation purpose.
out of 34 listed
1 pure antacids (as defined earlier)
5
preparation
2 having added simethicone
(dimethyl polysiloxanes)
23 preparations.
Thus if I want to prescribe an antacid for a patient of
Duodenal ulcer and I do not want simethicone1 to be given to him
I would have only choice of these 5 antacid preparations.
5. If we analyse still further these 5 antacid p_
preparation
none is suitable
for
j
---my patient
of duodenal ulcer. Demerits of
these 5 antacids are as below -
’
1.
Aiucinol - is basically aluminium containing antacid
and thus would be a weak antacid.
2.
Alludrox - contains only Al(0H)3. The alludrox NH contains
AI(0H)3:Mg(0H)3 in ratio of 3:1 -ideal ration being 1:1.
3.
Eugastrid - 4 antacids are combined of which 3 are weak
antacids.
4.
Gelusil - Magtrisillicate and aluminium hydroxide - both
are weak antacids.
5.
Magsil - 4 antacids combined.
6. Gelusil in India contains Magtrisillicate and aluminium
hydroxide while in United States af America Gelusil-1 contains
Al (0H)3 and Mg(0H)3.
7’ Most liquid preparations are available in very small packing
e.g. Almagel in 175 ml, Allugel in 210 ml. Digene Gel in 210 ml,
Diovol in 175 ml, Gelusil in 175 ml. This wo'cld be hardly sufficient
for (1 ) day! This itself suggests that most antacid are working
as placeto rather than antacids.
8. If a liquid preparation is prescribed 41 ml x 7 times in a
day for 6 wks, a person may require 12600 ml, of antacid meaning
that ho has to buy 60 bottles of 210 ml packing.
9. If antacid containing methylpolysiloxane is prescribed
for CDU than a person would be taking and paying fur
fcr 63000 mgm of
methylpolysiloxane extra. A person taking 3/4 kilo of methylpolysiloxane without any benefit (antacid contains average 25 mgm^b ml
and if requirement
ml
.
- -- is
— 12600
antacid
it would come to 63000 mgm).
Review of Promotional literature
As I mentioned in the starting of this paper (quoting the
standard textbook of pharmacology) that because of irresponsible
advertising, antacids are
most abused drugs. This state of
affairs is not present only in India but all over the world.
’Rennie1 one of the most popular brand of antacid available on
the counter in UK writes ’Digestif Rennie - for on the spot
relief’ • This tablet contains 680 mgm of calcium carbonate and
80 mgm of light magnesium carbonate. The other caption which is
written on the package is ’Digestif Rennie relieves acid indigestion,
heart burn, nervous indigestion, acidity, flatulence upset stomach
and dyspepsia’.
I-
- 9 As it is with this Rennie tablets most of the antacids are
promoted as the drug for antiflatulence. No where it is written
that antacid relieves the flatulence on the contrary antacids like
NaHCO3, MgC03 liberate C02 which might produce belching*
The other common finding is almost all antacid preparations
are promoted for variety of conditions.
However scientific indications of antacids are few and specific.
Many a times it is promoted for indigestion. How are the antacids
going to improve the digestion , As mentioned by Kurt Kroenke in his
article on polypharmacy that pharmaceuticals adopt foot in the door
policy. The drug like antacids was marketed and accepted by the
medical science as antiulcer drug had a foot inside and thus it is
now promoted for indigestion.
Practices and Malpractices, followed by the GP
Physicians are not less responsible for misusing the antacids.
Most of the times it is prescribed to give placebo effect. When a
patient comes to a doctor for pain in abdomen, something has-to be
prescribed and that is in form of antacids. In the indicated
patients it is prescribed in smaller doses. Many a times because
of lack of time knowledge and diagnostic skill antacids are
prescribed which is moreso by the unscientific doctors. Again there
is a belief that ante^ids are harmless and thus they are prescribed
for a very long tim
’Buch belief is common among the doctor
and also in public. Many Indian patients are fussy about their
habit of passing stools every day in the morning. They find
magnesium containing antacids useful for their bavel habits. This
feeling is reinforced by the doctor by saying that ’yotf are passing stool
because you get better digestion with help of the pills*.
Other antiulcer drugs and surgery in the management of peptic ulcer
H2 receptor antagonist cimetidine is now widelv used in the
treatment of duodenal ulcer*.84
~ % patients develops nealing in th@
ulcer by cimethidino therapy
The other H2 receptor antagonists
like ranitidine and Omeprezol have also been tried in the management
of duodenal ulcer.
Anticholinergics have been used for many year$ to decrease
gastric acid secretion..Because of their side effects and advent of
H2 receptor antagonists they are used much less frequently as antisecretory agents. Recently a selective antimusipgrinic type of
anticholinergic PIERENZEPIM has been developed .
Surcalfale (carafate) a drug that coats ulcer crater them
from acid and pepsin is also been used. Prostaglandin E2 is also under
experimental stage.
Current medical treatment of duodenal ulcer, be it with
cimetidine, ranitidine, sucralfate, deNol, prostaglanotin or
antacids ..........
is successful
in not more than 75-80 %'of patients and
... 1 -J
____________ J ____ A. * Z+
thus surgery would
be required
in the rest
Role of Gastric antacid in the management of peptic ulcer
What share antaci'd has today in the management of peptic
ulcer , Today we have so many new drugs especially H2 recepter
blocker drugs. The Goodman-Gillman*s text book writes *The
status of antacid is presently in a stage of evolution. The use
of cimetidine will^undoubtedly decrease but will not abolish the
need for antacids* .
10 -
much more convenient, is advantageous m that bavel function is
not altered and is no more expensive^2.
Hollander and Harlan did not find any significant difference
antacids and placebo in its effectiveness in a double blind
tKialH L p contrast to this another double blind clinical trial
better
^r9° dose ®nta?ld renimer. had statistically significant
better ulcer healing rates m comparison with placebo^ulcer
lnTf^ receiving placebo while in 78% treated
with antacid)
Though antacid efficacy is proved by this study
and is accepted by most text books also the question is that if Z
uleer healing xs occurs in 45% of patient with placebo why to give
antacid , Again the same article has proved that ANTACID WAS NOT
MORE EFFECTIVE than PLACEBO IN RELIEVING ULCER SYMPTOM.
^hGrfPyncan be useful in patient who has cimetidine
resistant duodenal ulcer. Most studies show that H2 receotor
antagonists 4 heal about 85% of duodenal ulcer after 2 months but
relapse rates on withdrawal of the drugs are very high16 A ’
multicentric trial of cimetidine versus intensive antacid therapy
for duodenal ulcer showed similar rates of healing with both the form
of therapy. 80% of cimetidine beated patients bt-'ame asymptomatic
by week 4, as did 63% of antacid treated patients (p
pregnant patients antacid is preferred to cimetidine therapy.
Gangers of Antacids2
The presence bf an antacid in the gastric contents Iticreases the
volume of gastric juice secreted and the output of HG1. An elevated
’> ' j11 uces the pyloric antrum to release gastsin. In patients with
duodenal ulcer this is more marked. Acid rebound is known to occur
with many antacids like CaC03, Mg(0H)2, NaHC03. Gastric alkalinization
may lead to increased susceptibility to various acid sensitive
microbial pathogens such as Brucella abortus,. Antacids like Mg(0B)2
and GaGO3 can cause significant elevation of urinary pH and
predispose to UTI and urolithiasis. Antacid interact with other
drugs by pH related and other mechanisms.
■HlllslPJllijogical aspects of peptic ulcer
The absolute prevalence is not known. For duodenal ulcer
estimates have ranged from 6 to 15'per cent. This variation may be
related to the population examined, differences in study design,
diagnostic method and perhaps to actual changes in frequency of
duodenal ulcer disease. It is suggested that 10% of the population
has a clinical evidence of duodenal ulcer at sometime in their life time.
It seems.that duodenal ulcers are declining^®. Susser and Stein
reported decline in.death rates in England and Wales after 1950
due to peptic ulcer . Similar finding is from Germany20. The same
fact was observed by Sonnerberg in Switzerland. He compiled
mortality figures as follows .
c ■'untry
. G.UD.U,
Population
Poppiation
------- -_naJ-e,____
-- female
England and
Wales------- 35.3
52.1
23?881,300
35.5
29.1
25,186,100
West Germany 59.3
29.6
29>348,400
34.0
11.8
32,205,000
Switzerland 36.8
28.1
3,074,700
35.0
16.6
3,228,100
The figures refer to the averages of the period 1971-80. The
death rate of gastric ulcer and duodenal ulcer are expressed
per million living men or women per year.
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As far as epidemiology of peptic ulcgx; in India is
concerned following differences are noted
Peptic ulcer affects maximum subjects a decade
1.
earlier than west.
2.
Duodenal ulcer is more prevalent than gastric ulcer.
Significant difference is noted in the' incidence of
peptic ulcer in southern and northern parts of India and
is believed by some th t the incidence is more in so#th
in comparison with north. Many studies have correlated this
difference with food habits and customs. However no
conclusive ifroof is evident. In India pepti^2u^cer ^Iso
affects those in poor socio economic strata .
Brief clinical aspects of Peptic Ulceft
Peptic ulcer is a term used to refer a group of
ulcerative disorders of upper gastrointestinal tract, which
appear to have in common participation of acid pepsin in
their pathogenesis. The Zollinger Ellison syndrome
(gastrinoma) may be considered a form of peptic ulcer.
Epigastric pain of burning or gnawing character is the
most frequent symptom which occurs from 90 mm to 3 hour after
eating which is relieved by food and antacids. Change in
the character of pain often indicate the presence of
combinations. The complications of peptic ulcer includes
bleeding, gastric outlet obstruction perforation,
penetration and lutractability.
:
New studies have demonstrated following facts which
have important bearings in the management of peptic ulcer.
They are g
1.
Ulcer symptoms may resolve even though the ulcer is not
healed.
2.
Many patients with active disease have no ulcer
symptoms and may present with complications.
3.
Many patients with ulcer like symptoms may have no
evidence of an ulcer even after careful readiographic
and endoscopic examination.
Preventive aspects
23
1.
The prevalance of duxodenal
dmxodenal ulcer disease is mgner
higher
in aggregate smokers than in non smokers. The frequency of
the anodation apparently increases in proportion to the
amount of smoking.
2.
Alcohol, a gastric secretons stimulant should be
avoided. It damages the gastric mucosal barrier.
3.
High dose of aspirin ingestion is anociated with
an increased incidence of gastritis and gastric ulcer and
should be avoided in patients with an active or healed pep
tic ulcer. Other drugs, such as respine, indomethacin
or phynylbutazone may cause epigastrine distresg but there
is no evidence that they cause peptic ulceration .
12
Coffee, tea an^meat extractives are to be avoided
4.
for the same reason ,
There is no evidence that Bland diets are beneficial
5.
in beating ulcer disease. Therefore regular diet should be
prescribed. Milk is a poor buffer and its protein and
calcium content promotes acid secretion.
6.
Reduction of stress some patients have undue stress
at work or at home and sometimes modification of the work
or home situation cum reduce anxiety*.
Issues ? I could bring out five issues from this paper.
they are :
What is role of antacids in todays management of peptic
1.
ulcer disease when we have their better drugs available ?
2.
Which is the best antacid ?
What should be dosage of antacid in Indians situation
3.
where we take meals twice in a day
4,
What is hyperacidity
5,
What is role of pris
antacids
The first three issues I have discussed earlier and
I have presented my view. The last two are discussed beldw.
What is HYPERACIDITY.
'This is very common diagnosis made by general
practitioner and a physician, however a question would
arise whether such condition really exist ? Textbook of
medicine.and journals mentions about peptic ulcer but no
where the clinical entity like hyperacidity exists. Many a
times Hyperacidity is taken as symonyms for Peptic ulcer.
Agains any patient having upper abdominal discomfort
is stamped having hyperacidity and then he is loaded
with antacids. Does Hyperacidity exists without an
ulcer ? Many pharmaceuticals literature writes in indications
of antacid therapy peptic ulcer and hyperacidity
separately.
It is described by the workers that many patient with
ulcer like symptoms may have no evidence of Ulcer even
after careful radiographic and endoscopic examination.
A dilemma exists especially for the Indian, situation
where diagnostic facility of endoscopy and radiology
is available to an average middle class Indian patient,
is so small that confirmation of diagnosis by endoscopy or
radiology and then starting management would be
impracticable and costly. Nevertheless healing patient
under broad umbrella of hyperacidity means we are misusing
antiulcer drugs especially antacids.
- 13 Role of pru Antacids
In USA antacids are taken in pru form. This
means when patient has pain they wopld take antacids.
Such practice is also observed in India. However
there is no evidence on the effectiveness of
antacid pm to prevent ulcer recurrence.
The oilier question is does antacid relieve the pain
of peptic ulcer ? In a multicentric double blind
while accepted clinical trial it was shown that
antacid regimen was not more effective in relieving ulcer
symptoms. and pain so I feel that placebo can do same
job as vzhat antacids are doing.
Action plan suggested to LOCQST
1.
Education of lay public, general practitioners and
physicians to give correct idea of antacid therapy. They
should be informed that ANTACIDS ARE NOT FREE FROM
DANGERS >.ND IT HAS NOTHING TO DO with DIGESTION.
2W
Counter sale of antacids should be discouraged.
3.
If L^COST desires to manufacture antacids it
should be liquid preparation of Mg(0H)2 and Al(0H)3 in
ratio of 1:1 (without adding simethicone) which would
have high neutrilising capacity. The preparation should
be like 4»Mqalox which is very popular in west.
4.
To f\nd out neutralising capacity of various
antacid brands available in India.
To
find out whether adding of simethicone increasing
5.
•
toxicity decreases the effectiv eness and increases the
cost of available antacids in India. .
CONCLUSION
On concluding this paper I feel that antacids
are more misused than used moreso in Indian situation.
Again we are lacking in many scientific details.
Regarding present paper I have shown my personal view
which may be biased and I am open to correction.
- Dr.J.D.Lakhani,
!•
References
1.
Kroente Kurt : "Polypharmacy ~ Causes, consequences
and cure", Ammmerical Journal of Medicine,Aug. 85.p
2.
Harvey S.C.: Gastric Antacids and p Digestants from
Goodman and Gilman’s. The pharmacological basis of •
therapeutics, MacMillan' Publishing Co. New York
Sixth Edition, page 988."
3.
McGuigan J.E.s Peptic ulcer from Harrison’s Principles
of Internal Medicine edited by Isselbacher K.J. et'al,
McGraw Hill, Kogakusha Ltd. Tokyo, Ninth Edition 1980
page 1371
4.
Stenson W.F.: Gastrointestinal Diseases from Manual
of Medical Therapeuticc edited by Campbell and Frisse,
Little Brown and Company, Boston,24th Edition, 1983
page 249.
5.
Satoskar R.S. Bhandarkar S.D.s Pharmacotherapy of
peptic ulcer from Pharmacology and Pharmacotherapeutics,
Popular Prakashan, Bombay, 7th Edition, 1980. page 478.
6.
Lam S.K. et.a! s Randomised Crossover trial of tripottssium dicitrate bismuthate versus high dose
cimetidine for duodenal ulcer resistant to standard
dose of cimetidine. Gut 1984, 25 s 703~t6.
7.
Lee F.I. et al ; Comparison of Tripotassium dicitrate
bismuthate tablets with Ranitidine in healing and
relapse of duodenal ulcers. Lancet Sth June 85 :(i) p1299-13tl.
8.
Martin D.F. et al g Differences in relapse rates of
D^uodenal ulcer healing with cimetidine or tripotassium
dicitrate bismuthate. Lancet 81, 1; p.7-10
9.
Richardson C.T.s Peptic ulcer disease from Stein's
textbook of internal Medicine edited by Stein J.H.
Little Brown and Company, Boston, 1st edition, 1983
page 93-104.
10.
Peterson W.L. et al s
Healing of Duodenal ulcer with an antacid regimen.
The New England Journal of Medicine 1*77, 297 p.341-345
11.
12.
Gulhati C.M.s Antacids ; MIMS India, 1982, 2.10- p.-13
Hetzel D.J.s Cimetidine treatment of Duodenal ulceration
Gast^oentrelogy 1978, 74 p.389-392
13.
Feldman M.s Inhibition of gastric acid secretion by
selective and non selective Anticholinergics.
GastrCentrology 1984, 86 p.361-366.
14.
McManus J.P.s Gastroentrology 1984, 86 p-205-l«
comment to article of Heppell J. et al on ’Not anther
ulcer' Ann. Surg 1983 (198(1):1-4(July).
15.
Hollander D. et al s Antacids Vs. Placebos in peptic
ulcer therapy, a controlled double blind investigation.
JAMA 1973, 226 p.1181-1185
16.
Editorial article: Cimetidine resistant p Duodenal
ulcers Lancet 1985, (i) p-23-24(of Jan.5, 1985)
17.
Ippolite AF et al ; Cimetidine versus Intensive Antacid
therapy for duodenal ijlcer Gastroentrology 1978,
74 p.393-395
cont1d
►
S-
References (cent1d)
18.
Mendelo F.F. A.I.: What has been happening to
duodenal ulcer ? Gastroentrology 1974, 67 p..
1020-1022.
15.
Susser M et al s Civilisation and peptic ulcer,
Lancet 1962, 1 p.115-115
Sonnenberg A et al s Changing mortality of peptic
ulcer disease in Germany. Gastroentrology 1983,
84 p-1553, 1557.
Sonnenberg k : Occurance of Cohort phenomenon in
peptic ulcer mortality from Switzerland, Gastroantrology 1984, 86 p.398-4tl.
20.
21.
22.
Chaltane C.S.s Epidemiology of Peptic ulcer in
India, from Progress in
clinical medicine in
India edited by Ahuja M.M.S., Arnold-Heinemann
Publishers, New Delhi, Third Series 1979p.207-227
23.
from
Bockus H.L. s The therapy of peptic ulcer rrom
textbook of Gastroentrology edited by Bockus H.L.
et al, W.B. Squanders Company, Philadelphia,
Vol. 1, Third Edition, 1974. p.697.
#
•ii
*
■w
■4
-i
-
DRUG - J^UTRIEi£T
INTERACTION
- Sagun Desai, M.D.
I * _ In tr o du c tip n
’Health for all by 2000 A.D. 1 is the declaration of W.H.O.
A cherished goal for us all. To achieve this goal, we all need to
play our role and in many ways,. One of them is striving hard for
reaching essential and quality medicines to all those who need.
The other is rational therapy for all those patients who need it.
Rational therapy also calle for individualisation of therapy. In
doing so, many factors need to be considered. Most of these factors
are laid down well in standard books and publications. However,
most of this knowledge is borrowed by us from Western Literature
which seriously lacks in one aspect and that is consideration of
nutritional status of the patient. Probably, undernutrition is not
a problem in the well developed western countries and therefore
not much attention is.paid to this. On the other hand undernutrition
is a serious problem in the underdeveloped and developing countries.
According to IWO 500 million patients were suffering from
undernutrition in the world in 1976. Nutrient drug interaction
represents two sides of a pharmacological coin.
1.
Effects of drugs on nutritional status determined by nutrient
intake, storage, genetic variability, dose and duration of
drug therapy and combination of the drugs.
2.
On the other hand is the complicated effect of nutritional
status on the disposition and fate of the drug directly
influencing the clinical response, either efficacy or toxicity.
Successful and toxicity mx free use of chemotherapeutic
agents requires detailed knowledge of how frequently in what dosages
and in what combinations these agents mus4 be administered to a
large population. Equally important is the knowledge of what effects,
if any, disease e state, age, sex, ethnicity, diet, nutritional
status, drug metabolites, gastrointestinal flora and other environmental
factors^will have on the in-vivo behaviour, effectiveness and
toxicityes of chemotherapeutic agents when they are beine used in
clinical practice.
In short, the interaction between drugs on one side and diet
anVor nutritional status on the other become an important considera
tion for rational therapeutic in our country where undernutrition
is widely prevalent.
..Induced Nutritional Deficiencies
This is somewhat better known aspect. When drugs are being
used for treatment of various diseases, nutritional deficiencies of
various types and grades may ensur as a result of therapeutics^.
The risk of drug induced nutritional deficiencies varies
depending on the chemistry and pharmacological action of the drugs
concerned. Drugs can affect protein, carbohydrate, fat, vitamin and
mineral Requirements (ROe, 1976). Many of the changes are not
of ten clinically significant under circumstances of normal nutrition,
but clearlyj imay become important in states of malnutrition or
undernutrition as exist
---- ».iina tropical environment.
-2~
2
The common symptoms due to drug induced malnutrition
are weight loss, growth retardation, diarrhoea, dermatitis,
parasmesiae, bone pains, bleeding gums, anorexia and
anaemia. Such side effects are induced because drugs can
interfere with intake, absorption binding, excretion and
metabolism of nutrientso
Cjjmrrionly encountered drug induced
Nutritional Deficiencies
!♦ Effects on Intake s
a) anocrectic drugs s e.g. amphetamines phenfluramine
b) G I T disturbances s e.g. antibiotics.
2. Effects on absorption :
a) Intestinal hurry laxatives
b) Mucosal alterations - neomycin,, colchicine,
c) Sequestration of bile salts leading to malabsorption
of fat and fat soluble vitamins - cholestyramine,
neomycin
d) Inhibition of specific absorption of nutrients like
Vit*B12, Folate (biguanides, PAS, DPH, sulfasalazine/
chlorpromazine and chloramphenicol).
e) Nutritional drug interaction in the gut lumen tetracycline and iron.
3. Effects on Metabolism :
a) Drugs altering Metabolism of nutrients
i) affecting Vit.K metabolism-antibiotics,
analgesics, steroids, anticonvulsants
ii) affecting many nutrients like Vit.A, B
complex vitamins and ascorbic acid-oral
contraceptives
iii) induction of enzymes increasing Vit.D
metabolism - anticonvulsants.
b) Drugs inferfering with the metabolic functions of
nutrients (antimetabolites)
i) antifolates s cystostatic drugs, anti malarials,
trimethoprim, triamterene anti convulsants.
ii) Vit B6 (pyridoxin) antagonists - INH hydralazine
4.
Hyperexcretion and tissue depletion s
a) phosphates - antacids
b) calcium and magnesium - diuretics
c) zinc and copper - D-penicillamine
d) Vit. B6 and flavins - INH, borates
e) Increased urinary excretion of Vit.C - aspirin,
barbiturates, tetracyclineso
A number of agents (steroids, antibiotics, contraceptives,
phenothiazines, thiazides) interfere with aminoacid absorption,
nitrogen balance, or carbohydrate and fat metabolism.
-3-
3
Adopted from an article ‘Diseases of a Tropical
Environment1 by Kamala Krishnaswamy and P.C.Teoh, published
in ’Drug Treatment1 (2nd edition) edited by Graeme S.Avery.
III, Nutrition and Behaviour of drugs
In the preceding section we considered what do the
drugs do to the nutritional status. Here we shall consider
what does a body do to the behaviour of drugs in relation
to the nutritional status, leading to alteration in the
pharmacokinetic and pharmacodynamic behaviour of a drug.
Rational use of drugs based on pharmacokinetic and
pharmacodynamic studies in tropical countries are lacking
because i) most of the drug regimens -are standardised on
western populations who are genetically different and
are placed in a different environment.
ii) populations differ widely in relation to their
physiological and/or biochemical constitution
For ex. lactic acidosis is a commonly reported
adverse effect of phenformin (an oral antidiabetic
banned in USA) but not feo in Indians. There cogld be
two causes of these -
a) inadequate reporting services about ADR in India.
But atleast clinically also this condition would
have been detected in several diabetics.
b) personal discussion with several diabetologists
in Baroda (this whole example is my personal
impression and has no support of literature - SVD)
has revealed that lactic acidosis following
phenformin is not common in India probably due
to less consumption of meat in the diet, less
consumption of alcohol, lesser dose of phenformin
employed (less kixx than 100 mg per day, lactic
acidosis is more common with dose more than 100 mg/
day) and probably ethnic differences.
Over and above the conventional contributors, the
additional determinants of dose and dosage schedules in
tropical countries are -
1.
2.
3.
4.
Genetic profile
Body weight
Nutritional status and dietary habits
Tropical environment.
a) w climatological factors
b) infections and infestations
c) environmental pollutants.
From the above here we would focus only on point
no.2 and 3 as they are relevant.
Body weight s
is often an important consequence of nutritional
status. Drug doses are often fixed for an average weight
of 70 kg. as is a case in western populations. Whereas,
average weight of Indians and most Asians is 55 kg. Therefore,
when Absolute doses are extrapolated to asian patients
they receive about 30% more drug or dose based on
recommendation for most developed populations (Salafsky,1976).
-4-
4
Chloroquine in malaria is a classical example of
this. The recommended treatment in acute malaria is 4 tabs
stat, followed by 2 tabs, after 6 hrs. followed by 2 tabs
on two subsequent days i.e. 10 tablets of 250 mg. of
chloroquine phosphate each (equivalent to 150 mg. of
chloroquineb base) in 3 days. Thus an adult patient would
receive 1.5 kg of base which works out to be approx. 21.5 mg/
kg. A man of 55 kg. at this dose should receive about
1180 mg. of base, instead he is given 1500 mg. (about 2 tabs,
more than required). Is it possible that a poorly complying
patient gets cured of malaria even when he takes less
number of tablets or a well complying patient complains
toxicity with conventional dose, due to this fHxx
factor ? This needs investigation. There could be several
more examples like this.
The problem is more acute in children since dosage
of a number of drugs is based on age and for the same age,
the body
weights and growth patterns are entirely
different for the well developed western and less developed
eastern populations (Teoh, 1977).
The solution lies in the fact that drug doses should
be recommended on a body weight basis, rather than on the
basis of adje or on absolute fixed quantity.
Nutritional status s
One of the most important environmental factors
vzhich may influence drug response is the nutritional status
of an individual. Nutritional status of an individual
can considerably modify a number of pharmacokinetic
processes (Krishnaswamy, 1978), which may ultimately
determine the efficacy and side effects of drugs.
As mentioned earlier thel problem of malnutrition
in tropical and subtropical countries is enormous (WHO,1976)
It is usually complex - many deficiencies occuring
simultaneously. Changes occur in almost every organ of
the body (Krishnaswamy, 1978). Apart from protein energy
malnutrition, vitamin, mineral and trace metal deficiencies
will further modify the pathological changes and metabolic
and functional responses. Nutritional drug interactions may
lead to altered drug responses and therefore, drug dosages
m^y have to be altered depending on the nutritional status,
the type of nutrient deficiency and the extent of change in
the pharmacokinetics of a drug.
Infections diseases constitute the main cause of
morbidity and mortality in the tropics. Nutritional
disorders are predominant in these areas. Standards of
environmental hygiene are quite low due to over population
and inadequate sanitary facilities, which further contribute
to spread of infections and infestations. This triad of
malnutrition, infection and unhygienic enviromment is
likely to lead to alteration of processes of
1. absorption of drugs
2. binding and distribution of drugs
3. biotransformation of drugs
4. excretion - both billiary and renal of drugs and
5. tissue uptake, localisation and response to
drugs (drug receptor interactions).
All those can ultimately alter the clinical response
to the drugs and therefore, need to be considered for
rational drug therapy.
-5-
5
AY-*..
Pharmacokinetic Processes
As7 Inf luenced~by Malnutrition
1 • P^ug absorption and bioavailability ?
Absorption of drugs from the gastrointestinal tract
is an important aspect of drug therapy, which requires
careful consideration in malnutrition. Many patient
characteristics like pH in the lumen, gastric emptying
time, intestinal transit time, surface„area of the GIT,
intestinal villi (number and histological character),
messenteric blood flow, metabolism by gut bacteria and
enzymes in the gut wall, and presence of infections and
infestations determine the drug absorption (SJoqvist et al 1976).
Although most drugs are absorbed passively, the above
mentioned factors consideraly influence the rate and extent
of absorption of drugs. Malnutrition produces histological
changes.in GIT (Rosenberg and Scrimshaw 1972; Viteri and Schneider - 1974 and Suskind ~ 1975) and
hence it is likely that the rate and extent of absorption
may be altered in malnourished individual... Defective oral
Absorption of tetracyclines has been reported by Shastri
and Krishnaswamy (1976) and Raghuram and Krishnaswamy (1977)
m undernourished individuals.
Presence .of food in the gut can directly affect
absorption.of?drugs or can alter gastric emptying time
and intestinal transit time leading to altered absorption
of drugs.
Examples s
1. Calcium in milk or antacids retards absorption of
tetracyclines
2. Ferrous sulphate (as a nutrient) may decrease
absorption of tetracycline from. gut
3. Presence of food decre uses both the rate 'and extent
of rifampian absorption (Reiss,, 1968 and Keberle,1971).
4. F
Presence of glucose decreases absorption of INH
(Kakemi et al 1965 and Rao et al, 1971).
Drug uptake and elimination of drugs by the liver
during the first passage of drug from the portal circulation
(hepatic blood flow) has a ;significant
\ ‘"f
effect on the amount
of drug reaching the systemic circulation (hepatic: first pass
effect) or receptor sites for certain drugs, This may be
directly related to hepatic blood flow and/or the efficiency
of cardiovascular system (Wilkinson, 1975).. In malnutrition
these processes^ may be afzected altering drugj absorption
and/or bioavailability.
In.addition, different diets per se may modify drug
absorption? Populations in different parts of the world and
individuals within the same population differ widely in their
diets, therefore it is not possible to extrapolate data from
one country to another. Hence apart from nutritional status,
food habits may profoundly influence drug absorption and
the steady state concentration of drug.
-6-
6
2. ^^^otejuvbinding and distribution ;
interactions frequently^etermin^t-h11111031 imPlications. Such
are absorbed from the git eJt
t^ejrate at which drugs
eliminated from the bodv oroi-?nP°rted tO the tissues and
alters plasma and tis=-iie h . tn ener9y malnutrition
qualitatively. Albumin'is th,-103 • SU^titativeiy and also
and hypoalbuminaemia is a characteristic1^ Pfotein in plasma
malnutrition. The rate of a
ctenstic finding in
to the level of nroft^ • ^b™ln synthesis is directly related
(Whaterlow, 1975) The
G
amino acid supply
globulins and other carrilh^n^ • P1f
Proteins (albumin,
energy
malnuSitS Jl?Jo5o^
in protc^
acid glycoproteins whicS'tSsX? ba^ P^ticularly,
likely to be altered in mXSSSon
3130
of distribution1!? tetr^lSe!
aspect. Volume
available Ifor this
this aspect.
Volume
s ^
was found
to be :significantly
'
PatiG
<Sh^ri
and Krishnawwa]imy.
a number of
fluoxacillin.
sSS2«?Sfa:sL°so^°z:ietjrp“to"t'ph!"i'ii)utaz°--
serum albumin levels (Buchanan
tUS tO the lowered
Shastri and Krishnaswamy/
-^977,^rishnaswamy et al. 1981,
fullyCevSiSte!ig2ecr!S!
SUCh 3 Nation is yet not
to increased free drug conc!nt??hprotey binding would lead
toxicityx would be anticipated htill^b hence increased
not be altered since increasSWi!
therapeutic effect may
3 °f the/drug /free
would lead to more rapid elSnS^n*
two situations it mayPbecome shHowever in following"
(i) in case of druos-ithX,
necessary to exert care
increase in free d?!g'plasma1™^^° indeX' Sudden
of toxicity (ii) inXfe
a!
^crease the chance
elimination kinet^s
t h F ^lth dose indent
with
to decreased therapeuSc^sp^se^
f°r bindin^ may lead
3.
^Iptransfonnation 2
(xenobioticSdha!!etoCb!PIumin-t?dhfare J°reign to the body
are metabolised in the live! S mSab!?^
b°dy- Most drugs
in the microsomal, mitochondria!
present
Therapeutic efficacy and toxicitv !f SO1ubh fractions.
related to their rate of metabn lie
dr?gs are directly
diseases lead to impaired ab-iii-t- m by the liver. Liver
drugs (Blaschke, 1977) Severe on 2'•metabolislng several
is r&pbrted to produce' fattv inff??61?• calori<? malnutrition
impaired synthesis of lipoprotei!^nh10? °f 1±Ver and
Protein energy malnutritfon
? (Knshnaswamy, 1978) .
endoplasmic reticulum which ■?nvolves functioning of
of enzymes (Bhamarapravat^ 1975?Sp°nsabl® for Production
lead to impaired activitv Afm'a fUCh chanPes ultimately
which alters'metabolism of dr!^!^ function oxidases (MFO)
metab!irsmV!f1!hi!ro!Si!eS
dscreased rate of
Phenicol. Malnutrition Zso !™^2r°e^hYlene' and chlorammetabolism dara^ e? a? 197! Tthe rate °f antipyrine
Buchanpan et al. 1930 and
rishnaswamy and Naidu / 1977.
-L.
and Buchanan et al 1979).
-7-
7
of_^torations in drug metabolism in
human subjects in malnutrition-------------
A) Protein calorie malnutrition
1. Tetrachloroethylene
Metabolism
2. Chloroquine Metabolism
3.
4.
5.
6.
Chloramphenicol
Conjugation
Antipyrine metabolic
Clearance
Antipyrine Metabolism
in children with PCM
Protein binding of
many drugs
Balmer et al 1970
Wharton and
McChesney, 1970
Mehta et al 1975
Krishnaswamy and
Naidu, 1977
Narang et al 1977
Buchanan et al 1977
Undernutrition
(Mild and moderate forms)
Tetracycline t
and
Sastry and
volume distribution
Krishnaswamy,
1976
2. Steady state concentrations
Raghuram and
of tetracycline in plasma
Krishnaswamy, 1977
3. Antipyrine metabolic
Krishnaswamy and
clearance
Naidu, 1977
4» Streptomycin kinetics
Prasad and
Krishnaswamy, 1977
5. Acetylation of sulfadizine
Shastri and
Krishnaswamy, 1978
Diet and metabolism
1.
inclusion of meat in the diet on a regular basis
increases microsomal enzyme activity as revealed by the
to3o;olSc1to™9«a?la“t(g5“„i"tn°7^S"1!'vlgeta
rlil„s
compared
Jntake associated with the use of meat could
responsible for the differences in antipyrine kinetics
in vegetarians and non vegetarians. This hypothesis is
supported by the observation that ’
ypotnesis is
in white vegetarians
consuming similar dairy proteins as non
r---vegetarians, there were
no significant differences in the clearance
-- j of antipyrine.
i^Cete^01 and Phenacetin (Brodie et al 1980) Factors other
than protein consumption may
may also
also contribute
contribute to the
tneophylline, while increased carbohydrate diet redneck
SMra!ei±ati°- “?ap?’s et al- 1976>obseSaSS
£ man is S oraa?UJv ?" =an influence drug metabolism
vatiL 'Ketw=‘
. among
oraohVc 7
and cultural groups. Even within one
one geoWPo
location, changes in dietary habits have been
noted
LactIZettrXns
°n drUg ^netils^S knoS:
doses of
a
general might need lower average daily
toS: t°L 1T arUgS
appear t0 have a
capacity
to metaDollse drugs.
-8-
8 -r
There is some evidence that in malnutrition oxidation,
conjugation and polymorphic acetylation pathways are
impaired. Changes observed in the rate of polymorphic
acetylation and microsomal oxidation are of sufficient
magnitude to suggest that care needs to be taken in adminis
tering drugs which undergo these metabolic pathways in
children with Kwashiorkar. The importance of nutritional
factor on the ability of the body to handle drugs is also
demonstrated by the improved clearance of acetanilide and
cefoxitin. Following nutritional rehabilitation of patients
with Kwashiorkar (Buchanan et al 1980).
4-. Diet and Excretion of drugs
Diet can also bring about changes in the kinetics of
certain drug through their influence on urinary pH. Alkaline
urine is.often termed with largely vegetarian diet whereas
a diet rich in animal proteins results in an acidic
urine. Alkaline urine facilitates reabsorption of basic
drugs and hence pFeteins prolongs the half life of basic
drugs, whereas acidic urine decreases, the t^ of basic drugs.
The elimination half life and area under the plasma
e concentration curve of diethylcarbamazine, under alkaline pH
(pH 8) are significantly higher compared to that under acidic
urine (pH 5) (Edwards et al, 1981). Under alkaline pH of urine,
accumulation of diethylcarbamazine may predispose to toxicity
whereas under acidic urine pH, therapeutically effective
plasma concentration may not be maintained over the dosing
interval. Diets through their effect on urinary pH may alter
the disposition of a number of drugs and hence may necessitate
a change in dosing regimen.
Malnutrition modifies renal function and children
with PEM have <a decreased rate of glomerular filtration and
renal plasma.
Flow (Alleyne, 1967). This may reduce
the renal clearance of drugs.
5. Ethnic differences combined with undernutrition
In Kenyan subjects the hypotensive response to
propanolol was less, particularly in the presence of segere
undernutrition (obel and vere, 1978). The mechanisms responsible
for such observations are not clear. Pharmacokinetic or
pharmacodynamic factors may contribute to the observed
differences.
V. Special Problems ?
Anaemias due to iron and/or folic acid deficiency are
commonly encountered in India and other developing countries.
Iron is an important constituent of mixed function oxidases
in liver. Iron may be depleted from MFO system in anaemia
leading to altered metabolism of drugs. Mehta et al (1984)
and Shah et al (1985, unpublished observations) have demonstra
ted that antipyrine t^ is prolonged in iron deficiency anaemia
which is corrected on 3rd day following psrenteral
iron therapy (TDl) even before haemoglobin starts rising.
Important implication of this observation is that drug
regimens may have to be adjusted in patients who have iron
deficiency anaemia.
9
Folate deficiency is a common
cl.
problem in a tropical
environment
and
the
small
body
c
‘
,
. n
n n
- -V store of folate can easily
be depleted during growth, in pregnancy,
pregnancyt or in the presence
of infections or increased production of RBC as in hemolytic
anaemia, in addition, many drugs can adversely affect folate
metabolism and in combination with these factors may
eventually precipitate folate deficiency into frank
megaloblastic anaemia. Drugs which affect folate metabolism
include pyrimethamine, trimethoprim, sulfonamide,
sulfones, antiepileptics, antimetabolites etc.jwhere diet is
inadequate, these drugs should be given with folate supplements.
VI. Conclusion
The article has been written probably in more technical
terms, may be not to compromise with the scientific acumen.
However the message is clear.
1#
Drugs can alter nutritional -status of an individual.
2.
3.
Nutritional status can alter various pharmacokinetic
processes in th8 body and thereby alter the drug
response either producing toxicity or subtherapeutic effect.
Ours is a developing country where malnutrition is not
a small problem.
4.
Most drug regimens are directly borrowed from western
literature which does not take factor of malnutrition
into account as that is not their problem.
5.
However, we cannot be blind to this important determinant
of drug action.
6o
Moreover, factors of ethinicity, genetics and dietary
habits also modify drug responses and should be consi
dered in planning of rational therapeutics alongwith the
factor of nutritional status.
Is sue s
LOCOST is aiming at rational therapy. Most of its
target population dwells in rural areasw where malnutrition
is $ major problem. For this reason, this article should
be found relevant. The issues which can be easily raised are
1.
Should body weight not become important criterion
for deciding dose ? For this jreason
--should we not consider
modification of dosage from suitable
-‘ to our needs ?
ex,s chloroquine.
2.
Our beneficiaries are living in varied conditions
having varied dietary composition and habits. Can we
makes a brief survey of them and draw some guidelines
for rational therapy ?
3.
Often we talk of toxicity of drugs even when they are
given in ‘therapeutic range1 and sometimes we come
across clinical benefits even with ’sub—therapeutic
doses1 . Can this be reconciled in the light of
undernutrition ?
4.
We often tend to ignore adverse reactions to drugs
complained by our patients, just because they are not
documented. Could these not be manifestations of
drug nutrient interactions ?
5,
Iron and folic acid deficiency anaemia are quite common.
Can we draw some recommendations for use of drugs in
these conditions ?
6.
Can LOCOST take up some studies in this field (Drug
nutrient interactions) at later stage ?
-10-
10
REFERENCES
- Alleyne G.A.O. Paediatrics 39s400(1967)
- Balmer, S; Howells, G. and Wharten, BOA.:
Journal of Tropical Pediatrics 16s20-23 (1970)
- Bhamarapravati,N. s in CDlson (Ed)
Protein Calorie Malnutrition. P.299-307
(Academic Press, New York, 1975)
- Blashhke, T.F. Clin Pharmacokin. 2s32 (1977)
- Brodie, M.J. et al. Br. J.Clin. Pharmac 9s523 (1980)
- Buchanan, W. African Med. J. 52s733 (1977)
- Buchanan et al Br. J. Clin, Pharmac.
10s363 (1980)
- Buchanan et al S.Afr. Med. J. 56 : 299 (1979)
- Buchanan et al Br. J.Clin. Pharmac
9s623 (1980)
- Edwards, G et al. Br. J.Clin. Pharmac.
12:807 (1981)
- Kakemi, K.T. et al Chem. Pharma. Bull. 13:551 (1965)
- Kappas, A. et al. Clin. Pharma. & Ther.
20:643 (1976)
- Keberla, H. Acta. Pharmaool. 7^
29; suppl. 3:30 (1971)
- Krishnaswamy, K. Clin. Pharmacokin.’
3:216-240 (1978)
- Krishnaswamy, K. and Nadamuni Naidu, A. s
British Medical Journal 1 s538-540 (1977)
;
- Krishnaswamy, K. et al. Clin. Pharmacokin
6:152 (1981)’
- Mehta, S.; Kalsi, H.K.; Jayaraman, 8 and Mathur,
V.S. Am. J. Clin. Nutr. 28^977-981 (1975)
- Mucklow, J.C. <et al Br, J.Clin, Pharmac, 13;481m (1982)
- Narang, R.K. Mehta, S and Mathur, V.S. Am. J.Clin.Nutr,
30:1979-1982 (1977)
- Obel,r A.O.K. and Vere, D.W. East Afr. Med. J.55:20 (1978)
- Prasad, PS.J. and Krishnaswamy, K.s Chemotherapy 24:
333-337 (1978)
- Raghuram, T.C. and Krishnaswamy, ]K. Bur. J. Clin.
Pharmac 12:281 (1977)
- Rao, K.V.N. et al, Ind. J. Med. Res. 50;1343 (1971)
- Reiss, W.
- Roe, D.A.(1976), Drug induced nutritional deficiencies.
The AVI publishing company, Inc. Connecticut.
- Rojsseriberg, I.H. and Scimshaw, N.S. Workshop on
malabsorption and malnutrition. Am. J.Clin.Nutr
25: 1046, 1225 (1972)
.iNurr.
“
B. J. of Tropical Medicine and Hygiene, 79:
49 (1976)
- Shastri, RoA. Br. J.Clin. Pharmac. 10g499 (1980)
- Shastfci, R.Ae and ^rishnaswamy, K.
Clinica Chimica Acdja 66s 157 (1976)
- Shastri R.A. and Krishnaswamy, K. Br.J.Clin. Pharmac.
7:69 (1979)
- gjoqvist, F. Berga, 0. and Orme; M.L.E. Fundamentals of
clinical pharmaco.logy. In drug treatment. Ed. G.S. Avery
(Adits Press, Sydney)1976 1.
- Teoh, P.C. Drug dosage for Southeast Asian patients.
Medical Progress 4:11 (Feb.1977)
- Waterlow, J.C.: Adaptation to low protein intakes, in Olson
(Ed.) Protein calorie Malnutrition p.23 (Academic Press,
New York. 1975)
-Wharton, B.A. and Mcchesney, E.W. (1970), Chloroquine
metabolism in Kwashiorkar. Journal of Tropical Paediatrics.
16,130
- World Health Organisation in TRS No.§83 584, p.9-10(19768)
Probably since there are so may areas begging clarity, any such
organisations (LOCOST like or otherwise) can start with a minimum
programme of participation, clearly delineating the areas and
decision categories and with time limits wherever necessary.
A matrix of such choices to be made arc given in Table 1.
Participation of the above 'IcirTdis ultimately a state of mind.
One may have all the features of democracy and opportunities for
participating but i an individual or group could still feel
’cribbed, cabinned and confined 1 . Participation is no substitute
for a certain amount of basic trust and give- and take.
OPERATIONAL ISSUES
1.
(a)
Alternative Technology
The case has been put forth for looking into alternative/appropriate technology for pharmaceutics, 'i'his is a desirable goal
per se. However, one should consider whether we can be in any
more radically simpler/more appropriate, technology wise, thai>
that is being practised at present in a loan licence unit,
or say at A.I.M.T.I., Bangarpet? A comparison may be made
with some of the medium and large scale drug units. fhe answer
is that considerable amount of simplification has already been
achieved. That theoretical possibilities of further simpli
fication or achievement of alternative appropriate technology/
techniques are there. But any such further inside can come
only from doing it. LOCOST may consider floating special
research schemes with’ concerned.scholars in pharmaceutics to
look into the same.
(b)
Review Mechanisms
Review mechanisms and prioritisation of issues to be considered
could be left to thj task force, that could include the above
research scholars.
2<
Is There A Reasonable Profit ?
Minimum profit is determined by break even point of production,
at the simplest scale of technology. Surplus profit may be
channelised to a research/development fund or mark up inay be
reduced with increasing sales, after taking care of depreciation
interest,etc.
Primary concern should be living and livable wages for all
staff. Thus salaries may be increased appropriately, so that
the hand to mouth existence levels are avoided. It ought to be
remarked that the legitamacy of salary scales should not be
derived from Government bench marks for drug industry or fisx
from that of other small scale units. Both have their own
political economy of how they get fixed. For instance,
notice the glaring disparities between government scales for
its own staff and what government recommends as desirable
minimum for various industry categories. Does the tablet puEh
punch operator have an easier life than the government
1 pattawala * that he gets only one third of Jormor’s salary.
There is little merit in paying your workers at so called legal
industry norms (govt, fixed) especially when you are making
good profits.
contd.... 4
4
3„
Ethical Dilemmas
It has been suggested that when work
related ethical
dilemmas confront the individual, the whole group (to be
defined) should be taken into confidence, if necessary,
t least immediately after the event. However, during
discussions, more weightage should be given to the arguments
of the person who is actually doing the job.
4.
Statutory Requirements
Statutory requirements need to be scrutinised for their
.iPJig term solution to these ?
and so
amenable
----------------
implying probably that we would be more
if we were a company or partnership?
-•■.v '
TABLE 1 : PARTICIPATORY POSSIBILITIES .
Participating
Sroup___________
..rea of possible
participation
~~TT~
I
i
he j
<Z'.
• /) i
1 'c'
f-' I
•.u
I
: -•( !j. j -- a
■J 0
't* <?
=
I 5 I
<
■
2
‘J
i
V i
'<■
C 'i
;
4
|i
... &
O
•’->
■
gU
0
« <■'7
\ ^..,..3
b--
0
rz?'1-
Personnel
Practises
•Vage Admn.
i
Marketing
-md Sales
Pricing
olicies
!
’hoice of
' j rugs
Long term
planning
I
..
'.ality
Jontrol
1
i
Production
L Productivity
strategies for
Sthical dilemmas
f
i
£dueAl.
programme
1
j
financial pla
ning & mgmt.
(profit,price,etc^!
issues in inter
facing with FDA,
sales tax, etc.
I
r
I
I
.....
i
I
“I'
Research
■‘rogrammes
I
Other
1herapies
i
i
i
--r-;
!
T
\ i-
r,L
i
fe - ' • $ ■
Table 1 g Participatory
Possibilities contd.
The matrix of decisions one has to make to exten.J participation
in a LOCOST like organisation ;is given in Table 1.-
For each cell of the matrix one may decide to have no participation
(complete directiveness), some participation or complete partici
pation o
It is important to remember a time frame is necessary - a trade
of between participatory decision making and operational efficiency an ability to say we freeze discussion at this point and act now.
Itis also to import to list a hierarchy of goals and objective for
LOCOST like organisations,
primacy being given to the attainment
of the most important goal, namely, production and supply of
essential drugs in an economically viable manner^propogation of
rational drug therapy,:< Otherwise the theatre oE action for the
participatory philosophy would be missing, and we will be left with
the situation of the grin without the cat.
A related issue to be thought of is whether a charitable trust
is an appropriate form of organisation for practicising participatory management, If not, what is the appropriate form and
structure ?
II
I
4
3^ I L : 3
ETHICAL ISSUES s SOME REFLECTIONS
ON PARTICIPATION ;
P^?TiC^PAT'?’VE
has come to be regarded as a desirable
™°st settings: Some form of participation is consi,, r d desirable for.especially developmental work, done either
hrough formal organisations or actualised through sturggles,
movement^, etc._ Usually there is a lack of consensus on what
actually participation means in various situations. However,
we may define participation as an attempt by all the actors in
a situation to define and direct the future through a process of
mutual discussion and dialogue conducted in an equitable manner.
In industrial settings it has taken
caAcn ^ome
wnar perrunctory
some what
perfunctory expreshare options
for
workers,
and/or,
for workers, and/or, workers' representative(s) on the board. A heartening recent example is the
take over of Kamani Tubes, by theJ union.
uniono But then again, will the
trade union bosses be rmore participative then their capitalist
not
predecessors ? Possibly not,
considering the inherent lack of
democracy in most unions or for that matter in socialist countries
A true aggregation of social preferences, or a true participation
is probably not possible (Arrow's theorem in Social Choice Theorv
says precisely this) for it implies that every participant is an
autonomous, independent thinking individual. None of us are
really so, however intellectually or psychologically competent
we may be. We are prisoners of our human condition, influenced
by atleast some others,, and in turn wanting to influence. It may
be said in ddefence
that such influencing or wanting to influence
take place consciously
then it is alright. What about then,
---- ,J
the subconscious/unconscious
------- ; process that take place between any
two
individuals or
in groups? (Who any way, xis conscious?)
t
_ —
Since all human beings do not tend to be equal - inspite of our
nobles intentions - chartsma, competence, expertise, ralerEtb,
moral power (or.the illusion of such), Ihave a role to play and
inevitably upset the applecart of "true>*' participation in any
situations by unwittingly intimidating or persuading the many
iriito acquiescence at the hands of a chosen few.
Participation, or true
participation, if you will, is then
ideally possible only with truly autonomous individuals experien
cing and capable of experiencing personal freedom, human beings who
regard themselves as unique persons, non-comparable with any
other human beings because the word ’comparison' does not exist
in their vocabulary.
Even as death is the great leveller, knowledge and especially
unequal access.to knowledge (also include expertise skill, etc.)
is the great disleveller. The situation is really lop-sided
in a health care situation, were the doctor - be at the expert
specialist or the (quack - in spite of his/her best efforts, is
the more powerful person, and the vulnerable patient is submitting
umseIf/herself* inspite . of or constantly struggling to restore
the balance by holding the sword of the legal suit over the
doctors head. Whither participation, when we are so bound.
contd
1.
Often such token owner*ship is pirefer'r'ed. to the bunden of
management which is left to technocrats
2
/2/
An equally disturbing issue is the use of 1 participating* and •
participatory techniques (like participatory research) for
unstated goals, hidden agendas, etc. One can appear to parti
cipate but actually be directive if not manipulative. Related
£SSU^iS the USe of the ParticiPatory agenda as a humane gesture,
tor the enactment and/or resolution of underlying power struggles,
ego conflects, etc.
(This fate of misuse by clever adapters is
shared by other concepts like patriarchy, appropriate technologv,
consciousness, openness, authenticity, self actualisation, etc./
Who has not felt humiliated at time by the humility of the
others oppressed by the inherent violence of those who want peace?
Similarly with the best of participatory motions and postures,
we orten acquiesce against our will but cannot put the finger
on the reets of our unease.
The participatory need and the participator^^ instinct is h therefore
an’^expression
expression of our struggle to be free and autonomous individually
and collectively, ]hoping
-- • •
2
that the creation
of participatory
atmosphere will
be
a
- --- a precursor to collective .and individual liberation.
But as we have, seen,you truly participate only when
you are tryly experiencing and capable of experiencing freedom.
An inherent assumption in participation is that the potential
participant wants to participate or have the time to participate
(how many of us conscientiously vote in every elections, local
state and national, or actively deliberate on major problems
concerning our country or even the central health budget ?)
Quiet.often than not, workers/employees may be satisfied, it is
they are. consulted Or their opinions are taken into account
in their most primary concerns (hygiene need) vis-a-vis the orga
nisation (say, salaries, leave or certain facilities). Does one
e icit participation in matter of policy technical/scientific
matters concerning production, choice of drugs, pricing policy
and so on ? Even if the staff do participate to what extent do
we go by principle of minority opinion (which may not be the
right optimum for an organisation at a particular time) ? What
is the tradeoff and demarcation line between informed discussion
and consent thereof and directive decision making ? What is the
process of empowerment and education of every staff member so that
there could be.informed participation ? What is the role of such
F^rticipation in times of crisis or in times of adversarial
positions taken by various groups, cliques and cacuses especially
tTx en
not
represented through electoral processes’’
What is the role of representative parliamentarianism ? To what
accessions and situations should it be limited ? How does accoun
tability of the group and the individual get ensured in the
process.of participation ? How do we ensure mechanism for mutual
responsibility, of those reporting to and of those reported to ?
VjJhat is the reference group for (participatory) decision making
end reporting for various categories of issues or decisions ?
Qhat is to be reported, to who, where, and when ?
Should there be limit to discussion (meaning, freeze discussion
x. a
_ certain
---•
•
■
) ) ?
at
point
and act
Should individuals and key decision ’■makers
'‘
'have operational
autonomy ? Should complete freedom of information
---------- in all matters
be mad& available.
available, if not, what are the lines of demarcation ?
contd. <» o o 3
/
LOG OST
GPO Box 134
BARODA-390001 .
By s
Dr. Sa gun Desai
ERUGS IN PULMONARY TUBERCULOSIS
The treatment of pulmonary tuberculosis presents a
fascinating challenge to the respiratory physician since
modern chemotherapeutic agents offer the near certainLty of
cure, provided that a proven regimen ef treatment is applied
assiduously for a sufficient length of time. The difficulty
lies in maintaining treatment with a combination of potenti
ally toxic drugs ibr a long time, since the regimens which
embody "standard" chemotherapy require sustained treatment
for 9 to 18 months, although the efficacy of shorter regimens
lasting 4 to 6 months is being investigated.
Objectives of combination chemotherapy (essential in
TB; :
1.
to prevent emergence of resistance
2.
to eradicate the infection in the shortest" possible
time
1).
to reduce the incidence of AER,
t
IMP s 1 •
To keep the no, of drugs to minimum which can achieve
above objectives.
2<
For successful anti TB Rx, regular surveillance
throughout the course of treatment by an experienced
health care team so as. to reduce the total dosage
or duration of Rx.
Anti - TB drugs
"Fir^t -line" drugs
.....
INH
Most
Rifam*
effective
Etham
Least
SM
Toxic,
Pyrazinamide
-K-
Used in Rx of
infection resist E7D
7 ’’ r~T •*! ..7; ant to the first"Secjond-bine-.-zdrugs
PAS
Thiacetazane
Ethionamide
Cydoserine
Capreomycin
Viomycin
Kanamicin
bacteriostatic for "resting11 bacilli but bactericidal.
for rapidly dividing micro.
Tuberculostatic cone : 0,025 to 0,05
8/m,
Penetrates cells easily effective against intra
cellular org.
y
V
2
FIRST-LINE ERUGS :
INH °o
1 ,
Isonicot.tnic acid hydrazine, Isoniazid,
Highly effective, primary drug for chemo of TB,
bactericidal
anti TB agent, mainstay of anti-TB R.
included in all current chemotherapeutic regimens
against susceptible mycobacteria.
History :
Observation that nicotinamide was tuberculo
static, Fortuitous discover (1945) - Chorine,
Chemi st ry:
Hydrazide of isonicotinic acid
1,
' y’
...
C
Al ; J
Iproniazid - Lso^rQpyl
derivatives of isonicotinic
acid - too toxic for use
in TB, used as MA01,
i !r
A—
* Mechanism to spedrum of Action :
,
ac Live ly
effective against /
growing mycobacteria but
less so against resting organisms.
mode of action precisely not known.
Possibly inhibits synthesis of mycolic acids which
are components of mycobacterial cell walls,.
•
Selective toxicity against myco.
only because of
the above mech, since mycotic acid is not present
in mammalian cells or other micro-organisms.
Spectrum - 7 of mech,
only myco,
mycobacteria an resistant.
Some atypical
If used alone myco, develop resistance against it
very rapidly
never used alone (except for
preventive Rx x# in certain specific situations).
Always used with one more agent at least.
Re
Clinical Fharmacology :-
readily absorbed from the GIT - nearly always,
administered by the oral route
Aluminium containing antacids - interfere with
absorption.
*
There is no conclusive evidence of a difference in
therapeutic efficacy or in the incidence of toxicity
related to rate of acetylation of INH in Pts receiving
the drug every day.
: 3
a large oral dose —> peak serum level of 10-15
yyg/ml in 1-2 hr (GG - 3-5 /ig/ml in 1-2 hr).
Widely distributed in all body tissues including
pleural effusion and CSF,
*
penetrates caseous tissue and macrophages, thus
effective against intracellular organisms^
t i
rapid inactivators
slow inactivators
M?ta<
INH ...
0,5 - 1 -0 hr,0 GO
070 min
2-4 hrs.
5 3 hr.
In liver.
N-ace ty It ransferase
—_——..—_>
acetylation
Acetyl isoniazid —>
excreted largely in the urine,, small amount
excreted unchanged.
Img ; In pts with severe renal failure (creatinine
clearance
dosage
lOml/min.) and slow inactivators
modification necessary, monitor
Plasma levels of
INH.
It is not clear whether dosage adjustment is
necessary in Pts with impaired hepatic function, although
there is some evidence that serum iscniazid levels are
increased in chronic liver disease.
*
Importance of Genetic (Acetylator status);
In vitro - myco. exposed to inhibitory concentrations
of INH for 10 h or morelose viability. But ifbthe
inhibition is short-lived they slowly recover the
capacity to synthesise mycotic acid. This observation
may explain the loss of therapeutic effectiveness of
INH in pts, who are rapid in activators and who are
Hxed by intermittent dosage regimens. If the doses are
spaced too far apart i.e, less often than twice weekly.
In contrast, the neurotoxic effects of INH are
more likely to occur in slow inactivators who have
a greater tendency to accumulate the drug, particularly
those treated by high dosage intermittent regimens,
and some authorities advocate the administration of
prophylactic pyridoxine to all patients receiving
INH therapy in order to prevent possible neuropathic
side-effects.
It has been suggested that hepatctoxic meta
bolites are more likely to accumulate in rapid
inactivators who would therefore be more liable to
isoniazid induced hepatic nee rosis, but measurements
have
shown that the actual exposure of rapid
inactivators to the relevant compound, acetylhydrazine,
is no greater than that of slow inactivators, and
clinical studies confirm that therp is no increased
risk of hepatic toxicity among rapid inactivators of
INH whether treated with INH alone or with a combi
nation of INH and rifampicin.
^4-
— o
Administration & Dosage :
----- --- -- '
uu: -■
—fx..-
.w
<c
o —
k*
Normally administered by mouth , either as tablets or as a
syrup/elixir, Also IM ./ those who are vomitting or /inj. for
unable to-take oral Rx,
Dose in adults : 5 mg/kg - max, 300 mg as a single daily
dose.
Children (since tolerate higher doses) 10-15 mg/kg.
For pts on twice weekly regimen 2
15 mg/kg.
''(give 10 mg/g pyridoxine to all pts taking INH in order
to avoid possibility of neuro-toxic side effects, R.B. Cole) - personal view.
This precaution is particularly important in adults
receiving large doses of 10 mg/kg or more of INH/d or
in those who may be predisposed to peripheral neuropathies
by other conditions such as alcoholism or malnutrition.
Slow release INH preparations (matrix INH) have
been studied in an attempt to provide an effective once-,
weekly intermittent regimen, but these have proved.unsatis
factory'.' the blood cone, achieved in rapid INH inacti
vators are inadequate except with doses which wrould be
likely to cause toxicity in slow inactivators.
Toxic Effects :
Neurotoxic effects - dose related, more likely to occur
in slow than in rapid inactivators.
def.
1
1,
of
Peri^hera
1 peuropathy -• due to pyridoxine def,
excessive^excretion of pyridoxine in pts. receiving INH
-respond to pyridoxine Rx - tingling in legs/feet and
occasionally in hands.
CHS effects - dizziness(related to high dose), insomnia,
CNS
restlessness and memory loss (at ordinary dose) , may ppt
fits in previously stable epileptics,, excessive overdosage
—acute psychosis, convulsions and coma,
Occ - muscle
pa in s, art hr opat hy, and ’’frozen shoulder”.
Hypersensitivity reactions - not common - occasionally
fever or skin rashes. It is one of the drugs which can
induce the syndrome of SEE - though this is rare, anti
nuclear antibodies can be found in a substantial proportion
of pts —■> vasculitis.
-x-
Pyridcxine (15-50 mg/d) - especially in malnourished,
predisposed to neuropathy, (i.e, elderly, pregnant
women, diabetics, alcohoTic. and uremics; - G.G.
-s 5
Haematological reactions
Other toxic_ effects__j
{agranulccytcsis, ecsihophilla t hr om o c c yt ope s ia,
metha ine- -glcbinemia ? t innit us j. urir.ry retortion
Most important reaction is hepatotoxicjty usually
occurs as a reversible asymptomatic elevation of serum
transaminase, occasionally manifests as clinical
jaundice proceeded by GIT symptoms, rarely leading to
massive hepatic necrosis. Hepatotoxicity may occur at
any time during the cause of INH therapy in approximately
20% of individuals who receive the drug and in about
5% it has to be withdrawn
,• of developing hepatoce
llular damage. In the great majority of pts the
abnormalities subside without any alteration in the INH
regimen, and it is usual to persist with treatment unless
the serum glutamic oxalaceti.c transaminase (SGOT) value
exceeds 5 times the upper limit of normal cr if symptoms
and signs of hepatitis develop.
The development of INH he pat ot cxiciJ:y does not
correlate with the plasma drug concentration and is
probably unrelated to be due to an allergic phenomenon
for which the exact mechanism is at present undefined.
INH is commonly administered concurrently with other
hepatotoxic antituberculai1 drugs, especially rifampicin,
and most evidences suggest that rifampin hepatotoxicity
is enhanced by INH, particularly in slow inactivators
who have higher INH serum levels.
Drug. ,Int eract icns °
Concurrent administration of TNH inhibits the
metabolism of DPI! —->■ <.• <<-ed serum levels —>CNS toxicity
(disorientation,; drowsiness., lethargy, ataxia, nystagmus,
psychotic behaviour and coma ) INH inteiieres with the
parahydr oxylat ioh of DPH which is the rare-limit ing step
in DPH metabolism, exact mecb. is not known. Slow acetylla-* r'rs are more at risk, but not invariably so :
In practice, dosage reduction of DPH from 300 to
100-200 mg daily is indicated if clinical signs of toxicity
are encduntered, and if facilities are available for
measuring serum DPH cone, it is advisable to avoid
levels
20 ^g/ml.
Clinical Use
rw, 11
*
— Titn.r —« ■
Most widely used of the anti-TB agents
a
f
mi i.l-
of its
effectiveness
cheapness and
relative lack of toxicity
It is part cf most regimens for IB
Use in ^pr eve nt i on :
Used as a single agent in the preven
tive
of~TuTTsometimes called “disease prophylaxis”),
in which chemotherapy is given to individuals who show
evidence of infection although there is no sign of disease
at that time. The use of INH alone for chemoprophylaxis
has only very rarely led to the emergence of resistant
strains cf ML, tuberculosis., Based on the code of practice
-2 6
recommended by the American Thoracic Society and the U.S.
Public Health Service Centre for Disease Control joint
statement
•c
....
The indications for preventive therapy with INH can be
categorised as follows :
1.
Household contacts of an active case of TB,
2,
Radiological evidence of apparently inactive TB.
3.
Positive tuberculin reactors : either recently converted
from negative to positive within the past two years or
with increased susceptibility to the disease
of
complicating factors such as long term corticosteroid
or immunosuppressive therapy, D.M. or silicoses, or
below the age of 35 years who have not received BCG
vaccine.
The reason for giving preventive INH therapy to
positive reactors below the age of 35 years is based on the
argument that these individuals have a relatively high risk
of developing active disease but little likelihood of
suffering INH hepatotoxicity, which occurs mainly in older
age groups.
Single chemotherapy with
INH also
has a- place in
------- -------------- -----the Rx of progressive
BCG infection,
whichrarely
rarelycomplicompli
.
'
* ’ ’_i, which
cates BCG vaccination. Such cases are usually characterised
C“‘ —
\
_.__1 1
___ 11__ ' abscesses.
by —
regional
lympl oi< nitis_ and
localised
Treatment with INH in the usual dosage for 3 months is
sufficient to control the infection.
2, Rifampin (Rifampicin)
,
Semi- synthetic derivative of the antibiotic rifamycin B p
which was isolated from streptomyces mediterrance.
Of established importance in anti TB chemotherapy,
of its effectiveness in short-course treatment
One
of the main drawbacks - high cost.
Besides TB, talso
"
~ ~ in Rx of a wide range of
useful
bacterial infections and some systemic mycoses,
_o^ pct i_ori^ :
.
bactericidal
acts by inhibiting the activity of DNA-dependent
RNA polymerase, which is the enzyme responsible
for catalysing the polymerisation of certain
ribonucleotides into RNA molecules, a step which
transfers genetic data from DNA to RNA. The
selective toxicity of rifampin depends xz upon the
relative insensitivity of mammalian RNA polymerase
to the drug.
7
Bactericidal for both intracellular and extracellular
org.
* Spectrum of act ion .;
.
.
Highly active against M. Tuberculosis and M,Leprae.
active against gram positive cocci including peni
cillin and methicillin-resistant S. aureus and
against Neisseria species.
»
lower degree of activity against gram negative bacilli.
.
potential synergistic action with trimethoprim
against gram negative pathogens and with amphotericin
B against fungi (under investigation).
Primary resistance to rifampicin is low but resi
stance develops rapidly during therapy among most micro
organisms which are initially sensitive, usually resulting
from a single, large-step mutation which alters the confor
mation of DNA-dependent RNA polymerases and prevents
rifampin binding. In the therapy of TB, it is therefore
always used in combination with other drugs.
* £Einica^l Pharmac ology^ :
.
readily absorbed from theG.XwT*, but the presence of
food diminishes absorption and rifampin is therefore
usually administered on an empty stomach.
.
A normal oral dose of 600 mg ——> peak blood level of
about 7 -ng/ml after 1.5-3 hours and effective therapeu
tic levels are maintained for i2-24 hours.
.
The drug is widely distributed in all body tissues
including CSF and pleural exudate, and because, it is
lipid^soluble it •enetrates cells and kills intracellular
bout 85% is protein bound
microorganisms,
agin ■ .■ it
i i»
nfcjunnniffa «-aT-y-r.
in" wi »ti
>jTiwif w •-* -
•
t 1/2 - 1.5 - 5 hrs, increased in presence of hepatic
damage. Decreasedin pts receiving INH concurrently
who are slow inactivators progressive decreased t J- in
first 14 days due to induction of hepatic enzyme.
.
partly deacetylated in the liver and is excreted in the
bile in both the deacetylated form and as the unaltered
drug.. The latter is reabsorbed and recirculates through
the liver, but the metabolite is very largely excreted
in the feces. Eventually about 60% of the drug is
excreted in this way. Slight accumulation may occur in
patients with hepatic dysfunction due to cirrhosis,
suggesting that care should be exercised in the use of
rifampin in the presence of liver disease.
.
Rifampin induces hepatic metabolising enzymes, includ
ing those responsible for its own metabolism, leading
to a gradual reduction in the serum half-life during
the first week of therapy, but this is insufficient
to alter the therapeutic effectiveness of the drug
and no dosage adjustment is necessary.
.
Rifampin and its deacetylated metabolite are also
excreted to a lesser extent in the urine, but it does
not accumulate in patients with impaired renal function
and no reduction in dose is indicated.
-2 8
*
Admin i st rat i on^and^ Do sage_ g
.
Normally b given by mouth in a l
single daily dose in the
early morning 1 hr before breakfast.
y Usual dose in adults is approximately 10 mg/kg body wt,,
often standardised to 450 mg/day in those weighing
50 kg and 600 mg/day for the remainder, In children
the recommended dose is 10-20 mg/kg upto a maximum of
600 mg/d.
•
*
also used in intermittent twice weekly anti TB regimens
using doses of 600 mg or 900 mg twice weekly.
Toxicity ;
Although rifampin can cause a wide range of adverse
effects, they are relatively infrequent, and only rarely do
they necessiate the withdrawal. They inclucdethe following:-
1.
G.I. disturbances = nausea, abdominal distension,
epigastric discomfort and diarrhoea which seldom require
a change of therapy.
2.
Drug-induced hepatitis, difficult to attribute specifi
cally to rifampin;* the drug is commonly used in combi
nation with other hepatotoxic agents, notably INH,
•
transient elevation in liver enzymes during early weeks
or Rx, subsides spontaneously whether Rx is conto or
not,
Occ 0 increase in serum bilirubin or clinical jaundice 9
sign for immediate withdrawal.
Jaundice more likely to occur in elderly, in alcoholics
or those with pre-existing liver damage, but the risk of
hepatitis in patients with normal liver function appears
to be slight.
3.
Hypersensitivity reactions - rare. Rashes,
urticaria
itching of skinx, redness and watering of eye, may occ,
require witndrawal, Anaphylatic shock can also occur.
4
Neurological symptosm = headache, drowsiness, dizziness,
occ. rarely - acute psychosis.
and ataxia
Several other imp, adverse reactions are largely
but not entirely confined to patients Rxed with high
dosage intermittent regimens or who take their Rx irregularly
with long intervals between doses.
These effects include the following
5.
An influenza-like reaction ('Flu syndrome"), characterised
by fever, chills, muscle aching,nausea and vomittmg,
may come on several weeks or months after the commence
ment of Rx, usually, ppted 1 or 2 hrs after the ingestion
of a dose. It subsides spontaneously after a few hours^
but recurs with subsequent doses and is much more common
in patients on once weekly regimens who are taking higher
doses, i.e. 1200 mg cr mere. It is attributed to an
9 s-
immunological reaction, preventable by cent, Rx which is
thought to result ika in neutralisation of rifampin
antibodies. This can be avoided by reverting to daily
administration.
6>
Thrombocytopenia------ ->bleeding (with high-dose intermittent
Rx, appears to have an immunological basis. Contra-indicated
if thrombocytopenia observed.
7#
Renal failure with intermittant Rx or when resumed after
an interval,. Usually due to acute tubular necrosis which
may.have an immunological basis, since high titres of anti
bodies to rifam have been observed. Withdrawal of rifam
• ^recovery of renal function, but further use of rifam
is contra-indicated,
teratogenicity
Potential■'
junknown, best to avoid the use of
Rifam during pregnancy. It crosses placenta.
89
9.*
Other b iologicajl. effects 1
(Which are of interest but which do not appear to
affect the clinical use of the drug. )
•
Immunosuppressive effects on both humoral and cellmediated immunity, readily reversed afterFbx is
discontinued.
•
Associated with light chain proteinuria in the
majority of patients.
•
Harmless reddish discoloration d£ the urine and faeces,
sometimes also affecting tears, saliva and sweat
(due to both active drug and metabolites) - warn the
Pt
pt,, in order to allay unnecessary anxiety.
*
Drug Interactions s
(appears after 5-8 days of admin,
and persists fa? 5-7 days after
st opped)
Rifam-- '- induction of hepatic microsomal enzymes
responsible for drug metabolism--- —increased rate of
elimination of several important drugs if administered
concurrently
with
'
....them., They are 1.-
WarTarin, leading .to the need for an unusually high
dose to maintain effective anticoagulation
2.
Tolbutamide, digit oxin, quinidine, propranolol,
met opr old, clc fibrate, ketocanazole
3.
C ort ic ost er oids.
Oestrogens --—menstrual irregularity and unwanted
pregnancy in pts taking OC agents.
5,
Concurrent admh, of PAS impairs the^3/^^^0^
of' rifam
•car ful spacing required
(8-12 hrs).
* Suppresses T cell function and cutaneous, hypersensitivity
tuberculin. Immunosuppresseht
T--’ •
observed
in animals but not
delitarious effect in burners.
10
*
Cl.inica 1 _Use^s_ :
Primary role in Rx of mycobacterial infections in
combination with other chemotherapeutic agents.
rifampicin
INH combination - essential element in
most of the successful short-course regimens.
Used in Rx of pts who did notreceive the drug during
initial therapy, in Rx of extra-pulmonary TB i.e,
TBM, Rx of Ir.f, due to atypica mycobacteria like
M, Kansasii,
Not used in Rx of pulmonary infections due to
strepto/staph though effective o ■ o .of availability
of o thereffective antibiotics,
its use can —
delay in
cf underlying TB or---- £> development
of resistant bacteria.
Legionnaire’s dis, that fails to respond to erythro
mycin or tetracycline since Legionella pheumephilia
is highly susceptible.
multiple-resistant pa.eumococcal pheumonia
re si slant staphy loc occa 1 endocard.it is
preventive Rx of nasopharyngeal carriers of meningo
cocci.
Leprosy,
Ethambutol
The value of ethambutol in the initial treatment of
TB is wall established and the drug is used in most
of the current standard regimens.
Synthetic, tuberculostatic agent, discovered in 1961
^dv : relatively cheap, low toxicity, effective
by oral administration.
M/A - uncertain, thought to inhibit RNA synthesis
by mycobacteria.
-)e Spectrum of Activity :
limited to m'/-cobacteria only
primary resistance of M. tuberculosis to Etham
is low, but increased when used alone.,
used in
combination with one or more other effective anti-TB
agents.
Clinical Pharmacology."
about^ 80% absorption orally, remainder excreted unchanged
in feces.
P.O. 25 mg/kg—> max. serum cone, of 2-6 pg/ml after
2-4 h -a 0w4 ug/ml at 10 hr, elimination half-time
4 h, in pt with normal renal function.
11
70% of ingested dose excreted unchanged by the kidneys
and upto 15% metabolised to inactive compounds
excreted in urine.
Widely distributed in body tissues but therapeutic cone,
cone
achieved in CSF only in presence of meningeal inflammation
Hammalian cone, in RBC 1-2 times more than in plasma,
thus RBC serve as a depot - for Etham.
preferentially, concentrated in RBC and about 20-30%
protein bound.
* Administration and Dosage :
.
Administered by mouth in a single daily dose of 15-25
mg/kg body weight in adults and children^ 10 years
< 10 years —35 mg/kg in order to achieve peak
serum cone, of
2 pg/ml. (Notes in this dose the risk
of ocular toxicity and the difficulty of recognising it
in small children must be remembered).
•
Commonly used in the first an 2 months of combined
anti-TB Rx in a dose of 25 mg/kg body weight and is then
either stopped or in some regimens maintained at a lower
dose of 15 mg/kg throughout the continuation phase of
Rx in order to decrease the risk of ocular toxicity
which is dose related. Still to be on safer side, use
15 mg/kg dose even during initial therapy, since it has
prevdd to be clinically effective (R.B. cole).
Modification of dosage essential in pts with renal
failure
elimination is largely dependent upon
renal function.
This can be achieved by giving the usual dose of 25 mg/kg
at interval of
36-48 h when creatine clearance 10-50 ml/min.
48 h or large if creatine clearance <10 ml/min*
estimation of serum ethambutcl ccnc. desirable as a
guide tc dosage - aim at obtaining (max. not 2> 5 pg/ml at
2 h, declining tc 0.5 ^g/ml before the next dose.
.
Clearance increased by peritoneal and haemodialysis
dosage supplementation necessary.
* Toxic Effects
M IMP adverse effect
Retrobulbar Neuritis.
•’-> progressive less of peripheral vision cr impaired
visual acuity, particularly to green,-—
central .scotoma
12
Optic neuritis - incidence 1% when dose is 25 mg/kg initially
for 2 months and then 15 mg/kg or maintenance (customary
regimen), 5% when higher dose continued for 6 months.
changes usually but not always reversible on withdrawal
of the drug
Good to carry out a comprehensive opthoImomological
examination periodic check up and monitoring.of vision 9
reporting of any visual disturbance promptly.
Other complications - rare
peripheral neuropathy independent of INH Rx,
nephrotoxicity, reversed on withdrawal.
Hyperuricemia - quite common /, of decreased renal
clearance of uric acid -—>occ. pptn, of ac, gout.
allergic skin reactions.
•Ar*
* Clinical Uses »
,
important component of combination Rx, especially in
the initial phase of therapy in standard xf 9 month
regimen.
If does not contribute significantly to- 6-month short
course chemotherapy, and in this role it is less
effective than pyrazinamide in preventing relapse,
effective in twice-weekly interminent chemotherapy
when combined with INH after a 2 or 3 month initial
phase of daily triple therapy.
usually INH alone is used for chemoprophylaxis,9 but
some clinicians prefer to use a combination of INH and
Ethambutcl, especially in pts from a community in which
prevalence of INH resistance is high i,e, Asians.
In the chemoprophylaxis of contacts of patients with
INH-resistant TB it has been suggested that ethambutol
may be used as an alternative preventive agent,
Ethambutol is effective in Rx of TB infect ions resist
ant to other chemotherapeutic agents and is used
successfully in treating some atypical mycobacterial
infections
infections, such as those due to M, Kansas!!,
fyrazinamide'
sythetic pyrazine derivative of nicctinamide.
bactericidal in vitro
at a slightly acidic pH,
though bacteriostatic activity of Pyrazinamide was
recognised as long ago as 1952, until recently its use
has largely been confined to the Rx of infections
resistant to the standard drugs, •,* of its low in
vitro activity and significant record of hepatotoxicity.
But in the last few years there has been increasing
clinical evidence to suggest that pyrazinamide can make
an effective contribution to 6-month regimens possibly
by using it only during the first two months of
**
Other toxicity s pruritus, joint pain, GIT upset, abdominal
pain, malaise, headache, dizziness, mental confusion,
diserientation, hallucination.
T
13
combined Rx, The role of PZ therefore is undergoing
reappraisal, and it appears that the risk of hepatitis
from the use of PZ in these short-course regimens is
much lower than was suggested by earlier studies, in
which larger doses were used for longer periods.
PZ
.
a synthetic derivative of nicotinamide.
No antimycobacterial activity at neutral pH, but it is
effective against phagocytosed living tubercle bacilli,
presumably due to the acid pH within macrophages.
effective only against M* tuberculosis which rapidly
develops resistance to PZ unless the drug is used in
combination with ether effective anti-TB agents.
* Olihical Pharmacology :
t
readily and nearly completely absorbed from
GIT,
single oral dose,of 20 mg/kgJ-- -—> 0 max of 65 ug/ml
within 2 hours. (45
( ’ mg/mT at 2 h, 10 ug/ml at 15 hj - GG.
t
6 h»
.
penetrates into liver, kidneys, lungs, therapeutic levels
in CSF in TBM.
,
active drug and meta (pyrazinoic and 5-hydroxypyrazinoic
acid) filtered by glameruli. Nearly all of the unchanged
drug reabsorbed from renal teulf tubules while meta
excreted in the urine. Urinary cone. 50-100 ug/ml for
several h. after a
•
pyrazinoic acid decreases tub.., ♦ar secretion of uric acid
,d occ*
occ, to clinical gout*
which leads to hyperuricemia .*xd
.
accumulates in jaundiced pt, suggesting that it is
metabolised in liver.
* Administration and Dosage s
,
Early trials - daily dose of 40-50 mg/kg---Unacceptably high incidence of hepatitis—^clinicians
discarded it as a first, line drug.
more recent assessment —> revision of view.
Risk of hepatic toxicity is small when lower doses are
used in 6-month regimens of combined chemotherapy
(Hong-Kong trials).
.
Now adult daily dose 20-35 mg/kg* in 2-3 divided doses,
0.5 gm tablets available, commonly 1 g. bd or
0,5 g tds.
In intermittent regimensi, 40-60 mg/kg 2-3 times a week
or even 90 mg/kg once a week without serious incidence of
side effects.
*
Toxicity :
,
MIMP adverse effect of PZ is its tendency to cause hepa
titis. Effect-dose relatedt u. Symptoms of hepatitis,
|iver enlargement and rarely death due to hepatic necrosis
14 :
in pts Rxed for 3-6 months with PZ in the dose of 40-50
mg/kg/d i.e. 3 g/d.
Incidence of hepatitis decreased with dose of 20-35( mg/kg
although an increase in hepatic enzyme levels in upto
9% pts.
If is sensible ho
avoid use of PZ in people with impaired hepatic function
withdrawal the drug if SCOT increase very much
during the course of Rx,
advise pt to report prompty all S/S suggestive of
hepatic toxicity.
Arthralgia - mainly of shoulders,knees, fingers - c ommon,
i Increase serum uric acid in patients on daily therapy.
Usually improves spontaneously after a few weeks. aspirin
in Rxing
appears to be more effective than allopurinol
it sym pt omat ic a 1 ly.
t
Concurrent PZ and probenceid
affects tubular excretion
of uric acid and may enhance urate retention.
Ct her s: anorexia, nausea, vomiting, dysuria, malaise,
fever.
•x- Clinical Uses □
■
I-W1H«'
7 whim
.bi
■ ■ wiwtw
,
Use of PZ in primary Rx of TB witji modern short-course
chemo, regimens throughout the world both with daily
and intermittent Rx, highly encouraging and the incidence
of troublesome or serious toxicity has been small,with
dosage used now.
,
More evidence on the drug’s toxicity is needed to show
whether PZ has a place in routine anti-TB regimens.
.
At present PZ is occ. used in the technically advanced
countries for the Rx of IB infections resistant to more
a effective and less toxic agents. In developing
countries where drug-resistant TB is more common,
satisfactory results have been obtained in Rx regimens
using PZ in various drug combinations with ethionamide
and cycloserine and with PAS and streptomycin.
5, Streptocycin
•X-
Until the introduction of rifam. and etham, into routine
anti TB axd Rx within the last few years, Sb! with INH and
PAS provided a standard chemotherapeutic regimen which
was reliable and highly effective.
First clinically effective drug to become available
for Rx of Miste IB - from 1947-52 - only effective
agent available to Rx TBr
15
Usual course tes all 3 for initial 2-4 months,
stop SM at this stage, cont, remaining 2 until a total
duration of 18-24 months.
Nov/ Rifam + INH + Etham,
But SM still used -
1,
When oral drugs cannot be administered
2,
In Rx of infections resistant to other drugs but
sensitive to SM,
3,
In Rxing large pulmonary lesions with cavity.
4.
In some short--course regimens.
5.
In some completely supervised twice-weekly regimens
especially when the administration of the infection
provides an excuse or supervision of concurrent oral
therapy in out-patients who cannot be relied upon to
take medication.
Need for IM inj.
toxicity
Sufficiently serious drawbacks of SM
to discourage its use for .Rxing
pulm TB when the other drugs arereadily available, but
amongst poorer population and in developing countries
where cost is a highly important consideration in the
choice of Rxi SM still appears to play a useful and
relatively inexpensive part in short course and supervised
intermittent regimens,
TJ1j-Q-c
g.z one_ j
Although more toxic and rather less effective than the
others, TZ currently has a place among the first-line
anti TB drugs in developing countries
of its
cheapness.
9
A thicsemicarbazene, fairly active against M, tuber.
Toxicity - considerable variation in different communities
- due to differing standards of observation or
interpretation*
Resistance emerges during course of Rx? unless TZ is
used in conjunction with atleast one other effective
anti TB agent.
Cmax of
Well absorbed from the gut, 150 mg P,C,
1-2 pg/ml in 4-6 h, 20% excreted unchanged in the
urine,
*
Administration. and Dosage ;
adult dose - 150 mg as single daily dose, administered
with INH (300 mg) as a single tab,. Twice weekly
(intermittent regimen) dose = 450 mg TZ + INH 15 mg/kg
twice a week.
-: 1 6 : ’x’ ^Qxjicity
Incidence of toxicity low in above doses.
Commonest side effects -“ aiorexia,
aio rexia. nausea, vomitting
and occ, diarrhoea. Ototoxicity
dizzness and rarely
to ataxia, BM depresion
agranulocytosis & anaemia.
Allergic s^in reactions (not usually serious) but occ,
Steven -J h ison syndrome & e f oliative dermatitis which
necessiatc- withdrawal of drug. Hepatitis also reported
but may be due to companian drug i,e, INH,
*
Cl in ica 1 Uses j_
The only indication for using TZ in the primary Rx of
pulm TB is in developing countries where cost is the
predominant factor in determining the choice of TB Rx
programmev
/greater
than
Widely used in Africa and Asia, usually combined with
INH in a daily oral regimen lasting 18 months with SM
f°r the first 4-8 weeks. / 90% success with this regimen
in East Africa, but less effective in Singapore, and
more toxic.
TZ has a possible role in twice weekly interminent Rx
of pulm TB, but ® ineffective in short course regimen.
SECOND LINE LRUGS
More toxic and generally less effective than the firstline drugs
use largely confined to the Rx of
infections which are resistant to the usual anti TB drug.
As with the other drugs, resistance is likely to emerge
during Rx unless at lea st one other effective drug is
used coneurrently,
1.
Para -aminosa licy lie Ac id (_PA Sj j
,
Until recently PAS was an essential component of the
’’classical” antituberculosis regimen, which also
included SM and INH, but it has now been displaced
from standard chemotherapy in the developed countries
by Etham and Rifam, which produce fewer side effects
and fewer interruptions of Rx,
bacteriostatic, <effective
' *
only against M, tuber, and
occ. strain of M,. Kansas!!,
”
11, MTC - 1 ug/ml,
,
m/a - competitive antagenism with PABA—^inhibition
of synthesis of microbial folate----- ^inhibition of myco
bacterial growth, (similar to sulfonamides) specific for myco.
•
Well absorbed from gut, widely distributed in the
body including the pleural fluid and caseous tissue,
4- g ■ —
.
'^75 ug/ml in 1.5 - 2 h,
t1/2 - 0,75 h
acetylated in liver, excreted in urine.
-c
17
o-
t /2
increased in presence of impaired renal function,
avoid in severe renal failure.
Usual daily dosage in adults
doses, often combined with INH,
*
12 g given in 2 divided
Side^ Effect
Major - GIT irritation - - anorexia, nausea, vomitting,
abdominal pain, diarrhoea in 25^4O?/o of cases, decreased
when taken with food, this effect —
•> decreased
pt compliance.
Others :
generalised malaise, joint pains, sore throat,
skin eruptions of various types, leucopenia
agranulocytcsis, eosinophilia, lymphccytcsis,
thrombocytopesia, ac. haemolytic anaemia.
Hypersensitivity reactions - Fever, rashes.
pathy, eosinophilf-a, in 5% pts.
He pat it is
lymphadenc-
hepatic necrosis may occur,
Others - BM depression, hypokalemia, (secondary to GIT
disturbances) and goitre.
2, Cycloserine ;
an antibiotic with a bacteriostatic effect against
mycobacteria and some other organisms i.e. E.Coli,
m/a - inhibition of bacterial cell wall synthesis,
Well Ehsfir absorbed from gut, widely distributed
through oat the body tissues. including CSF,
Excreted in the urine -
as unchanged and
as unidentified metabolites.
Accumulates in pts with impaired renal Fn
dosage adjustment if necessary.
needing
Usual dosage in adults - 250 mg bd, increased to 500 mg
bd in seriously ill pts - but higher dose may not be
tolerated due to nephrotoxicity.
Toxicity can decreased by adjusting the dose to give
plasma levels.not / 30 pg/ml,
-greater than
MIMP AIR : on CNS - headache, insomnia, tramatas,
convulsions, various psychotic disturbances, incidence
of mental/neurological toxicity - 16% in pts receiving
500 mg/d, (Hong-Kong study). Rarely peripheral
neuropathy.
Contraindicated in epileptic pts, use cautiously in those
with mental disturbances such as depression or anxiety.
Toxic symptoms resolve when cycloserine is discontinued.
18 °o
*
Ethionamide s
WMB. <—
rn-
- !■
—,• —~
derivative of isonicotinic acid
bacteriostatic against mycob, tuber but little activity
against other mycobacteria.
well absorbed after oral administration and widely distri
buted in tissues, reaching significant cone, in CSF.
metabolished
1% excreted unchanged in urine.
largely /
in liver,
available as tabs of 125 & 250 mg. Usual adult dose
250 mg bd, which may be increased to a maximum of
1.0 g/d. depending on the pt’s ability to tolerate the
GIT side effects. This can be minimised by taking with
means or as a single bedtime dose.
*
AIR,
Others :
Most common
taste.
Severe postural hypotension.
anorexia, nausea and vomiting. metallic
depression, psychological disturbances - quite common.
Neurological symptoms - headache, restlessness, visual
and olfactory disturbances, tremors, convulsions, and •
peripheral neuropathy have been reported.
Allergic skin reactions, gynaec oma st ia, alopec ia.
hepatitis - particularly in diabetics.
teratogenic in animals
avoid during pregnancy,
C max - 20 pg/ml in 3 hr. after 1.00 g P.O.
Propionamide - n-propyl derivative of ethio, with
similar anti TB activity and equivalent toxicity,
no advantage over ethionamide.
polypeptide antibiotic derived from streptomyces
ca pre olus,
bacteriostatic action against M, tuber with some in vitro
activity against
other mycobacteria.
effective against organisms resistant to the more
commonly used anti TB drugs.
cross resistance between capteomycin and viamycin
is the rule
, and it frequently occurs between
capreomycin and kanamycin.
oral absorption unsatisfactory,
I M inje
Adult dose of 1 gm------ >
administered by
Cmax of 30 ug/ml in 2 hrs.
-s 19 s
50% excreted unchanged in the urine - remainder meta
but mode 2 site of inactivation unknown.
daily dose - 15 mg/kg (adult 1 g) by a single IM inj.,
usually for a period of 4-6 months.
dosage reduction advisable in pts -with renal dysfn.
-x-
ALR s
rather similar to those of SM
Nephrotoxicity - protein, casts and cells in urine,
hypokalemia 0
uremia and renal K+ loss
^totoxicity - vertigom tinnitus, deafness,
likely to occur in the elderly.
More
allergic reactions - eosinophilia. fever, rashes.
5,
Vi omyc in _£
bacteriostatJc against M. tuberculosis which is
1/4M - 1/2 that of Streptomycin,
obtained from stepto, puniceus.
effective against SM - resistant organisms,
exhibits cross resistance with capreo, and Kana.
•^ose s by im
, daily dose of 1-2 g, for a period of
2-3 weeks and thereafter in doses of 1-2g/2 or 3 times
per week.
*
Am j
vesticular disturbances, deafness.
ne phr ot ox ic it y
allergic reactions.
Npte;- avoid the use of viomycin in conjunction with other
ototoxic, or nephrotoxic drugs, such as kanamycin and
capreomycin, although it has been used successfully with SM.
Therapeutic efficacy of viomycin appears to be low.
TREATMENT OF PULMONARY TUBERCULOSIS 2
Before the availability of Etham and Rifam, the "Classical"
regimen of chemotherapy for TB included - SM, INH & PAS.
SM - daily by inj for 2-3 months with INH & PAS.
then INH + PAS in twice daily regimen for period
upto 18 months, for 12 months in mild infections
and 2 years in case of severe cavitary disease.
This type of therapy provided (1)
guard against chance resistance of organisms
against one of the drug.
20
2)
conformed with the concept of two phases in
chemotherapy - an initial period of
intensive drug therapy when the bacillary population
is large, followed by a less intense phase of
continuation therapy when the number of organism
has substantially decreased.
This regimen was highly successful when properly super
vised and it has been the standard against which modern
regimens have been measured.
Disadvantages °
If M in j, of SM
lenghhy dependence on pt compliance and
significant toxicities of PAS & SM
In developing countries - similar regimen was used where
J50 mg of TZ substituted PAS as a comparion drug to
INH
of its relative cheapness.
Benefits of Etham, & Rifam.
greater efficacy
relative lack of toxicity
permitted introduction
of shorter and less
toxic, regimens.
Also led to the introduction of a wider variety of
regimens of Rx whiqh allow greater flexibility in
circumventing adverse effects, improving supervision by
means of intermittent administration and shortening the
duration of therapy.
Cardinal rules of therapy - unchanged i,e.
requiring careful attention to detail in the
application of an approved regimen and
skilled supervision throughout the duration of
therapy to ensure that drugs are taken as prescribedc
*
Ct andard Chemctheragy^
In U>S«A . daily oral INH + Etham fur 18 months + daily
IM of SM for first 3 months in the case of extensive
cavitary lesions or if the pt comes from an area wkssK
where drug resistant infection is prevalent.
ApPJ^ptu_d modificat ions_ : -
1,
Fur extensive dis, - oral rifampin & 1NH-may be used
throughout instead of the J drug regimen.
2,
If parenteral therapy is necessary during the early
stage of Rx, a combination of SM and INH may be used
for the first 3 months (Strepto-erbazide ),
3.
PAS is preferable to etham as a companion drug to INH
in young children *, * of the difficulty of recognising
visual toxic symptoms in this age grcup.
21
4,
INH with Etham is the preferred combination for.the
Rx of TB in pregnancy,
of possible teratogenic
effects of Rifampin.
In Australia ; a rathei- similar regimen, initial^daily
3-drug therapy with INH & Rifam + either SM or
.
Ethanu given for 2-4 months, followed by continuation
Rx with INH and Rifam to complete 18 months.
0
In .Britain :
9-month short-course regimen.
(see below)
* Intermittent Chemotherapy.
The main indication for intermittent chemo is in the Rx
of individuals who cannot be relied on to take daily .
Rx unsupervised but who can be interviewed once or twice
weekly and watched while they take their drugs.
.
generally speaking intermittent regimens are less toxic
than daily ones, and they can be combined with, short;
course chemotherapy (see below) to produce regimens
which are highly effective in urban populations where
every dose is supervised.
.
Intermittent chemo can be successful, if given through
out the course of Rx, even in short-course regimens oi
only 9 months, but at oresent most authoritiesfavour an
initial phase of intensive daily therapy followed by a
twice-weekly continuation regimens.
some drugs, such as INH, are unsuitable for once weekly
administration, and twice-weekly regimens are currently
considered safer and more effective. The advantage of
three-weekly schedules have yet to be defined,
.
Recommended intermittent regimen in USA :
-
K-
daily conventional Rx for 1-4 months, followed by
twice weekly INH 15 mg/kg orally + 25-50 mg/kg
IM or INH 15 mg/kg + Etham 50 mg/kg - both orally
- maintained for 18 months.
.
Recent reoorts show that prolongation of intermittent
regimen beyond 1 yr is unnecessary when fully supervised.
.
The twice weekly combination of INH 15 mg/kg + Rifam
600 mg with or without an initial phase of daily Rx,
has produced good results with a low level of adverse
effects, although intermittent rifampin in higher dosage
is more likely to cause systemic reactions.
our se C he mot herapy_,__L
Advantages (Fox & Mitchison)
reduction in cost of Rx
reduction in chronic drug toxicity
of drug used is less.
total quantity
improvement in patient cooperation
improvement in surveillance of Rx
diminished likelihood of relapse if pts default early from
the Rx.
-o 22
Various experimental studies to determine and compare
the frequency of bacteriological relapre in chemotheraP3utic regimens ranging ircm 4-12 months.
7'^ .
Recommendat iOxi :
(adopted in UK)
INH 300' mg
Rifam 450-600 mg
daily for 9 months
Etham 15-25 mg/kg or y daily for 1st
2 months
Strepto
Note: - The use of strepto instead of etham for the initial
____
phase of Rx is equally effective but leads to a greater
incidence of side-fffeets.
Shorter f treatment regimens lasting 6 or 4 months
have shown considerable promise and are particularly
relevant in developing countries where the problem of
cost and the difficulties of lengthy supervision are
overriding considerations,
Streptomycin + INH + Rifam + PZ
daily for first 2 months.
followed by a continuation phase
of daily INH + Rifam for 4 months
Q
0
Singapore trial,
highly successful.
When cont, phase reduced to 2 months, relapse
rate 8-24%#
«
Most recent development - in order to decrease the costs,
inconvenience and toxicity of anti TB chemo has been
the trial of 3-month and 2-month regimens of daily
SM + INH + Rifam + PZ for the Rx of pts for whom the
diagnosis of pulm TB seems likely on clinical and
radiological grounds but for whom microscopy
sputum reveals no AFB, Observations after 1 year of
follow-up suggest that those with negative cultures
show a very low incidence of subsequent relapse if Rx is
stopped after 2 or 3 months, but in those with
positive cultures the incidence of relapse was at a
level which would generally be regarded as unacceptable.
The potential of these observations lies in the
possibility of safely
stopping Rx at 3 months if
the initial cultures have proved negative, but a
longer period of observation will be needed before
reliable conclusions can be drawn.
Combination of intermitent Rx with short-course chemo
provides an alternative choice of regimen which
minimises the total drug load and permits full
supervision of every dose,
A high level of effectivexiess has been obtained
by giving SM + INH + Rifam + PZ daily for an initial
phase of 1-2 months followed by a continuation phase
consisting of twice weekly SM + INH + PZ to a total
Rx duration of 6-3 months.
USax Lrial - unsupervised
INH 300 mg
Rifam 600 mg
followed by
daily orally for 1 month
23
INH 900 mg
Rifam 600 mg
twice weekly for a further 8 months.
Further work necessary to demonstrate the
superiority of this type of regimen over others.
’x' N^aagement :
of Pulm TB
Objective eradication of infection in every person
with active disease by administering a therapeutic
regimen of proven efficacy for its full duration.
The objective should be to achieve success with the
least possible disturbance in the normal life of the
pt or his family.
Major management problems to be considered are -
*
(1)
Choice of regimen
(2)
Selection of patients for hospital Rx
(3)
Supervision of therapy and
(4)
Retre^tment chemotherapy.
Choice of Regimen ;
In the routine management of pulm TB the initial
regimen is customarily a standard schedule of Rx which
has been shown by trial and experience to be effective in
that population. Preliminary assessment is necessary to
identify any factors which may give rise to modification
of the standard regimen.
Such common factors
M_odi fi ca t_i on rec omme nde d
Modifying factors
Retreatment regimen, if
possible with-ho Id Rx
until sensitivities of the
infecting micro ascertained.
Previous anti TB chemo
Pt originates from an
area where resistant
organisms common.
,
Always use 3 drugs in the
initial phase of therapy,
or until sensitivities
ascertained.
Unstable social background , consider fully supervised
due to psychiatric demestic interminent chemo regimen.
or financial difficulties
Pregnancy
Avoid rifampin during the
first trimester.
Serious disturbance of
vision young children,
and the aged.
Avoid ethambutol.
2k
*
,
Impaired renal function
•
Impaired hepatic function
-
Once the decision is made the patient should be fully
informed of the nature and duration of the therapeutic
regimen to which he is submitting himself, including
the possibility and character of adverse effects,
so that te can adjust to the constraints which will be
placed on him and learn the importance of strict
adherence to the Rx schedule/
<
Modify dosage of SM,
Etham, & PAS, or
avoid use,
Avoid rifam or monitor
hepatic enzyme cone.
for Hospital Treatment :
SgjgJltion^^
Hospital admission at the start of therapy is not
necessary for the routine management of pulm TB,
out certain categories of patients are best treated
.in hospital initially, They include the following :
«
■? -W-.
..
I'M t4- .
z~> -»«-»-+-
1)
Very ill patients requiring supportive therapy
and nursing care
2)
Uncooperative patients - with unfavourable
social or domestic circumstances, h/o poor
cooperation, mental disturbance, alcoholism, or
drug addiction. Hospital admission is usually
-ic-cessary for the duration of the/intensive
initial phase of Rx which preceedes a fully
supervised out-patient intermittent continuation
phase.
3)
Patients with drug resistant disease who require
Rx with second-line drugs of high toxicity.
4)
Infectious patients with highly susceptible
domestic contacts such as tuberculin-negative
children or family members with impaired immuno
logical defence mechanisms.
Img,:
There is strong evidence to show that the risk of
infection to contacts is minimal once the index case
has started Rx.
:
__________
«
-x-
—
-orn rt
The choice between hospital and out-patient therapy
must depend on the individual circumstances of the
patient and the facilities which are available in the
location for safe and efficient ambulatory case,
-SyrXeiIIaQce of Therapy °0
Imp s
The aims of treatment supervision be clear -
1.
To ensure adherence to the recommended regimens.
2.
To detect evidence of adverse effects as early as
possible and take corrective steps if indicated.
possible,
o° 25
-X-
o-
3.
To monitor recovery by regular examination, smear,
and culture examination of sputum, including
sensitivity testing if compliance is suspect, and
radiographic examination of chest.
4.
To terminate Rx as soon as the approved regimen
has been completed<
.
Most physicians with experience, develop their own
schemes for treating pulm TB for achieving these
objectives which suit local circumstances.
.
Follow-up of the patients is a must, because the
maintenance of an unbroken therapeutic regimen becomes
increasingly important as treatment schedules are
shortened and the total number of doses is progressively
reduced.
,
If is probably safe to discharge the patient from
further follow-up, once an approved regimen of Rx is
completed, provided that the physician is satisfied
that compliance has been good and there is adequate
bacteriological, clinical and radiological evidence
of successful treatment.
.
Only patients who are known or thought to have had
irregular chemotherapy or an inadequate duration of Rx
should be followed for a limited period, but routine
chest radiography, or sputum cultures rarely lead to
the detection of reactivation disease, almost all
cases presenting with symptoms. The discharged
patient must therefore be encouraged to return to the
clinic promptly if he develops symptoms that might
indicate a relapse.
Retreatment Chemotherapy
■if—ii ■■-r.wy -a-; ttert* A. .^;v, jba.-w —t
_x. —
Recurrence of infection during or after a course of
anti TB •
chemotherapy calls for a careful reassessment
to determine the reasons for treatment failure.
Causes of Treatment
Failure in Pulm TB
Failure
mnww
—i—•.an-u*,, i —
Infection with resistant
micro-organisms
<
Choice of an inadequate
regimen
Cause
previous ineffectual Rx
primary resistance,
most common in develop
ing countries.
Single drug therapy
One or more drugs given
in insufficient dosage
I na de q uat e durat i on
of Rx,
26
Failure of adherence
to the prescribed
regimen
Inadequate explanation
and/or supervision of
therapy.
Intolerable side effects.
,
Therapeutic.errors such as single drug Rxr insufficient
dosage, or inadequate duration of therapy are common
in developing countries and have led to a substantial
pool of resistant organisms in some countries.
Primary resistance to one or more anti-TB drugs
occurs overall in / 10% of infections in the highly /less thai
developed countries" but the rate' is considerably higher
in developing countries and immigrant populations from
such countries.
>
A much more important reason for treatment failure is
lack of cooperation with the recommended regimen, and
the great majority of failures is found among individuals
of low intelligence, vagrants, alcoholics, and drug
addicts.
,
In planning the retreatment of patients who have had
previous chemotherapy it is therefore necessary to take
account of the ethnic and geographical origins of.the
individual, the social background, and the precise
nature and duration of earlier treatment. The current
sensitivities of sputum cultures should be obtained
to enable the cpt''wol '"’rug regimen ‘lg be determined,
and in general no Rx should be given until the results
of reliable resistance tests are available.
The following principles, provide a guide to
the successful chemotherapy of,.patients with resistant
infection
.
1.
Patients should be assessed prior to Rx for
possible increased risk of hepatic or renal
toxicityP and close 'monitoring for adverse
effects should be maintained throughout, including
me a* sure me nt s of plasma drug levels where necessary.
2.
Treatment should begin vzith at least. 3 drugs to
which bhe organisms are known to be sensitive,
using the most. effective of the available drugs
and taking into consideration theii’ potential
for toxicity in any given patients
3,
Drugs should be adrainismered under strict super
vision, initially in hospital, A parenteral drug
is useful when patients progress co outpatient
therapy since it provides an opportunity for
supervising pill swallowing when the patient
attends for injections,.
t
: 27
4
4,
5.
♦
Frequent tests of sputum microscopy culture and
drug susceptibilities be made during Rx,
more than
Prolonged therapy for / 18 months may be required
and adjunctive surgery is occasionally indicated.
Since most patients vith drug-resistant disease have
acquired it
Of failure to adhere to previously
recommended Rx, the success of Rx depends to a very large
extent upon the establishment of a sympathetic
relationship between doctor and patient.
(Paper prepared for Rational Therapy Cell of LOCOST)
It: !>
SURVEY PROTOCOL FOR ROLE OF PECTIN ANO KAOLIN
IN ACUTE DIARRHOEA OF INFANCY AND CHILDHOOD
Anita Srivastava
Sagun Desai
Introduction
Diarrhoea is the frequent passage of loose stools.
Diarrhoeas are extremely common and endemic in our country.
Almost every child upto the age of 5 years gets 1-2
episodes of acute diarrhoea in a year. It is the dominant
cause of excessive morbidity and mortality in the young
population of developing countries. It is closely related
to the socio economic and cultural conditions which impose
upon these people a suboptimal nutrition, a marginal
sanitation and limited medical services, In the complex
etiology of diarrhoeal disease these factors come into
play : the environmental background, the host and the pathogens
which gain access to the intestinal tract.
The treatment of diarrhoeal disease involves measures
aimed at reversing the altered physiological reactions set in
motion by the losses of water and electrolytes.
Aim
Use of oral rehydration salts in diarrhoea is now an
established, rational approach. However, conventional use of
binding mixtures (usually containing pectin and kaolin)
is still a common practice with many. One reason for this
could be that pectin and kaolin are considered non toxic.
Although, recently two arguments have been raised against their
use;(i) giving mixtures containing pectin and kaolin, gives a
false sense of security to the patients and/or relatives and
also to the treating doctor (ii) it allows longer stay of
irritants / noxious substances in the gut which are responsible
for continuation of diarrhoea and harmful effects. Except
for these, pectin and kaolin have been long in use and no
serious adverse effects have been acredited to them.
The purpose of the present study is to find out whether
pectin and kaolin given in addition to ORT has any further
beneficial effect without adverse reactions.
Material and Methods
A proposed study outline is presented in Appendix I.
Where the study will be conducted
Pediatric Ward of S.S.G. Hospital will be the main place
of this study. In addition, patients admitted in K.G.Hospital,
Karelibaug will also be included.
/pto/
M.D.
M.D.
- 2
Time duration of study
March 1986 - for pilot experiments.
April 1986 - December 1986 - actual study and
collection of data.
Jan. - Feb. 1987 - analysis of data and final
report preparation.
Total 1 year.
Financial implications
Part time medical investigator (for one year) paid
at the rate of Rs.200/- per month.
Drug s, stationery etc.
Total cost of the study
Rs. 600/-
to. 3000/-.
Appendix
Survey Protocol for Role of Pectin and Kaolin
in acute diarrhoea of infancy and childhood
I
Selection of cases
1.
a 100 fresh pts. spread over various age group
a)
(l mnth to 6 yrs./l2 yrs.)
b) Diarrhoea of
72 hrs. duration
Follow up for
72 hrs.
c) To be kept under observation.
2.
Patients are divided into two groups - Group A and Group 3.
Selection strictly on ilternate basis.
Treatment Protoco1
Group A
ORT only
Group B
ORT + Pectin and Kaolin
Dose of Pectin and Kaolin : Mixture of Kaolin (20%) +
Pectin (1%) in a sweetened and flavoured tragacanth
suspension. Dose s 20-30 ml. x 6 hourly.
PROFORMA
Name
yrs./mnths.
Address
Age_
Sex
Date of admission
Date of discharge
Weight
Height
M / F
History on admission
1.
2.
3.
Duration of diarrhoea
Number of stools
Nature of stools
days / hrs.
/ 24 hrs.
amount
colour
consistency
odour
4.
Other symptoms
associated blood/pus/worms
Vomiting
/24 hrs.
fever
thirst
convulsions
5.
Treatment received so far :
/pto/
- 2 Examination
Temp.
Pulse
Dehydration :
Resp.
Absent / mild / mod / severe
Nutritional status : Normal / PCM I /
Anemia :
Hb.
II /
Infection :
Investigations
Others ;
III /
gm % / mild / mod / severe
Other nutritional deficiencies ;
Stool Exam. :
B.P.
macro
micro
IV
No.
Name
FQLLOW UP SHEET
Day
1
Obs.1
Pulse
Resp.
Temp.
Wt.
Stool
amt.
consis
tency
colour
odour
Ass.
blood
pus
Vomiting
Dehydration
Other
features
Remarks ;
2
Obs.2
3
4
J) I
.
5 RIGHTS
It is said that ’’medicine has had its own scheme of ethics
for at least 2500 years, and although the moral rules of the Hipp
ocratic Oath have undergone considerable development and modifica
tion, much of modern medical practice is at least officially
ethically inspired by its modern successors, the World Medical
Association’s declaration, including those of Geneva, London (tne
international code of medical ethics), Helsinki, Lisbon, Sidney/
Oslo, Tokyo, Hawaii and Venice.”1 Scrutiny of these codes reveals
that (among other things) there is a progressively increasing
awareness, recognition and respect for ’autonomy*of the patient
in medical care. The importance of the need for recognition of
autonomy of patient becomes appearent when one realizes that (a)
the very nature of medical persuit leads to intervention into a
person or personality (as in case of psychiatry) and (b) the
specialization and super-specialization in medicine has ’lured’
the practitioners to be more concerned with ’parts’ of a person
rather than the whole person. It is in this light that guarding
autonomy of patients becomes important. Again religion and medicine
have always been associated in the past. History of medicine has
references to priest-medicine man or witchdoctor trying to employ
special ’powers’ including communication with ’God* to effect
healing. Perhaps this (now realized) erroneous self-perception of
the healers had led them to take on a ’superior breed’ position.
The legacy of 'superior breed' position, unfortunately, still
lingers in the attitudes of many a practitioner and this also
seriously challenges the autonomy of patients. Fortunately
periodical reflective retrospection amongst the members of medical
fraternity has resulted in progressively upgrading the . ethic a...
norms of professional approaches to medical practice, in a manner
conducive to autonomy of patients. Predictably, the transition
has been gradual. The following excerpt from the book Morals and
Medicine by J. Fletcher^ illustrates this :
,’The most consistent treatment of the subject (medical
ethics) / based upon experience of a high order, is to
be found in the George Washington Gay Lectures delive
red from time to time at the Harward Medical School.
To be frank/ a typical discussion of medical ethics is
not a very serious or challenging enterprize in moral
judgement. The extant literature on it consists for
the most part in homilies on the bedside manner and
such calculated questions of property and prudence as
shined shoes, pressed trousers, tobacco odors, whether
to drink Maderia, and the avoidancewof split infiniti
ves s It is composed, in a phrase, of manuals or
exhortations on competitive success.
”Dr. George Jacoby gives medical ethics a somewhat
liftier definition. He has expressed the view that it
deals with 'the question of the general attitude of the
physician toward the patient • to what extent his duty
obligates him to intervene in the patient's interest,
and what demands the physician has a right and duty to
make upon the patient's relatives in regard to obedience
and subordination for the purpose of treatment.’
Dr* Jacoby's use of such essentially ethical terms as
’’right" and ’’duty" brings us much closer to what we
mean by "ethics of medical care” as distinguished from
medical (professional) ethics. But first it is worth
our while to take full note of Dr. Jacoby's words *
Nowhere among them is there anything about what
demands the patient has ”a right and duty to make"
upon his physician..**
2
The words ’Patient’s Rights’ might conjure (in the minds
of some medical practitioners) an alarming picture of someone
trying to snatch away something that has been the exclusive domain
of medical practitioners and might enlist an unnecessarily confrontist response stemming from a sub-conscious (and self-imposed)
feeling of vulnerability that plagues human minds. On the other
hand ’duties towards patients1 is something that might be more
amenable to doctor’s frame of mind/ for he/she is consciously or
sub-consciously aware of the ethical requirements of profession.
Let us understand here and now/ that concepWally the doctor s
duties towards his patients and the Patient s Rights are in tact/
two sides of the same coin/ and the two are completely and wholely
compatible with each other.
WORLD MEDICAL ASSOCIATION DECLARATIONS (CODES) : TRANSITION
FROM ’DUTIES’ OF DOCTORS TO ’RIGHTS’ OF PATIENTS.
The spirit of the various Declarations of World Medical
Association/ made from time to time substantiates the point made
above. What is interesting is a noticable shift from doctor s
duties in earlier codes to patient’s rights in later codes.
(Salient features of pertinent codes are given in annexure I) • in
1948 The Declaration of Geneva (revised in 1968 and.1983) dealt
with the requirement for doctor to consecrate his life.to<the
service of humanity; to make ’’the health of my patient his first
consideration. In 1949 The World Medical Association’s interna
tional code of medical echics adopted in London stated (among
other things) physician shall owe his patients ccmplete
^7
and be a resource of all his science as also physician shall
provide absolute.confidentiality,.on all he knows about his patient
even after the patient has died. (Observe the shift in favou o
patient’s right). And in 1981/ The Declaration of Lisbon in fact/
concerns itself with the rights of the patients viz. Rj9nt to
choose the physician freely? the right to be cared for by a
physician whose ethical judgements are free from
ference; to refuse treatment after receiving adequate information;
to have confidences respected? to die in dignity; and to receive
or call for spiritual and moral comfort including the help of a
minister of appropriate religion^
adherence to THE DECLARATIONS s MORAL BINDING ON INDIAN COUNTERPART.
in la is a member of World Medical Association and there
fore a signatory to these declarations and therefore in spirit
the medical fraternity of the country endorses the codes# 11
therefore incumbent on Indian Medical Council to work out a mech
anism to ensure their implementation.
For implementation of the code(s) into action it is of
vital importance to ensure clarity of rules. .Fortunately kin
this case) such an enunciation of Patient’s Rights is avallab
in the American Hospital Association’s Bill of Patient s Rights/
which predominately reflects the spirit of t^e
™e
salient features of this Bill are reproduced0 in annexure II.
Out of the 12 rights of the patient mentioned it is neceto
discuss here atleast two viz. Right No.2/ which concerns
ssary
information
in respect of diagnosis, treatment and prognosis
the :
Tnd Right No.3 which deals with informed consent, since despite
y
- • - 1 * I** still exists areas
widespread
debate
there
grey in these matters.
Moreover these are more pertinent
L—-*
4in
- 4-the
n— Indian context.
1.
the patient can be reasonably expected to understand, vWhen it is not medically advisable to give such informatio .
3
to the patient, the information should be made available
to an appropriate person on his behalf. He has a right
to know, by name, the physician responsible for coordi
nating his carec
There are three arguments that are often forwarded for
limited disclosure and deception in therapeutic settings.,
These are adequately dealt with by Beauchamp & Childress
in their book Principles of Biomedical Ethics - 2nd.
Edition* The pertinent portions are reproduced 3a in
annexure III for reference.
However there is one case for non-disclosure that is
different and that is pertinent to present scene in
India® Under the Maharashtra State Act dealing v/idi
amniocentesis and prevention, of foeticide (female) ,f the
doctor is forbiden from disclosing the results of amnio
Dogs
centesis to the patient as well as his relatives
this contravene with the spirit of the codes^? How does
the physician reconcile with this situation 1
These arc indeed difficult questions to answer but not
entirely unresolvable* An attempt is made here to
resolve the dilemmao
(a) The Declaration of Geneva (see annexure I) implores
the physicians "not to use his medical knowledge corflict.
the laws of human!ty.
Since revealing the results of
amniocentesis test to patients has been, found to lead to
adverse discrimination against female foetus (which
contravenes with laws of humanity}^ It is incumbent on
the physician rot to divulge the results of amniocentesis
test to the patient or his relativeSn
<b) Now let us consider the Declaration of Oslo (1970)
(revised 1983) on abortion* It is the most equivocal of
all the declarations for it requires doctors both to
maintain the utmost respect for human life from its
beginning and to accept that, attitudes towards the
life of the unborn child are diverse and "a matter of
„ndividual conviction and conscience which must be
respected*" Subject to a host of qualifications toe
declaration has always sanctioned to eropentic abortion
At first sight it would seem that this code tends to
support the position that if the patient :wants’ the female
foetus to be aborted, the physician should accede to the
vzishes* However, when one also considers that 'mere1
knowledge of the sex of the healthy foetus cannot and
should not serve as a sole criterion for therapeutic
abortion, for "therapeutic" connotes ame 1 *i or a ticn
conditions resulting from 1 abnormality1f 1 ill-health*,
or unwanted pregnancy. If this interpretation is
acceptable, tier it ought not to be incumbent on toe
physician to ’reveal3 the sex of the foetus to the
patient* Again this approach would also be compatible
with "urmost respect for human life*11
INFORMED CONSENT
Informed consent is a requirement under our law for
certain types of medical interventionso Unfortunately,
the way it is observed, virtually always the spirit of
informed consent is abandoned and it merely serves as
a 1 legal passport' for the treating physician to get
away with anything* It is therefore necessary to dwell
4
on this subject for some length. Beauchamp and Childress
have dealt with the subject exceedingly well. We repro
duce some relevent portions here.
3
“FUNCTIONS AND JUSTIFICATION OF INFORMED CONSENT"
In recent years virtually all medical and research codes
of ethics have held that physicians must obtain the informed
consent of patients before undertaking significant thera
peutic or research procedures. These consent measures have
been designed largely to protect the autonomy of patients
and subjects/ but they serve other important functions as
well. Alexander Capron fully identified several important
functions.
1.
The promotion of individual autonomy
2.
3.
4.
The protection of patients and subjects
The avoidance of fraud and duress
The encouragement of self-scrutiny by medical
professionals
The promotion of rational decisions
5*
6.
The involvement of the public (in promoting
autonomy as a general social value and in con
trolling biomedical research*
"Medical and research codes/ as well as federal regulations?
have traditionally emphasized that the act of consent must
be genuinely voluntary and that there must be adequate
disclosure o^TThf ormation* However/ there are . several
elements of informed consent/ each presenting distinct
issues. The information component of informed consent
refers to adequate disclosure of information and adequate
comprehension by patients or subjects of what is disclosed/
while the consent component refers to a voluntary decision
on the part of a competent person. But how much and what
types of information must be imparted/ and how well must
it be understood ?
Is cosent valid if it is given under
conditions of social/ institutional/ or family pressure
or if the consent is irresponsible ? Beneath these
questions is the need for a detailed analysis of the
concept of informed consent that probes moral problems
unique to each element."
(Pertinent portions of this analysis are given in Annexure IV) .
CODE CONCEPTS AND MEDICAL PRACTICE AT VARIANCE.
Despite the fact that these codes are formulated by Medical
bodies comprizing of Medical Practitioners/ it is well,recognized
that much of medical practice (particularly in India) is found
wanting in the exercise of ethics. There could be a number of
reasons for this and each would need a separate remedial measure*
Some of these relating to patient's rights are discussed below,
(For convenience/ these are taken up at three levels viz.
impedence at (i) Doctor1 s level (ii) Patient’s level and
(iii) Institution level.
DOCTOR1S LEVEL s
1.
Intrinsic calousness : There have been reports that
some of the doctors have been sending some healthy but
poor patients to U.K. oni lure of small monetory incen
tives/ violating all ethical norms/ for kidney donations^
5
Such an attitude reveals complete calousness and these
doctors are not fit to be doctors. There registrations
*
need to be cancelled.
2.
Some doctors are not aware of the various
Ignorance s
ethical codes in existence. It is unfortunate that in
none of our medical colleges# medical ethics is taught.
as a separate subject, There is an urgent need for this
subject to be included in the curriculum.
The tendency to "why bother with ethics when we cannot
make adequate medical service available in the first
place" is a hazardous approach. In India 13600 doctors
are "churned out" through 114 (officially 106^ medical
colleges (compare this with 4000 doctors from 30 medical
colleges in Britain). If this ‘crop’ is not grounded
well in medical ethics, there would be a chaotic situa
tion.
Incompetence in analysing practice in ethical ^amewcdc :
Many doctors are unable to analyse their practice in
ethical terms# even if they are aware of. the codes <£
medical ethics, This is one of the results of not
having7 ethics as a separate subject in medical colleges.
Also there is not enough debate on the subject of
medical ethics in various forums, and Medical Journals
in India never seem to discuss the issues relating to
T.n contrast
medicali ethics. ((in
contrast almost
almost every
every issue
issue of
of BMJ
BMJ
has something or the other on such matters). (in U.K.
U.K*
there is an Institute of Medical Ethics as also a^
Journal is
Journal of Medical Ethics. ,■This important
,
not subscribed to by any library in Indial - so much so
for our concern for medical ethics.)
4.
Tendency to benevolent paternalism s Hie traditions of
our jciety has always been to adopt paternalistic
approach.. This is even more evident in some medical
practitioners. This seemingly 'humane1 approach leads
to suppressing decision-making capacities in the patient
it more often than not against the interest of patients.
Through regular debates in various forums this needs to
be changed.
5.
Weak moral fibre s This is also the bane of the society
in general. Doctets constantly (and not seldom willing y;
yield to pressures and influences to act unethically. For
instance, when a doctor prescribes drugs to suit the
needs of pharmaceutical industry rather than requirements
of patients, he/she is harming the interests of patients
and violating ethics. Again fraternity nexus and pressures
impede doctors from exposing incompetence and malpractice
amongst colleagues.
6<
Pressure of work s Quite often the doctor is burdened
ouraeneu
with such heavy work load that he/she finds it difficult
to “observe all ethical norms. This area needs to be
earnestly addressed to. It is important in such a case
to week out all superfluous activities. It is ..interest
ing to note that by following rational therapeutic
practice, Drs. Abhay and Rani Bang could demonstrate
saving in expenditure (Rs. 50,000/—) and time (for nurses
and doctors) from a small 30 bed district hospital.
6
7.
Difficult to resolve cases s Seme cases ethical issues
encountered in practice are indeed very difficult to
resolve. Recently there was a case of Siamese twins
in AIMSI, at Delhi where Dr> M. Rotagi. operated on them
to separate them into two independent individual babies.
The mother had rejected the baby twins and the grand
father got the twins to AIMSI. The ethical codes make
it the prerogative of the parent to take decision on
behalf of the children. In this case it was an irres
ponsible action. How does the doctor respond to such a
situation in ethical terms ? Again at the time of
operation if one twin had to be sacrificed, how could
the doctor respond in ethical terms ?
1
‘ ♦r Unfor
These are serious questions for intense
debate
tunately this case^has not been discussed in ethical
terms at all.
PATIENT'S LEVEL :
!•
Ignorance of Patient1 s Rights.
Unprimed capabilities for, competent autonomous response.
3>
Inertia to change.
All the above three need sustained educational support by
all (medical institutions/ doctors, voluntary organiza
tions and press) to change this situation.
INSTITUTION LEVEL 2
!•
It is incumbent on the Indian Medical Council as also^the
state medical councils to ensure adherence to codes ox
ethics. Unfortunately these institutions have shield away
from this responsibility. Throughout the two years of
Lentin Commission inquiry (and even now) both IMC and
Maharashtra Medical Council have not taken any action
against those indicted in the commission's report. There
■ must be a provision to change the non-functional members
of the councils.
2.
Hospitals must set up medical ethics committees to main
tain ethical standards and patients must have (a) infor
mation about these and (b) access to these in case of
grievance.
"Senior citizen groups" could bo enlisted to help hospitals
(at least a few) to help the institution in improving
patient rapport.
CONCLUSIONS :
Patient's Rights are a special form of human rights and
they must be looked upon as such by all concerned^ The attitude
of regarding 'patients' as mere "objects” in therapeutic practice
and "subjects" in biomedical research needs to.be abandoned. For
successful outcome in both the spheres 'participation o
individuals' (or patients) is essential, without which any
intervention is both incomplete and unsuccessful. It is nece
ssary to look up to 'patients' as active "participants
the
common goal of medical intervention. Then perhaps, respect for
patient's rights would come naturally to medical Practitioners.
Respect for patient* s right must span from before birth to after
death. When this happens medical profession could be regarded
7
as "truely noble", and the- simple test for existence of such a
'climate' is when it will be evident that ■'post-mortem" exami
nations are carried out in the. same degnified manner as
operation on an operating table.
REFERENCES s
1.
"Medical
codes." Raanan Gilon,
•'Medical oaths, declarations and codes.
British Medical Journal Vol. 290; 20th April, 1985,
pgs. 1194-1195.
2.
Morals and Medicine by Joseph Fletcher (Princeton
versity Press, Princeton, New Jersey) 1979, pg. 5 & o.
3.
“
Principles of Biomedical Ethics by^Torn
L Beauchamp and
Oxford University Press,
James F. Childress 2nd
2-2 Edition;
"22'
pgs. 336-339.
3a<
^bid pgs* 225-226.
3b<
Ibid pgs. 70-93.
4*
'’ ’ ,
Medical education in India.- in poor health.
5.
Tessa
290;
13th
Richards, British Medical Journal Vol.
April 1985; pgs. 1132-1135.
Pricing Medical Cc.re in Government Hospitals. Dr. Abhay
Bang and Dr. Rani Bang; Economic and Political Weekly
Vol. XXIII; April 2-9, 1988.
'i'-r! i
■;
ANNEXURE
I
DECLARATIONS OF THE WORLD MEDICAL ASSOCIATION
The Declaration of Geneva (1948, revised 1968 and 1983) is a sort
of updated version of the Hippocratic Oath* It requires the
doctor to consecrate his life to the service of.humanity; to make
toe health of my patient” his first consideration) to respect
his patient s secrets (even after the patient’s death); to prevent
considerations of religion, nationality, race> party politics, or
socia- standing (intervening) between my •duty and my patient”; to
maintain utmost respect for human life from its beginning” (until
1983 toe wording of this clause required "utmost respect for human
lire from that of conception”) ; and not to use his medical knowledge
conflict laws of humanity.’’
The World Medical Association’s international code of medical ethics
adopted m London in 1949 and revised in 1968 and 1983, respects
respects
among other things, adherence to toe Declaration of Geneva’s highest
professional standards, clinical decisions uninfluenced toe profit
motive, honesty with patients and colleagues and exposure of incom
petent and immoral colleagues. It states .that "physician shall owe
his patients complete loyalty and be a resources of his science";
and it says that "a physician shall maintain absolute confidentia
lity on all he knows about his patient even after the patient has
died."
The Declaration of Helsinki (1964, revised 1975 and 1983) governs
biomedical research in human subjects, and among its principles in
toe stipulation that "toe interests of the subjects shall always
prevail over toe interests of science and society." It requires
that in any research the doctor should "obtain toe such freely
given informed consent."
The Declaration of Lisbon (1981) concerns the rights of the patient.
These are declared to include the rights to choose hisphysician
freely; to be cared for by a doctor whose clinical and ethical
judgements are free from outside interference; to accept or refuse
treabnent after receiving adequate information; to have his/her
confidences respected; to die in dignity; and to receive or give
spiritual and moral comfort including the help of a minister of
appropriate religion.
The Declaration of Sydney (1968, revised 1983), on death, among
other blings that ’’clinical interest lies not in the state of pre
servation of isolated cells but in the fate of a person” and it
^tipulates the much more specific rule that when transplantation
of a dead person* s organs is envisaged determination of death
should be by two doctors unconnected with the transplantation.
The Declsration of Oslo (1970, revised 1983), on abortion, remains,
even after its recent revision, vrtiich changed ’’human life from
conception” to ” human life from its beginning,” the most equivo
cal of all these declarations for it requires doctors both to
maintain the utmost respect for human life from its beginning and
to accept the attitudes towards the life of the unborn child are
diverse and "a matter of individual conviction and conscience
which must be respected.” Subject to a host of qualifications the
declaration has always sanctioned therapeutic abortion®
The Declaration of Tokyo (1975 revised 1983), on torture, is un
equivocal in forbidding doctors to ’’countenance, condone, or
participate in the practice of torture or other forms of cruel,
inhuman, or degrading procedures." It also forbids force feeding
of mentally competent hunger strikers.
9
The Declaration of Hawaii (1977, revised 1983), on psychiatric
ethics, requires inter alia : that patients be offered the best
treatment available and be given a choice when there is more than
one appropriate treatment? that compulsory treatment be given
only if the patient lacks the capacity to express his wishes,
or, owing to psychiatric illness, cannot, see what is in his best
interests or is a severe threat to others; -that there must be an>
independent and neutral appeal body for those treated compulsorily;
that "the psychiatrist must not participate in compulsory psy
chiatric treatment in -the absence of psychiatric illness"; -that
information about patients must be confidential unless the patient
consents to its release "or else vital common values or the
patient's best interest make disclosure cimperative"; that informed
consent for the patient’s participation in teaching must be
obtained; and that "in clinical research as in therapy every.sub
ject must be offered the best available treatment
■, be subject
to informed consent, " and have the right to withdraw at any time.
The Declaration of Venice (1983), the most recent declaration of
the World Medical Association, 1 reiterates the duty of the^
doctor to heal and, when possible, relieve suffering and sanctions
the withholding of treatment in terminal illness with the consent
of the patient’or, if the patient is unable to express his will,
that of the patient'' s immediate family. It allows the doctor to
’’refrain from employing any extraordinary means which would prove
of no benefit for the patient” and permits the maintenance of
organs for transplanta-cion after death has been certified, given
certain conditions.
In addition to these declarations, the World Medical Association
has issued other statements about medical ethics 2 on discrimina
tion in medicine, reiterating its abhorrence of such discri.mination on the basis of religion, nationality, race, colour, politics,
or social standing1? on medical secrecy, affirming the individual’s
’’fundamental right" to privacy1; and on the use cf computers in
medicine, again affirming the patient's right to privacy but
stating that the transfer of information rendered anonymous for
the purpose ofresearch is not a breach of confidentiaxity4’^ Other
statements concern medical regulations in time of armed conflict,
family planning, 12 principles of provision of health care,
pollution, the principles of health care for sports medicine,
recommendations concerning boxing, physician participation in
capital pin?’ shment? medical manpower, and medical care in rural
areas•
ANNEXURE
IT.
AMERICAN HOSPITAL ASSOCIATION
A PATIENT'S BILL OF. RIGHTS s
The American Hospital Association presents a Patient's Bill of
Rights witb the expectation that observance of these rights will
contribute to more effective patient care and greater satisfact
ion for the patient, his physician, and ‘the hospital organi
zation^ Further., the Association presents these rights in the
expectation that they will be supported by the hospital on
behalf of its patients, as an integral part of the.healing pro
cess* It is recognized that a personal relationship between the
physicia n and the patient is essential for the provision of ,
proper medical care. The traditional physician-patient relation
ship takes on a new dimension when care is rendered within an
organizational structure* Legal precedent has established tinat
the institution itself also has a responsibility to the patient*
10
It is in recognition of these factors that these rights are affirmed.
1,
The Patient has the right to considerate and respectful care.
The patient has the right to obtain from his physician complete
2.
current information concerning his diagnosis, treatment, and prognosis in terms the patient can be reasonable expected to understand.
When it is not medically advisable to give such information to the
patient, the information should be made available to an appropriate
person in his behalf. He has the right to know, by name, the
physician responsible for coordinating his care.
The patient has the right to receive from his physician in
3.
formation necessary to give informed consent prior to the start of
any procedure and or treatment. Except in emergencies, such
information for informed consent should include but not necessarily
be limited to the specific procedure and or treatment, the medi
cally significant risks involved, and the probable duration of
incapacitation. Where medically significant alternatives.for care
or treatment exist, or when the patient requests information con
cerning medical alternatives, the patient has the right to such
information. The patient also has the right to know the name of
the person responsible for -the procedures and/or treatment.
4u
The patient has the right to refuse treatment to the extent
permitted by law and to be informed of the medical consequences
of his action.
The patient has the right to every consideration of his
privacy concerning his own medical care program. Case discussion,
consultation, examination, and treatment are confidential and
should be conducted discreetly. Those not directly involved in
his care must have the permission of the patient to be present.
5.
The pacient has the right to expect that all communications
6.
and records pertaining to his care should be treated as confid
ential.
The patient has the right to expect that within its capacity
7e
a hospital must make reasonable response to the request of a
patient for services, The hospital must provide evaluation,
service, ano/or referral as indicated by the urgency of the case,
When medically permissible. the patient may be transferred to
another facility only after he has received complete information
and explanation concerning the needs for and alternatives for such
a transfer. The institution to which the patient is to be trans
ferred must first have accepted the patient for transfer.
The patient has the right to obtain information as to any
8.
relationship of his hospital to other health care and educational
institutions in so far as his care is concerned. The patient has
the right to obtain information as to the existence of any pro
fessional relationship among individuals, by name, who are
treating him,
The patient has the right to be advised if the hospital
9.
proposes to engage in or perform human experimentation affecting
his care or treatment. The patient has the right to refuse to
participate in such research projects.
The patient has the right to expect reasonable continuity
10.
of care. He has the right, to know in advance what appointment
times and physicians are available and where. The patient has the
right to expect that the hospital will provide a mechanism whereby
he is informed by his physician or a delegate of the physician of
the patient1 s
*-- ■»
11
The patient has the right to examine and receive an explana
tion of his bill regardless of source of payment.
11,
rIhe patient has the right to know what hospital rules and
12,
regulations apply to his conduct as a patient.
No catalog of rights can guarantee for the patient the kind of
treatment he has a right to expect, A hospital has many functirns
to perform, including the prevention and treatment of disease, the
education of both health professionals and patients, and the con
duct of clinical research. All these activities must be conducted
with an overriding concern for the patient, and, above all, the
recognition of his dignity as a human being. Success in achiev
ing this fecognition assures success in the defense of therights
of the patient.
(Approved by the American Hospital Association House of Delegates,
February 6, 1973, and reprinted by permission of the American
Hospital Association)•
ANNEXURE
III
The first argument for nondisclosure of some diagnoses and
gno^OC! in.: the therapeutic setting represents what Henry Sidgwick
called "benevolent deception," It holds that disclosure of a
diagnosis of cancer, for example, would violate the duties of bene
ficence and nonmaleficience by causing the patient anxiety ("What
you don’t know can’t hurt you")* by causing the patient to commit
suicide, and the like. This general line of argument is found
in our discussion of paternalism in Chapter 5.
1.
One objection to this argument is based on the uncertainty of
predicting consequences. As samuel Johnson put it s
I deny the lawfulness of telling a lie to a sick man for fear of
alarming him. You have no business with consequences; you are to
tell the truth. Besides, you are not sure twhat effects your
telling him that he is in danger may have. It may bring his
distemper to a crisis, and that may cure him. Of all lying, I
because
I believe it has
I have the greatest abhorrence of this, L
-been frecruently practised on myself. x
Such an objection is especially applicable to act-utilitarian
approaches to veracity. The more compelling objections to
"benevolent deception" stress violations of the principles of
respect for persons and fidelity, as well as the long-term threat
to the relationship of trust between physicians and patients.
2,
A second argument for nondisclosure and deception is mat
that
health care professionals cannot even know, let alone communicate/
the "whole truth", and if they could, many patients and subjects
would not be able to comprehend and understand the "whole truth".
Such an argument, however, does not undermine the duty of veracity,
understood as the duty to be truthful.
3.
A third argument for nondisclosure and deception is that some
patients, particularly the very sick and the dying,, do not really
want to know the truth about their condition, despite what opinion
surveys seem to reveal. According to this line of argument,
neither the duty of fidelity nor the duty of respect for persons
requires truthtelling, because patients indicate by various
signals — if not by actual words — that they do not want to hear
the truth. To the rejoinder that many, and perhaps most, patients
appear to want disclosure of relevant information, proponents of
this third argument fcr nondisclosure hold that the patients they
12
have in mind really do not want to know even when they say they do.
In some instances/ of course, patients genuinely do not want to
know. For example. some patients with a high risk of developing
Huntington’s chorea, an incurable genetic disease/ indicate that
they would not be interested in a simple/ safe, and accurate predictive test if one were developed.
In other cases-/ patients who suspect that they might have cancer
explicitly ask not to be informed of the diagnosis and prognosis.
What should health care professionals do when patients ask not to
be given certain information ? Some writers go so far as to
suggest that a patient has a duty to seek and appropriate the truth not merely a right to the truth.14 But to force unwanted informa
tion on a patient is generally to act paternal!stically and to
violate that patient1s autonomy. To force a person to confront the
truth seems to be an act of disrespect, though it might on occasion
bo justified - e.g., in cases of weak paternalism where a person
acts from false beliefs. However, respect entails allowing persons
to exercise the right not to know whenever they are adequately
informed and are acting autonomously#
DR I
L 0 C 0 S T
GPO Box 134
BARODA 390 001
DT s2
March, 1988.
UPDATE ON MALARIA
- DR. RAKESH GUPTA
Diagnosing Malaria - Importance of Parasitological Diagnosis
After having dreamed of malaria eradication in. early sixties.:
we are now facing the challenge of malaris in epidemic proportions.
In our area/ the plasmodial species found are - falciparam
and vivax; P.falciparam accounting for 60-80% of infections/ and is
more prevalent in the transmission season than in the dry months.
Of all the patients presenting with feverz 30-50% were
detected to be having slide positive malaria - positivity being
higher (by a single smear exm.) during active transmission months.
Of these patients/ many were provisionally diagnosed as having
URI/ UTI/ typhoid/ pneumonia/ secondary infection in pulmonary
Koch’s/ Amoebic dysentry/ viral Hepatitis.
The obvious message is that the parasite is able to outsmart
the clinician quet a number of times and that a parasitologically
proven diagnosis is essential for the proper treatment/ more soz
as an inadequate response to full doses of chloroquine does not rule
out malaria (as was the situation few years back), in the view of
increasing chloroquine resistance.
Considering the complexity of the problem and the simplicity
and sensitivity of thick smear examination for parasitological
diagnosis/ it is prudent on part of clinicians to utilise it
routinely.
CURRENT SITUATION IN OUR REGION s
1) Resurgence of malaria in epidemic proportions.
2) Species distribution :
P. Faleiparom - 60-80%
P. Vivax
— 20—40%
Increase in atypical manifestations s
increase in absolute numbers.
3)
- wider clinical spectrum.
4) Emergence of chloroquine resistance.
5) Misuse of 2nd line antimalarialsz
namely s Pyrimethamine - Sulfadoxine
combination.
LABORATORY DIAGNOSIS OF MALARIA -5
"Demonstration of parasites in blood is the^only method
available to confirm diagnosis of malaria,"
Sample
s
Finger prick or venous blood.
Frequency of blood Collection s
1st smear immediately.
Repeat smears every 12 hr?* for 2 days.
The Smear :
Thick and thin smears are prepared on same slide as shown
below. The thickness of thick smear should be such that news
print can be just seen through it. This is equivalent to about
... 2
2
10-20 WBC/oil immersion field under microscope.
r
■
i
i
i
%
o
r
r
i
i
i
i
i
i
i
i
i
i
_ _
i
i
i
i
i
i
t
Staining ;
Giemsa stain gives best results. A fresh dilution has to be
prepared every time from stock solution in phosphate buffer pH 7^2.
Staining time depends on strength of dilution used and varies wit/,
each batch of stain.
10% Giemsa - 10 min.
2% Giemsa - 30-40 min.
Dehemoglobinisation occurs simultaneously whilC staining.
Species diagnosis s
This can generally be done on thick smear examination alone
but in cases of doubt, thin smear should be seen to study the
morphology.
Interpretation of Smear :
Adequate examination of smear :
Ideally, at least 0.25 cmm of blood should be examined befor:
declaring the smear as negative.
The no. of fields that should be examined to cover 0.25 mm'
of blood depends on smear thickness.
Ideal thickness
- 10-20 WBC/Oil immersion field.
3
Taking average TWL.C. as 8000/mm t
3
if 20 WBC/field
- 100 fields = 0.25 mm of blood
if 10 WBC/field
-
200 fields
=
I!
Thus,
TLC (8000)_______
x 0.25
Mean No. of WBC1s
in 10 fields
No. of fields to be examined 3
that are equivalent to 0.25 mm
of blood.
COUNTING OF PARASITES :
Parasitaemia can be quantitated by 2 ways 1) As no. of parasites/cmm of blood on thick smear.
2) As % of RBC’s injected on thin smear.
1)
On thick smear s
A grid may be used in eyepiece to facilitate counting of
parasites.
In each field. no. of parasites and WBC’s are counted upw
100 field and added up.
(or no. of fields for adequate examination)
No. of parasites x TLC (8000)
No. of parasites/mm
counted
_________________
W3C 1s counted.
Thus if smear thickness =: 10 WBC/cm
.
.
lx 8000
4 par sites/cmm = —2000—- « 1 parasite/200 field.
if 20 WBC/field
-
1 parasitez100 fields = 4 parasites/cmm.
This count is considered to be the threshold for detection of
parasites in blood by microscopic examination.
-
Also called patency level.
3
3
Information gained from positive smear :
High parasitaemia correlates with severe disease
high mortality
but converse is not true. Complications and fatalities may occur
even if parasitaemia is scanty or if smear is negative.
Parasite counts
Mortality
10,000/mm3
i %
500,000/mm
50 %
Features suggestive of complicated disease
Parasite count
50z000/cmm
1)
>
5%
of
RBI
’
s
are
infected.
2)
Presence of schizonts of P« falciparum in pecipheral blood.
3)
Asymptomatic parasitaemial
In endemic areas/ parasites may be present in blood in smalJ.
numbers/ without causing any symptoms - This state of immunity is
called ‘premuaition"9
Thus, finding
finding parasites in blood does not always mean that
Thus/
sywptoS
are Se to parasites
Llaria although It la so most ot the tomes.
symptoms are due ■— --- Other possibilities should also be kept m mind and investigated.
Negative Smear when patient has malaria s
1. Inadequate examination of smear.
2. Prior administration of antimalarials which lowers parasite
count below microscopic threshold.
Subpatent parasitemia - i.e. below microscopic threshold
3.
e.g. - Non immune individuals
- very early stage of disease.
4. Failure to collect repeat smears - especially in Falciparom
malaria.
Sources of srror & Confusion
1)
2)
3)
4)
5)
6)
Dirt
Scratches on slides
Platelets
Ghost shadows of inmature arythrogytes
Skin bacteria
Spores/ yeast/ fungi/ etc.
CLINICAL DIAGNOSIS
Absence of fever in malaria s
While fever has been considered and is the hall mark of
malaria/ it should be appreciated that complicated malaria may
be present in absence of fever.
Generally/ these are patients with Cerebral malaria who present with abnormal behavior,or
A)
convulsions or unconciousness and found to be suffenng,from
malaria on basis of a positive smear, response to quinine
and absence of other attributable cause.
1.
B)
C)
2.
Some of these patients develop, fever later on
stay while some have had an episode or fever 10-15 days back
•which had subsided with treatment.
Severe anemia who do not respond to haematinics unless
malaria is cured.
Acute Gastroenteritis like picture who develop hypothermia
or do not manifest fever because of volume depletion.
Acute Hepatitis (Malarial or FaIciparom Hepatitis)
Not in frequently, falciparom malaria presents itaelf as an
acute hepatitis like syndrome. Hence it is importantto app ciate that hepatocellular jaundice can occur with malaria. S-rom
bilirubin levels as high as 20.00 mg/db have been - recorded. In
4
fact/ we have observed that jaundice
is more frequently hepato
jau
cellular rather than hemolytic.
hemolytic, Such patients are often dragnosea
and treated as viral hepatitis.
hepatitis, Persistence of fever after onset
of jaundice lshould
make the clinical alert to this possibility
--------- —
which can be confirmed by demonstrating parasites on smear exami
nation. Such patients respond rabidly to antimalarials and their
liver functions return to baseline within 7 days. Fatal hepatic
failure due to falciparom malaria has been reported.
•
Pregnancy and malaria
In endemic areas, clinical episodes of malaria arej more
frequent and more severe in pregnancy/ the primigravidae being
worst affected.
Many patients who develop abnormal behavior or.unconciousness are often misdiagnosed as peu;peral sepsis, cortical vein
thrombophlebitis or postpartum psychosis. Most of these patients
turn out to be having cerebral malaria and respond dramatical »y
to antimalarials.
DRUG RESISTANT MALARIA
Drug resistance has been defined as the ’abil-kty of a
parasite strain to multiply or to survive in the presence of con
centrations of a drug that normally destroy parasites of che same
species or prevent tiieir multiplication. Such resistance mavb.
relative (yielding to increased doses of drug tolerated by -h
host) or complete (withstanding maximum doses tolerated by host. ,
Drug resistant malaria commonly refers to chloroquin
resistance unless otherwise specified. Certain strains showing ,
resistance to multiple drugs are called multidrug resistant strains.
While p.falciparum has been shown to have developed, resist
to
all available drugs, the picture is not so grim with.
ance
p<vivax. P.vivax has developed resistance to pyrimethamine ana
progvanil< It is inherently less sensitive to suejonamide;-.
Recent reports from North East India suggest decreasing chlorogum
sensitivity of P-vivax.
DOCUMENTING DRUG
A)
In vivo Method
RESISTANCE
3
The WHO standard field test (7 day follow up) or extended
test (28 day follow up) is used.
It is based on observing the parasitological response to
the standard dose of_ chloroquine of 25 mg/kg by taking daily
smears on 1st 7 days and weekly upto 28 days. Parasite counts
are done on each smear and results are interpreted as follows.
Standard field test s
a)
b)
c)
d)
If no asexual parasites are found by day 6 and none are
present on day 71 the infection may be sensitive (S/ or
Resistant at R^. level.
If asexual parasites disappear for at least 2 consecutive
days^buPreturn”and are present on day 7, they are resistant
at R^ level.
y
clear but is reduced to 25'/If asexual parasitaemia does^not
original
pretest
level
or less of
x— — — — t during first 48 hrs. of
treatment/ the parasites are resistant at
If asexual parasitaemia is reduced’ by less than 75% during
continues"to
rise/ the parasites
the first 48 hrs. or if
if it
1-----’ ’
’
level.
are resistant to the standard dose at
••*
Developmental stage of malarial parasite
Drug
Sporozoile
Tissue
phase
____ Erythocytic phase
Arexual parasites
Gumetocytes
Quinine
Chloroquine
Amodiaquine
Primaquine
Fast action
Active -but
not used for
prophylaxis
Active - only
in toxic doses
Antirelapse
activity
Sporontocidal
action
Active against P,
vivax. No direct
action
P»
falciparum.
Direct and fast
action on all
species but parti
cularly P.falci
parum.
Q
§M
Highly
ac tive
Highly
active
S
H
§
H
Proguanil
Ac tive
Slow action
Highly
active
Pyrime th ami ne
Ac tive
SIow action
Little
evidence
cn
i
Sulfones and
Sulfonamides
Mefloquine
Possibly
active
Moderate action
vhen given
alone
Marked action
w
H
As quinine
M
<
H
§
6
INTERPRETATION OF EXTENDED FIELD TEST
a)
If no asexual parasites are found by day 6 and parasites do
not reappear by day 28, the parasites are sensitive.
b)
if asexual parasites disappear as in (a) but return within
28 days, reinfection having been excluded, the parasites
are resistant at R^ level.
For R-j.^ & Rui level resistance Same as in standard field test.
c)
d)
Sensitivity (S)
_ _„Eate-niiyi
0
•H
1
s
__
o
-P
•<H
W
- Delayed
_ _-recruder cenee
i
0
M
0
ft
£
f
2
escence.
C ord -
ft
•H
U
0
Li____
ft
(0
d
X
0
. ..... ........ ....... ............
I. ...
Days after start of treatment on Day
Standard
test
0.
------ *
Extended test
IN VUR'O METHODS
Macrotechnique
microtechnique
require^ 8-10 ml venous blood
requires 100 ml of finger prick bio ^d
La aero technique is simpler and consists of collecting blood
containing parasites in ring stage and disposing 1 ml alicuots in
vials containing 5 mg. glucose and required amount of drug followed
by incubation at 38-40°C for 24-30 hrs. After incubation, smears
are prepared and stained and effect of drug is measured by
counting the number of schizouts formed during incubation.
Interpre tati on
1.
‘2.
3V
Total inhibition of schizont maturation at chloroquine con
centration of 1 umol/lit indicates susceptibility to
standard chloroquine treatment.
Schizont maturation at 1.5 jimol/lit of chloroquine concen
tration or more indicates resistance.
Schizont maturation at 1.00 .iimol/lit but inhibition at 1.5
pmol/lit may still be compatible with a satisfactory
response to chloroquine.
CHOICE OF ANTIMA1ARIALS IN AN APEA
KNOWN CHLOROQUINE RESISTANCE
U no ompl ic a ted
Complicated
i
i
i
Chloroquine
Quinine
2. No response
de ter iorat: >r
1, Good
response
i
i
i
i
i
i
Quinine
*
Para sitological
response +
*
Pt. improving
i
i
i
i
Pati
clir.
stal
Waith and
watch
t.
t
J
«
v
Sulfadoxine/
Pyrime thomi ne
our area
Thus/ in
in our
area/# it is important to note that iJy
cation of sulfadoxine/pyrimethamine is in an unconr
chloroquin resistant P.falciparom malaria, Quinine
employea/ 'the
— moment
—
•patient deteriorates.
■< ■
I'
CHLOROQUIN AND QUININE
Dosage and Route of Ad
ministration
Chloroquine :
The standard regime remains as giving 25 mg/.
quine base over 3 days as 10 mg/kg stat and 5 mg/kg after 6 hrs.
5 mg/kg on 2nd and 3rd day
The problem arises because most people are a:
the loading dose for fear of producing gastritis.
the
It has been an observation
------ of
-- most
------- people
* ,
with food or milk, this dose does not cause vorrutii
quently as is believed. Of course, it does cause
discomfort. Vomiting is possibly more out of fear
patients which is not put to rest by us with proper
>
-T
i:
.3
:
■
)
8
but is rather aggravated by our own apprehensions.
It is to avoid this problem of vomiting people use chloroqui.
in various dosage
The WHO recommendation in this regard reads "Adults should receive a course of treatment totalling
25 mg/kg of chloroquine base in several doses over a period of
3 days. Variations of this regimen are used in different countries but more are based on administration of 900 mg (in 2 - 3
divided doses) on first day followed by smaller doses on subseduent days*.1’
The rationale for a loading dose is that chloroquine has a large
volume of distribution, being concentrated in various tissues.
Hence a loading dose is required to saturate thesesites so that
high plasma levels can be obtained as fast as possible.
In a semi-immune population, the need to achieve a high
plasma level immediately may not be as great as in non.immunes.
Since chloruquin has a long half life of 2 - 3 days, high plasma
levels can still be obtained (although few hrs. later), if the
1st day dose is given in 3 divided doses. The delay of few
hours in achieving that very high plasma level will not be cri
tical in semi-immune patients with uncomplicated malaria.
However, any regime providing for less than 15 mg/kg on
1st day should be considered inadequate.
Oral route should be u^ed as far as possible and all effort
should be made including use of antiemetics and antacids to make
oral treatment possible.
The risk of parentral chloroquine is mainly Hypotension
which may be fatal. The degree of Hypotension has been corre
lated with plasma chloroquine levels. It has been demonstrated
that peak plasma concentrations are higher and reach toxic
levels with I M chloroquine more frequently than when it is
diven intravenously as a slow infusion at a controlled rate.
The risk of Hypotension is much more in children.
More over/ the patient/ whose clinical condition demands
parentral treatment, generally requires Intravenous treatment.
Other advantages of IV chloroquine is such condition are -
-
The initial loading dose of 10 mg/kg base can be given
(highly desirable) which would not be possible with
IM route.
The Infusion can be discontinued as soon as hypotension
develops*,
Thus, there is little justification in the widespread use
of IM chloroquine as we find it today, tv
IV chloroquine is given
in following dose :
a) A loading dose of 10 mg/kg base diluted in 10 ml/kg of
Normal saline or 5% Dextrose infused at a constant
rate over at least 4 hrs. and
b) Maintenance dose of 5 mg/kg infused over 2 ~ 4 hours
at 12 hour intervals to a total dose of 25 mg/kg.
... 9
I
9
QUININE
The requirement of quinine varies in different geographical
regions according to sensitivity of para-ites. Thus, high doses
are required in south-east Asia while twice a day regime suffices
in Africa.
Since the level of sensitivity has not been measured in our
region by in vitro methods# the recommendation is 10 mg/kg quinine dihydrochloride thrice a day for 7-14 days
depending on clinical response. Oral and parentral dosages are
same.
Intravenous quinine is given as 10 mg/kg of dihydrochloride
salt diluted in 10 ml/kg of 5% dextrose solution over a period of
3-4 hrs. Severe hypoglycemia may develop during quinine infusion
and should be continuously looked for.
ROLE OF STEROIDS IN CEREBRAL MALARIA
The role of steroids as usual has generated considerable
controversy but the current recommendation is that steroid should
not be used in patients of cerebral malaria.
This is based on a double blind trial conducted in Thailand
(1982) in which it was found that there is no significant diff
erence in mortality in the control group and steroid group the
duration of unconciousness was significantly increased in steroid
group.
POPHYLAXIS
Choice of drugs :
Available drugs for prophylaxis are
!•
2.
3.
4.
5.
6*
Chloroquine or
Amodiaquine
Progvanil
Pyrime th ami ne
Pyrimethamine +
Sulfadoxine
Pyrimethamine +
Dapsone
Mefloquine
300 mg base/once a week.
100 mg/day
25 mg/once a week
25/500 mg / once a week
(1 tablet)
12.5/100 mg / once a week
(1 tablet)
25C mg/once a week
In areas of chloroquine sensitive strains/ Amodiaquine
offers no advantage over chloroquine.
Pyrimethamine alone is no longer recommended as resistance
develops to it very rapidly and in most areas where it has been
in prolonged use - both/ P. vivox and P.falciparom have become
resistant to it.
The status of proguanil is uncertain and is not recommended.
Suf adoxine/pyrime th amine used for prophylaxis has been
reported to cause various side effects - most threatening one
being S-J syndrome. Hence/ it is no longer recommended for use
as prophylactic except in long term travellers to malarious areas.
Mefloquine is a highly effective drug but is not available
in our country.
Thus# the choice of prophylactic would be -
•
10
10
(
In chloroquine sensitive areas
- Chloroquine.
A)
■
In areas of chloroquine resistance s
B)
Mefloquine
Pyrimethamine/Daps one
Pyrime th amine/Sulfadoxine
a)
b)
c)
Indications for prophylaxis
Non immune travellers to malarious areas.
Among semi immune resi^d'.ents of malarious areas Pregnant women
Special- risk groups e.g. sickle cell disease,
splenectomised patients/ Aggregation of
labourers/ police forces/ Army units/ refugees
in camps.
1)
2)
REFERRAL SYSTEM FOR MALARIA
Looking at the magnitude of problem and lack of medical
facilities/ all patients cannot be provided expert medical
attention.
However, a working syscem of referral has been proposed by
an expert committee to optimally utilize meagre resources. An
operational definition of complicated malaria is used depending
on competence of health care, personnel and laboratory facilities
available.
Three levels of health services hnve been postulated Level - I
Most peripheral
Level
II
Staff with basic training only,
No laboratory facility.
Only oral medication
No clinical judgement.
Better training.
Can use stethoscope and exercise some
clinical judgement.
Facility for smear examination may be theref
IM or SC injections can be given.
Level-III
Central Level
Qualified medical personal with laboratory
facilities. IV therapy can be given.
Definition of severe malaria at different
___________
Level f
2
A) Clinic al Assessment s
+
1. Too weak to walk
(in absence of obvious
other cause)
2. Cerebral Malaria
3. Vomiting of oral
treatment.
(b)
+
+
+ (c)
+
4... 11
1
Level 1
4. Bleeding and clotting
disorders.
5. Severe Anemia
6. Jaundice
7. Hypothermia
8. Circulatory Collapse
9. Haemoglobinuria
10. Fluid/electrolyte disturbance
11. Complicating infection
12;, Pulmonary edema
13. Hypoglycemia
3
+
+
+
+
+
4-
+
4-
VV-
v-
B)
Exclusion of other diagnoses
C)
Parasitological diagnosis
Hyperparasitaemia
4- = means assessment can be made at this level.
a) Reasons for referral include failure to respond to
initial treatment*
b) Confusion/ drowsiness/ fits*
c) Exclude meningitis (Neck rigidity/ photophobia)•
d) Exclude meningitis (Lumbar puncture).
• ••o0o< • •
2
-F
+/-
+/-
j.
4-
f
i-
HaEMATINICS
Part I s Pharmacological zlspects
- Dr.Sagun Desai
Dr.Rajul Desai
Introduction
Anaemia is a common problem in India which may be due to
several causes but nutritional deficiency - especially of iron
and folic acid - contribute to this to a large extent. A
decrease in the oxygen carrying capacity of the blood is termed
’anaemia*. A reduction in the blood haemoglobin level and in
the number of circulating red blood cells are the characteristics
of anaemia. Drugs to correct anaemia are called *Haematinics1.
/A large number of such preparations are marketed in India which
vary not only in their ingredients but also in their cost. And
most often they are irrational combinations.
Dr. Pierre Blaud, early in 19th Century recognised many of
the principles of iron therapy. He said that iron should be
given at first and increased gradually. He introduced his pills,
containing ferrous carbonate and sulfate. Unfortunately, a number
of eminent physicians towards the end of the last century
considered for purely theoretical reasons that inorganic iron
could not be absorbed, so that many expensive and relatively
ineffective iron preparations were developed (unfortunately the
practice is continued in modern era, even with knowledge, a
paradox). Modern research has shown that Dr. Blaud was right.
Some facts about iron metabolism in body
The total body iron is about 2 to 6 gms.
Males - 50 mg/kgo of body wt.
Females - 35 mg/kg. of body wt.
Of the total iron nearly 2/3rd is present in the form
of haemoglobin and rest is storage iron.
Approximate daily requirement of elemental iron is
8 - 18 mg. in children
15 - 20 mgo in menstruating women*
10 - 15 mg. in adult males
20 - 25 mg. in pregnant and lactatingw women **
Note s Of the available elemental iron about 5-10% is absorbed
in health, this increases upto 30% in anaemic subjects.
* Monthly blood loss during menstruation roughly is
50 ml. which is equivalent to 25 mg. of elemental
iron. This works out to be a loss of 0.3 to 0.6 mg./
day, sometimes upto 1.5 mg./day.
** Fetus accumulates 200-400 mg. of iron, mainly in
the last trimester. Further, iron is lost
during child birth and later during lactation.
-2-
2
Sources of iron s
Milk and milk products are a poor source of iron. Use
of iron cooking utensils
-----j increases the iron content of food.
Iron content of various foods
High iron content
(more than 5 mg/
100 mg.)
Non-veg.
Liver
Heart
Et^g Yolk
Veg,
Intermediate iron
content
1 to 5 mg/100 g.
Non-veg.
Wheat germ Muscle
meat
Certain
Fish
dried beans
and fruits
Low iron content
(less than Img/
100 g.)
Veg,
Non-veg.
Most green
Veg.
Milk and
milk
products
Vegetables
cereals
Non green
vegetables
Iron is absorbed from the f
''
food' throughout
the gut, but
chiefly in upper part of small intestine where
---j
the
acid medium
-enhances solubility.
Most iron in food is present in ferric form.
Ferrous iron is more rapidly
:
*
absorbed than ferric, iron,
therefore a reducing agent such
r~
-_h as ascerbic acid (Vit.C) greatly
increases the amount of ferrous form.
However substantial doses
(200 mg. 8 hoyirly with the iron)
are
needed
to produce clinical
effect and combined formulations often do not contain enough.
for absSotion Jt?1Ven ir\lar9e doses, the control mechanism
tor absorption fails, resulting in excess absorption and
eventually haemosiaerosis. Abnormalities of small intestine
may interfere with either the absorption of iron as in the
malabsorption syndroms and
disease or possibly with the
conversion of iron into'<a soluble and reduced form. Partial
gastrectomy often leads to decreased
----- 1 iron absorption.
In alkaline medium of most of the small intestine iron
is converted into insoluble iron salts ^(phytates
k
and „
phosphates).
°f m°st °f tl“ orally takeni iron
even in severe iron deficiency.
When iron is given alongwith
leading to inabsorption of both to tetracycline it gets bound
a clinically significant degree,
Therefore the doses of both should be
separated by atleast
three hours.
Iron Therapy
2fth"C°y'S
i. to respond
2ththae 5K
Iron therapy is not .indicated to anaemia of chronic
disease
like rheumatoid
a.
. ., .
---- -—arthritis
as there is failure of
utilising stored iron
and
-- —d not the lack of iron.
-3-
1
1
- 3 When oral therapy is used, it is reasonable to assume that
about 30% of the iron will be absorbed and to give about 180 mg.
of elemental iron daily. However calculations are not necessary
except when iron is given by injection.
Total iron (i.v.
required in mg)
= 4.4 x body weight in kg. x Hb deficit
in g / 100 ml. blood.
This formula allows about 0.5 g to replenish stores. It
is important to remember that with iron dextran (i.v.) all the
iron is biologically available but with i.m. iron dextran about
30% of iron remains bound to muscle and with iron sorbitol
i.m. about 30% is lost by renal excretion. This is taken itit©
account .^hen calculating an i.m.'course of iron 40 mg. i.m. =
30 m.g. i.v. In pregnancy it is usual to add 0.5 g for needs
of placenta, fetus' and blood loss at delivery.
Iron stores are less easily replenished by oral therapy than
by injection and oral therapy should be continued for at.least
two months after the haemoglobin concentration has returned
to normal. It is illogical to give iron in haemolytic
anaemias unless there is also haemoglobinuria for the iron from
the lysed cells remains in the body and haemosiderosis may
ultimately occur.
Indications for Iron Therapy
1.
In iron deficiency anaemia due to chronic blood loss.
2.
In pregnancy - the foetus taken upto 600 mg. of iron
from the mother even if she is iron deficient, but the
iron stores of a baby born to an iron deficient mother
may be abnormally low. Dietary iron is seldom adequate
and iron should be given from the fourth month to
pregnant women.
3.
In varioijs abnormalities of the gastro intestinal tract
i.e. mai-absorption syndromes.
4
Premature babies and babies wearied late.
5.
During the treatment of pernicious anaemia alongwith
hydroxoc obalamin.
Oril Iron Preparations
There is an enormous variety of official and proprietary
iron preparations. For each mg. of elemental iron taken
by mouth, ferrous sulphate is as effective and no more
toxic than more expensive preparations.
Iron given a in mixtures may combine with sulphide
irons in the mouth and the resultant black iron sulphide
causes blackening of the teeth. Besides liquid preparations
are more costly.
■
-4-
4
It is particularly important to avoid initial overdosage
with iron as the resulting symptoms may cause the patient to
abandon therppy. A small dose is given initially and increased
after a few days.
If given on a full stomach iron causes less gastro
intestinal upsets but less is absorbed than if it is given
between the meals.
Common preparations
Elemental iron
Preparations
Strength
Ferrous sulphate
200 mg.
60 mg.
1-3 tabs./day
Ferrous gluconate
300 mg.
35 mg.el
Ferrous fumerate
200 mg.
65 mg.
1-4 tabs./day
1-3 tabs./day.
Choice of oral iron preparations
-------------------------- ----------
Dose
...
The Evidence as to which preparation provides best iron
absorption with least adverse effects is conflicting. Unfortu
nately many of the studies on which claims for rival prepara
tions are made are found on close inspection to be inadequate.
There is little doubt that valid comparisons can only be made
with doses of preparations containing equal amount of elemental
iron and undef- strict double blind conditions. It has been
shown that gastro intestinal upsets can be greatly influenced by
expectation.
The widespread use of iron preparations has stimulated many
attempts to find formulations that may provide better therppy.
This is a good thing. Unfortunately it has also stimulated some
to make© claims for their products that go beyond the evidence
e.g. ignoring unfavourable and quoting only favourable evidence
regardless of its scientific quality.
A suggested course for iron therapy ?
- Start a patient on ferrous sulphate
- If gastro intestinal upsets, try ferrous gluconate/
succintte/furmerate
- Addition of Vitm. C increases the amount of iron
absorbed. Therefore lesser dose can be given which
would decrease gastro intestinal upsets.
If simple preparations fail (this is unlikely) then
pharmaceutically sophisticated and expensive preparations
(slow release forms, enteric coated etc.) may be tried. From
these preparations iron is slowly released resulting in
decreased absorption. A similar result can be had at less
cost by reducing the dose of conventional preparations.
Duration of therapy
In general a full dose as described earlier should be
given until haemoglobin level comes to normal and then continued
at reduced dose for two months to replenish the stores.
-5-
5
Parenteral iron administration
Indications s
1.
Ineffective absorption from gut.
2o
If a certain response is essential in a severe iron
deficiency anaemia as in late pregnancy ( a blood
transfussion preferred).
3.
Failure of oral iron for unknown reasons.
Poor patient compliance.
4.
Imp.: The speed of response is not quicker (as would
be believed) than that with full doses of oral iron reliably
taken and normally absorbed, for both provide as much iron as
an activemxx marrow can use. Intramuscular iron sorbitol is
satisfactory, but some prefer iron dextran.
Intravenous
iron dextran is used. Total dose infusion (TDI) is
preferred over intermitent injections.
Folic acid deficiency may be unmarked by effective iron
therapy. This is liable to happen in pregnancy and so folic
acid is commonly given to all pregnant women having anaemia.
A similar thing happens in malabsorption syndrome.
Adverse reactions
Mild gastro intestinal disturbances like nausea, abdominal
pain constipation or diarrhoea. These can be minimised by
giving it after food and initial small amounts which can
then be gradually increased.
Adjuvants to iron therapy
Various substances claimed to enhance the efficacy of iron
are Vitamin C, cobalt copper and manganxese. Vit.C may
increase the iron absorption but it is not necessary to
use costly iron preparations incorporating Vit.C to achieve
this effect. Copper is said to mobilise iron from storage,
while cobalt is claimed to stimulate erythropoietin
production. Cobalt is potentially toxic. Angina, goitre and
congrestive cardiac failure are some of the adverse effects
reported with the use of cobaltous chloride. The therapeutic
value of these agents in the treatment of iron deficiency anaemia
is doubtful.
In the treatment of pure iron deficiency anaemia, the use
of ’shotgun' therapy containing a wide variety of expensive
minerals and vitamins alongwith iron is unnecessary and wasteful.
Vitamin B12 (cyanocobalamin)
For clinical use hydroxocobalamin is preferred.
Deficiency of vitamin Bl2 in the body leads to
i) pernicious anaemia (a megaloblastic anaemia)
ii) subacute combined degeneration (degeneration of
brain, spinal cord and peripheral nerves)
iii) abnormalities of epithetial tissues, particularly
of the alimentary tract (e.g. sore tongue and
mal absorption)
-6-
6
Function of Vit<>B12 and cause of magalobiastosis s
Uncertain. Vit B12 is a conenzyme for an essential stage
in folate metabolism and may affect folate transport into
cells.
Daily requirement s 1 mcg. absorption mainly from ileum.
Several
Several years
years11 supply are normally stored throughout the body;
mainly in the liver and its half life is about a year.
Man gets most of his cobalamin from meat. Cobalamin does
not occur in plants (except in legumes in which it is made by
bacteria in root nodules). Dietary deficiency can occur
occur in
in
strict vegetarians.
Indications for Vitamin B12 =
Prevention and cure of conditions dy.e to its deficiency.
1. Pernicious (addisonian) anaemia
2. Malabsorption syndromes
3. Tobacco amblyopia (hydroxocobalamin used)
4. Empirically in variety of neutological conditionsperipheral neuritis (esp. diabetic).
Note : As the daily Vit.B12 requirement is very small
nutritional deficiency is uncommon even among the
vegetarians in India. Majority of nutritional megaloblastic
anaemias observed in India are due to folic acid deficiency.
Folic acid (Pteroylmonoglutamic acid).
' One of the B group of vitamins.
Functions s
- By itself it is inactive.
— It is converted into biologicallysactive coenzyme
tetrahydrofolinic acid which is important in the
biosynthesis of aminoacids and nucleic acids.
Deficiency of folic acid leads to megaloblastic anaemia
probably because it is necessary for the production of purines
and pyrimidines which are essential precursors of DNA.
Sources and requirements Folic acid is widely distributed especially in green
vegetables yeast and liver. Daily requirement s about 50 mcg.
A diet containing 400 mcg. poly glutamates will provide this.
Body stores are adequate for several months only.
Indications : prevention and cure of the megaloblastic
anaemia due to deficiency at folic acid, s
1.
Dietary deficiency - more common in the economically
backward areas of the world.
2.
Malabsorption syndromes
Pregnancy — requirement of folate increases from
400 mcg/day to 800 mcg/day. Mild deficiency is
common with a few cases developing severe megaloblastic
anaemia. For this reason many now consider that
routine folic acid administration should be added
to routine iron administration. The dose needed is
about 300 mcg/day vigorous iron therapy in pregnancy
may unmask a folic acid deficiency.
In chronic haemolytic states folic acid requirement
is increased.
3.
4.
-7-
7
5.
Drug induced folate deficiency — anticonvulsants
like phenytoin primidone phenobarbitone,
antimalarials like pyrimethamine and urinary
antiseptics like nitrofurantoin cause folate
deficiency in the body.
Notes
1.
2.
If Vit.B12 is injected only the amount necessary for
the saturation of binding sites is retained. The
remaining excess is excreted in the urine. It is
calculated that 80-95% of a 50 mcg dose of injected
Vit.B12 is retained. As the dose exceeds 100 mcg
large proportions (50-98%) of the injected dose may
appear in the urine within 48 hrs. in healthy individuals.
Prolonged boiling of food during cooking destroys
practically most of the folatex in the food.
Liver Preparations
Crude liver extract owes its activity to the
presence of both Vit B12 and folic acid. Being a biological
product liver extract is not very stable, its effect is
less prompt and it is costly. The injection is painful and
can give rise to allergic reactions which could be severe.
Orally these preparations are not so effective and often
not palatable. Because of their lower efficiency and other
disadvantages, liver preparations are no more advocated in
the treatment of folic acid and Vit; B12 deficiency anaemia.
In fact liver preparations have become obsolete since folic
acid and Vit B12 are available in the pure form.
(
1 Shotgun1 antianaemia preparations
The use of antianaemic preparations containing multiple
ingredients like liver, iron, folic acid, Vit.B12 copper
cobalt and manganese must be deplored for various reasons.
Some of these ingredients are unnecessary, wasteful and
only increase the cost of therapy. Mixed therapy can also
cloud the clinical picture and may delay the accurate diagnosis
of the underlying disease. Thus a favourable response to
Vitamin B12 in a case of megalablastic anaemia secondary
to gastro intestinal pathology may foster false and thus
abscure the correct diagnosis. The danger of giving folic
acid with inadequate Vit. B12 in case of undiagnosed
pernicious anaemia is well known. Patients with pure iron
deficiency anaemia respond to simple iron administration and
an addition of Vitamin B 12 or folic acid is not justifiable.
Moreover, it should be noted that whenever a commercial
preparation contains multiple ingredients in a mixture
(combination) most of these ingredients are usually present
in inadequate amounts.
These 1 shotguns 1 formulations are promoted to
preserve the aged in health, for anaemia and as tornics. Both
their indiscriminate promotion by commercial interests and
their use by physicians in undiagnosed cases shows a
disregard for patients1 interests that is inconsiderate at
best and callous at worst.
-8-
*
b
8
References
1.
Goodman and Gilman's 'The Pharmacological Basis
of Therapeutics', 6th edition, 1980.
2.
Clinical Pharmacology by D.R.
Laurence, Sth edition.
1980.
3.
Pharmacology and Pharmacotherapeutics by
Satoskar and S.D. Bhandarkar, Sth edition,
i yo o •
/
*
HAEMATINICS
- Dr.Anita Srivastava.
Part II s Some clinical aspects
A.
Haematinics in children
■Irori s Since dietary iron in children rarely provides
sufficient replacement a supplement is required.
Oral therapy is always preferred unless the patient is
unable to tolerate it or the family is not considered
sufficiently dependable to administer the dose regularly.
The regular response of iron deficiency anaemia to adequate
amounts of iron is an important diagnostic as well as
therapeutic feature.
Oral Therapy
Oral administration of simple ferrous salts (sulfate,
gluconate, frumerate) provides inexpensive and satisfactory
therapy).
The recommended therapeutic dose is 4-6 mg./kg./day of
elemental iron given in three daily doses. Ferrous sytlfate is
probably the most effective and least expensive iron containing
drug. Since it consists of 20% elemental iron by weight the
usual daily dose is 30 mg./kg. Doses of elemental iron in excess
of 6 mg./kg/day do not result in a more rapid haematological
response. :Ingestion of large, amounts on milk may significantly
decrease absorption of iron^ > Intolerance to oral iron is
extremely rare, malabsorption of oral iron is more frequently
invoked than demonstrated.
While adequate iron medication is given the family must be
edudated about the patient’s diet and consumption of milk should
be limited to a reasonable quantity preferably 500 ml./day or less.
Folic acid deficiency
A dose of 1-5 mg. orally daily for 4-5 weeks is usually
adequate to replenish the body stores even in patients with
malabsorption. Patients with simple dietary deficiency can
usually stop therapy at this point, if they are on a proper diet,
while patients with malabsorption or increased need for folate
may require therapy indefinitely.
Vit B-12 deficiency
(a) Therapeutic trial ? f
* * mcg Vit.B 12 daily i.m.
Give 1-3
for 10 days. If the pt. is B12 deficient^, the response will b&
as follows ?
Within 24-48 hrs. the marrow will convert from megaloblastic
to normoblastic morphology. Reticulocytosis should appear within
3 days and peak around the fifth day. Haemaglobin should return
to normal level within 4-8 weeks.(Although folate deficient
patients may respond to very high doses of B 12 they will not
respond to this very low dose).
(b) Subsequently 100 mcg/day i.m. for 2 weeks should be
given to replenish body stores. Then 100-1000 mcg i.m. once
monthly for the rest of life or until underlying disorder is cured.
(c) Life threatening hypokatenia may occur during early
treatment and rerun K+ values should be carefully monitored.
(d) A rise in serum uric acid frequently accompanies the
necticulocyt 'Sis usually reaching its neck at about the fourth
day after the start of treatment. This may be prevented, by
allopurinol.
References? (1) Manual of Paediatric Therapeutics.Ed.John W.
Graef Thomas E ,Cone Jr. 2nd Edition. (2) Maison’s Textbook of
Paediatrics 12th edition.
-2-
2
(B)
Haematinics in Obstetries
-Dr.L.N. Chauhan
Anaemia may antedate conception. It is often aggravated
by pregnancy and the accidents of labour may perpetuate it.
The mean minimum accountable Hb level to the WHO is 11.0
gm/dl ( WHO 1972 ) .
Adopting 10 gm % of Hb the incidence of anaemia in India
ranges from 40-80%. In the developed countries the incidence
ranges from 10-20%. Anaemia accounts from 15 to 20 % of all
maternal deaths in this country mostly contributing to rather
than being directly responsible, for maternal deaths.
In pregnancy the demand for haematinics mostly Iron and
Folic Acid and less commonly Vit. B 12 is increased to meet the
needs of the expanding red cells mass (maximum) and requirements
of the developing fetus placenta and uterine hypertrophy.
I
■
i,
Iron
Total requirement of iron ranges from 700 to 1400 mg
during pregnancy. Overall requirement for iron is 4 mg/day
and 6.6 mg/day in last 4 weeks of pregnancy. This can be met only
by mobilising iron stores in addition to achieving maximum
absorption of diatery iron because a normal mixed diet supplies
about 14 mg of iron each day or which only 1-2 mg (5t15%) is
absorbed. Dietary iron would still not provide enough iron
for the needs of pregnancy purperium and the lactation for a
woman on a normal mixed diet. It would be still less in
vegetarian diet. Since many women enter pregnancy with
depleted stores. The commonest haematological problem in pregnancy
is anaemia resulting from iron deficiency.
!
Over the years there have been many studies which have
proved without doubt that iron supplements prevent the development
of anaemia and that even in skmem women on a good diet who are
not apparently anaemic at looking the mean Hb level can be
raised by oral iron therapy throughout pregnancy.
A reduction of Hb is preceded by a depletion of iron
stores. It is those women who enter- pregnancy in precarious
iron balance with normal Hb who present the most difficult
diagnostic problems.
I
The WHO recommended the supplements of 30-60 mg/day to those
pregnant women who have normal iron stores and 120-240 mg. with none.
Whether all pregnant women need iron is controversial, but if
it is accepted that iron is necessary a bewildering number of
preparations of varying expenses are available for use.
In those women to whom additional iron cannot be given by
the oral route either because of non compliance or because of
unacceptable side effects parenteral route can be used.
There is no haematological benefit in giving parenteral as
opposed to oral iron but the failure, rate of some women to take
oral preparations is high and the sole advantage is tht the
physician can be sure that they have relieved adequate supplementation.
The majority of women tolerate the chopper preparations with
no significant side effects and in the interests of economy
these should be tried first.
-3-
3
Folic Acid
Over and above pregnancy problem lactation provides an
added folate stress. A folate content of 5 mcg/100 ml. of human
milk and a yield of 400 to 500 ml daily implies a loss of
20 to 25 mcg folate daily in breast milk. The cause of
megaloblastic anaemia in pregnancy is nearly always folate
deficiency. Vita B.12 is onlji rafcely implicated.
Requirement according to WHO recommendations (1972) :
800 mcg during ante natal period
600 mgg during lactation period
400 mcg non pregnant adult.
«
j.
i
«
The incidence of megoloblastic anaemia in the developing
world is considerably greater and is thought to reflect the
nutritional standards of the population - to the poor socio
economic status of their patients. Food folates are only
partially available and the amount of folate supplied in the
diet is difficult to quantify.
The main point at issue over recent years however is
whether the apparently intrinsic folate deficiency of pregnancy
can predispose the mother to a wide variety of other obstetric
abnormalities and complications in particular
abortions,
fetal deformity, prematurity and ante partum haemorrhage. The
extensive literature would seem to be almost equally divided in
its opinion however a more recent report (Smithells et al 1980)
suggests that this supplementation may prevent neural tubal defects.
Folic acid should never be given without supplemental
iron. A wide variety of preparations supplying both iron and
folate are available and provided that the folate is not less than
100 mcg daily, all are satisfactory for prophylaxis in pregnancy.
Vitamin B12 : Pregnancy does not make a great impact on
maternal Vit. B12 stores. Addisonian pernicious anaemia does not
usually occur during the reproductive years. However severe
Vit. B 12 deficiency may be present without morphological
changes in haemopoietic and other tissues. Pregnancy in such
patients may be followed by death in utero or may proceed
uneventfully (Chanarian 1979). It may be associated with chronic
tropical sprue.
The megaloblastic anaemia which developes is due to long
standing Vit. B12 deficiency and super added folate deficiency.
The recommended intake of Vit B12 is 2.0 mcg/day in non pregnant
and 3.0 mcg/day during pregnancy (WHO 1972).
This will be met by almost any diet which contains animal
products. Strict vegans who will not ear any animal derived
substances may have a deficient intake of Vit B12 and their
diet should, be supplemented during pregnancy.
•i
b
I
Part
~~ Preparation of _cornmenly use Ct Hae mat in ic s
Sr.
No.
Compound (Name)
formulation
1.
Akt ivakid
Syrap (Each
5 ml.
contains)
Liver fraction
Ferric glycerophosph
Ye art Extract
Lysine mono-HCL
Vit B-12
125 mg
60 mg
Capaules
(Each cap.
contains)
Ferrous Fumerate
Folic Acid
Vit.B-1 2
Cal. Carbonate
Vit .D
Vit C
560 mg
1 -5 mg
1 5 mcg
200 mg
400 IU
Ferrous Numerate
Vit.B-1
Vit.B-6
Niac inamide
Folic acid
Vit B 12
Vit C
500 mg
5
1.5 mg
2.
3.
4.
Anemadox
Numasules
l\ori—A
Capsules
(Each cap.
contains)
Tab lets (Each
Ihgrec iants and their quantity
Ferrous Fumerate
Company
Or o Raj u 1 De s a i T;x. D. (fharamac ology )
Dr. Sagun Desai M.D. (Fharmacology)
Cost.
Bs.
Bose
German
Remedies
10.12/
100 ml
5H5 ml. thrice daily
before or after meals
Kferck
11-31/
28 Cap.
1 Cap. daily
Pf izer
29.52/
15 mg
25 mg
1 .0 mg
75 mg
100
2 Cap. daily, 1 each
softer breakfast and
Dinner
18.69/500
Adults & Children Over
12 yers.: 1 Tab.thrice
daily and children
6.12 yrs. i tab.thrice
daily after food.
50 ng
0.75 mg
7.5 mcg
75 mg
200 mg
Wellcome
....2.
1
2
Sr.
No.
5.
6.
7.
8.
9.
Compound (Kame)
Eisocal
1'efol Spansules
Folvron—F
Ferradd
Fesovit
Formulation
ihgrediants and their quantity
Company
Cost
Cose
----- I'ferl_____
Tablets (each
tab.contains)
Iron Calc. Complex
550-mg
Cipla
Vit-A
1000 iu
Vit D-2
200 IN
Vit.B-1
1 mg
Vit.B-2
0.5 ng
Vit.B-6
0.5 mg
Vit.B-12
1 mcg
Vit C.
25 mg
Niacinamide
7.5 mg
Folic acid
0.5 mg'
Copper Citrate
0.1 mg
Molybelenum trioxide
0.05 ng
__ ____ ?^£±.citrate_~
____21.25J3E___
6.47/30
1 to 2 tabethrice
daily preferably
after meals.
^skay Lab.
8.47/15
1 Cap. daily through
out pregnancy &
lactation
Gel. Capsules
(each cap.
contains)
Dried Ferrous Sulphate
1 50 mg
-Folic acid
0.5 mg
Capsules
(Each cap.
contains)
Folic acid
1.7 mg
Ferrous Fume rate
1 94 mg
(64 mg. of metallic iron)
Cyanamid
4.25/30
5 capsules daily
Liquid
(each 5 ml.
contains)
Vit.A
2500 IN
Vit.D-5
200 IN
Vit.B-l
1_
Vit.B-2
-J
Iron and ammonium citrate 45 ng
Nicotinamide
15
Parke Davis
45.47/
Adults: 10 ml.
thrice daily
Child.: 2.5 ml.,1.5 ml
thrice daily
Capsules
(Each cap.
Vit.c
Vit.B-2
Vit.B-l
Nicot inamide
Vit.B-6
Pantothenic acid
rrous sulph.
Eskay Lab.
8.47/15
1-2 Cap. daily
Children 1 cap.
daily.
50 mg
2 mg
2 mg
15 mg
1 mg
2.5 mg
__1_50_mg
...5.
%
3
Sr •
Nq^
Compound. ( Name)
_
10.
Folinate
B-12
Formulat ion
(a) Capsules
(each cap.
contains)
„
12.
Hematrine
Heptaglobin
Company
Cost
___ ___________
Ferrous Numerate
Folic Acid
Vit.B-12
Ale mb ic
21 .58/100
250 mg
2.5 mg
0.25
______ 21L-C ___ _ ___
(b) Liquid (each
10 ml.
contains)
11.
Ingredients and. their quantity
Ferrous '.Numerate
Folic acid
Vit B-12
250 mg
4.0 ng
50 mg
Ferrous succinate
Succinic acid
Folic acid
Vit.C
Vit.B-12
------------------------- ^Sicot inamide__ _ _
Liquid (each
Proteolysed liver
15 ml.
Qxyhae moglob in
contains)
fbptene
Iron & Ammon.Citrate
Nicotinic Acid
Vit.B-12
Capsules(each
cap.contains)
1 00 ng
Sandoz
110 mg
0.5 mg
25 mg
2.5 mcg
------ li^mg_____________
1.2 mg
Raptakos
250 ng
750 mg
200 mg
Dosc1 Ca,p. daily
”15.(77
450 ml.
Adults: 10 mi.daily '
Child.: 1.25 ml-2.5 ml/
d-ay
Z^lSl^l^mltdail^r
112.36/
1 Cap.thrice daily
or as required.
19.12/
300 ml.
1 5 ml.two or three
times daily
28.33/100
One Cap. daily
8.22/110 ml.
5“1 0 ml. daily
3
6 mcg
___ ml.______
__ __ _
13.
Idoglobin
(a<) Capsules
(each can,
contains;
Ferrous Fumerate
Vit.B-12
Vit.B-2
Vit.B-1
Folic acid
Nicot inamide
_.JLit,.£
(b) Liquid (each
5 ml.
contains)
Vit .B-l
Nicotinamide
Folic acid.
Vit.B-12
Ferric ammon.citrate
Vit.B-2
300 mg
IDPL
1 0 mcg
2 mg
1 0 mg
2 mg
25 ng
75 mg______
5 mg
10 mg
0.5 ng
5 mcg
225 ng
2.74 mg
...4.
Sr.
Do.
Compound (name)
u.
Iberol
15.
Livibran
Formulation
(a)Film tablets
(each. tab.
contains)
Ingrediants and their quantity
Company
&
Bose
Ferrous sulphate
Vit.B-1 2
Liver desiccated
Vit.C
Folic acid
Vit.B-1
Vit.B-2
Nicolinamide
Vit .B-6
Abbot
18.36/100
1-2 tab.daily
525 mg
12.5 mcg
1 00 mg
75 mg
1 mg
3 mg
3 mg
15
1 <>5 mg
Cal t Pant ot he nate
(b)Liquid (each
5 ml.
contains )
Ferrous sulph.
Vit.C
Vit.B-1 2
Vit.B-1
Vit. B-2
Nicot inamide
Vit.B-6
Jhnthenol
Alcohol
_
(c) Iberol-500
Liquid (each
5 ml.contains)
Ferrous Sulphate
131 mg
Vit. C
125 ng
Vit.B-12
6.25 mcg
Vit.B-1
1 .5 mg
Vit. B-2
1.5 mg
Ficot inamide
7.5 ng
Vit.B-6
1.25 mg
J^.nthe nol
2.5 mg
Alcohol
_____ 22.5.ml_
Abbot
14*94/24O ml. 10 ml.twice daily
Elixir (each
10 ml.contains)
Liver concentrate
Vit.B-1
Vit .B-2
V it o B—12
Ferrous Sulphate
Mang.Citrate Soluble
Alcohol (12$ V/U)
Parke-Davis
10.05/
228 ml.
131 mg
Abbot
37.5 mg
'6.25 mcg
1 *5 mg
1 .5 mg
7.5 mg
1.25 mg
2.5 mg
_____ O.£jnl.________
116.25 ng
2.5 mg
8.00/240 ml
2.5 mg
5 mcg
273.74 mg
5.7 ng
1.25 ml.
...5.
10 ml.twice daily
10 ml.before food,
twice daily
5 mg
5
Sr.
No.
Compound (name)
16.
Livoge n
Capsules(each
cap.contains J
17.
Sangobion
Capsules
(each cap.
contains)
Ferrous Glucc
Mang.Sulph.
Copper Sulph.
Vit C
Vit.B-12
Folic acid
Sorbitol
Elixir (each
15 ml.
contains)
Cal. Glycerophos.
110 mg.
S od. Gly ce ro. Hio s •
80 mg.
Pot. Gly ce ro. pho s.
20 ng
Mang. Glycerophos.
10 ng
Ferric ammonium Cit
46.5 mg
Vit B-1
2.0 ng
Vit.B-2
1 .0 mg
Vit.B-6
5 mg
Niacinamide
15 mg
Cal. Pant he no 1
1 mg
Vit.B-12
____mcg
_
15
Alcohol(l1$ by volume) 1.7 ml.
18.
Formulat ion
Jhosfomin Iron
Ingrediants and their quantity
Company
Cost.
(Rs.)
Liver concentrate Powder 0.1 mg Allenburys
Dried Yeast
25 ng
Vit.B-1
5 mg
Vit.B-2
5 ng
Nicot inamide
45 mg
Cal.Pant othe nat e
5 ng
Folic Acid
1.5 ng
Vit.B 6
1.5 9g
Vit.B-12
10 mcg
Vit. B
75 mg
____ £errqus_Furnerate_________ _______________
250 ng
0.1 55 mg
0.2
Merck
10.26/30
1 Cap.daily
after meals
9.61/30
Initially 2 cap.thrice
daily after meals,
followed by 1 cap.
thrice daily.
15.57/
480 ml.
15 ml.thrice daily
or as required.
mg
50 mg
7.5 mcg
1 mg
,____25_mg________
Sarabhai
Dose
...6.
6
Sr.
Compound (name)
No.__
19.
Formulat ion
(a) Syrup (each
5 ml.
contains)
Tonoferon
(b) Props (each
1 ml.con
tains)
20.
Capsules (each
cap.contains)
Siderfol
Ihgrediants and their quantity
Company
East India
Colloidal Ferric Hydrox. 500 mg
Folic acid
1.75 mg
Vit B-12
7 mcg
Ethyl Alcohol(V/V)
_____
Colloidal Ferric Hyd.
50 mg
200 ng
East India
L-Lys ine mono-hd
1 0 mcg
Vit.B-1 2
Folic Acid
5 mg
Ferrous Fume rate
Vit.C
Folic Acid
5 00 mg
100 ng
5 mg;
Raplakes
Cost (Rs.)
Pose
22.00/
450 ml.
2.5 - 7.5 ml.
twice daily
5.42/15 ml
5 .r, 1 P drops with
m ilk 91 wo -three
times daily
Ethyl-Alaohciltv/V.
-------1 cap. daily after
11o85/50
meals or more
as neededo
_Mit^B±L2
21 .
Rubragan H.P.
Capsules(each
cap. contains )
22.
Rubraplox
Elixir (each
5 ml.contains)
25.
Rub rat one
Elixir (each
5 ml.contains)
Source:
Note s
One Cap.twice daily
Sarabhai
Ferrous Fume rate
500 ng
5.26/14
Vit.C
100 mg
Vit.B-6
10 ng
Folic Acid
2.5 mg
^Vit^B^L^__________________ 50_mcg____________
15.99/480 ml. 5 - 10^1.thrice
Elemental iron as ferric
Sarabhai
daily
58 mg
-■ amm.cit.& colloidal I
Vit.B-1
1 mg
1 mg
Vit.B-2
Niacinamide
5 mg
Vit.B-1 2
4 mcg
Vit.B-6
0.5
P-pantheno1
1.5 mg
____ 1_2_%____
Alcohol
Fe rr ic amm. C it.
Vit.B-12
Folic ax id
Aqcqhol________
220 mg
Sarabhai
4.17 mcg
0.28 mg
_____ 12j>______
15.69/480 ml
MP'E India, February, 1985
The above formulations are simply presented without comments.
You are requested to interprete them in the lifht of Scientific Notes.
10 mle thrice daily
LOCOS'
•«
F. O. Box No.
Baroda = 390 001.
Tel. No; 58481
DR
BRIEF NOTE ON ANALGESICS (PAIN KILLERS)
- Or.Arun Bal.
i
Introduction
Pain is probably the most fundamental and primitive sensation.
is distributed more or less all over the body. Analgesics (pain
killers) have a unique place in the medical therapy, this is on
account of the fact that these drugs are most essential to relieve the
sufferings but are being very commonly over used and over prescribed.
These drugs are divided into two major groups - Narcotic and Non
narcotic. Use of Analgesics in clinical practice requires
understanding of basic physiology of pain. Much of the over use and
over prescription of Analgesics occurs due to the lack of understanding
of basic physiology. Every analgesic drug relieves a specific type
of pain. Hence random use of any analgesic drug may not bring about
the desired effect.
It would be WDDthwhile to briefly outline the few salient
features of physiology of pain.
Physiology of pain
Pain is subserved by naked nerve endings consisting mostly of
non modulated fibres which terminate in the superficial layers of
Dermis. Bare nerve endings are also present in the serous surfaces
of viscera and cornea. Most of the pain impulses arising in the skil
travel to the central nervous system with Souratic nerves but some
oi those from deeper structures join autonomic nerves. All enter
Central Nervous System by the Lateral divisions of posterior nerve
roots, or by the cranial nerves. Broadly there are three varieties
of pam. These are (1 ) superficial pain (2) deep pain (3) visceral pain.
The pain endings
do not respond selectively to one variety
of stimulus but to any type whether mechanical, chemical, thermal,
provided it is sufficiently intense. The pain stimulus whatever it
may be, has one property in common, namely, that it is of a nature e
to cause injury. Sensation of pain serves a protective purpose oiving
warning of injurious stimuli.
H
yxvxuy
A distinction should be drawn between the perception of pain and
the reaction which results. Pain threshold is the level of intensity
of stimulus necessary to produce pain. This threshold may vary from
person to person. It may alter due to the local inflamation in the
area of nerve endings. It seems that thresholds to sensation on
the surface of the body do not vary greatly in different patients but
these patients have widely different.levels of reactivity. In other
words, the patient who appears to feel pain easily has probably the
same pain^threshold as ’normal* but reacts to it at a much lower
level of intensity. Any meaningful discussion of the actions of
analgesic agents must include some distinction between pain as a
specific sensation subserved by distinct neurophysiological structures
and pain as suffering with major emphasis on psychological aspect.
A patient s ability to tolerate the pain may be marked by increased
sensation even when the capacity to perceive the sensation is
relatively unaltered. Patient’s pain threshold plays important oart in
the treatment and selection of drugs.
(A)
We shall briefly consider the analgesic drugs now.
Narcotic Analgesics
This group include opioids 9 opioid antagonists and related
analgesics.
-2-
2
1*
Morphine : Opium is obtained from the milky exudate of the
incised unripe seed capsules of the poppy plant (papaver somniferum).
The milky juice is dried in the air and forms a brownish gummy
mass. This is further dried and powdered to make the official powdered
opium containing well over score of alkaloids. Only a few Morphine,
Codeine, popavarine-have clinical usefulness. The alkaloids
constitute about 25% by weight of opium. They can be divided into two
distinct chemical classes — Phenanthrenes and benzylisoquinolines,
which contrast sharply in their pharmacological properties (table no.1).
Pharmacological properties
There is ample evidence that opioids interact with more than
one neurotransmitter either directly or indirectly. Since the
opioids have multiple effects on the CNS, it is quite possible that
a given neurotransmitter may play a more critical role in one
effect (e.g. Analgesis) than it does in another (e.g. stimulation of
locomotor activity). In man opioid induced euphoria and analgesia
are enhanced by simultaneous administration of amphetamines
suggesting at least an additive role for norepinephrine and dopamine.
Morphine produces analgesia, drowsiness, changes in mood and
mental clouding. Analgesia occurs without loss of consciousness.
If morphine is given to a normal, pain free individual it sometimes
causes dysphoria. It also causes mental clouding characterised by
drowsiness, inability to concentrate, difficulty in mentation,
apathy, lessened physical activity, reduced visual activity and
lethargy.
The relief of pain by morphine and related compounds is
relatively selective. In therapeutic doses of morphine the painful
stimulus itself may be recognised but it mpy not be perceived as
painful. Continuous dull pain is more relieved than sharp acute pain.
Morphine related drugs neither alter the threshold or responsivity
of nerve endings to noxious stimulation nor impair the conduction of
the nerve impulse along peripheral nerves. It causes release of
anti diuretic hormone (AOK) and h thereby decrease urinary output.
It ilso suppresses release of FSH, LH, TSH. With therapeutic doses
moderate increase in blood sugar level may occur. EEG shows a shift
towards increased voltage and lower frequencies. Single dose of
Morphine suppresses the REM or naradoxical sleep. It causes miosis,
whidh is errs counteracted by atropine. It causes primary and
continuous depression of respiration. In man death following morophine
poisoning is always due to respiratory failure. Maximum respiratory
depression occurs within seven minutes after i.v. administration,
30 min. after i.m. and 90 min. following subcutaneous administration.
In addition to a marked depression of automatic regulations of
respiration, voluntary control of respiration may also be altered.
This may account in part for its s usefulness in pulmanory oedema.
Therapeutic doses of morphine causes dilation of cutaneous blood
vessels. These changes in skin are due to the release of Histaurine
and are partly responsible for the pruritis and sweating that
commonly follows administration of morphine.
Adverse Reactions s The development of tolerance and physical
dependence with repeated use is a characteristic feature of all
opioid drugs. This is a major limitation of their clinical use.
Morphine causes psychological dependence. It causes increase in
Biliary tract pressure, constipation, increase in tone of uretenic
muscles. Morphine effects may be exaggerated oy phenothiazines,
monoamine oxidase inhibitors, tricylic anti-depressant, Some but not
all phenothiazines reduce the amount of narcotic required for the
analgesic effect. Some phenothiazine derivatives enhance the
sedative effects but at the same time seem to be anti analgesic and
increase the amount of narcotic required to produce satisfactory
relief from pain.
i
- 3 -
Preparations
Opium USP is a light brown-powder supplied for chemical use in
capsule taolet or pill form. Official content of morphine in the
opium powder.is 10.0 - 10*5% by weight opium tincture is a
hydroalcoholic solution containing 10% of morphine. Average dose is
0.6 - 1.5 ml.(equivalent to 6-15 mgs. of morphine). Paregoric is
comphorated opium tincture in hydroalcoholic preparation in which there
is also benzoic acid (amphor and a nise oil. The usual dose is 5-10 ml.
(2-4 mgs of morphine. Morphine is available as alkaloidal base but is
prescribed only m-the form of its water soluble salts. Two common
salts.are morphine sulphate USP and morphine hydrochloride. Salts
are bitter, white powders that are quite soluble in water. Solutions
. of morphine saits are not irritating on injections. Morphine
sulphate injection USP is a sterile aqueous solution for oaranteral
use and usually contains 8,10,15, 30 mgs/ml. Hypodermically 10 mgs/
70 kg. of body wt. is generally considered as optimal initial dose.
It provides satisfactory analgesia to 70 % of patients with moderate
to.severe pain. It can be given i.v. to control severe post-operative
pain, as pre medication, in minor surgical procedures, severe renal
colic, pulmanory oedema. The usual i.v. dose is 4 mgs - 10 mgs.. The
analgesic effect,starts immediately and reaches peak in 20 minutes.
The maximum respiratory depression is seen within 10 minutes.
2.
Codeine
It is available as free alkaloidal base and in form of water
soluble salts. Most common salts are codeine sulphate and codeine
phosphate The tablet contains 15, 30,60 mgs. of the drug. Injection
contains 15,30,60 mgs/ml. of the salts. Also available is codeine
elixir used for cough and containing 10 gms. in 5 ml. dose. Codeine
has high oral parentaral ratio. Orally a dose of 32 mgs of codeine is
equivalent to 325 mgs to 600 mgs of aspirin. When these two drugs are
combined the analgesic effect equals that of 65 mgs of codeine.
•
.Apomoraphine
It is obtained by treating morphine molecule with strong mineral
acid. It produces stimulation of medgllary UTZ and excitation. Itsix
primary therapeutic effect is production of emesis. Usual dose is
0.1 mg/kg. given subcutaneously. Vomiting occurs within few minutes,
it also causes respiratory depression.
4>
Etomorphine hydrochi oride
It is an analogue of the pain used exclusively for immobalisinq
arge animals. In man it is 400 times more potent than morphine.
Therapeutic Uses
(a) Pain of Terminal Illness (b) post operative pain (c) obstetrical
analgesia,(d),sedation + analgesia (e) cough (f) pulmonary oedema
(g; constipating effect (h) special anesthesia for minor surgical
procedures. In the case of terminally ill patient the main object is
to keep the patient confortable and without pain. Oral marcotic drugs
should be used with non narcotic sedatives to start with. The dose
should be gradually increased but should be sufficient to relieve the
pam. No patient should even wish for death because of his physician’s
reluctance to use adequate amount of effective narcotics.
5•
Pjsth-1dine (Meperidine and conqeners)
It is a synthetic analgesic drug introduced in 1939. Its
actions,are quite similar to morphine so also its therapeutic uses
except in case of coygh and constipating effect. Available for
oral use as tablet (50 - 100 mgs) and as elixir containing 50 mgs/
b ml. It is also available as injections 2 ml» ampules containing
50 mgs/ ml.
-zp.
- 4 6.
Methadone.
Synthesised by German demists it came into clinic 1
at the end of World Wor tt Chemists it c.
rnw clinical use
Pharmacological
1^910!1 properties are similar
to morphine. It is primarilyPuserin
j
arily US
syndrome and in the treatment
ofed in treatment of narcotic abstinance
-heroin users.
7.
-Propoxyphene
Th’d°“- “18 -««»"
by aspirin. Its 00mbinatl
18 n°t adequately relieved
abuse liability of propoxvohono CSp™ucan be effective. The
It is available in
SOn,ewhat
than codeine.
8*
Pentazocine (Fortwin)
form or teaietrmd^njtotions^It’is154' ’‘o’ o''allable In the
It has been proved te tave a”Ute’‘etenSeT^i1' U"d 88 ’"’^o.
similar to morphine.
:
Its actions La cnd '>an cause dependence
its analgesic effect has a short time JpaJ^
"’^Phine. However
(3)
Non Narcotic Analgesic^
1.
Salicylates
antipyretic
glycoside called
it can only be used (
are used for systemic
osuiX:1,”)
Phorma^oloaical. properties
are tL^oJ^intlSiV^aXurT16 t0
myalgia, arthralgia, Xr’pSn ^^ structures rathe? than from visc^a
by
^™31316 are he^ache,
h” lnte9umental
to dependence and addiction Thn° \
chronic u_
use does not lead
peripheral as well as central or+5rG11IV®.pain by virtue of
synthesis of prostaalandin
°?* Sallcylates inhibit the
sensatization o? So
10 the inflammed tissues r
preventing
chemicals such as bradykininTlS^iu ™Jchanicaf stimulation
------ or to
hypothalamus. (2) AntiovresiZ
central action is
antipyretic effect is usually rapid^d^f '°'T
temp?I’ature« Its
out is rarely demonstrable in normal op-tq iect^e in fertile patients
’thermostat* for normal fomn
41.Persons. It acts to reset the
It stimulates respiratioS dirert?6 lr\hypotholamus
Respiration acid base imbalance. It dlr^X
It can cause
centre. (4) Acid base balX
K°7edUllarz respiratory
definite changes in acid base balanrP
?°Se °f salicy1ates produce
Initially it causes r?sni- nX
and electr°lyte pattern,
quickly. (5) Effect oTbilod^
Wh?bi?. compensated
Of bleeding time. A single dose of 0 ?|USeS deIinite prolongation
doubles the mean bleeding time of norntl9"15* °f aspirin approximately
4-7 days. It changes platent nrih
rmal Person for the period of
increases urinararv
+
4.^icosuric
effect - It
urinarary excretion
—n of Ureates.(7) Anti inflammatory action.
Salicylates c-----vomiting, epigastric
-It increases
increases bleeding time and
should be used with caution cells.
in
O=n ™.. toxicity „a;"o “v
i? ^dLidualc. High doses 4
tors, mental oo„flsio“ s„Xt?2
‘"’‘J9 *" ths
severe acid bas@ imbalance.
ssltude’ vomiting. It causes
-5-
5 Therapeutic usesj
(l) Analgesia (2) Antipyretic - dose is xusually 300 mgs lgm/4 hr. (3) Anti Rheumatic fever — dose. Adult 5—8 gms/day.
Children - 100-125 mgm/dav. (4) Rheumatoid Arthritis
(5) Venous Thrombosis. (6) Localise as Kertatolytic,
Preparations,
(a) Sodium Solicylate — is a white, wotex soluble powder with
sweet saline taste. Tablets contain 300-600 mgs. (b) Aspvin USP is a
white powder. It is available as tablet capsules and suppositories,
(c) Methyl Solicylate USP is a colourless liquid having characteristic
odour and taste of Wintergreen • It is only used as cutaneous
counter irritant in ligaments.(d) Salicylic acid USP is a white powder.
Its use is reserved for local application as a Keratolytic agent.
Route of administration is almost always oral. The usual dos@
varies between 300 mgs — 1 gm./4 hr. Rectal administration may be
necessary infants. Time release preparations are of limited value,
since the half time for elimination of salicylates is long. .Absorption
from enteric coated tablet is somewhat incomplete.
!
2•
.PJ?^nylbutazones and Oxyphenbutazone
It is congenor of antipyrine and aminopyrone introduced in
1949. It is effective anti inflammatory drug but toxicity precludes
its long term therapy. It inhibits synthesis of prostaglandins. Its
analgesic effect is inferior to salicylates. It is poorly tolerated
by many patients. Approximately 40% pts. show some side effects.
Nausea,7 vomiting, epigastric
discomfort,
skin
rashes dr©
are mo
mos4 common.
v-*m v. uun ux u f
Xi 1 xubiies
Peptic ulcer hyper sensitivity reaction of serious
sickness
- - — 7— ----- j typ e,
ulcerative stomatitis, agranulocytosis are some of the more serious
side effects. Its use is only justified in gout and Rheumatoid
Arthritis and that too under*close
medical supervision, it dass
-- ---------------If dose of 400-600 mgs/day for 7 days does not produce improvement then
the drug should be discontinued.
I
’
** **
3.
I
<
Indomethacin
It was a product of laboratory search for anti inflammatory drug.
It has anti pyretic action also. It was introduced in 1963. It is
more potent than aspirin but anti inflammatory effects of tolerated
doses are not superior to aspirin. Approximately 50% pts. receiving
the drug develop side effects. These consists of nausea, vomiting,
abdominal pains, peptic ulcor, severe frontal headache, dizziness,
vertigo, mental confusion. It should not be used in children,
pregnant women, persons operating machinery or patients with psychiatric
disorders. Its use as anti inflammatory drug is justified only in
cases where aspirin has proved ineffective. The dose is 25 mgs. twice
daily. It is gradually increased until total daily dose is 100-150 mgs,
4.
Ibuprofen
It is a phenycpropionic acid derivatives and is in clinical
use since 1960. Its anti inflammatory effect in recommended doses is
inferior to aspirin. It causes fewer gastrointestinal distress than
aspirin. Recommended dose for Rheumatoid Arthritis is 900-1600
mgs/day. -t The drug is expensive.
5,
Acetaminophen (Paracetamol)
It was first used in 1953. Its antipyretic and anolgesic effects
are similar to those of aspirin. It has weak anti inflammatory
action. It relieves pain of moderate intensity. Intense pain and pain
of visceral origin is not relieved. It reduces fever by direct action
on the heat regulating centre. In recommended doses it is quite well
tolerated. The most serious adverse effect of acute overdosage of
acetaminophen is dose dependent, potentially fatal hepatic necrosis.
)
i
6
In adults hepatic necrosis may occur after
a single dose of 10-15 gm (200
/Iadministration of
or more is potentiallv
£"250 m9s/Jr-?-)) A dose of 25 gms
purely symptomatic ConventTfeatment of overdosage is
325-650
exe^JXT fral ^herapeatic d^se is
f
It Should, not be given f;r
nOt exceed 2-6 gms.
substitute for aspirin, sllf medical
±S Stable
is not advised. If routine doses aS
* period of days
are unlikely to give relief.
ineffective higher dose
6.
I-
Phenacetin
I
causes Haemoly tic Anuria ^mif0 parfcetainol«
It additionally
used in combination with\^htha^mOglo^lnemia* It is sometimes
single dose 15-30 mgs. Total^of^Iho^f^^b fOrm* Average^
1- use is limlted gs its - £se should^^eed^.
7O
Arninopyrine (Amidopyrine)
i
aaalgesic, antropyretic^nd^tiinf 1^ 33 antipyretlc- It shows
similar to those of salicylates laflaran1atory Properties
limited
due
- --J tO fatal
"Se/S
20—25%. it should
•—d not be ordinarH Kr
i
-al^ty rate is
ItS USe with
chlorpromazine can cause seriouf bLnS
indicated, It is Withdrawn from cliSical^se
13 contraand is most controversial analgesic at prSsent"
Countries '
8.
Mefanamic acid ,J<etroprofen. Naproxen
Have limited value as long term, effective
should not be used primarily.
analgesics. They
Analgesic combinatjons
and mixtures
antipyretic, SucS^^codSne'^Sn^asSi
^10^ and ’an analgeaicof an 0
opioid
analgesic medication. Codeine
65 X
has a valid role in
Codeine 65
r -pirin
significantly to the analgesic
offer?
3*-FhaS been found to add
analgesic
most of the clinical tr-i
V
. effect
. ^ect of aspirin 65 0 mgs. in
trials relief < ~
mixture hue not bS Sperlor^rthtt
“ analgesic
r
superior to that of
S?
Of caffeine
c~ ' aS?lrin al°nO- It is
- ---- ' employed with the ergot
is 100 mgs and that
JsafoSyei6O6s“tS °£ S
^SJte ofa.f£^I’e-' yet the
analgesic
mixture
analgella 1E
vji"'
SnhanceJ
:Xlo:i^^ofeet^^L1o'sm^sar51rheSF
concurrently with an opioid AnalgesiciS administered
as analgesia is desired, It is fit
* Sedation as wel1
administration of a
£
' 4^.
Comments
available to^meaiJal’nr-CH t™8 analgesic preparations
sedative fixtures (Tablf
inC1Ude m“S' “H"*:
containing multiple druos
°f PreParation
be hazardous due to dangerous"'-id-f^iue and. moreover can
doses.
The eco^lc
i
7
?f theAcomblnatlori drugs are costly and have no added
Aspirin which is cheapest, safest and equally
anslgesic effect. It may be used with a dedative
administered separately rather than fixed dose combination
^aracetamo! can be used as alternative in case of aspirin
intolerance. The principle of Benefit Risk ratio should be
foremost in mind of a medical practitioner before
tionl^ailaMc ^na^esic Preparation. Many of the combina
tions _ available m the market are plainly dangerous and
Shich^is known°^S Combin"tion like Analgin and Chlorpromazine
b2hh
toown to cause fatal hypothermia,. Also the quality
of drugs is so variable that only advantage
‘
<2uaj-lty
for the manufacturers. Such ’cocktails’ for can be commercial
pain relief should
ko discarded from the clinical practice.
Table No,1
s
Alkaloids of
Class
Natural Alkaloid
Phenanthrene
Morphine
Codeine
Thebaine
Benzylisoquinoline
Papavarine
Noscapine
Table No,2
Brand Name
2
Beserol
Betatom
Codolsiv
Corbutyl
Dolopar
Dolopar Plus
Equagesic
Fortagesic
Malidens
Opium
Contents
Paracetamol 450 mgs.
Chlormezanone 100 mg.
Paracetamol 400 mgs.
Dextropropoxyphene 65 :mgs.
Oxyphenbutazone 100 mgs.
Drazepain 2 mgs.
Percentage in opium
10-0
0-5
0-2
1-0
6-0
Action
Analgesic + sedative
Analgesic -b sedative
Anti inflammatory
Hypnotic
tranquiliser.
Analgin 500 mgs.
Analgesic
Clidinium bromide 2-5 mgs. sedative
Dizepam
2.5 mgs.
Hypnotic
Dextropropoxyphene 65 mgs Sedative
Paracetamol 650 mgs.
Analgesic
Analgin 250 mgs.
Analgesic
Paracetamol 250 mgs.
Analgesic
Carreine 25 mgs.
Sedative
Dextropropoxyphene 65 :mgs Sedative
Acetaminophen 400 mgs.
Analgesic
Diagepaur 2 mgs.
Hyphotic
Etho^eptazine citriate
75 mgs
Sedative
Mecropecurate 150 mgs
Anxiolytic
Acetyl solicylic acid
25 mgs.
Analgesic
Paracetamol 500 mgs
Analgesic
Pentazocine 15 mgs.
Sedative
Paracetamol 250 mgs*
Analgesic
Solicylamide 250 mgs.
Analgesic
Caffeine 25 mgs.
-8-
I
8
Neogine
Paracetamol 250 mgs.
Analgin 200 mgs.
Chlorpromazine 7.5 imgs
Codeine 7.5 mgs.
Ssidsixx Caffeine 30 mgs.
Analgesic
Analgesic
Sedative
Sedative
Optalidon
Butalbital 50 mgs.
Accetylsalicylic acid
200 mgs
Paracetamol 200 mgs.
Caffeine 40 mgs.
.Analgin 500 mgs.
Diazepam 5 mgs.
Sedative
Pamagin
Proxyvon
Dextropropoxephene 65 mgs
Diozepam 2 mgs.
Ralcidin
Paracetamol 300 mgs.
Caffeine 16 mgs.
Chlorphenaramine
meleate
1.5 mgs.
Phrylephrine 1.5 mgs.
Noscapine & 15 mgs.
Acetylsolicylic acid
300 mgs.
Caffeine 30 mgs.
Chlorpheneramine 2 mgs.
Tuxyne
Analgesic
Analgesic
Analgesic
Hypnotic
Sedatius
Hypnotic
Analgesic
Antihistamon
-doSedative
Analgesic
Antihistaminic.
References
1.
Goodman and Gilman
The Pharmacological basis of Therapeutics.
2.
Best & Taylor
The Physiological basis of Medical Practice
3.
The Principle and Practice of Medicine by Davidson.
4.
Monthly index of Medical Specialities Vol. 4, No. 9.
r'
16; l<3
ASPECT OF MANAGEMENT OF PAIN
(With Particular reference to Analgin)
By Dr. Arun Bal & Dr* Anil Pilgaonkar
As with many aspects of medicine, the history of pain and
its management is shrouded in the mists of time* In ancient
China, about 2000 B.C., Shen Nury compiled a medical herbal, with
reference to use of wine for surgery* In the reign of Yu Hsing
acupuncture and "distraction" during surgery were described in
detail* Less accurate, but numerous references are made to the
use of herbs and poppy in ancient Egypt, Rome and Greece* The
Incas and ancients of Peru used concoctions containing hyoscine,
stropine opium,cocaine, mescaline and psilocypin.
Despite the great advances made in the period 585 B.C* to
200
the works of neither Hipprocrates nor Galen discuss pain
and pain management to any degree* The scientific approach, to
pain and its management was born during the renaissance and deve
loped slowly until mid-nineteenth century, when progress was rapid
on three fronts - administration of opiates and hypnotics,
inhalation of analgesic and anesthetic gases and administration
of local anesthetic agents by a variety of techniques*
Pain has been defined as "an unpleasant sensory and emo
tional experience associated with actual or potential tissue damage
or described in terms of such damage* There has been major advan
tages in understandings of pain physiology over the last 10 years.
The pain may be relieved by (a) reducing sensory inputs from the
damaged tissue (b) modulating transmission through central nervous
systems (c) altering emotional responses to such actual or per
ceived inpats* The Malzack and Wall "gate theory of pain" stimu
lated explosion of research into pain mechanism. The recent
restatement of the theory summarizes present concepts s
1)
Information about the presence of injury is transmitted to
the CON.S# by peripheral nerves-. Certain small diameter fibres
(A-delta
C; respond only to injury, whereas others with lower
thresholds increase their discharge- frequency if stimulations
reaches noxious levels*
2)
Cells in the spinal cord or 5th nerve nucleus which are
excited by these injury signals are also facilitated or inhibited
by other peripheral nerve fibres-, which carry''information about
innocuous events.
3)
Descending control systems originating in the brain,
modulate the excitability of the cell which transmits information
about injury.
The theory emphasized that perception of noxious stimuti
(and pain) depends not only on peripheral stimulation and trans
mission but also, on modulation occuring in the spinal cord and.
higher structures. Pain (and pain control) must be considered in
terms of both afferent pain pathways and descending pathways which
modify sensory message.
Treatment and management of pain requires adequate knowledge
of physiology of pain. Newer analgesics are being introduced in
the market as the understandings of the pain physiology and neuro
pharmacology improves. WHO's List of essential drugs, list only
5 analgesics. In India we have approximately 1500 analgesic for
mulations in the market. Pain is the commonest manifestation of
disease. The experience of pain and ’the emotional response to it
is largely determined by the personality of the patient. There
is great variation in the pain threshold of different patients*
4
2
The painkillers and its marketing has become a profitable business
for the drug industry.
Analgin (A s K,A, - metanizol or dipyrone) was introduced by
Hoechst in 1922. Since 1931/ the group of pyrozolones to which
dipyrone belongs has been suspected of causing a serious adverse
reaction like agranulocytosis. As early as 1934 the causal conne
ction between pyrozolones and agranulocytosis was proven. The
pharmacological basis of Therapeutics by Goodman & Gillman states
*'Aminopyrin and its close congeners Dipyrone and Phenulbutazone
are the only agents in the analgesic - antipyretic class that are
definitely known to cause agranulocytosis syndrome with possible
exception of entipyrine. The basic of disorder is hypersensitive
reaction. Even after 60 years of use the mode of its action is
still unknown. The metabolities od dipyrone which cause agranulo
cytosis are also not known. Aminophenazone has some similar
metabolities as dipyrone. Aminophenazone has been banned all over
the world because of severe side effects. There are 2 reports from
Japan that link dipyrone to a significant increase in liver tumors
in mice toxicity studies. It is worthwhile to note that Hoechst
has not challenged these reports. The history of Analgin marketing
reveals -the sinister aspect of the drug industry and its avarice.
Agranulocytosis caused by dipyronc is of immune type. In
1934 Madison and Squier proved beyond doubt that aminopyrine is
capable of inducing in suspectible individuals precipitious
Leucopenia accompanied by violent signs and symptoms. The drugs
implicated in immune agranulocytosis are listed in Annexure I,
•The prototype of drugs which appear to operate within immune
mechanism is aminopyrine and its derivatives dipyrone and phenulbutazone,- When a drug such as dipyrone is first given to a
patient/ it may be taken for varying period of time without any
deleterious effect. Apparently this is the time which lapses dur
ing build up of antibodies which would eventually result in immune
destruction of leucocytes. The most convincing evidence in support
of an immune mechanism in the case of dipyrone associated
agranulocytosis was found using in vivo challenge studies. Shortly
after the disease was shown to be secondary to the drug sensiti
zation/ Sg uier and Madison (1935) as well as Dameshek and Colmes
(1936) attempted to show skin reaction antibodies when drug serum
or drug mixtures were injected intradermatly. Moeschline and
Wagner (1952) gave aminopyrine to 2 volunteers who did not develop
any symptoms until they received 300 ml of plasma taken frem a
patient who had suffered agranulocytosis associated with amino
pyrine.
According to Martindale’s Extra pharmacopia ’’The risk of
agranulocytosis in patient taking aminopyrine is sufficiently felt
to render this drug unsuitable for use". Dipyrone has similar
properties. Its use is justified only in serious life threatening
situations where no alternative antipyretic is available. Thus
it is obvious1 that the fatal side effects of the drug have been
known for last 5 years. No textbook of Therapeutic Pharmacology
or medicine recommends this for management of routine pain,
Hoechst claims "Dipyrone has outstanding safety margins and has
proven itself since more than 60 years to be as effective and welltolerated analgesic substance. The booklet about Novalgin states
that "Novalgin1s antispamotic action derives from direct relaxant
effect on the smooth muscles." This statement is an outright lie
and has no scientific basic at all. Such brazen lie to promote
a hazardous drug needs to be condemned in strongest.terms. The
same booklet claims "Analgin’s wide safety margins is undispurted
and unequalled by other non-narcotic analgesics". Nothing can be
farther from the truth. The textbook of pharmacology by Satoskar
states "Dipyrone has antipyretic and analgesic actions only. It
doesn’t offer any advantage over Aspirin. It is risky and
unjustifiable to use this drug routinely simply to relieve pain
3
and fever when aspirin and paracetamol would be adequate. In an
attempt to prove the safety of the drug a case report has been cited
as a proof. It says that a girl, 18 years old, took 98 tablets of
Novalgin (Equivalent to 49 gms. or 10 times» "normal dose") and apart
from transient nausea and vomiting there were no side effects. This
is indeed a most remarkable way to prove the safety margin of any
drug.
BOSTON STUDY
This study should be really called as "Boston Bluff" J The
study was funded by Hoechst in collaboration with governments of
Hungary and Bulgaria. The study seems to be a subtle attempt to
manipulate die data to suit marketing strategies of Hoechst.
Hoechst has been using the findings of this study to promote the
drug. The company is sponsoring different seminars under the banner
of I.M.A. Many of the participants fall prey to the tactics of the
company to give only the data suitable to its product. The press
releases of these seminars are on the letter-heads of I.M.A.
However these are distributed by the Public Relation Department of
Hoechst 1
The following reasons make the findings of this study un
tenable and unscientific.
No adequate explanation has been given as to why Sao Paolo,
Djakarta were excluded from the study. Risk of Agranulocytosis might
have been underestimated as mild cases of Agranulocytosis were not
recognized. Z of cases died before diagnosis. Some cases were
treated outside catchment area. (incidence of Agranulocytosis was
much lower in Berlin and Ulus Community than average).
There was high percentage of exclusion. (31% in community
cases) .
All hospitaj- cases were left out as there were no proper
controls J
For both the studies Agranulocytosis as well as Aplastic
Anemia the same controls were used. They were mixed but
matched to all Agranulocytosis cases.
Interview (Drug Anamnesis) of controls defines denominator
(and also risk). But who can listen and remember a list
of 173 brand names (Barcelona) or 350 brand names (W.
Germany) ?_ There are no proper explanations:as.to how
"90% of sales” criterion for inclusion on the list was
worked out.
7
There seems to be obvious contraindications in the use
of dipyrone.
Country
Control who said they used
dipyrone
DDD pyrozolonel 1000
inhibitantg per day*
W. Germany
Spain
2.3%
1.2%
13.3%
12.0%
Italy
Israel
2.2%
11.0%
10.6%
3.3%
It is very unlikely this contra-indication has come about by
chance - Either IMS data is false or the control’s interviews are
false.
The Relative Risk (RR) is lower in Israel because the controls
say they use so much dipyrone and not because the percentage of AG
cases who say they used dipyrone isT low.
4
Berlin
Ulus
Barcelona
Israel
Budapest
35%
21%
30%
20%
13%
j
This means still in high percentage
of all AG cases the cause is
dipyrone even if the excess risk
is low.
- The regional varia bility (No risk in Israel or Sofia ?i*)
makes the result highly questionable. Could it be the faulty
methodology ? Or is it linked to specific brand names 7 (non
active ingredients) s It would be interesting to see if the vari
ability is lower if only Novalgin(R' isanalysed.
- The authors themselves state that the ’’methodology
problems must be considered” to explain the regional variabilj-ty.
— The Case Fatality Rate (CFR) is 9% overall but it was 10%
in community cases and 6% in hospital cases.
- Shapiro agreed that dipyrone use for lower than one weel^
increases the risk. He suggests the excess risk might be 3<3/10
if taken for more than 2 weeks. This means that it is impossible
to give anindividual risk estimate to the patient, The same thing
was reported by B.Ee Wiholm 3 years ago.
Therefore s
The study, inspite of its ambigeous conclusion,j proves that
dipyrone does cause Agranulocytosis. The incidence of Agranulocytosis
(all cases) is in order of 6-8/10
— Dipyrone may have a very low excess risk but it is used
so widely that it is still responsible for 27% of all .case of
Agranulocytosis.
- Hoechst confirmed that 20,000,000 DDD1s are used everyday
(25 tonnes) . This means 22 cases of Agranulocytosis are caused by
dipyrone everyday or 8000 per year worldwide.
^uropt; jl
±v/o, in East Block — 25% and
- If mortality■ m
in Europe
is» 10%,
dipyrone
kills
2200 people every year world
Third World 50%. The <
wide.
This study has methodological weakness (Exclusion
interview) and has unexplainable results.1
- It would be interesting to note that Dr, Laporte, one of
the investigators of the study, is a personal communication states
that Dipyrone^ antispasmodic action has not been proved,
choice (Annexure II).
should not be used as a drug of first
-— -------
The oft repeated claim by Hoechst is that there is no other
safe parenteral non-narcotic analgesic like Analgin. An attempt to
support this claim can be seen in a study done for treatment ot
post-op pain management. However no chronic safety date about.
dipyrone is available. Its kinetics in renal/hepatic dysfunction
or in elderly is not known. Its interaction with other drugs
(i.e. Antidiabetics) is not yet investigated. It is contraindi
cated in G-6-PD deficiency. It’s consequences for individuals
and its action regarding fast versus slow acctylators is not known.
It has risk of 0.4% after injections (Swiss data). There is no
data to prove that slow injection (iml/min.) can prevent this
side effect (shock, acute kidney failure).
5
* Many countries world over have banned/withdrawn dipyrone.
These countries are as follows s
Country
Year of Ban
U«K.
Canada
19 60
1960
1965
1965
1974
1976
1977
1978
1979
1986
Australia
New Zealand
Sweden
Norway
U.S.A.
Singapore
Denmark
Malaysia
Since 1986 the sale of dipyrene has been restricted in West
Germany. Fixed Dose Combinations of dipyrene have been banned in
West Germany since 1987. It is important to note that not a single
country has felt the need to revise the ban. Dipyrone has been
recommended by Hoechst for variety of indications e.g. cold QBrazil;
influenza (Mexico/ Brazil) dysmenorrhoea (Central America) Angina/
Bronchitis (Mexico). In Mexico it is even recommended for pain
caused during medical examination 1 In India it is recommended for
’’all types of pain like headaches/ neuralgia/ muscle pain/ post
operative pain/ dental procedures etc. It is also^sold in syrup
form for Paediatric cases 1 Sale of dipyrene in US $ 75 million
per year.
Many countries which have banned dipyrone have been
’’managing pain” without Analgin by using simple safe Analgesics. The
argument put forward by Hoechst that in India very few cases
Agranulocytosis are seen is incorrect. The adverse Drug Reaction
Monitory System is non-existant in India. Leading Haemotologists
who treat Agranulocytosis have, have always recommended ban on this
drug. Dr. B.C. Mehta states that he sees 10-12 per year. The
added risk is that sensitivity to'Agranulocytosis can be trans
ferred through blood transfusions.
Analgin has no place in Rational Drug Therapy.and management
of Pain (Annexure III, IV, Vf VI & VII) . All types of pain can be
effectively managed without even injectable dipyrone.
All the developed countries have been effectively managing
I--- use
-Acute Pain without resorting to the
of" ^algin.’ In fact the
evidence
suggests
that
the
use
of
opoids in Acute Pain
newe r c- ---- _
_
__
2
_222_ ' ’
j
The tendency
management doesn’t cause dependance and addiction,
of action of opoids have been
to overestimate potency and^duration
and fur?
recently documented. Editorials in prominent jo^^alshave drawn
problem as
attention to the fact that ”an apparently simp,
relief of post-op pain remains largely unsolved., These editorials
have drawn attention to poor post-op pain management for more wan
30 years. Rational use of opbids requires a flexible/ patien_
oriented approach to allow for variability in individual pain
experience and tolerance, as well as both the beneficial
adverse effects of the particular drug used. Qpoids react wi
specific receptors distributed throughout the central nervous system.
These receptors are usually site of action of endorphins/ a number
of endogeneous polypeptides with morphine like properties, It has
been postulated that there are four distinct types of opoid
6
receptors - muz delta# koppa and sigma and possibly fifth, the
epsilon receptor. The dose of an opoid should be decided on
Minimum Effective Analgesic Blood Concentration (MEC)• This has
been determined for Pethidine, Fentanyl, Methadone, Morphine. The
use of adjuvants to the opbids have improved Acute Pain Management.
Benzodiazepines, Barbiturates, Chlormethiozole, Etomidate, Chlor
promazine have all been used as ajuvents. The newest Intravenous
Benzodiazapine, Midazolam has overtaken older Benzodiazapines like
Diazepam and Lorezepam. Midazolam offers great promise as a
hypno tic/anxiolytic in the management of Acute Pain.
Thus it is obvious that the Acute Pain can be effectively
managed with judicious use of opoids without Analgin. In fact
none of the literature, paper and books on Acute pain management
even list dipyrone as a probable agent.
The spasmolytic atropine substitutes have also been used in
the treatment of colics. Hyoscine Butylbromide has specific
relaxant sntispasmodic action on smooth muscles of GI tract and
descending urinary tract. Oxephenonium (Antrenyl) , propanthelene
(Proban thine), Dicyclomine are quaternary and tertiary ammonium
compounds. They have been in use for varying length of time.
These are free from the side effects of Analgin. In fact a leading
university in USA uses only analgesics with propanthelene- for
treatment of Urological colics. (Letter from Johns Hopkins
University) .
The Consumer Groups need to coordinate their efforts to
effectively challenge falsehood being propagated by Hoechst, These
false claims need to be contested at all levels.
7
REFERENCES
1)
Acute Pain Management
Cousin & Philips
Churchill Livingstone, 1986.
2)
Hoechst - A cause of Illness
BUKO Pharma Kampagne
3)
Oxford Textbook of Clinical Pharmacology & Drug Therapy
by Smith & Arenson, 1984.
4)
Medical Management of Surgical Patient by F<G* Smiddy,
Edward Arnold Ltd., 1976.
5)
Drug Induced Agranulocytosis by V. Pisciotta - DRUGS
15 : 132-143 (1978)
6)
Martinadale1 s Pharma Copia 28th Ed*
7)
Recent Advances in Analgesics/ 1985 by Atkenson & Adams Churchill Livingstone,
8)
Drug Treatment by G.S, Avery, Churchill Livingstone 2nd Ed.
9)
Pharmacology and Pharmacotherapentics (Revised 10th
edition) by Satoskar & Bhandarkar,
8
ANNEXURE - I
Table
Listing of drugs implicated in agranulocytosis
through possible immunological mechanisms (AMA
Registry on Adverse Reactions,. 1963) •
Drug
given
alone
With other drugs
Inno Undeter- Toxic
mined
cent
Total
Carbimazole
3
2
5
Methimazole
17
Thiouracil
19 k
Aminopyrine
14
8
Dipyrone
Phenylbutazone
19
6
2
5
Drug
Immune Mechanisms.
Suphonamides
12
18
4
29
5
25
20
23
65
10
16
4
31
17
46
51
35
100
2
2
1
4
8
4
17
29
4
4
■
Chlorpropamide
Tolbutamide
3
Uncertain Mechanisms
Phenytoin
4
Mephenytoin
2
4
4
2
Chlorothiazide
4
6
11
Hydrochlorothiazide
2
6
10
6
7
14
4
4
21
N i trofuran toi n
1
Phenindione
9
Carbamazepine
Not entered in AMA Registry on
Adverse Reactions^
4
9
ANNEXURE
II
Divisio de Farmacologia Clinica
Unitat Docent de la Facultat de Medicina
Universitat Autonoma de Barcelona
Ciutat Sanitaria de la Vail d’Hebron'
P.Vall d’Hebron, s*n.
Barcelona - 32/35
Barcelona/ October 6/1986*
Dr. Arun Bal
e c re ta ry-ACA SH
Lawyers Chambers/ Room 21
RS Sapre Marg
Bombay 400 002
Dear Dr. Bal/
Thank you for your letter of August 27/ which I found on my desk
when coming back from Brasil yesterday*
I do not remember that during our discussion in.the Delhi meeting
it was pointed out that dipyrone has any specific anti-spasmodic
action* In fact, the companies manufacturing dipyrone (mainly
Hoechst) use to claim this./ but this has never been demonstrated,
at least on clinical grounds* What was said in the meeting was
that in acute renal colicy pain the usual therapeutic strategy is
firstly giving an oral analgesic in adequate doses (acetylsalicylic
acid or paracetamol)/ and if this is not enough (as is the case in
a proportion of patients) / opiate derivatives - preferably
meperidine (pethidine) - should be given. It was said however
that doctors in India are reluctant to use opiate derivatives/
mainly because this needs using a special prescription* The same
situation exists in my country and in other European and Latinamerican countries in this respect* This is due to the fact that
some clinical trials and the everyday clinical experience show that
90-95% of cases of colicy pain can be successfully treated with a
parenteral non-steroidal antiinflammatory drug. The meeting exam
ined this'question and considered some facts s (1) the only non
steroidal analgesic/antiinflammatory drug which is available for
parenteral administration in India is dipyrone; (2) it is
difficult to set up a list of ’’essentials1’ without taking into
account the therapeutic traditions s dipyrone is an effective
analgesic, while it seemed difficult recommending doctors not to
use it or not to use another parenteral antiinflammatory drug in
case it is marketed in the future.
Dipyrone/ like all drugs/? can cause adverse effects, sometimes
intravenous injection can cause
severe and even fatal. Rapid
J
hypotension and shock, particularly in patients who experienced
cutaneous rash or edema in previous treatments. It can also
cause agranulocytosis. The risk of hypotension can be minimized
by slow injection, according to the data we have from our
hospital, where dipyrone is used in these selected patients*
Because of the risk of agranulocytosis/ dipyrone does not seem
to be a first choice oral analgesic for any kind of pain. The
majority of clinical trials (not many) suggest that dipyrone is
as effective as aspirin, no more, no less, Aspirin increases the
risk of gastrointestinal hemorrhage (GIH). The risk of GIB
associated to dipyrone is not known, but it probably exists.
In fact, the use of a non-steroidal analgesic/antiinflammatory
agent always necessarily carries a risk of GIH.
10
The results of the International study on Agranulocytosis and
Plastic Anemia have been published in JAMA in October. I enclose
a copy of the paper. My summary regarding your questions would be
that agranulocytosis is a very rare disease, and a very rare
complication of dipyrone administration. Paradoxically however,
the risk of suffering agranulocytosis associated to the use of
dipyrone is high. “Risk" is a comparative and relative concept.
CUie risk of breaking one’s leg is low while you stay at home in
winter, with snow and ice outside. The risk increases by say 1,000
6r 10,000 if you go outside, but it is still very low. For
dipyrone, as indicated in table 5 of the manusceipt, the risk ,
may be 20-30 times the risk if you don’t take dipyrone, but it is
still of 1 in 100,000 or 1 in 1,000,000 if you do take dipyrone.
On the other side, the use of dipyrone does not seem to increase
the risk of aplastic anemia. Aplastic anemia has a mortality
rate of 49% two years after its diagnose, which compares with a
fatality rate of 9% for agranulocytosis. However, fatality rates
obtained in the study (Spain, Ita ly, Germany, Sweden, Hungary,
Bulgaria, Israel) cannot be qasily extrapolated to your country.
It is obvious that the results of the study - as with any studybwill be used by the company with promotional aims. What we need
is careful reading of this study, and then comparing different.
alternative drugs in the light of all the information on beneficial
and adverse effects that we have about them.
hope this letter will be helpful to you.
Yours sincerely.
Best regards.
Sd/
Joan-Ramon Laporte.
£;
c
i
11
ANNEXURE - III
DI PYRONE - WHAT ARE THE
ALTERNATIVES ?
Fever
Paracetamol (Acetaminophen) : 0,5 - 1g
Acetyl-salicylinc acid (ASA) 2 0.5- Igc
For children under 15 years paracetamol is the drug of first choice.
Children with otherwide harmless viral infections may develop a Reye
syndrome (liver wnecrosis with encephalopathy) after intake of ASA.
(1) Drug treatment has to be supported by physical measures such as
wet compresses around the lower legs. There are no adequate
studies proving the particular superiority of dipyrone in the treat
ment of fever so that this widely held notion seems to be unfounded.
Dysmenorrhea
Ibuprofen
Naproxen
Other non-steroidal anti-inflammatory drugs (NSAIDS)
Prostaglandin-synthesis-inhibitors such as ibuprofen and naproxen are
a logical and effective principle of treatment, because painful
abdominal cramps is caused by certain metabolites of the arachidonic
acid (prostaglandine). (2) Non-steroidal anti-inflammatory agents
are, therefore, superior to common analgesics.
Biliary Colic
Pethidine
Mosphine plus isosorbide dinitrate (ISDN)
The combination of morphine parenteral with ISDN is necessary in
order to compensate for the spasmogenic effect of morphine toi the
unstriated muscles of the biliary tract and the intestine,, The
efficacy of ISDN is better than that of spasmolytics, If necessary.
treatment can be continued with morphine oral and ISDN, Instead
of morphine, any other opiate can be taken.
Renal Colic
Viz* biliary colic. additionally diclofenac, 75mg i.m.
In a comparative analysis diclofenac 75mg i*m* proved to be more
effective than pethidine lOOmg i.m* (3) Further studies confirmed
this pain-killing effect for biliary colics, too, (4)
Postoperative and posttraumatic pain
Morphine
Bupre no rph i ne
Other opiates
Since at least during- the first few days after an operation or
trauma pain is severe and continuous, pain-relieving treatmen t
should be carried out according to the clock (such as morphine
every four hours, buprenorphine every six to eight hours) .
Dosage intervals vary according to the duration of effect of the
opiate used. NOn-steroidal anti-inflammatory agents or anti
ph logistics are contra-indicated for subsidence and pain-relief
due to the risk of renal insufficiency (5) and should not be
used before the fifth day post-traumatically and only in case of
normal renal function.
12
Tumor pain
Morphine oral
Other opiates
There are a number of therapeutic regimen which are all based
on the duration of effect of the drug in order to find out the
necessary analgesic dosage and to apply the drug according to the
clock. For the retarded morphine the duration of effect seems to
be eight hours/ just like for buprenorphine. The analgesic effect
of partial aigonists such as buprenorphine or pentazocine is
limited so that a higher dosage does not necessarily mean a higher
analgesic effect. When opiates are used permanently they regularly
cause spastic obstipation which can be treated with laxatives.
Other severe pain
Paracetamol (Acetaminophen) (0.5 - 1 g) plus codeine (50 - 100 mg)
When an analgesic such as acetyl-salicylic acid (ASA) or paracetamol
alone is not sufficient/ the analgesic effect can be increased by an
effective dosage of codeine (at least 50 mg). The effect of dura
tion is - for both substances five to six hours so that a painrelieving treatment is possible by an administration every four
hours.
Re suits s Dipyrone (NOVALGIN/ BARALGIN etc) can be replaced by
better tolerated or more appropriate analgesics in all fields of
indication. In many industrialized countries with a similar
health care system dipyrone has been banned/ without any restrict
ions of therapeutical possibilities in the care of patients being
documented.
---■
Source : Arznei-telegramm/ Berlin (FRG), November 1986/ p.l06-T07<
ANNEXURE
IV
Preparation-j
ASPIRIN BP Many commercial preparations” are available/ e.g Aspro
(Nicholas) •
Nu-seals Aspirin (Lilly) 9 Acetylsalicylic acid in enteric coated
table ts»
SOLUBLE ASPIRIN BP Once again many commercial preparations are
available e.g. ;Solprin (Reckitt and Coleman). Aspirin 300 mg/
Calcium carbonate 100 mg/ Anhydrous citric acid 30 mg.
AMYTRIPTYLINE BP Laroxyl (Roche) . Lentizol (Warner) . TryptizOl (MSD"*
BENZETROPINEMESYLATE BP Cogentin (MSD)
CHLORDIAZEPOXIDE HYDROCHLORIDE BP Librium (Roche)..
CHLORPROMAZINE BP Largactil (May and Baker) .
DEXTROPROPOXYPHENE HYDROCHLORIDE BP Colsan (Lilly). Dextropropoxyph eno
hydrochloride 100 mg and Acetyl salicylic acid 325 mg.
Doloxene (Lilly) , contains Dextropropoxyphene napsylate equivalent
to 65 mg of the hydrochloride.
Doloxene compound 65 (Lilly)/ formulated as for Doloxene but con
taining acetyl salicylic acid 227 mg/ Phena cetin 162 mg.
Caffeine 32.4 mg.
Distalgesic (Dista)t containing 32.5 mg. Dextropropoxyphene hydro
chloride and paracetamol 32.5 mg. Napsalgesic (Dista)/ which
contains 500 mg acetyl salicylic acid in addition to Dextropropo
xyphene napsylate 50 mg.
DIAZEPAM BP Valium (Roche) •
DIHYDROCODEIN TARTRATE BP D.F. 118 (Duncan/ Flockhart) •
DIPIPANONE HYDROCHLORIDE BP Deconal tablets or injection
(Burroughts Wellcome).
13
ETKOHEPTAZINE CITRATE USNF Equagesic (.Wyeth) # Ethoheptazine
citrate 75 mg/ Meprobamate 150 mg# Aspirin 250 mg and Calcium
carbonate 75 mg#
IMIPRAMINE BP Totranil (Geigy). Berkomine (Berk).
ISOCARBOXIDE BP Marplan (Roche).
MEPROBAMATE BP Equanil (Wyeth) . Miltown (Wallace labs)• MepavlonklCI)
NIALAMIDE BP Niamid (Pfizer).
.
.
NORTRIPTYLINE BP Aventy (Lilly)# Allegron (Dista) • Altilev( Squibb) .
PAPAVERETUM Omnopon (Roche).
t
.
PARACETAMOL BP Many proprietary preparations contain this compound.,
such as Panadol (Bayer). Myolgin (Duncan, Flockhart), paracetamol
200 mg< codeine phosphate 5 mg/ calcium aspirin 250 mg, caffeine
citrate 15 mg and acetomenapthone 1 mg.
PENTAZOCINE HYDROCHLORIDE FORTRAL (WINTHROP)
PHENELZINE BP NARDIL (Warner)
PROMAZINE BP Sparine (Wyeth).
THIORIDAZINE HYDROCHLORIDE BP Melleril (Sandoz)
TRANYLCYPROMINE SULPHATE BP Parnate (Smith/ Kline and French).
TRIFLUOPERAZINE BP Stellabid (Smith, Kline and French).
ANNEXURE VI
Table - Examples of appropriate analgesics for sane
clinical problems#
Analgesic
Condition
Sprained ankle
Simple headache
Pain following dental extra- !
c ti’on
;
Mild sciatic pain
Severe sciatic pain
Moderately severe post
operative pain
(e#g# orthopaedic)
!
Severe post-operative or
traumatic pain
Severe intractable pain of
malignant disease
Acute myocardial infarction
Acute abdominal pain
Pain of labour
Aspirin
Aspirin or paracetamol
Aspirin + codeine or
Paracetamol -I- dextropropoxyphene
Dihydrocodeine or buprenorphine
Dihydrocodeine or buprenorphine
Morphine, diamorphine, or
buprenorphine
Morphine, diamorphine, dipipanone,
dextromoramide etc# (see text)
Morphine or diamorphine
Pethidine
Pethidine
14
ANEXLTRE - VII
Table - Some pain syndromes with specific analgesic
treatments.
Treatment
Condition
—
.
•
■
■
Dysmenorrhoea
Bone pain from metastatic
malignant disease
Bone pain from metastatic
prostatic carcinoma
Trigeminal neuralgia
Diabetic neuropathy
Lightning pains of tabes
dor/salis
Migraine
Pains associated with giant
cell artcritics and poly
myalgia rheumatica
Post-herpetic neuralgia
■■■
aM>
a*
k ••
“•
Mefenamic acid
Narcotic analgesics + indomethacin
Stilboestrol
C arbamazepine
Acute - ergotamine/ paracetamol +
Me toelopramide
Prophylaxis - pizotifen (see p*509;
Corticosteroids
Carbamazepine or valproale 4- a
tricyclic antidepressant.
•“ •” — ‘
■
ANEXURE - VIII
Table - Drugs used in the symptomatic treatment of pain
Non-narcotic analgesics (mild to moderate pain)
Aspirin (p.740)
Paracetame 1 (p.721)
Some non-steroidal anti-inflammatory drugs (see Tabid 30.1)
Combinations of non-narcotic and weak narcotic analgesics
(mild to moderate pain).
Aspirin or paracetamol plus codeine.
Aspirin or paracetamol- plus dextropropoxyphene.
Narcotic analgesics (p.713)
Mild to moderate pain
(Codeine)
(Dextropropoxyphene)
D ihydr oc ode i ne
Bupre no rph i n e
Pentazocine
Severe pain
Morphine
Diamorphine
Buprenorphine
Pethidine
Dex tromoramide
Dipipanone
Methadond
: II .
L 0 C 0 S T
GPO Box 134
BARODz^ 390 001
DT z March, 1988.
UPDATE ON MALARIA
DR. RAKESH GUPTA
Diagnosing Malaria - Importance of Parasitological Diagnosis
After having dreamed of malaria eradication in.early sixties?
we are now facing the challenge of malaris in epidemic proportions^
In our area/ the plasmodial species found are - falciparam
and vivax; P.falciparam accounting for 60-80% of infections, and is
more prevalent in the transmission season than in the dry months.
Of all the patients presenting with fever, 30-50% were
detected to be having slide positive malaria - positivity being
higher (by a single smear exm.) during active transmission months.
Of these patients, many were provisionally diagnosed as having
URI, UTI, typhoid, pneumonia, secondary infection in pulmonary
Koch’s, Amoebic dysentry, viral Hepatitis.
The obvious message is that the parasite is able to outsmart
the clinician quet a number of times arid that a parasitologically
proven diagnosis is essential for the proper treatment, more so,
as an inadequate response to full doses of chloroquine does not rule
out malaria (as was the situation few years back), in the view of
increasing chloroquine resistance.
Considering the complexity of the problem and the simplicity
and sensitivity of thick smear examination.for parasitological
diagnosis, it is prudent on part of clinicians to utilise it
routinely.
CURRENT SITUATION IN OUR REGION- s
1) Resurgence of malaria in epidemic proportions.
2) Species distribution :
P. Faleiparom
- 60-80%
P. Vivax
*- 20-40%
3) Increase in atypical manifestations s
- increase in absolute numbers.
- wider clinical spectrum.
4) Emergence of chloroquine resistance.
5) Misuse of 2nd line antimalarials,
namely s Pyrimethamine - Sulfadoxine
combination.
LABORATORY DIAGNOSIS OF MALARIA •.
"Demonstration of parasites in blood is the^only method
available to confirm diagnosis of malaria.
Sample
?
Finger prick or venous blood.
Frequency of blood Collection s
1st smear immediately.
Repeat smears every 12 hrs. for 2 days.
The Smear s
Thick and thin smears are prepared oni same slide as shown
below. The thickness of thick smear■ should be such that newsprint can be just seen through it. This is equivalent to about
... 2
2
10-20 WBC/oil immersion field under microscope.
■fi
■
i
■
i
t
%
i
i
a- i-
i
i
i
i
i
i
i
Staining ?
Giemsa stain gives best results. A fresh dilution has to be
prepared every time from stock solution in phosphate buffer pH 7.2*.
Staining time depends on strength of dilution used and varies with
each batch of stain.
10% Giemsa - 10 min.
2% Giemsa - 30-40 min.
Dehemoglobinisation occurs simultaneously whilig. staining.
Species diagnosis ?
This can generally be done on thick smear examination alone
but in cases of doubt* thin smear should be seen to study the
morphology.
Interpretation of Smear s
Adequate examination of smear s
ideally* at least 0.25 cmm of blood should be examined before
declaring the smear as negative.
The no, of fields teat should be examined to cover 0.25 mm"
of blood depends on smear thickness.
Ideal thickness
-
if 10 WBC/field
-
10-20 WBC/Oil immersion field.
3
Taking average T.L.C. as 8000/mm *
3
0.25 rnm of blood
if 20 WBC/field
- 100 fields =
200 fields
=
ii
Thus*
TIC (8000)_______
Mean No, of WEC 1 s x 0.25
in 10 fields
No, of fields to be examined o
that are equivalent to 0*25 mm"
of blood.
COUNTING OF PARASITES :
Parasitaemia can be quantitated by 2 ways 1) As no. of parasites/cmm of blood on thick smear.
2) As % of NEC’s injected on thin smear.
1)
On thick smear s
A grid may be used in eyepiece to facilitate counting of
parasites.
In each field* no. of parasites and WBC1s are counted upto
100 field and added up.
(or no • of fields for adequate examination)
3
No. of parasites x TLC (8000)
No. of parasites/mm
counted____________ _________
W3C’s counted, ’
: 10 WBC/cm
Thus if smear thickness
1
x
8000
- ® 1 parasite/200 field.
4 parsites/cmm =
2000
if 20 WBC/field
- 1 parasite'100 fields
4 parasites/cmm.
This count is considered to be the threshold for detection of
parasites in blood by microscopic examination.
-
Also called patency level.
3
3
Information gained from positive smear :
High parasitaemia correlates, with severe disease
but converse is not true. Complications and fatalities may occur
even if parasitaemia is scanty or if smear is negative.
Parasite counts
10/000/mm3
500/000/mm^
Mortality
1 %
50 %
Features suggestive of complicated disease
Parasite count
50#000/cmm
1)
>
5%
of
R
b
V
s
are
infected.
2)
falcipairun; in pecipheral blood.
3) Presence of schizonts of P,
Asymptomatic parasitaemia!
In endemic areas# parasites may 1
bej present in blood in small
numbers# without causing any symptoms - This state of immunity is
called 1 premunition" •
Thus, finding parasites in blood does not alw^s
symptoms are due to malaria although it is so most of the times.
Other possibilities should also be kept in mind and investigated.
Negative Smear when patient has malaria 2
Inadequate examination of smear,
Prior^dministration of antimalarials which lowers parasite
count below microscopic threshold.
Subpatent parasitemia - i.e. below microscopic threshold
3.
e.g. - Non immune individuals
— very early stage of disease.
4. Failure to collect repeat smears - especially in Falciparom
malaria.
Sources of Error & Confusion
Dirt
1)
Scratches on slides
2)
Platelets
3)
Ghost shadows of inmature arythroeytes
4)
Skin bacteria
5)
Spores# yeast# fungi# etc.
6)
1.
2.
CLINICAL DIAGNOSIS
i
Absence of fever in malaria :
While fever has been considered and is the hall mark of
malaria, it should be appreciated that complicated malaria may
be present in absence of fever.
Generally# these are patients with Cerebral malaria who present with abnormal be^vior or
A)
convulsions or unconciousness and found to be ^ff^ring
malaria on basis of a positive smear, response to quinin
and absence of other attributable cause.
:n during hospital
Some of these patients develop fever laterror
of
fever
10-15 days back
stay while some have had an episode c- —
which had subsided with treatment.
Severe anemia who do not respond to haematinics unless
B)
malaria is cured.
Acute Gastroenteritis like picture who develop hypothermia
C)
or do not manifest fever because of volume depletion.
Acute Hepatitis (Malarial or Falciparom Hepatitis)
1.
2.
Not in frequently, falciparom malaria presents itseif as an
acute hepatitis like syndrome. Hence it is importan w
“
that hepatocellular jaundice can occur with malaria. Sc.rom
bilirubin levels as high ai 20.00 mg/db have been - recorded. Jn
4
fact/ we have observed that jaundice is more frequently heputocellular rather than hemolytic, Such patients are often diagnose:
and treated as viral hepatitis. Persistence of fever after onset
of jaundice should make the clinical alert to this possibility
... can . be __
-- -—----4—-. on smear exami-which
confirmed ■*- by demonstrating
parasites
Such
patients
respond
rauidly
to
entimalarials
and their
nation. i
Fatal
hepatic
liver functions return to baseline within 7 days,
failure due to falciparom malaria has been reported.
3.
Pregnancy and malaria
In endemic areas/ clinical episodes of malaria are more
frequent and more severe in pregnancy/ the primigravidae being
worst affected.
Many patients who develop abnormal behavior or unconciousness are often misdiagnosed as pecrperal sepsis/ cortical vein
thrombophlebitis or postpartum psychosis. Most of these patients
turn out to be having cerebral malaria and respond dramatically
to antimalarials.
DRUG RESISTANT MALARIA
Drug resistance has been defined as the 'ability of a
parasite strain to multiply or to survive in the presence of con
centrations of a drug that normally destroy parasites of the same
species or prevent their multiplication. Such resistance may be
relative (yielding to increased doses of drug tolerated by the
host) or complete (withstanding maximum doses tolerated by host)
Drug resistant malaria commonly refers to chloroquin
resistance unless otherwise specified. Certain strains showing
resistance to multiple drugs are called multidrug resistant,strains
While p.falciparum has been shown to have developed resistance to all1 dvdlldblc
available Gj.uyS/
drugs, the picture is not so grim with
p<vivax. F.vivax has developed resistance to pyrimethamine and
progvanil. It is inherently less sensitive to suejonamides.
Recent reports from North East India suggest decreasing chloroqurn
sensitivity of P-vivax.
DOCUMENTING DRUG
A)
RESISTANCE
In vivo Method ?
The WHO standard field test (7 day follow up) or extended
test (28 day follow up) is used.
It is based on observing the parasitological response to
the standard dose of chloroquine of 25 mg/kg by taking daily
smears on 1st 7 days and weekly upto 28 days. Parasite counts
are done on each smear and results are interpreted as follows*
Standard field test s
a)
b)
c)
d)
If no asexual parasites are found by day 6 and none are
present on day 7/ the infection may be sensitive (s) or
Resistant at R^. level.
If asexual parasites disappear for at least 2 consecutive
days but return and are present on day 7/ they are resistant
~
u
at Rj_ level.
If asexual parasitaemia does not clear but is reduced to
of
or less of original pretest level during first 48 hrs. of
treatment/ the parasites are resistant at
level.
If asexual parasitaemia is reduced by less than 75% during
the parasites
parasites
the first 48 hrs. or if it continues to rise/ the
are resistant to the standard dose at
level.
5
Developmental stage of malarial parasite
Sporozoile
Drug
Quinine
Tissue
phase
j
Fast action
Chloroquine
Amodiaquine
Primaquine
____ Erythocytic phase
_________
Asexual parasites
Gumetocytes
Active -but
not used for
prophylaxis
Active - only
in toxic doses
Froguanil
Ac tive
Slow action
Pyrimethamine
Ac tive
Slow action
Antirelapse
activity
Sporontocidal
action
Active against P>
vivax. No direct
action §^P,
falciparum.
Direct and fast
action on all
species but parti
cularly P.falci
parum.
Q
§
Highly
ac tive
Highly
active
§
H
Highly
active
Little
evidence
£
H
cn
l
Sulfones and
Sulfonamides
Mefloquine
Possibly
ac tive
Moderate action
when given
alone
Marked action
>
H
As quinine
w
H
§
m
6
INTERPRETATION OF EXTENDED FIELD TEST
a)
If no asexual parasites are found by day 6 and parasites do
not reappear by day 28, the parasites are sensitive.
b)
If asexual parasites disappear as in (a) but return within
28 days, reinfection having been excluded, the parasites
are resistant at R^. level.
For R-j-j & Rjjj level resistance Same as in standard field test.
c)
d)
Sen s i tivi ty ( S)
(0
•H
£
o
o
-p
•H
to
to
M
to
i
i
T
g
- Delayed
^-recrudescence
.^Earl^re c ord escence.
2to
•H
U
r-1
to
hl
ft
'to
X
(D
w
ir—
Standard ‘
test
—.—..—*
——
Days after start of treatment on Day
o.
_
$
Ex tended te s t
IN VTTR’O METHODS
Macrotechnique
microtechnique
requirer 8-10 ml venous blood
requires 100 ml of finger prick blood
Macro technique is simpler and consists of collecting blood
1 ml aliouots m
containing parasites in ring stage uul
and disposing
required
amount
of drug folxowec
vials containing 5 mg.^glucose and req
Tnrubation at 38-40°C for 24-30 hrs. After incubation, smears
by \n^S^PH and stained and effect of drug is measured by
and stained and
are prepared
x
counting the number of schizouts formed during incubation.
Interpre tation
1.
3v
Total inhibition of schizont maturation at chloroquine concentration of 1 umol/lit indicates susceptibility to
standard chloroquine treatment.
Schizont maturation at 1.5 umol/lit of chloroquine concentration or more indicates resistance.
Schizont maturation at 1.00 /imol/lit but inhibition at 1.5
Ajmol/lit may still be compatible with a satisfactory
;
response to chloroquine.
CHOICE OF ANTIMALARIALS IN AN ARSA
KNOWN CHLOROQUINE RESISTANCE
.?
Uncomplicated
Complicated
i
i
i
Quinine
Chloroquine
2. No response
deteriorat:
1, Good
response
r
i
i
i
i
i
i
Quinine
*
Para sitological
re.^ponre +
Pt. improving
i
i
I
i
t
PatJ
clir
stat
Waith and
watch
i
Sulfadoxine/
Pyrime thomi ne
Thus, in our area/
area, it is important to note that th<
Thus
cation of sulfadoxine/pyrimethamine is in an uncotm
chloroquin resistant P.falciparom malaria. Quinin*
Quinin<
employed, the moment patient deteriorates.
CHLOROQUIN AND QUININE
Dosage and Route of Ad
ministration
Chloroquine :
The standard regime remains as giving 25 mg/,
quine base over 3 days as 10 mg/kg stat and 5 mg/kg after 6 hrs.
5 mg/kg on 2nd and 3rd day
The problem arises because most people are a:
loading
dose for fear of producing gastritis.
the
j.
i
5
It has been an observation of most people th;
with food or milk# this dose does not cause vomitii
r ; b '.••yr.'
quently as is believed. Of course, it does cause
f
pre3
discomfort. Vomiting is possibly more out of fear
er;
ax . c
patients which is not put to rest by us with prope:
8
but is ratlier aggravated by our own apprehensions.
It is to avoid this problem of vomiting people use chloroquin
in various dosages.
The WHO recommendation in this regard reads "Adults should receive a course of treatment totalling
25 mg/kg of chloroquine base in several doses over a period of
3 days. Variations of this regimen are used in different coun
coun-
■
i administration
of 900 of
mg900
(inmg2-3
tries but
more are based
on administration
(in 2 - 3
divided doses; on first day followed by smaller doses on subse—
quent days.”
The rationale for a loading dose is that chloroquine has a large
volume of distribution/ being concentrated in various tissues.
Hence a loading dose is required to saturate these.sites so that
high plasma levels can be obtained as fast as possible.
In a semi-immune population, the need to achieve a high
plasma level immediately may not be as great as in non immunes.
Since chloruquin has a long half life of 2 - 3 days, high plasn-a
levels can still be obtained (although few hrs. later), if the
1st day dose is given in' 3 divided doses. The delay of few
hours in achieving that very high plasma level will not be cri
tical in semi-immune patients with uncomplicated malaria.
However, any regime providing for less than 15 mg/kg on
1st day should be considered inadequate.
Oral route should be u^ed as far as possible and all efforts
should be made including use of antiemetics and antacids to make
oral treatment possible.
The risk of parentral chloroquine is mainly Hypotension
which may be fatal. The degree of Hypotension has been corre
lated with plasma chloroquine levels- , It has been demonstrated
that peak plasma concentrations are higher and reach toxic
levels with I M chloroquine more frequently than when it is
given intravenously as a slow infusion at a controlled rate.
The risk of Hypotension is much more in children.
More over, the patient, whose clinical condition demands
parentral treatment, generally requires Intravenous treatment.
Other advantages of IV chloroquine is such condition are -
-
-
The initial loading dose of 10 mg/kg base can be.given
(highly desirable) which would not be possible with
IM route.
The Infusion can be discontinued as soon as hypotension
develops.
Thus, there is little justification in the widespread use
is given
of IM chloroquine as we find it today. IV
I’" chloroquine
’
T
in following dose :
a) A loading dose of 10 mg/kg base diluted in 10 ml/kg of
Normal saline or 5% Dextrose infused at a constant
rate over at least 4 hrs. and
b) Maintenance dose of 5 mg/kg infused over 2-4 hours
at 12 hour intervals to a total dose of 25 mg/kg.
... 9
9
QUININE
The requirement of quinine varies in different geographical
regions according to sensitivity of pararites. Thus, high doses
are required in south-east Asia while twice a day regime suffices
in Africa,
Since the level of sensitivity has not been measured in our
region by in vitro methods, the recommendation is -
10 mg/kg quinine dihydrochloride thrice a day for 7-14 days
depending on clinical response. Oral and parentral dosages are
same.
Intravenous quinine is given as 10 mg/kg of dihydrochloride
salt diluted in 10 ml/kg of 5% dextrose solution over a period of
3-4 hrs. Severe hypoglycemia may develop during quinine infusion
and should be continuously looked for.
ROLE OF STEROIDS IN CEREBRAL MALARIA
The role of steroids as usual has generated considerable
controversy but the current recommendation is that steroid should
not be used in patients of cerebral malaria.
This is based on a double blind trial conducted in Thailand
(1982) in which it was found that there is no significant diff
erence in mortality in the control group and steroid, group the
duration of unconciousness was significantly increased in steroid
group.
.
“
POPHYLAXIS
Choice of drugs :
Available drugs for prophylaxis are
1<
2,
3,
4,
5.
6*
Chloroquine or
Amodiaquine
Progvanil
Pyrime th ami ne
Pyrimethamine +
Sulfadoxine
Pyrimethamine +
Dapsone
Mefloquine
300 mg base/once a week.
100 mg/day
25 mg/once a week
25/500 mg / once a week
(1 tablet)
12.5/100 mg / once a week
(1 tablet)
250 mg/once a week
In areas of chloroquine sensitive strains/ Amodiaquine
offers no advantage over chloroquine.
Pyrimethamine alone is no longer recommended as resistance
develops to it very rapidly and in most areas where it has been
in prolonged use - both/ P. vivex and P.falciparom have become
resistant to it.
The status of proguanil is uncertain and is not recommended.
Suf ad oxine/pyrime th amine used for prophylaxis has been
reported to cause various side effects - most threatening one
being S-J syndrome. Hence/ it is no longer recommended for use
as prophylactic except in long term travellers to malarious areas.
Mefloquine is a highly effective drug but is not available
in our country.
Thus# the choice of prophylactic would be -
10
10
A)
In chloroquine sensitive areas
-
Chloroquine.
In areas of chloroquine resistance s
B)
a)
b)
c)
Mefloquine
Pyrimeth -jnine/Dapsone
Pyrime th amine/Sulf adoxine
Indications for prophylaxis s
1)
Non immune travellers to malarious areas.
2)
Among semi immune resi^d'.ents of malarious areas Pregnant women
Special risk groups e.g. sickle cell disease/
splenectomised patients/ Aggregation of
labourers/ police forces/ Army units/ refugees
in camps.
REFERRAL SYSTEM FOR MALARIA
Looking at the magnitude of problem and lack of medical
facilities/ all patients cannot be provided expert medical
attention.
Howeverz a working system of referral has been proposed by
an expert committee to optimally utilize meagre resources. An
operational definition of complicated malaria is used depending
on competence of health care personnel and laboratory facilities
available.
Three levels of health services have been postulated Level - I
Most peripheral
Staff with basic training only.
No laboratory facility.
Only oral medication
No clinical judgement.
Level
Better training.
Can use stethoscope and exercise seme
clinical judgement.
Facility for smear examination may be therer
IM or SC injections can be given.
II
Qualified medical personal with laboratory
facilities. IV therapy can be given.
Level-III
Central Level
Definition of severe malaria at different
___________
Level
2
3
+
4-
+
4 (b)
+
+
+
A) Clinical Assessment ?
1. Too weak to walk
(in absence of obvious
other cause)
2. Cerebral Malaria
3. Vomiting of oral
treatment.
+U)
+
... 11
X.
3
Level l^a)
4. Bleeding and clotting
disorders.
5. Severe Anemia
6. Jaundice
7. Hypothermia
8. Circulatory Collapse
9. Haemoglobinuria
10. Fluid/electrolyte disturbance
11. Complicating infection
12. Pulmonary edema
13. Hypoglycemia
B)
Exclusion of other diagnoses
C)
Parasitological diagnosis
Hyperpara si taemi a
2
3
4-
4-
V-
+
+
+
+/-
4-
-u
4-
4-
4“
4-
4-
V-
4I-
-
4- = means assessment can be made at this level.
a) Reasons for referral include failure to respond to
initial treatment.
b) Confusion/ drowsiness# fits.
c) Exclude meningitis (Neck rigidity/ photophobia) •
d) Exclude meningitis (Lumbar puncture).
• ••o0o« • •
JX
ANTJDIARRHQEAL DRUGS ~
IZ.
- Dr«Y«K« Amdekar
SYMPTOMATIC MEASURES
Diarrhoea ranks amongst the most common diseases especially
in children. Specific treatment depends upon the cause. Infeations
are the major contributing factors. Majority infections are viral
and it is increasingly felt that even bacterial infections may not
always justify antibiotic therapy. In absence of definite
etiological diagnosis, especially in sick babies, use of antibiotics
become inevitable. Simple guidelines cannot be formulated to decide
the use of antibiotics or otherwise and it is ysually left to the
judgement of the treating physician and each case needs to be
treated on its own merit. Oral xRehydration Therapy has made a
tremendous impact on outcome of diarrhoea in children and is most
universally accepted. Replacement of fluid and electrolyte losses is
the mainstay of treatment of diarrhoea however it is necessary to
curtail the losses as early as possible. Whether this should be left
to the natural course of the disease or be hopefully aided by some
symptomatic measures is a debatable issue. This paper discusses the
pros and cons of this problem.
Symptomatic measures are employed to reduce frequency of
loQse stools. Three types of drugs are available (1) Gastrointestinal
protecti^es and adsorbents (2) Antimotility drugs (3) Miscellaneous
First type of drugs have been traditionally used for years and
include Bismuth, Kaolin and Pectin. They form protective coating
over the intestinal mucosa and adsorb gases, toxins and other harmful
products. Antimotility drugs act either through autonomic nerve
endings or directly on the intestinal musculature and include drugs
like Diphenoxylate and Loperamide. Miscellaneous group includes
drugs like Berberine, whose mechanism of action is not known and
nutmeg, which probably acts as a prostaglandin inhibitor. Aspirin
has been tried in diarrhoea on the same basis.
Do w^ need bo use such drugs at all ? If specific therapy for
most of the diarrhoeas is often lacking and natural course of the
disease may not be always short, reduction of frequency of stools
is certainly desirable to shorten the course of the illness. Hence
need for such drugs is quite rational. In a recent Pediatric
National Conference, opinion was sought from large number of
pediatricians whether they use such drugs and the answer was
universally affirmative. Most important question is which drug to
use and which kind of patient to select.
When to use ? Patients with nonspecific diarrhoea of
noninfective variety of many diverse etiologies would find relief
with such drugs. Such symptomatic measures must be used for a short
period and that too in just Bight doses. In general, one does not need
to continue such drugs for more than 2-3 days; by then, self limiting
diseases get better and others may need further management. Opinions
vary whether to use such drugs for the patients with infective
diarrhoea. In case of acute bacterial infections with endotoxemia,
these drugs should not be used in view of the possible danger. But
in other infections, especially viral, they may be used with caution.
In patients with abdominal distention such therapy is contra
indicated, as it may further precipitate paralytic ileus. Whenever
used for the right kind of patients, proper dosage and freqnency must
be well decided and adhered to.
'Which drugs to use ? Gastrointestinal protectives and adsorbents
are the oldest and safest. Antimotility drugs are more potent
and hence need to be used in very small doses. Moreover therapeutic
ratio of these drugs is very small and hence especially in very
small children, overdosage and poisoning is a distinct possibility.
Available in concentrated form, extra caution needs to be exercised,
and instructions regarding the dosages and frequency of administration
must be well understood by the patients and meticulously followed.
In practice, this is rather difficult and hence such drugs are better
avoided.
/pto/
2 Safety of drugs ? Safety of antimotility drugs has been
extensively studied under controlled conditions. Published
clinical trials in India have proved that these drugs are fairly
safe if used in proper dosage. Reports about toxicity of such
drugs are abundant in the western literature but they relate to
overdosage and accidental poisoning and hence cannot be considered
against the drug itself. However such reports have brought home
the point that the patients taking these drugs are rather
vulnerable to accidental overdosage even in the best of the
conditions. It may be safe to conclude that antimotility drugs
should be avoided as far as possible.
Combinations of symptomatic and specific measures : As mentioned
above, use of symptomatic measures in acute bacterial infections
is not warranted and hence fixed combinations of antibiotics
with such drugs is highly irrational,. Nonabsorbable antibiotics
like neomycin, colistin or framycetin may not be allowed to act in
presence of gastrointestinal protectives and adsorbents and
moreover the dosages cannot bQ tailored to the needs of an
individual patient. Specific antibiotic therapy may have to be
continued longer than the symptomatic measures and such adjustments
cannot be done in case of fixed dose drug combinations.
In conclusion, use of symptomatic antidiarrhoeals should be
restricted to noinfective diarrhoeas. In any case, dosage.and
frequency of administration should be kept to the ideal minimum.
Presence of- infection demands a great deal of caution in use of
such drugs. Abdominal distension and toxic state of the patient
are definite contraindications for such therapy. /Antimotility
drugs have a low therapeutic ratio and hence should be avoided
especially in smaller children.
i
• I$
JD
anti amoebic drugs
- Dr.Arun Bal
Introduction
Amoebiasis is fan infection
* with Entamoeba Histolytica.
Infection occurs from
the ingestion
contaminated food and drink?9
" of the cyst, usually in
a
Amoebiasis is in world wise
Si cSt S;/1
no 10n9er
cAIea
--- ■ 1 as tropical disease,
ne cyst release trophozites in the rgastrointestinal
tract,
cjsts deJe?n TUrS by fission of the c
trophozites.
Further*
SnsmXX°PS S
±n the f-ces
and cause
invade the mucosa
ThC ^P^sites ,multiply and may
of the tropho21?i:sc^:?gtgp"Xflask shaped U1C^’
Some
cause, extra intestinal
and
of Amoebiasil. The^JjSt^of^atients^ith"10511 manifstation
do not have dysyntry. The
t!? ^oobic infection
the bowel lumen, producino cvsh=:
remain as commensal in
symptoms. Before definative
W1$hout any clinical
is most important that ^ther^?^05^ °f Amoc'biQsis is
made it
human colon are not mistaken ?
Pathogenic Amoebae found in
not mistaken for E. Histolytica.
of the
tooebiasis
food and twater,
-- •
or by flies or by other c.
chlorinationi of water and
of flies and cockroaches r
more than 24 hrs after
8 ?"testlnes
the endemic <areas milk and
■d »?ter should hi boiled
The use of uncooked
avoided. Application vegetables and1 unskinned fruits should be
of Potassium Permangnate solution does not
destroy the cysts.
Classification of Anfi Amoebic
1.
2.
3.
4.
5.
Drugs
Anti amoebic drugs are
classified as ;
Direct racting
'
amoebicides ____
lumen such as quinoline derivatives,
acting in the bowel
Diloxanide Paromamycin.
■’ arsenioal derivatives,
Indirect acting amoebicides a
wall such as Tetracycline andacting in the bowel lumen and
3. other antibiotics with
amoebicida1 activity.
Tissue r
liver such <
wall and
dihydroemetine.
Tissue amoebicides aCt±ng Principally
Chloroquin?
in lever shch
as
Amoebicides effective
at all the sites such as
and Niridazole.
Metronidazole
Principles of Treatment
its tlsLrdKSLItf^n^h^acL'?^? amo®blc1^ is decided
by
Niridazole, Tinidazole are
1Stlcs- Metronidazole,
of the infection. HowIvS i?
™ at 311 the common sites
or more amoebicides concomitantl? t??
tO give two
amoebiasis includes the treatment* eh m°dern therapy of
amoebic dysyntry but also of^hose^rS
patients with acute
amoebiasis without acute symptoms Lnox- W?° have intestinal
brain, lungs may develone i^Pcar-r-: Amoebic abcesses of liver
symptoms of intestinal ImoebiS?12!?
° ?aVe had few °r no'
remember that hepatic amoebiasis ir/a-i
v1S° lmPortanf to
treatment with amoebicides
?
knOWn to occur during
of infection.
^iges acting only at the intestinal sit?
2
The longer the intestinal amoebiasis is allowed to
C°n^^e' H}6
is to cure. Chronic amoebic infection
IS difficult to eradicate. Chronicity should be prevented at
a i costs. In addition to the amoebicides the adjuvant
measures can also be employed. The diet should be low in residue
and carbohydrate. Belladona, Opoids and the binding mixtures
may have to be employed.
The criterion for cure of intestinal amoebiasis is based
on laboratory, not clinical examination. Disappearance of the
Disappearance of the
symptoms does^not mean cure of amoebiasis. Cure is considered
accomplished if.no Histolytica species are found in stool^1^
Histolytica species are found in stool
specimens examined at weekly intervals for six weeks after
e treatment, at monthly interval for six months and half yearly
interval for two years. Repeated courses of medication are
sometimes required to effect the cure. Treatment should be
resumed whenever the stools again become positive.
Metronidazole
It is a white
wnite to pale yellow powder. It is directly
amoebicidal in low concentrations. It is readily absorbed
from G. I. Tract, :rectal
----- " mucosa and is widely distributed in
the
tissues.
Maximum
concentrations
occur--in the serum after one
n
-rx. -i •
---- -----hour.
It diffuses iacross placenta
t“
and is found in the breast
milk of nursing- mothers in concentrations
---------- - 3 equivalent to those
in the serum, It is commonly used in the doses of 200-400 mg/
three times <a day for 7 to 10 days. The maximum parenteral dose
is 2 gms/day.» In acute amoebic dysyntry the dose of 800 mgs/
three times a day for 5-10 days has been us<2d. For the treatment
of hepatic amoebiasis a single sixxx dose of 2 gms/day for
2 days has been used.
A suggested dose for the children with amoebiasis is s
upto 3 yeaSs of age one quarter, 3-7 yrs. one third, 7-10 yrs
one half of the adult dose. Side effects of I'i-v Metronidazole
include gastrointestinal discomfort, anorexia, nausea, metallic
taste, headache, vomiting, diarrhoea, vertigo, ataxia,
darkening of the urine. Metronidazole should not be used in
patients with blood dyscrasias or with active GNS disease. Its
use should be avoided in pregnancy. When given in conjunction
with alcohol, metronidazole may provoke a disulfiram like reaction
Emetine and Dihydroemetine
These drugs have direct lethal action against E.Histolytica.
It is more effective against motile forms than cysts. After
injection emetine is concentrated in the liver. Appreciable
concentrations appear in kidneys, lungs and spleen. Very
little of the parenteral dose is secreted in the intestinal
lumen. It causes local reaction. It is characterised by aching
tenderness, sthiffness and weakness of muscles. The reaction
is believed to be due to myositis. Cardiovascular effects are
considered serious and include precordia pain, hypotension
Changes in ECG particularly flattening of inversion of T waves
and prolongation of QT interval occur in many patients. Large
and prolonged doses may give rise to the lesions in the heart,
kidneys. G.I. Tract, and skeletal muscles. It should be
prescribed cautiously in children. Because it does not eradicate
cysts, emetine does not cure intestinal amoebiasis. In acute
intestinal amoebiasis symptoms are cleared fast by emetine.
However many of the patients continue to pass cysts. It is given
deep intramuscularly. The dose of Emetine should never be
more than 60 mgm/day and courses should not be longer than
10 days. It should not be repeated at interval of less than
8 weeks. Children may be <tjiven 500 micrograms per kg. body weight
twice daily for 4-6 days. It is advisable for the patients to
remain in bed during the emetine treatment and careful watch
3
should be kept
on cardiac function with ECG
giloxanide Fuorate
monitoring.
treatment of intestin^l^mn
20"62-1 i™en r ' y
and is used in
powder which is very sli2htfblaSt* Zt is a white
crytalline
is less effectivi Z
y.S°luble in the '
water, it ix
infection. It gives hioh
^yntry than in
asymptomatic
possibly more effective th-^M^1131 concentrations
• and is
• in the •treatment
’
vomiting./ pruritis.
day for 7-10 days. The aose°S
the children is
mgs/kg./day.
Glioquinol (gain. anated Hydro'
uinolines)
gBS:ISnRH^8« x.
has ]proved.
--It has been used in the7^0"^10 ncuroPathy)
■ the aosoo of i“Jbb S“Xntsg Jnt“tbbab
amoebiasis
in
Sin7?1? dayS’ Howeve^ doses’
n.
1:0 Slx times a daxr
than 7 days are known to «»
r
aaJSsJ Ss S?/d?y £°r more
stains clothing yellow, it
t may .tag’^8^^- CUogulno!
Tinidazole
It is
from G.l. tr“S1Ttais0givenkL",aS?of2So’ It 18 absorbed
for 3 days,• It can be concomitantly used
drugs.
Chloroquine
It r-amoebicidal
than Hydroxyquinoli in liver and has amoebicidal
actions greater
conventional dose If Chi13.nOt always curative, The
or Chloroquine
is 1 gm/day for 2 days
and when' for extra /intestinal amoebiasis
i 500 mgs/day for 2—3 weeks.
Antibiotics and other drugs
Tetracyclines, Paromamycin
and er ''
actions. Their use in
have amoebicidal
the treatment ofrythromycin
7
^Amoebiasis
is limited t2 1
intestinal amoebiasis. They are
with other anti amoebic drugs. commonly used- in
—i conjunction
Discussion
F or the rCOm^
u 2, ertilUSe°rtooiespeSiS thxorouph ^d
repeated treatment
trophozites
.
--- 3 c___
Qnd cyst is required HP ~ dmens are negative for
rigid criteria is difficile plcrtcX1" P^ctice such
regular follow up examinations htmoeM t since it requires
CaUSeS more
morbidity than mortality. Prim^rXv
directed at relieliyy .primarily the
presenting
s¥mpi'oms Qnthe
d then
r '
essentlal’tothe further
^e^;
XnSoiSf
J
e^dication «
of amoebiasis can nefer
=“b«-Ayion
drinking
nti amoebic drugs provide only a
parhal water is
---- answer.
I
X
4
Proper selection of an antiamoebic drug, depending upon
patients site of infection is essential. Many of the
preparations available in the market are fixed dose combinations.
Some of these contain Hydroquinolines in higher doses o (Z^MICLINE) .
The anti amoebic drugs, if necessary are preferably used in
conjunction but not as a fixed dose combination. Fixed
dose combinations available do not offer any added
advantage. Treatment of chronic amoebiasis may require proper
diet control and use of adjuvant therapy. Repeated courses
of anti amoebic drugs in the absence of positive stool
examination serves no purpose. The course of anti amoebic
drugs should follow a positive stool examination. Metronidazole
offers more advantages than other anti amoebic drugs. However
it is less effective - in asymptomatic cyst passers. Clioquinol
and other hydroxyquinolines should not be used except in
rare circumstances. They offer no extra advantage over
Metronidazole.
References
1.
2.
3.
4.
5.
MIMS INDIA
Martindale Pharmacopoeia - 28th edition
Pharmacological Basis of Therapeutics by
Goodman and Gillman.
Textbook of Medical Treatment by Dunlop, Alstead,
MacGregor.
The Principles and Practice of Medicine by Davidson.
1
-
aspect of management of pain
(With Particular reference to Analgin)
By Dr. Arun Bal & Dr, Anil Pilgaonkar
As with many aspects of medicine, the history of pain and
its management is shrouded in the mists of time. In ancient
China, about 2000 B.C., Shen Nury compiled a medical herbal. with
reference to use of wine for surgery, In the reign of Yu Hsing
during surgery were described in
acupuncture and ”distraction"
(
detail. Less accurate, but numerous references are made to the
use of herbs and poppy in ancient Egypt, Rome and .Greece. The
Incas and ancients of Peru used concoctions containing hyoscine,
stropine opium,cocaine, mescaline and psilocypin.
Despite the great advances made in the period 585 B.c. to.
200 A*D., the works of neither Hipprocrates nor Galen discuss pain
and pain management to any degree. The scientific approach, to
pain and its management was born during the renaissance and deve
loped slowly until mid-nineteenth century, when progress was rapid
on three fronts - administration of opiates and hypnotics,
inhalation of analgesic and anasthetic gases and administration
of local anasthetic agents by a variety of techniques.
Pain has been defined as "an unpleasant sensory and emo
tional experience associated with actual or potential tissue damage
or described in terms of such damage* There has been major advan
tages in understandings of pain physiology over the last 10 years.
The pain may be relieved by (a) reducing sensory inputs from the
damaged tissue (b) modulating transmission through central nervous
systems (c) altering emotional responses to such actual or per
ceived inputs. The Malzack and Wall “gate theory of pain" stimu
lated explosion of research into pain, mechanism. The recent
restatement of the theory summarizes present concepts s
1)
Information about the presence of injury is transmitted to
the CfcNaS* by peripheral nerves* Certain small diameter fibres
(A-delta & C) respond only to injury, whereas others with lower
thresholds increase their discharge frequency if stimulations
reaches noxious levels•
2)
Cells in the spinal cord or 5th nerve nucleus which are
excited by these injury signals are also facilitated or inhibited
by other peripheral nerve fibres-.which
fibres-.which carry'information about
innocuous events.
3)
Descending control systems originating in the brain,
modulate the excitability of the cell which transmits information
about injury.
The theory emphasized that perception of noxious stimuti
(and pain) depends not only on peripheral stimulation and trans
mission but also, on modulation occuring in the spinal cord and.
higher structures. Pain (and pain control) must be considered in
terms of both afferent pain pathways and descending pathways which
modify sensory message.
Treatment and management of pain requires- adequate knowledge
of physiology of pain. Newer analgesics are being introduced in
the market as the understandings of the pain physiology and neuro
pharmacology -improves. WHO’s List of essential drugs, list only
5 analgesics. In India we have approximately 1500 analgesic for
mulations in the market. Pain is the commonest manifestation of
disease. The experience of pain and the emotional response to it
is largely determined by the personality of the patient. There
is great variation in the pain threshold of different patients.
2
The painkillers and its marketing has become a profitable business
for the drug industry.
Analgin (A s K.A# - metanizol or dipyrone) was introduced by
Hoechst in 1922. Since 1931/ the group of pyrozolones to which
dipyrone belongs has been suspected of causing a serious adverse
reaction like agranulocytosis• As early as 1934 the causal conne
ction between pyrozolones and agranulocytosis was proven. The
pharmacological basis of Therapeutics by Goodman '& Gillman states
"Aminopyrin and its close congeners Dipyrone and Phenulbutazone
are the only agents in the analgesic - antipyretic class that are
definitely known to cause agranulocytosis syndrome with possible
exception of entipyrine. The basic of disorder is hypersensitive
reaction. Even after 60 years of use the mode of its action is
still unknown. The metabolities od dipyrone which cause agranulo
cytosis are also not known. Aminophenazone has some similar
metabolities as dipyrone. Aminophenazone has been banned all over
the world because of severe side effects. There are 2 reports from
Japan that link dipyrone to a significant increase in liver tumors
in mice toxicity studies. It is worthwhile to note that Hoechst
has not challenged these reports. The history of Analgin marketing
reveals the sinister aspect of the drug industry and its avarice.
Agranulocytosis caused by dipyrone is of immune type. In
1934 Madison and Squier proved beyond doubt that aminopyrine is
capable of inducing in suspectible individuals precipitious
Leucopenia accompanied by violent signs and symptoms. The drugs
implicated in immune. agranulocytosis are listed in Annexure I.
The prototype of drugs which appear to operate within immune
mechanism is aminopyrine and its derivatives dipyrone and phenul
butazone.- When a drug such as dipyrone is first given to a
patient/ it may be taken for varying period of time. without any
deleterious effect. Apparently this is the time wThich lapses dur
ing build up of antibodies which would eventually result in immune
destruction of leucocytes. The most convincing evidence in support
of an immune mechanism in the case of dipyrone associated
agranulocytosis was found using in vivo challenge studies. Shortly
after the disease was shown to be secondary to the drug sensiti
zation/ Sq uier and Madison (1935) as well as Dameshek and Colmes
(1936) attempted to show skin reaction antibodies when drug serum
or drug mixtures were injected in trade rmatly. Moeschline and
Wagner (1952) gave aminopyrine to 2 volunteers who did not develop
any symptoms until they received 300 ml of plasma taken fran a
patient who had suffered agranulocytosis associated with amino
pyrine.
According to Martindale’s Extra pharmacopia "The risk of
agranulocytosis in patient taking aminopyrine is sufficiently felt
to render this drug unsuitable for use". Dipyrone has similar
properties. Its use is justified only in serious life threatening
situations where no alternative antipyretic is available. Thus
it is obvious that the fatal side effects of the drug have been
known for last 5 years. No textbook of Therapeutic Pharmacology
or medicine recommends this for management of routine pain.
Hoechst claims "Dipyrone has outstanding safety margins and has
proven itself since more than 60 years to be as effective and welltolerated analgesic substance. The booklet about Novalgin states
that "Novalgin1s antispamotic action derives from direct relaxant
effect on the smooth muscles." This statement is an outright lie
and has no scientific basic at all. Such brazen lie to promote
a hazardous drug needs to be condemned in strongest^terms. The
same booklet claims "Analgin’s wide safety margins is undispurted
and unequalled by other non-narcotic analgesics". Nothing can be
farther from the truth. The textbook of pharmacology by Satoskar
states "Dipyrone has antipyretic and analgesic.actions only. It
doesn't offer any advantage over Aspirin, It is risky.and
unjustifiable to"use this drug routinely simply to relieve pain
3
‘ , In an
and fever when aspirin and paracetamol would
report
has
been cited
attempt to prove the safety of the drug a case
ci,
took
98
tablets
of
as a proof. It says that a girl, 18 years old
normal
dose
”
)
and
apart
Novalgin (Equivalent to 49 gms. or 10 times ifrom transient nausea and vomiting there were no side effects. This
is indeed a most remarkable way to prove the
-,:1/ safety margin of any
drug.
BOSTON STUDY
"Boston oruzx
Bluff” •1 The
This study should be really^called as "boston
* i collaboration with governments of
study was funded by
------- a subtle attempt to
Hungary and Bulgaria* The study seems to be a subtle attempt to
suit marketing strategies of Hoechst,
SoecC^has^een^ting the findings of this
study to
this study
to Promo^
promote une
the
drug. The company is sponsering different seminars un e
KSSKa5eb?nt£ePublic
PuSS=rRe?atlo°
o£
Relation Departoent
Department of
Hoechst ’
The following reasons make the findings-‘Of this study untenable and unscientific*
No adequate explanation has been given as to why.Sao Paolo,
Djakarta wSe^xcluded from the study. Risk of Agranulocytosis might
have been underestimated as mild cases of A^anulocy^sis were not
recognized. Z of cases died before diagnosis. Some cases were
treated outside catchment area. (Incidence of Agranulocytosis wa
much lower in Berlin and Ulus Community than average).
-
There was high percentage of exclusion. (31% in community
-
Alfhospitai cases were left out as there were no proper
-
For^both the studies Agranulocytosis as well as Aplastic
Anemia the same controls were used. They were mixed but
.
defines aen.~r
Germany) ? There are no proper explanations as to how
"90% of sales " criterion for inclusion on the list was
worked out^.
There seems to be obvious contraindications in the use
of dipyrone.
Country
W. Germany
Spain
Italy
Israel
Control who said they used
________ dipyrone _ _______ ___
DDD pyrozolonel 1000
inhibitantg per davr
2.3%
1.2%
13.3%
12.0%
2.2%
10.6%
11.0%
3*3%
a -indication has ccme about by
It is very unlikely this contra-.
the control’s interviews are
chance - Either IMS data, is false or th
false.
- 'because
a -die controls
The Relative -•
Risk (RR) is lower in Israel
dipyrone and not because ■_the percentage of AG
say they use so much
i
cases who say’they used dipyrone is
is Tow
low.#
4
Berlin
35%
Ulus
Barcelona
21%
Israel
20%
13%
Budapest
30%
This means still in high percentage
of all AG cases the cause is
dipyrone even if the excess risk
is low.
I Q
/
- The regional varia bility (No risk in Israel or Sofia 7- «♦
makes the result highly questionable. Could it be the faulty
methodology ? Or is it linked to specific brand names 7 (non
active ingredients) : It would be interesting to see if the vari
ability is lower if only NovalgimR) isanalysed.
- The authors themselves state that the ” methodology
problems must be considered” to explain the regional variability.
- The Case Fatality Rate (CFR) is 9% overall but it was 10%
in community cases and 6% in hospital cases.
- Shapiro agreed that dipyrone use for lower than one week
inc
r
eases
increases the risk.
risk, He suggests the excess risk might be 3»3/10
if taken for more than 2 weeks, This means that it is impossible
to give anindividual risk estimate to the patient, The same thing
was reported by B.E. Wiholm 3 years ago.
Therefore s
The study, inspite of its ambigeous conclusion,^, proves that
incidence
dipyrone does cause Agranulocytosis. The
T.. —
-I' - of Agranulocytosis
(all cases) is in order of 6-8/10
— Dipyrone may have a very low excess risk but it is used
so widely that it is still responsible for 27% of all case of
Agranulocyto si s.
- Hoechst confirmed that 20,000,000 DDD1s are used everyday
(25 tonnes). This means 22 cases of Agranulocytosis are caused by
dipyrone everyday or 8000 per year worldwide*
- If mortality in Europe is 10%,
10%z in East Block - 25%
Third World 50%. The dipyrone kills 2200 people every year world
wide.
- This study has methodological weakness (Exclusion
interview) and has unexplainable results.
It would be interesting to note that Dr. Laporte, one of
the investigators of the study, is a personal communication^states
that Dipyrone’s antispasmodic action has not boen^proved.
should not be used as a drug of first choice (Annexure II) .
The oft repeated claim by Hoechst is that there is no other
safe parenteral non-narcotic analgesic like Analgin. An attempt to
support this claim can be seen in a study done for treatment of
no chronic
safety date about,
post-op pain management. However
N
'
kinetics
in
renal/hepatic
dysfunction
dipyrone is available.. Its
Its
interaction
with
other
drugs
or in elderly is not known.
It
is
contraindi(i.e. Antidiabetics) is not yet investigated,
cated in G-6-PD deficiency. It’s consequences for individuals
and its action regarding fast versus slow acctylators is not known.
It has risk of 0.4% after injections (Swiss data).» There
There is
is no
no
data to prove that slow injection (iml/min.) can prevent this
side effect, (shock, acute kidney failure).
5
Many countries world over have banned/withdrawn dipyrone.
These countries are as follows s
Country
Year of Ban
U.K*
Canada
19 60
Australia
New Zealand
1965
1965
Sweden
1974
Norway
197 6
1977
U.SoAe
Singapore
Denmark
Malaysia
I960
1978
1979
1986
Since 1986 the sale of dipyrene has been restricted in West
Germany. Fixed Dose Combinations of dipyrone have been banned in
West Germany since 1987c It is important to note that not a single
country has felt the need to revise the ban. Dipyrone has been
recommended by Hoechst for variety of indications e.g. cold (Brazil)
influenza (Mexico- Brazil) dysmenorrhoea (Central America) Angina/
Bronchitis (Mexico). In Mexico it is even recommended for pain
caused during medical examination ' In India it is recommended for
"all types of pain like headaches, neuralgia, muscle pain, post
operative pain, dental procedures etc..- It is also sold in. syrup
form for Paediatric cases 1 Sale of dipyrene in US $ 75 million
per year.
Many countries which have banned dipyrone have been
“managing pain” without Analgin by using simple safe Analgesics, The
argument put forward by Hoechst that in India very few cases
Agranulocytosis are seen is incorrect. The adverse Drug Reaction
Monitory System is non-existent in India. Leading Haemotologists
who treat Agranulocytosis have, have always recommended ban on this
drug. Dr. B»C* Mehta states thathe sees 10-12 per year. The
added risk is that sensitivity to’Agranulocytosis can be trans
ferred through blood transfusions^
Analgin has no place in Rational Drug Iherapy and management
of Pain (Annexure III/IV, V. VI & VII) . All types of pain can be
effectively managed without even injectable dipyrone.
All the developed countries have been effectively managing
Acute Pain without resorting to the use of Analgin. In fact the
newer evidence suggests that the use of opoids in Acute Pain
management doesn’t cause dependance and addiction. The tendency
to overestimate potency and duration of action of opoids have been
recently documented.. Editorials in prominent journals have drawn
attention to the fact chat "an apparently simple problem as
relief of post-op pain remains largely unsolved. These editorials
have drawn attention to poor post-op pain management for more than
30 years. Rational use of opbids requires a flexible, patient
oriented approach to allow for variability in individual pain
experience and tolerance,, as well as both the beneficial and
adverse effects of the particular drug used. Opoids react with
specific receptors distributed throughout the central nervous system.
a number
These receptors are usually site of action of endorphins, u
of endogeneous polypeptides with morphine like properties, It has
been postulated that there are four distinct types of opoid
6
receptors - mu.» delta/ koppa and sigma and possibly fifth/ the
epsilon receptor. The dose of an opoid should be decided on
Minimum Effective Analgesic Blood Concentration (MEC)• This has
been determined for Pethidine/ Fentanyl/ Methadone/ Morphine* The
use of adjuvants to the opoids have improved Acute Pain Management*
Benzodiazepines/ Barbiturates# Chlormethiozole/ Etomidate/ Chlor
promazine have all been used as ajuvents* The newest Intravenous
Benzodiazepine# Midazolam has overtaken older Benzodiazapines like
Diazepam and Lorezepam. Midazolam offers great promise as a
hypnotic/anxiolytic in the management of Acute Pain*
Thus it is obvious that the Acute Pain can be effectively
managed with judicious use of opoids without Analgin. In fact
none of the literature/ paper and books on Acute pain management
even list dipyrone as a probable agent.
The spasmolytic atropine substitutes have also been, used in
the treatment of colics. Hyoscine Butylbromide has specific
relaxant antispasmodic action on smooth muscles of GT tract and
descending urinary tract-, Oxephenonium (Antrenyl) t propanthelene
(Probanthine) g Dicyclomine are quaternary and tertiary ammonium
compounds^ They have been in use for varying length of time.
These are free from the side effects of Analgin. In fact a leading
university in USA uses only analgesics with propanthelene for
treatment of Urological colics*
(Letter from Johns Hopkins
University) >
The Consumer Groups need to coordinate their efforts to
These
effectively challenge falsehood being propagated by Hoechst. T
false claims need to be contested at all levels.
7
REFERENCES
1)
Acute Pain Management
Cousin & Philips
Churchill Livingstone, 1986.
2)
Hoechst - A cause of Illness
BUKO Pharma Kampagne
3)
Oxford Textbook of Clinical Pharmacology & Drug Therapy
by Smith & Arenson, 1984.
4)
Medical Management of Surgical Patient by F.G. Smiddy/
Edward Arnold Ltd., 1976.
5)
Drug Induced Agranulocytosis by V. Pisciotta - DRUGS
15 ; 132-143 (1978)
6)
Martinadale1 s Pharma Copia 28th Ed.
7)
Recent Advances in Analgesics, 1985 by Atkenson & Adams Churchill Livingstone.
8)
Drug Treatment by G.S. Avery, Churchill Livingstone 2nd Ed.
9)
Pharmacology and Pharmacotherapentics (Revised 10th
edition) by Satoskar & Bhandarkar.
8
ANNEXURE - I
Table
Listing of drugs implicated in agranulocytosis
through possible immunological mechanisms (AMA
Registry on Adverse Reactions, 1963) •
Drug
Drug
given
alone
With other drugs
Inno Undeter- Toxic
mined
cent
Total
Immune Mechanisms.
5
Carbimazole
3
Methimazole
17
4
Thiouracil
19
1
Aminopyrine
14
8
Dipyrone
19
Ph e nyIbu ta z o ne
Suphonamides
12
18
4
29
5
25
20
23
65
6
10
16
2
4
31
17
46
51
35
100
2
2
1
4
8
4
17
29
5
4
Chlorpropamide
Tolbutamide
3
Uncertain, Mechanisms
Phenytoin
4
Mephenytoin
2
4
1
Chlorothiazide
4
2
4
6
11
Hydrochlorothiazide
2
2
6
10
Nitrofurantoin
1
6
7
14
Phenindione
9
4
4
21
Carbamazepine
Not entered in AMA Registry on
4
Adverse Reactions.
9
ANNEXURE
II
Divisio de Farmacologia Clinica
Unitat Docent de la Facultat de Medicina
Universitat Autonoma de Barcelona
Ciutat Sanitaria de la Vail d’Hebron
P.Vall d‘Hebron, s.n.
Barcelona - 32/35
Barcelona/ October 6, 1986.
Dr. Arun Eal
^ec re tary-ACASH
Lawyers Chambers, Room 21
RS Sapre Marg
Bombay 4C0 002
Dear Dr. Bal,
Thank you for your letter of August 27/ which I found on my desk
when coming back from Brasil yesterday.
I do not remember that during our discussion in the Delhi meeting
it was pointed out that dipyrone has any specific anti-spasmodic
action. In fact, the companies manufacturing dipyrone (mainly
Hoechst) use to claim this/ but this has never been demonstrated,
at least on clinical grounds. What was said in the meeting was
that in acute renal colicy pain the usual therapeutic strategy is
firstly giving an oral analgesic in adequate doses (acetylsalicylic
acid or paracetamol), and if this is not enough (as is the case in
a proportion of patients) t opiate derivatives - preferably
meperidine (pethidine) - should be given. It was said however
that doctors in India are reluctant to use opiate derivatives,
mainly because this reeds using a special prescription. The same
situation exists in my country and in other European and Latinamerican countries in this respect. This is due to the fact that
some clinical trials and the everyday clinical experience show that
90-95% of cases of colicy pain can be successfully treated with a
parenteral non-steroidal antiinflammatory drug. The meeting exam
ined this question and considered some facts s (1) the only non
steroidal analgesic/antiinflammatory-drug which is available for
parenteral administration in India is dipyrone; (2) it is
difficult to set up a list of "essentials1' without taking into
account the therapeutic traditions s dipyrone is an effective
analgesic, while it seemed difficult recommending doctors not to
use it or not to use another parenteral antiinflammatory drug in
case it is marketed in the future.
Dipyrcne, like all drugs, can cause adverse effects, sometimes
severe and even fatal, Rapid intravenous injection can cause
hypotension and shockj. particularly in patients who experienced
cutaneous rash or edema in previous treatments, It can also
cause agranulocytosis. The risk of hypotension can be minimised
by slow injection..: according to the data we have from our
hospital, where dipyrone is used in these selected patientsBecause of the risk of agranulocytosis/ dipyrone does not seem
to be a first choice oral analgesic for any kind of pain. The
majority of clinical trials (not many) suggest that dipyrone is
as effective as aspirin, no more, no less. Aspirin increases the
risk of gastrointestinal hemorrhage (GIH). The risk of GIB
associated to dipyrone is not known, but it probably exists.
In fact, the use of a non-steroidal analgesic/antiinflammatory
agent always necessarily carries a risk of GIH.
10
The results of the International study on Agranulocytosis and
Plastic Anemia have been published in JAMA in October. I enclose
a copy of the paper. My summary regarding your questions would be
that agranulocytosis is a very rare disease, and a very rare
complication of dipyrone administration. Paradoxically however#
the risk' of suffering agranulocytosis associated to the use of
dipyrone is high. "Risk"
Risk is a comparative and relative concept.
The risk of breaking one’s leg is low while you stay at home in
winter, with snow and ice outside. The risk increases by say 1/000
or 10/000 if you go outside, but it is still very low. For
dipyrone, as indicated in table 5 of the manusceipt, the risk ,
may bo 20-30 times the risk if you don't take dipyrone, but it is
still of 1 in 100,000 or 1 in 1,000,000 if you do take dipyrone.
On the other side, the use of dipyrone does not seem to increase
the risk of aplastic anemia. Aplastic anemia has a mortality
rate of 49% two years after its diagnose, which compares with a
fatality rate of 9% for agranulocytosis. However, fatality rates
obtained in the study (Spain, Ita ly# Germany, Sweden, Hungary,
Bulgaria, Israel) cannot be easily extrapolated to your country.
It is obvious that the results of the study - as with any studybwill be used by the company with promotional aims. What we need
is careful reading of this study# and then comparing different
alternative drugs in the light of all the information on beneficial
and adverse. effects that we have about them.
I hope this letter will be helpful to you.
Yours sincerely#
.■••.■■J
’
-■?
Best regards#
Sd/- Joan-Ramon Laporte*
11
ANN EXU RE
III
DIPYRONE - WHAT ARE THE
ALTERNATIVES ?
Fever
Paracetamol (Acetaminophen) s 0.5 - 1g
Acetyl-salicylinc acid (ASA) 2 0.5- Igc
For children under 15 years paracetamol is the drug of first choice,
j viral infections may develop a Reye
Children with otherwide harmless
encephalopathy)
after intake of ,ASA.
svndrome (liver necrosis with c...—j.--- x-—
(1) Drug treatment has to be supported by physical measures such as
wet compresses around tee lower legs. There are no adequa e
studies proving the particular superiority of dipyrone in the treat
ment of fever so that this widely held notion seems to be unfounded.
Dysmenorrhea
Ibuprofen
Naproxen
Other non-steroidal anti-inflammatory drugs (NSAIDS)
ibuprofen and naproxen are
■ Moause psltol
.
abdominal cramps is caused by certain metabolites of the arachidonic
acid (prostaglandine). (2) Non-steroidal anti-inflammatory agents
are/ therefore/ superior to common analgesics.
Biliary Colio
Pethidine
Mosphine plus isosorbide dinitrate (ISDN)
The combination of morphine parenteral with ISDN is neces|ary in
order to compensate for the spasmogenic effect of morphine to the
unstriated muscles of "he biliary tract and the intestine.
efficacy of ISDN is better than that of spasmolytics. If necessary,
treatment can be continued with morphine oral and ISDN. Instead
of morphine, any other opiate can be taken.
Renal Colic
Viz. .biliary colic. additionally diclofenac, 7Smg i.m.
In a comparative analysis diclofenac 75mg i.m, Prjved to be more
effective than pethidine lOOmg i.m. (3) Further studies confirmed
this pain-killing effect for biliary colics, too. U)
Postoperative and posttraumatic pain
Morphine
Buprenorphine
Other opiates
"■ ■ an operation or
Since at least during the first few days after
pain-relieving
treatment
trauma pain is severe and continuous/ 1
should be carried out according to the clocx (such as morphm
every four hours, buprenorphine every six to eight hours) •
of effect
of the
Dosage intervals vary according to the
th_ duration
--- -=ntiopiate used. NOn-steroidal anti-inflammatory agents or anti
pain-relief
Phlogistics are contra-indicated for subsidence and pam-r^lidue to the risk of renal insufficiency (5) and should not h
used before the fifth day post-traumatically and only m case of
normal renal function.
-
’
•
-
12
Tumor pain
Morphine oral
Other opiates
There are a number of therapeutic regimen which are all based
on the duration of effect of the drug in order to find out the
necessary analgesic dosage and to apply the drug according to the
clock. For the retarded morphine the duration of effect seems to
be eight hours/ just like for buprenorphine. The analgesic effect
of partial agonists such as buprenorphine or pentazocine is
limited so that a higher dosage does not necessarily mean a higher
analgesic effect.. When opiates are used permanently they regularly
cause spastic obstipation which can be treated with laxatives.
Other severe pain
Paracetamol (Acetaminophen)
(0*5 - 1 g) plus codeine (50 - 100 mg)
When an analgesic such as acetyl-salicylic acid (ASA) or paracetamol
alone is not sufficitrc the analgesic effect can be increased by an
effective dosage of codeine (at least 50 mg) . The effect of duration is - for both substances five to six hours so that a painrelieving treatment is possible by an administration every four
hours.
Results s Dipyrone (NOVALGIN, 3ARALGIN etc) can be replaced by
better tolerated or more appropriate- analgesics in all fields of
indication. In many industrialized countries with a similar
health care system dipyrone has been banned, without any restrict
ions of therapeutical possibilities in the care of patients being
documented.
Source s Arznei-telegramm, Berlin (FRG), November 1986/ p.106-107.
AWEXURE
IV
Prepare tic .n r
ASPIRIN BP Many commercial preparations are available/ e.g. Aspro
(Nicholas)
”
Nu-seals Aspirin (Lilly). Acetylsalicylic acid in enteric coated
tablets.
SOLUBLE ASPIRIN BP Once again many commercial preparations are
available e.g. Solprin (Reckitt and Coleman). Aspirin 300 mg/
Calcium carbonate 100 mg/ Anhydrous citric acid 30 mg.
AMYTRIPTYLINE BP Laroxyl (Roche). Lentizol (Warner). Tryptizol (MSD).
BENZETROPINEMESYLATE BP Cogentin (MSD).
CHLORDIAZEPOXIDE HYDROCHLORIDE BP Librium (Roche).
CHLORPROMAZINE BP Largactil (May and Baker).
DEXTRO PROPOXYPHENE HYDROCHLORIDE BP Colsan (Lilly) . Dextropropoxyphene
hydrochloride 100 mg and Acetyl salicylic acid 325 mg.
Doloxene (Lilly) , contains Dextropropoxyphene napsylate equivalent
to 6.5 mg of the hydrochloride.
Doloxene compound 65 (Lilly) z formulated as for Doloxene but con
taining acetyl salicylic acid 227 mgz Phena cetin 162 mg/
Caffeine 32.4 mg.
Distalgesic (Dista), containing 32,5 mg. Dextropropoxyphene hydro
chloride and paracetamol 32.5 mg. Napsalgesic (Dista), which
contains 500 mg acetyl salicylic acid in addition to Dextropropo
xyphene napsylate 50 mg.
DIAZEPAM BP Valium (Roche) .
’» 118 (Duncan/ Flockhart).
DIHYDROCODEIN TARTRATE BP D.F.
tablets or injection
DIPIPANONE HYDROCHLORIDE BP Deconal
1
(Burroughts Wellcome) •
13
ETHOHEPTAZINE CITRATE USNF Equagesic (Wyeth) • Ethoheptazine
citrate 75 mg. Meprobamate 150 mg. Aspirin 250 mg and Calcium
carbonate 75 mg,
IMIPR.AMINE BP Totranil (Geigy) . Berkomine (Berk).
ISOCARBOXIDE BP Marplnn (Roche) .
MEPROBAMATE BP Eguanil (Wyeth) . Miltown (Wallace labs)♦ Mepavlon(lCI)
NIALAMIDE BP Niamid (Pfizer).
NORTRIPTYLINE BP Aventy (Lilly), Allegron (Dista) . Altilev(Squibb).
PAPAVERETUM Omnopon (Roche) .
PARACETAMOL BP Many proprietary preparations contain this compound,
such as Panadol (Bayer) , Myolgin (Duncan, Flockhart), paracetamol
200 mg, codeine phosphate 5 mg, calcium aspirin 250 mg, caffeine
citrate 15 mg and acetomenapthone 1 mg.
PENTAZOCINE HYDROCHLORIDE FORTRAL (WINTHROP)
PHENELZINE BP NAt^DIL (Warner)
PROMAZINE BP Sparine (Wyeth) .
THIORIDAZINE HYDROCHLORIDE BP Melleril (Sandoz)
TRANYLCYPROMINE SULPHATE BP Parnate (Smith, Kline and French).
TRIFLUOPERAZINE EP Stellabid (Smith, Kline and French).
ANNEXURE VI
Table - Examples of appropriate analgesics for seme
clinical problems•
Analgesic
Condition
Sprained ankle
Simple headache
Aspirin
Aspirin or paracetamol
Pain following dental extra
ction
Aspirin 4- codeine or
Mild sciatic pain
)
Paracetamol -1- dextropropoxyphene
Severe sciatic pain
Moderately severe post
operative pain
(e.g. orthopaedic)
Dihydrocodeine or buprenorphine
Dihydrocodeine or buprenorphine
Severe post-operative or
traumatic pair
Severe intractable pain of
malignant disease
Acuta myocardial infarction
Morphine, diamorphine, or
buprenorphine
Morphine, diamorphine, dipipanone,
dextromoramide etc. (see text)
Morphine or diamorphine
Acute abdominal pain
Pethidine
Pethidine
Pain of labour
14
ANEXLTRE - VII
Table - Some pain syndromes with specific analgesic
treatments*
Condition
Treatment
Dy sme norrh oe a
Bone pain from metastatic
malignant disease
Bone pain from metastatic
pro s tatic carc inoma
Trigeminal neuralgia
Diabetic neuropathy
Lightning pains of tabes
dor/sails
Migraine
Mefenamic acid
Narcotic analgesics + indomethacin
Pains associated with giant
cell artcritics and poly
myalgia rheumatica
Post-herpetic neuralgia
Stilboestrol
Carbamazepine
Acute - ergotamine/ paracetamol +
Me toelopramide
Prophylaxis - pizotifen (see p.509)
C ortic o s teroid s
Carbamazepine or valproale + a
tricyclic antidepressants
ANEXURE - VIII
Table - Drugs used in the symptomatic treatment of pain
Non-narcotic analgesics (mild to moderate pain)
Aspirin (p., 740)
Paracetam i (p#721)
Some non-steroidal anti-inflammatory drugs (see Tabid 30,1)
Combinations of non-narcotic and weak narcotic analgesics
(mild, to moderate pain) <
Aspirin or paracetamol plus..codeine>
Aspirin or paracetamol • plus dextropropoxyphene.
Narcotic analgesics (p.713)
Mild to moderate pain
(Codeine)
(Dex tropropoxyph ene)
Dihydrocodeine
Buprenorphine
Pentazocine
Severe pain
Morphine
Diamorphine
Buprenorphine
Pethidine
Dex tremoramide
Dipipanone
Methadone
LEPROSY FOR THE GENERAL PRACTITIONER
Dr. Yogesh S. lYlarfatia, IY1.D.
28, Sonali Society
3o_qk 1 et by
BOIY1BA.Y LEPROSY PROJECT
6/27, Amar Bhuvan,
Si on' (East)
Bombay 400 022
Kareli 8aug
Baroda
LEPROSY
Defi niti cn
- Leprosy cr Hansen’s disease is a chronic infectious disease.
- Affecting primarily the peripheral nerves, also the skin,
mucous membrane and some internal organs excluding the spinal
cord and the brain.
Causative organism
V
- Fycobacterium leprae.
- Discovered by A. Hansen in 1873 in Noriuay.
- Nontoxic and of low pathogenicity.
- Rod-shaped bacillus.
- Stained pink by Siehl-Neelscn stain (Acid-fast).
- Uniformly stained bacilli are ' ccnsid.ersd to be viable.
- Fragmented or unevenly stained bacilli are possibly1 dead.
- E.ultiplication time is 12-13 days.
- Can survive uptc 40 days (experimental evidence) outside the
human body.
- Da net grow in the artificial culture media,
- Can multiply to a limited extent in the foot-pad of mouse in
the laboratory.
- Grew well in animal called the Armadillo found in North and
South America (A possible basis for a vaccine).
Incubation period
- 2-5 years.
- Rarely may be as short as 6 months cr even more than 10 years.
Transmission
“ Rsssrvoir of infection (source); Untreated infectious1 cases
fiepromatous andTHrHerline lepromatous cases).
- Untreated lepromatous cases harbour millions of viable bacilli.
“ Sites Mainly nasal mucosa and infiltrated skin of lepromatous
leprosy.
“ Exit °F
Leprae?
- Discharged while nose blowing and sneezing.
2
- Through the ulcerated skin cr nodules cf lepromatous cases.
“ ll-lt.13 = Bacilli are not discharged through the commonly 38 sn
plantar ulcers (which, are caused by other factors).
"" Rcuts cf entry ?
— Most likely to b.e the Respiratory tract thrcu□ h droplet or
airborne infection.
- Direct skin-tc skin transmission or prolonged contact is less
important (conjugal leprosy incidence is very low).
- Cnee the bacilli enter the body, they are transported to other
sites by the blood stream.
- Whatever, the method of transmission > only a small proportion cf
suscsptibles develop ths disease.Immunopathology
As in other diseases susceptibility to the organism determines
the severity and extent of infection.
~ The majority of the population is immune to the di soase.
- A small percentage is susceptible (about 1-2%).
- Only those who cannot develop adequate immunity are likely to
develop one of the types of leprosy.
- Bacilli lodge preferentially in the Schwann cells of dermal and
peripheral nerves.
CLASSIFICATION OF LEPROSY
(Simplified)
Noni nf ecti o us
Indeter
minate
1 ep ro sy
Tuber
culoid
leprosy
Ii
Neuritic
leprosy
Mildly
infectious
Highly
infectious
I
Corderline
Lepromatous
leprosy (or leprosy
mixed type)
These near
Tuberculoid
side are less
inf ecti ous
International Classification of Leprosy of Ridley-Jopling
(for Research purpose)
Indeterminate
_________
I
Tuberculoid
(TT)
Borderline
tuberculoid
(BT)
Mid Borderline
(BB)
Borderline
lepromatous
(BL)
Lepromatous
(LL)
3
CLINICAL FEATURES
Type c f
leprosy
Clini cal
Descript!on
Indeter
minate (l)
I nFectivity
Diagnesi s
Prognosis
One or Feu
(limited
number) Faint,
hypepigmented,
Fla t patches,
anywhere on
body with
anaesthesia or
hyposthesia.
Nerves not
t hi ck ened.
Skin smears
From patches
are negative
For IY]. leprae.
Noni nFecti ous.
Clinically
diagnosa ble;
skin biepsy
may ba
necessary
in doubtFul
cases.
Excellent;
completely
curable,
possibly
lui t h
residual
scar or
sensory
, changes.
Tuberculoid
m
One or more
(1-3), raised,
well-deFined,
hypepigmented
or pink,
anaest heti c
patches;
cutaneous
nerves may be
thickened.
Smears From
skin patches
are negative
For Fl.leprae.
Non
in Fectio us.
Clinically
diagne sable;
skin biepsy
not
required.
Excellent;
completely
curable,
possibly
ui t h
residual
scar or
sensory
changes.
Borderline
(B)
Multiple raised
or Flat,
hypopigrnented
or red, Hi
de F i n e d margins,
hypesthetic
skin patches;
ulnar, and
personeally
nerves may be
thickened.
Smears From
skin patches
may be
mi Idly
positive For
Fi. leprae.
Fiildly
inFecticus.
Clinically
d i a g n o s a b 1 c;
skin biopsy
not
necessary.
Good ;
reactions
likely to
occur.
Curable
iF treated
eFFici entiy.
Lepromatous
(L)
c.' PU3LIC HEALTH
I .TPO STANCE.
Generalized
Smears Frc?m
Clinipally
Good, iF
inFiltration,
earlobes or •'
o'
i a gnosa bls treated
shiny Face, ,
any part oF
eFFicientears, partial
body and.
•ly.
loss oF (eyebrows, nasal
- mucosa
Reactions
swelling and
scrapings
generally
nodules on
are highly
occur.
earlobes, Face,
posi ti ve
Drug
or other parts,
For Fl.leprae.
resistance
edematous hands Highly
possible
and Feet, nasal inFecticus.
iF inade
stuFF iness;
quately
one or more
treated.
nerves may be
t hi ck ened.
OF GREAT PU3LIC HEALTH
IMPORTANCE.
4
Nerve Involvement in Leprosy
□ amagc-Uy,
or
sensori-motcr (if mixed nerves-are damaged).
Thfe following nerves which are easily pclpiable are commonly involved^
Fa c e ?
Supracrbital and Infraorbital nerves.
(Though the
facial (Vllth C racial) nerve is invelved, it'is not
palpable).
Neck s
Great auricular nerve.
Upper limb;
Ulnar, radial cutaneous and medical cutaneous
nerve of forearm.
_Loluer limb2
Common peroneal, superficial peroneal (musculo
cutaneous), sural and posterior tibial nerves.
Types cf Neuritic leprosy
(A) Neuritic leprosy net associated with
skin lesions, (primary
neuri ti c).
A single cutaneous nerve, nerve trunk
or multiple nerves may be
involved.
Nun-infectious.
Clinically diagnosable.
Nerve biopsy may be necessary
necessary sometimes.
sometimes
Thts prognosis is good if chemotherapy
x
-r-/
and
physiotherapy
are given
and anaesthetic ?limbs
'
•
protected
from injury.
(B) Neuritic leprosy associated with
skin Issions.
Nerve damage is iseen 1..
w
;,
w
in ths_entire spectrum of the disease from
tuberculoid to lepromatous leprosy,
Single to multiple nerve
involvement is seen.
Clinically diagnosable.
Note
(A) 75-80fa of leprosy cases are Non-infecticus.
They do not
aischarge ffl. leprae either through nose or skin ulcers.
- They are not a Public health Problem.
(B) 20-20% of cases are Infectious.
They discharge Hi.leprae either
through nose or ulcerated skin.
They are a Public health Problem.
(C) Smear positive case or positive
case ?
IT;, leprae in his skin smears.
A patient showing
(D) Negative case; A patient one who does not
show DI. lepras in
his skin smears (Non-infsetious case).
(£)
shnflfnnar^iiiUS C3?S ^oomin9 negative; A patient previously
ln hiS Skin smcarsNow does not she
7
SfctKS!’as a
°f ■'l’quals
w any
rendered
5
COmmON CLINICAL PRESENTATIONS:
A patient may come for —
A
0
1) Skin patches.
2) Areas of
anaesthesia.
3) Shiny, red face
or cars.
4) Nodules on face
or ears.
5) Nasal bleeding
with stuffiness.
6) Neuritic pain
or joint pain.
7) Sudden swelling
of face, hands
and feet.
8) Eruption of
red lesions
sometimes
after
delivery.
r
1) Anaesthetic hands
and feet.
2) Tingling and
numbness.
3) Clawing of fing er s
or toes and
oedema of the
f set.
4) il/sakness of muscles
of limbs.
5)
1) Recurrent
burns or
blisters
while ccoking
or smoking.
2) Non-healing
plantar ulcers.
Foot drop.
DIAGNOSIS OF LEPROSY
(A) Obvious case
I
v
’4'
Non—itchy skin
patches,
hypo-pigmented
and anaesthetic.
Generali sed
inf iIt rati on
or
Shiny nodules
(Positive for
Hl. leprae) .
Thi ck cned
nerves.with
or without
tenderness
+ peripheral
anaesthesia,
\i/
Deformities of
hands and feet
with anaesthesia
with or without
nerve thickening
(similarly with
plantar, ulcers).
(b) Doubtful case*
Shiny skin
Skin smears
Lor iT. leprae.
*
Skin patch
Sensory
changes
Plantar
ulcer
Sensory c r
motor changes
Skin biopsy.
Nerve
biop sy.
Ne r ve
biopsy.
Electromyography.
Even
with ■
a 3p%£
on clinical grounds
9 family history of
Il
6
leprosy especially of theinfectious type.
Such cases may be referred to leprologists for investigations
orkept under observation for 6-12 months. During this period
clinical signs may become more evident.
Note
1)
To test for anaesthesia, use pin (pain) , cc?ttcn wool (touch) and
hot water in test tube (temperature),
One of the modalities
may be lost.
2)
For skin smears — doctors may contact nearest leprosy.organ!ra
tion and avail themselves of the facility.
DIFFERENTIAL DIAGNOSIS
Leprosy
A)
c)
Flat
patch
Nodules
Other diseases
Leprosy
Other diseases
1) Tineaversi color.
2 A vi tami nosis.
3 Helminthiasis.
4) Seborrheic
dermatitis.
5 Vitiligo.
5 Qirth marks.
7) Scars.
a)
1) FiiUltiple
neurofi
broma .
0)
Peripheral
Nouropa thy
with or
wi thcut
plan ta r
ulcer.
1) Alcoholic
neuropathy.
2) Hereditary
Sensory
neuropathy.
3) Diabetic
neuropathy.
4) Cervical and
lumbar spinal
syndromes.
Raised
pat ches
Psoriasis.
Ringworm.
Lupus Vulgaris.
Lupus
cry thsmstosus.
5) Secondary
syphilis.
1)
2)
3)
4)
6) Drug reaction.
7) Urticaria.
2) Cutaneous
leishma
niasis.
E)
Claw
hand
1) Nerve
injury.
2) Pressure
neuro
pat hi es.
F)
Foot
drop
Lateral
popliteal
injury or
pressure on
the same
nerve.
2) Lumbar disc
syndromes.
G)
F a ci al
palsy
1)
Bell's
palsy
H)
UJri st
drop
(rare)
1) Injury to
radial nerve
(e.g.injections)
!■
1)
7
REACTIONS IN LEPROSY
(Acute episodes in the otherwise quiescent course of disease)
Precipi tati n-g
cters
_ ’> ? ■ Any infection (septic foci, tuberculosis,
malaria, f ilariaj~ common
c:...
ccld, delivery, physical and mental stress,
and drugs.
JJithout Neuritis
'Jith Neuritis
Pure nerve
reaction
Type-I:
Tuberculoid
and
Borderline
cases
(Reversal
type).
Existing skin
lesions become
red, edematous,
new lesions may
appear. Nerves
are not tender.
Along with skin
manifestations;
Nerves become
severely tenderNerve palsy,
may result.
(Type I & II)
lithcut any
skin manifes
tations, only
nerves may
become severely
tender and
painful;
nerve palsy
may result.
Type-II?
Leprcmatous
and
Borderline
1 epromatous
cases
(Erythema
Nodosum
Leprosum-ENL)
a ) Erythematous ,
tender,
cutaneous
nodules (ENL)
or
Marked nerve
pain,
tenderness
with ENL or
SON.
b) Subcutaneous
tender,
nodules (SON)
with or without
joint pain.
Usually Type-II reactions are associated with systemic manifestations like fever, body-ache , joint pain, malaise etc.depending
on the severity of reaction.
Sequelae of Reactions in Leprosy
1)
Paralytic defcrmities?
2)
Non-paralytic deformities? C__
Due to involvement of small joints
and soft tissues of hands and feet.
3)
Eye complications?
4)
Nephropathy s
amyloidosis.
INTEGRATE
Due to increased nerve damage•
Iriti s, lagophthalmos and finally blindness.
Recurrent, improperly treated ENL predisposes to
LEPROSY
INTO
GENERAL
HEALTH
SERVICES
8
Availability of Antileprosy drugs
1)
Tab. Dapscne or Novcphone available in 100
mg., 50 mg. , 25 mg. ,
10 mg. strength.
2)
Cap. Rifampicin available in 150 mg. and 300 mg. strength.
3)
Cap. Hansepran (clofazimine) available in 100 mg. strength.
NOTE ON ANTILEPROSY DRUGS
Dapsone
1)
Administered any time after cr before meals.
2)
Specific bacteriostatic, rvery safe and cheap drug.
continued for many years),
3)
llith daily dosage of log
without a break, infectious patients
become less infectious within 9-12 months.
(Can be
iSBfun9dn!= bs a^inistsrsd throughout the period of pregnancy
in full dose.
It has no deleterious effect on embryo or foetus.
5)
In anaemic patients, dapsone is given with antianaemic
6)
Irregular and inadequate treatment leads to
emergence of dapsone
resistant strains of IY), leprae.
2)
Dapsone therapy is not the main
r ‘
causative factor for the
development of reactions in leprosy,
,. Hence it should be
continued in full doses during the period of reaction in
combination with anti react!cnal drugs.
8)
Very occasionally dermatitis, jaundice and fixed drug eruptions
maybeobssrved.
?
therapy.
Rif ampicin
1)
2)
Administered on empty stomach in a single dose.
antileprosy drug.
makes infectious
patient much less infectious within 4-5 weeks.
(However these
p tients do not become smear negative within this period).
3)
Irregular therapy may lead to rifampicin resistance.
r
It should be always given in combination with dapsone or other
antiisprosy drugs.
5)
During rifampicin therapy oral contraceptives become ineffective
and steriods become less effective.
6)
Hepatotoxic drug (Use the drug with care and stop if Jaundice
appears).
7 )
Occasionally causes anaemia, itching and rarely renal failure.
■
Clofazimine
1)
Best administered after meals.
4
Bacteriostatic action, similar to dapsone.
3)
Useful in lepra reactions if used in higher doses.
I
9
4)
The following side effects should be explained to the patient.
a) Coppery red pigmentation of body.
b) lothyotic changes in ths skin of extremities.
c) Red coloration of conjunctiva , urine and sputum,
d) Occasional acute abdominal ppain with vomiting and
diarrhoea (drug to be stepped temporarily).
------------ ------------j.
VJJ.U4O
I G l_, u o
a ) ,
(b),
The drug need not
be —discontinued
for Olside
effects
(a)
and (c), discoloration
c4-’-- 1-- x
will- gradually subside after cessation
of clofazimine therapy.
5)
No side effect on pregnancy or foetus (baby may have a temporary
red colour),
5)
Irregular therapy may lead to drug resistance.
TREATMENT OF REACTIONS IN LEPROSY
Type I
(reaction in tuberculoid and borderline leprosy)
Type II (ENL in lepromatous cases).
Without neuritis
(A)
Tab. Chlcroquine 9 250 mgm.
1 TDS x 7 day s
1 BD x 7 days
1 0D x till reaction
subsides
(retinal toxicity
to be kept in mind)
And/or Inj.Calcium
gluconate.
10 cc 10% i.v.
daily x 5 days.
Aspirin 1 TDS.
With neuritis
(0)
Tab.Prednisolone (or any ether steroid)
5 mgm.
30-40 mg, daily x 7 days
(SHOULD BE
USED WITH
25—30 mg. daily x 7 day s
CARE AND
20-25 mg. daily x 7 day s
PATIENTS
PROPERLY
15-20 mg. daily x 7 day s
10-15 mg.
daily x 7 days
5-10 mg.
daily x 7 days
2.5 mg. continued till patient
improves.
Continue Dapsone in full
doses.
+ Antacids.
+
Continue Dapsone in
full doses.
Recurrent, Uncontrolled
(Refractory), or steroid
dependent Type I and II
reactions..
Hansepran (Clofazimine)
100 mgm.
1 TDS x 4 ueeks
1 BD x 12 weeks
1 00 x 24 weeks
FOLLOWED
UP, )
No response with Hansepran
(only in Type-II reaction)
Tab.
1
1
1
1
Thalidomide (00-217) 100 mgm .*
QDS x 7 days
TDS x 7 days
RD x 7 days
0D x 7 days
i 0D
cont 'di
I
-10-
10 -
1 Cap. alternate day
or twice a week,
x 8-10 weeks.
(Total duration of antireacticnal therapy is
about 12 months)
Hansepran exerts its antireactional effect only
in high doses only after
4-6 weeks of administration.
Lower doses are without effect
in reaction.
continued till patient improves
+
Dapsene in full dose.
NO STEROIDS
Exerts its effect within 24-48 hours.
Very useful in patients with severe
neuritis.
+
Steroid dose as shown in
Column (B)
+
Dapsons in full doses.
Thalidomide tablets are not available in India. fPatients needing
thalidomide therapy should be referred to specialist centres,,
It
must not be used in female patients.
1)
2)
In addition to above treatment, symptomatic treatment with
immobilization of affected limbs and rest to inflammed parts is
advised, especially in cases with acute neuritis.
In acute nerve palsies (facial palsy, foot-drop), rest with
splints in acute phase, exercises (during recovery phase) are
advised.
3)
Ulcerating pustular reactions may require treatment with
appropriate antibiotics.
The dosage schedule may be altered depending upon the response in a
given case cf reaction.
DEFORMITY IN LEPROSY
(A) Deformity in leprosy occurs mainly due to neuropathy as a result
of inflammatory changes occurring in the nerves.
a) Onset and progress of disease.
b) Effects of damage due to anaesthesia.
c) Reactions (neuritis).
d) Damage to small joints during severe tNL reaction.
(B) Progress of deformities is due to the neglect on the part of
medical persons as well as patients.
Deformities occur due to sensori—motor nerve damage.
i
Sensory changes^ Anaesthesia resulting in recurrent injuries
and secondary infection.
Motor changes s Muscle weakness and contractures.
Types of deformities
Hand; Anaesthesia, clawing and contractures of fingers and
absorption of phalanges.
Fopt; Anaesthesia, clawing and contractures to toes, foot drop,
plantar ulcers, absorption of toes.
Fys j Lagophthalmos, corneal anaesthesia, corneal ulceration.
Management of deformitiess
Proper physiotherapy advise is essential, which can be obtained
from physiotherapists or leprosy specialists.
(Microcellular rubber (MCR) footwear used for anaesthetic feet may be
obtained from leprosy organizations.)
1
Appendix
MULTI-DRUG TREATMENT REGIMENS:
I. lYlultibacillary cases:
(1)
Two weeks intensive treatment at the clinic tui t h dai ly
doses of?
15 Yrs+
600 mg
100 mg
100 mg
Rifampi ci n
Olofazimine
Dap sone
(2)
10-14 Yrs
45 0 mg
50 mg
50 mg
6-9 Yrs
300 mg
50 mg
50 mg
Continuation phase of multibacillary treatment regimen:
(a) Once monthly Doses ior 24 months at the clinic:
Ri f ampi ci n
6 00 mg
450 mg
3 00 mg
Clofazimine
3 00 mg
150 mg
100 mg
Dap sone
100 mg
50 mg
25 mg
(b ) _Daily Domiciliary Doses for 24 months:
Olof azimine
50 mg
50 mg
50 mg
(daily) (alternate days) (twi cs
weekly )
100 mg
5 0 mg
25 mg
Dap sene
11• Paucibacillary cases:
(a) Once monthly Doses for 6 months at the
clini c:
15 Yrs+
Rif ampi cin
Dap sone
600 mg
100 mg
10—14 yrs
450 mg
50 mg
(b) Daily Domiciliary Dosess
Dapsone
loo mg
50 mg
6—9 Yrs
3 00 mg
25 mg
1~ 5 Yrs
150 mg
10 mg
25 mg
10 mg
Nete:
1.
Treatment should be given to („
U1L1
multibacillary
cases
p
month along with domiciliary daily/ treatment for 24once
months.
Patients who remain smear positive at the end of the
prescrioed treatment period should preferably continue the
regimen until bacteriological negativity is achieved"
2.
^ration of 6 months treatment is considered adequate
or paucibacillary cases. However patients who durinq this
puricdof treatment develop now lesions or have extention
regiment8
considered for multibacillary treatment
I C • /&
CABLE:'LOCOST1
LOCOST
134
GPO BOX:
BARODA - 390001
PHONE : 6 396 2
News Letter No. 27/MARCH,90
MEDICINES IN PREGNANCY
Far more care needs to be exercised when medicines are
prescribed to pregnant women than in normal cases. A decision
to use a drug must he made after weighing the possible good
’effects Against the harmful effects it might cause to the
fetus ftnd the mother. Drugs are capable of crossing the
placental barrier and modifying the development of the fetus.
The most vulnerable period for major abnormality ie teratogenesis are weeks ‘ 3-10 of intrauterine life. A safe rule
would therefore. »bo that no medicine should be prescribed
unless absolutely essential.
Following Is a categorisation of some drugs done by
Australian Drug Evaluation Committee. This categorization has
•taken into account all known harmful effects of the drugs on
the developing baby, regardless of mechanism, including the
potential to cause bitth defects, the potential to cause
unwanted pharmacological effects arougd the time of birth
(effects which may or may not be reversible)and the potential
to cause the development of cancer in later life.
This categorisation applies only to recommended ... .
therapeutic doses in women in the reproductive age group. In
conditions such as overdose, occupational exposure and other
conditions where the recommended therapeutic dose is exceeded
it cannot be assumed that the classifications assigned to
individual drugs are valid. When a phamaceutical product
contains two or more active ingredients, the categorisation
of the combiriatJon is based on the most restrictive category
of its ingredients. The categor.i sahi.on is as follows -
Category A :
Drugs which have been taken by a large nunibe
of pregnant women and women of chiIdb^aring
age without an increase in the frequency of
malformations or other direct or indirect
harmful effects on the fetus having been observed.
Category B •
Drugs which have been taken by only a limited
number of pregnant women and women of child
bearing age, without an increase in the '
frequency of malformation or other direct.or
indirect harmful effects on the human fetus
having been observed. This is further -1
classified into-
Group Bl :
Studies in animals have not shown
evidence of an increased occurrence of fetal
^damage.
Group B2 :
Studies in animals are inadequate
and may be lacking, but available data show
no evidence of an increased occurrence of
fetal damage.
Group B3 s Studies in animals have shown •
evidence of an increased occurrence of fetal
damage, the significance of which is condidered
uncertain in humans.
C afc-ego ry q :
Drugs which owing to their pharmacological
effects, have caused or may be
suspected of causing, harmful effects on the
human fetus or neonate without causing • J.
malformations. These effects may be reversible.
(Accompanying texts should be-: consulted for
further details.)
Category. D
Drugs which have caused an increased incidence
of human fetal malformations or irreversible
damage. These drugs may also have adverse
pharmacological effects. ( Accompanying text’s
should be consulted for further details.)
Category X :
Drugs that have such a high risk of causing
permanent damage to the fetus that they.should
not be used in pregnancy or when there is
■'. '‘possibility of pregnancy.
ANALGESICS AND ANAESTHETICS
Opioid analgesics
Pentazocine, Methadone, Morphine,Pethidine
Dextrapropoxyphene.
C
C
Narcotic analgesics may cause respiratory depression in
the newborn infant
during the last 2-3 hours before
expected delivery^ these products should therefore.only
be used after weighing the needs of the mother against
the fetus.
Codeine
A
52iicSteraidal _ anti-inf larnmator^^drugs^
Ibuprofen), Ketoprofen. Naproxen, Phenylbutazone,
Salicylamide, Sodium Salicylate.
Indomethacin, Dielofenac, Piroxicam,
C
C
c
Non-steroidal anti-inflammatory drugs have an inhibitory
effect on prostaglandin synthesis and, when given during
the latter part of pregnancy, may cause closure of the
fetal ductus arteriosus. When given at term, they prolong
labour and delay parturition. Continuous treatment with non
steroidal anti-inflammatory drugs during the last month
of pregnancy should only be given on sound indications.
During the last few days before expected parturition,
agents with an inhibitory effect on prostaglandin synthesis
should be avoided.
Aspirin
Animal studies have shown that aspirin can cause birth
defects in numerous species. There is no conclusive
evidence that aspirin causes malformations in humans.
Drugs such as aspirin with a peripheral inhibitory
effect on prostaglandin synthesis, when given during the
latter part of pregnancy, may cause premature closure of
the fetal ductus arteriosus in animal experiments. When
given at term, they prolong labour and delay parturition.
There is evidence that this also applies to humans.
Intake of aspirin increases the bleeding tendency both
in the newborn child and in the mother. Products
containing aspirin should be avoided in late pregnancy.
C
//
A
Paracetamol
ANTIHISTAMINES AND ANTIEMETICS
Phenothiazines
Prochlorperazine, Promethazine,Trimeprazine,
Thiethylperazine
C
C
When given in high doses during late pregnancy,
phenothiazines have caused prolonged extrapyramidal
disturbances in the child .
Others
Meclozine, Cyclizine, Chldrrcyclizine, Hydroxyzine,
A
Meclozine and related compounds have been shown to cause
birth defects in animals. Studies in humans indicate that
administration of meclozine at recommended doses to women
in pregnancy has not been associated with a statistically
significant increase in the incidence of birth defects.
Brompheniramine, Chlorpheniramine, Dexchlorpheniramine
Diphenhydramine, Diphenylamne, Metoclopramide,
Triprolidine, Cyproheptadine, Clemastine,
Dimeahydrinate, Doxylamine, Mebhydrolin.
A
A
A
A
Azatadine, Terfenadine
B2
ANTIMICROBIALS
Aminoglycosides
Gentamicin, Kanamycin, Neomycin, Tobramyc in Amikac in,
Netilmicin.
D
D
Gentamicin and other aminoglycosides are known to cross
the placenta. There is evidence of selective uptake of
gentamicin by the fetal kidney resulting in cellular
damage (probably reversible) to immature nephrone. Eighth
cranial nerve damage has also been reported following
.in-utero exposure to some of the aminoglycosides. Because
of their chemical similarity, all aminoglycosides must
be considered potentially nephrotoxic and ototoxic to '
the fetus, it should also be noted that therapeutic blood
levels in the mother do not equate with safety for the fetus
Cephalosporins
Cephalexin, Cephalothin,other cephalosporins
\A
Penicillins
Amoxycillin, ampicillin, bacampicillin,
phenoxymethyIpenici1lin, benzyIpenici 1lin,
carbenicillin, cioxacillin.
A
Amoxycillin with clavulanic acid
Flucioxacillin, Mezlocillin, Piperacillin,Ticarcillin
Bl
B2
Quinolones
Nalidixic acid
A
A
A
. ♦ 4. .
//
4
//
Sulphonamide s
Sulphamethoxazole, sulphadiazine, sulfadoxine.
phthalylsulphathiazole .
C
c
Sulphonamides may cause kernicterus in babies during
the first month of life by displacing bilirubin from
plasma albumin. Sulphonamides should therefore be
avoided as far as possible during the last month of
pregnancy.
bapsone
82
1^tracyolines
D
During the period of mineralisation of a child's teeth
(the second and third trimester of pregnancy, the
neonatal period and the first 8 years of life) tetra
tetracyclines may induce hypoplasia of the enamel and di
discoloration of the teeth. Tetracyclines also accumulate
In the growing skeleton. These products should be avoided
during the second and third trimesters of pregnancy.
'
Miscellaneous antibiotics
dhlora^iphenicol
C
Chloramphenicol enters the fetal circulation and, if given
to the mother shortly before parturition, may cause the
drey baby syndrome' with cyanosis and hypothermia, owing
yo the limited glucuronidating capacity of the newborn
infant’s liver. Chloramphenicol treatment should therefore
be avoided during the last week before parturition and
during breastfeeding.
E rythromyc in
A
Metronidazole
32
Natamycin, nystatin
A
C
N i t ro furant io n
Nitrofurantion has had widespread clinical use for many years,
Studies, tx_,
d~.
to date,
have not shown a potential for rm
nitrofurantion
---- 1 to cause birth defects. Nitrofurantion
Gi
j_k.. oo'— o
crosses
the placenta,and caution should be exercised when
:
administering nitrofurantion
at term or to infants under
one month of age because of the possiblity of producing
a haemolytic anaemia due to immature enzyme systems in the
early neonatal period.
Tinidazole
B3
I
Trimethoprim
83
Trimethopriniiay 'interfere with folic acid metabolism and
animal experiments have shown that administration of very
high doses of trimethoprim during organ development may give
rise to birth defects typical of folic acid antagonism.
If trimethoprim is given during pregnancy, folic acid
supplementation may be required.
Trimethoprim- Sulphonamide combinations
C
Sulphonamides may cause kernicterus in babies during the
first month of life by displacing‘bili.rubin from plasma
albumin. Sulphonamides should therefore be avoided as far
as possible during .the last month of pregnancy. Trimeth
oprim may interfere with folic acid metabolism and animal
..5..
k
//
5
//
experiments have shouwn that administration of very high
doses of trimethoprim during organ development may give
rise
5^
Se to,birth defects typical of folic acid antagonism.
If a trimethopim-sulphonamide
combination
iss given
gl
_ during
'
- .
---------- —
pregnancy, folic acid supplementation may be required.
__
J
Antimalarials
ft ' B3
>>
Pyrimethamine
Pyrimethamine may interefere with folic acid metabolism a
and animal experiments have shown that administration of
very high doses of pyrimethamine during organ development
may give rise to birth defects typical of folic acid"
antagonism. If pyrimethamine is given during pregnancy.
folic acid supplementation may be required.
Chloroquihe, hydroxychloroquine
D
Chloroquine and related substances may cause neurological
disturbances in the fetus and interference with hearing
balance and vision. The use of these drugs in the prophy
laxis of malaria is accepted because the small risk to the
fetus with the low doses used is our weighed by the benefits
to the mother and fetus. The use of higher doses in the
treatment of malaria and in the second line treatment of
hepatic amoebiasis is accepted because the lifesaving benefit
of the treatment of the mother and fetus outweigh the risk.
Quinne
D
In high doses quinine causes fetal injuries in the form of
deafness, development disturbances and malformations of the
extremities and cranium in both animals and humans. Its
ability to induce uterine contractions also constitute . a
risk of abortion. In view of the chemical similarity, the^e
comments should also apply to quinidine.
Pyrimethamine-dapsone combination
Pyrimethamine-suIfadoxine combination
B3
Pyrimethamine may interfere with fo‘lic acid metabolism and
if pyrimethamine is given during pregnancy folic acid
supplementation may be required. Sulfadoxine may cause
kernicterus in babies during the first month of life by
displacing bilirubin from plasma albumin. Sulfadoxine
should therefore be avoided during the last month of
pregnancy.
....TO BE CONTINUED IN THE
NEXT NEWS LETTER.
SOURCE^ ’Medicines in Pregnamcy1-Australian Drug Evaluation committee
I.
LOCOST NEWS
On the 24th and 25th of Febroary a workshop was held bv
LOCOST at Bharuch. The aim of the workshop was to discuss the
future role of LOCOST. An evaluation of the present functioning
was also done. Health activitists from all over the country.
some partners, LOCOST
-- advisory group members and LOCOST staff-in all 25 participants
\
5 were present at the workshop. The report
of the workshop will be circulated to all our partners and
other interested individuals shortly.
Ms. Gayatri K Patro has joined LOCOST from Mar 15th.
She would be working in the school health programme and also
assist in publishing Aapnu Swasthaya.
• s RATIONAL THERAPY OF ECZ.EMA s s
Dr. Yogesh S.Marfatia
i
The word Eczema is derived from Greek word "ekzein11 meaning
” to boil out ,l or " to effervesce
Definition ; It is a pruritic papulovesicular process. Its /Acute
phase is associated with erythema & oedema which in its cnronic
phase, while retaining some of its papulovesicular features, is
dominated by thickening lichenification leaning accentuation
of normal skin markings,so that affected skin surface resembles
tree bark-or leather and scaling.) ’ Dermatitis 1 is a loose term
which inclundes all types of cutaneous inflammation, So all'Eczema
are dermatitis,
but no-d* all dermatitis is eczema
Classification
Exogenous Eczemas
1. Irritant dermatitis
2. Allergic Contact dermatitis
3. Infective dermatitis
4. Photo-allergic Contact dermatitis
5. Eczematous Polymorphic light eruption
6. Eczematous dermatophytosis
7. Dermatophytide
Endogenous eczemas
Atopic
Asteatotic eczema ( Xerotic eczema)
Nummular eczema
Gravitational eczema
Pompholyx
Eczema accounts for a very large proporation of all skin (.
disease. Out of 100 patients with skin diseases, 20 to 30 suffer
from one or other form of eczema.
1.
2.
3.
4.
5.
Endogenous Eczemas
The term endogenous eczema implies that the cause or origin
of the eczematous condition is not due to 'exogenous1 or exte
rnal^ environmental factors but mediated by processes orignating
within the body.
■ The most important example is 1 Atopic dermatitis.
Atogic Dermatitis (Atopic eczema)
zYtopy is a genetically determined disorder in which there is an
increased liability to form IgE (reagin) antibodies and an inc
rease susceptibility to certain diseases, especially asthma, hay
atopic dermatitis, in which such antibodies may
fever and
play some role. Atopic dermatitis is the characteristic clinical
type of dermatitis usually associated with atopy. It may be
divided into 3 stages
1. Infantile eczema occuring from 2 months to 2 years of age.
2. Childhood eczema, from 2 to 10 years.
3. Adolescent and adult stage.
The cardinal symptom of all the stages is severe itching,
It is said that in atopic dermatitis, it is ” an itch that
rashes rather than a rash that itches”. This is a chronic
fluctuating condition which may occur at any age.
Infantile Eczema ( Infantile Atopic Dermatitis )s Age of
onset is between 2 and 6 months in majority of cases. Onset
before 2 months is exceptional because coordinated scratching
does not occur before this time.
Sites
Cheeks are the commonest sites ^calp, neck, forehead.
wrist, extremities may be involved.
Moist type is very common. In dry type, there is an excessive
dryness and xerosis that predisposes to eczematization. Popli
teal antecubital fossae are commonly involved.
o
..... •
Exacerbations are observed after vaccination, teething,,respira
tory infections and emotional upsets. Foods may sometimes play
role in early infantile eczema,, Common offending substances are
egg white, wheat, milk and orange. Less than half the cases
clear up by the age of 18 months and in remainder the pattern
changes into that of the childhood phase.
2. Childhood eczema
Classic locations are the antecubital and
popliteal spaces, the wrists, eyelids, face and neck. The constant
feature is pruritus leading to -scratdhingof skin which in turn
results in thickening and lichenification of skin. The condition
is less acute and less exudative but more chronic and more dry
type. There is an increase in sensitization to wool, cat’s hair,
dog’s hair and pollens.
Adult phase : The picture is essentially similar to that in
later childhood with severe itching and lichenification especi
ally of the flexures and hands. Housewives with hand eczema
are frequently atopic individuals. Itching usually occurs in
crisos or paroxysms and is typically absent inbetween emotional
upsets. Sweat retention makes it worse. A chracteristic psycho
somatic relationship is present in many atopies. The other tri
ggering factors may be skin dryness, wool irritation, clothing
and perhaps food. Atopic dermatitis becomes less severe as the
patient grows alder and is rare after middle life.
Points to remember for diagnosisHistory of severe itching followed by appearance of dermatitis
in prefered locations, family history of either asthma, hay fever
or eczema.
2. __________________
Asteatotic Eczema / Xerotic eczema / Winter itch ;- Seen typpically in elderly in winter . Most frequently it occurs on the
extremities, especially on the shins of elderly. Here, the skin
is dehydrated and shows redness, dry scaling and fine crackling.
3. Nummular eczema / Discoid eczema : it is characterised by
a siggle, non-specific morphological feature, the coin shaped
or discoid configuration of plaques of eczema.
Sites preferred are dorse of hands, extensor surfaces of
extremities, buttocks, breastsand nipples. Changes of acute as
well as chronic eczema are seen. Pruritus is usually severe and
of paroxysmal compulsive quality. Emotional stress is usually
present.
Gravitational Eczema - This occurs secondary to venous
hypertension and an increased perfusion of tissues. The terms
"statis eczema ” or ” Varicose eczema ” should now be abondoned
because varicosity of vein is not essential for its development.
The eczema develops suddenly or insidiously, usually on lower
legs and the patients are commonly middle aged or elderly femal
The eczema is usually accompanied by varicose veins, oedema,
purpura, hyperpigmentation and ulcer.
Exogenous eczemas
Con t act De_J_
rmat
it is
Generally
there are two types of dermatitis
caused by substances coming in content with the skin Irritant
dermatitis and Allergic Contact dermatitis..
Irritant dermatitis is due to a non-allergic inflammatory
reaction of the skin resulting from exposure to an irritating
substance . This may be the result of an acute toxic insult to
the skin, as with accidental expoure to acids, alkalis etc., or
due to repeated and cumulative damage from more marginal irrita
nts, both physical and chemical. No previous exposure is nece
•X
ssary. A dry and thick is less reactive than moist and thin.
CQmmQQ^l^ritaQts^s.
Alkalis such as soaps, detergents, bleaches, ammonia prepa
rations, drain pipe cleaners, toilet cleansers.
Acids
Chlorine, Iodine , Bromine, Fluorine
-
Insecticide dust and gases, hydrocarbons.
// 3
//
Occupations with a high risk of cummulative irritant dermatitis
are housework, catering, cleaning, nursing building construction,
hair dressing, gardening and horticulture engineering, motor
mechanics.
2. Allergic contact dermatitis : It is due to allergic sensitiz
ation to various substances that produces inflammatory reaction
in those and only those, who have acquired hypersensitivity
to the allergens as a result of previous exposure to it. It
results from a specific acquired hypersensitivity of the delayed
type which is also known as ’Cell-mediated- immunity1. Persons
may be exposures may be exposed to allergens for years before
finally developing hypersensitivity. Occasionally derm atitis
may be induced upon a sensitised area of skin when the allergen
is taken internally, e.g. Antihistaminics,
sulfonamide.
’Any thing under the sun including the sun.can cause allergy’
Frequent Sensitizers s
Rhus (Poison ivy/dak),
Para>phenylenediamine ^Hair dye, rubber. Photodeveloper,
Nickle (Coinsm Keys, artificial J.wellaries wrist watch, earr
ings ) In fact, we are constantly exposed to nickle and nickle
dermatitis is a fcequent occurence, especially among women due
to presemue of nickle in clothing accessories (hooks, snaps)
Rubber compounds- e.g. Rubber gloves, girdles, garters,Panties,
diaper, sheets, condoms, elastics, boots. Dichromates- in cement,
dyes, paints, shoe leather. Mercury bichloride present in merccurial remedies e.g. mercurochrome and ammoniated mercury.
Mercaptobenzothiazole present in rubber products. Terpentine
Oil present in paints, :^,-.lnt thinners, waxes, varnishes
f'ormaldehyde Solution used in preparing fabrics .
Other Sensitizersj
Plants- trees, grasses flowers, Vegetables like onion# garlic
and fruits like citrous fruits, weeds, etc.
Textile and clothing - Dyes and finishes of fabrics cause derma
titis. Dermatitis is seen in areas of sweating and friction.
Shoe dermatitis- dichrcmate
rubber, dyes.
Metals like Cobalt ( It is combined with nickle as a contaminant)
Arsenic (present in dyes).
Cosmetics- Antiperspirants and deodorants.
- Hair dyes, bleaches, sprays, depilatories.
- Nail Polish, Nail polish remover
- Lipsticks
- Eye make ups
- Sunscreens
- Depigmenting creams
- Mouth washes and dentrifrices
injections.
- Perfumes
/
Applied medicaments - Penicilln, Streptormycin (While giving) /
Sulphonamides, Neomycin, Furacin , M^ercuria,
j
Compound
Antihistamine cream
Local anaesthetic (Caladryl)
Vehicles like lanolin
Preservatives like parabens/ ethylenediamine.
I autors affecting eczema ;
In any dermatitis that persists for 2 or 3 weeks, certain se
condary factors become operative. They are as follows .
Itching s She effects of excoriation and other means used
1.
to relieve itching are important in all types of dermatitis
and these may v^ry from simple rubbing of skin to extreme
trail ma produced in many ways. In addition to mechanical
injury, dermatitis is frequently subjected to the irritant
and sensitizing effects of topical medication and hot water.
// 4 //
2,
Secondary Infection In an area of skin affected by
persistant dermatitis, normal bacterial flora is displaced
by coagulase positive S. aureus, betahemolytic streptococci,
pseudomonas and other bacteria. Fungal infection is
common, as are viral diseases such as herpes simplex.
3.
Seondary Contact Dermatitis from Applied medication ;During an attack of acute dermatitis, the skin is highly
vulnerable. The stratum corneum which acts as protective
barrier is lost and the basal portion of epidermis and
even the dermis of subcutaneous tissues, may be easily
accessible to substances apolied to the subcutaneous
tissues, may be easily accessible to substances applied
to the surface. Lower parts of legs in older persons
are susceptible to allergic contact dermatitis due to
age related structural changes in skin. A chemical that
has been shown to have a low sensitising index on hundreds
of normal skins may show a higher incidence when used
on patients with acute dermatitis.
The failure to recognize irritant or sensitization reac
tions from applied medication is an extremely common error in
the management of dermatitiso
Management of Ecyema
Accurate diagnosis and full assessment of aetiological factors
are of prime importance. Properly elicited history helps a lot
in diagnosis.
Household remedies modify clinical features,.
History
2. Use of OTC products containing Salicylic acid in
high concentration. Vigorous rubbing of such medica
ments lead to chronic Dermatitis.
3. Occupation in detail
4. Hobbies such as Paintin f Gardening, etc.
5. History of a topic tendency is very important.
Avoid contact with known irritant / sensitiyer.
such as Detol
/Avoid antiseptics
Drug therapy *
Systemic - Steroids,
Antibiotics
Antihistaminics
Topical- Plain Steroid
Combination
Others.
Principles of Treatment
Acute eczema4”
Topical application should be bland i.e. without medication)
Wet dressing in form of Pot. Permanganate Soaks is excellent.
It is antiseptic also. Just 1 to 2 crystals in a bowl of
warm water may be sufficient. Its major advantage is that it
is cheap but it causes staining and irritation sometimes.
Avoid shake lotions in oozing conditions, e.g. use of Calamine
lotion leads to crust formation. Warm water / normal saline
hypertonic saline may be used.
Aqueous cream and zinc cream are soothing & valuable.
Moderate potency steroid steroid > antibacterial - combination
(in non-greasy base). /Avoid ointments which have greasy base.
Oralsedative / hypnotic agent may be given if needed.
Extensive eczema may require treatment with systemic Steroid
antibaeteria1 / antihistaminic agents.
. .5. .
...5. .. .
Subacute Eczema - If acute eczema fails to clear in 3- 4 weeks,
carefully seek for perpetuating factors, like exposure to
sensitiyer.
intoleramce to treatment
inadequate or imporper treatment.
Use of domestic remedies instead of proper treatment
Continnous severe itching after starting treatment may be due
to continnous emotional stress.
In such cases of subacute eczema, local application of Cream /
oint / paste / Ichthamol / tar / Salicylic acid, may help.
Continue treatment until healing is complete. Warn the patient
about extreme vulnerability of skin for few weeks.
After discontnuation of treatment, keep the patient under
Supervision Until physical & emotional rehabilitation is complete.
Chronic Eczema a- Secondary factors are of greater importance.
effects of rubbing
Secondary infection.
Sensitization to applied medication amy dominate clinical
picture.
- Persistent eczema may lead to loss of employment & severe
anxiety.
Exclude underlying, systemic disease.
Advise local application of ointment paste of cortico steroid
t tar / salicylic acid and Occlusive dressing.
Intralesional injection of steroid are not required, due to
availability of potent steroids & effecacy of occlusive
dressing, skillful psychologial handling of the patient is
of vital importance. To prevent recurrence, prophylactic use
of emollients & psychotherapy are important.
-
Agent
POPICAL THERAPY
Acute
PRINCIPLES
Subacute
+
1.
Wet dressings
2.
Creams, lotions
3.
4.
Paste
Emollients
+
5.
Corticosteroids
t-!-
6.
Tar, ichthammol
Polythelene occlu sion
Intralesional
steroids
4-
7.
8.
10.
Sedation, rest
Psychotherapy
1 1.
Rehabilitation
+-J-
Chronic
t
++
+
tt
4-+
+
++
4-
tJr
44*
TOPICAL STEROID
CLASSIFICATION
3 methods - direct application
- under occlusion
- intralesional
1.
Class I
Weakest
e.g. Hydrocortisone
Low atrophogenic
Prepered in younger age group / facial skin -
good for maintainance treatment.
Intermediate
e.g. Dexamethasone (Dexatopic)
2.
Flucortolone (Colsipan)
Class II ( Moderately potent )
e.g. Triamcinolone acetonide (cortrima)
3O
Fluocinolone acetanide (Flucort)
Prednisolone , Clobetasone 17 Oc butyrate (Eumosune)
Hydrocortisane bulyrate (Locoid)
Class III (Potent)
e.g. Betamethasone - 17-valerate (Betnovate)
Haleinonide ( Halog^
Beclomethasone ( JBeclate)
4o
Class (IV)
(YgEY_goterit)_
e.g. Clobetasol- 17- proprionate (Tenovate, exel)
Betamethasone 17 x 21 propionate (Diprolene)
Potency is increased under occlusive condition (grain,
axilla, polythelene occlusion )
Gel, lotion, solution preferred in hairy regians.
Ointment proffered in chronic cond
I
1.
Eczema is a steroid responsive condition . So moderate
potency steroids are preferred.
2.
Vehicle selection - Gel, Solution, lotion are prefened
for Acnte dematitis and for eczema in hairy region. Whereas
cream and ointTmay be used fpr sinacite. chromic dermatitis
and eczema on Non-hairy skin.
3.
Drug selection- use more potent agents initially, which
may be tapered to less potent agents slowly.
..7.o
.. 7
4.
Amount prescribed- Theoretically 1-3 gm per 9 % body
surface or 20-30 gm for entire body in 1 application
is prescribed. In practice somce ot os difficult to calculate
the patient should be advised to apply it sparingly over
the patches, 2-3 times a day.
Side effects of topical
corticosteroids
Systemic 2
Suppression of adrenal pituitary axis,
in children growth impairment (neonatal / children skin
more permeable, so more absorption)
cushing syvidrame- in extreme cases.
More observed with - potent steroids
- prolonged appMn.
- occlusiono
Local 2
atrophyStriae
bruices
rosacea like dermatitis.
Perioral dermatitis
Under occlusion 2
Pustvles ( caused by staph)
miliaria ( Sterile pustules)
candidiasis.
Rare side effects
allergic eczemators dermatitis (steroid, base, preservative)
glavcoma (use of potent steroid around eyes for long period)
masking of skin infection (bacterial, fungal)
C 2 Steroid + antibiotic / antifungal combination.
Indications 2
1.
Atopic dermatitis - used initially for 1-2 wks.
2.
Eczema with infection
Eczema in areas like axilla, groin, perianal region.
3.
Use of combinations 2 cortico steroid with antibacterial
or antifungal agents may be advocated under certain circu
mstances only They are.,
.atopic dermatitis with high staph, count eczema with
infection, eczema in axilla, groin or perianal region.
CorticoSteroid with antibacterial_agent like
Neomycin sensitivity is more common over leg and
areas around the eye.
. .8...
8
Pramycetion
Povidone iodine is good becamse it is less sencitizing.
)
Gentamycin
These drugs should be sponed for systemic
Tetracycline ) use only since development of resistance
E. mycin^.
)
& sensitivity of skin may occur.
Corticosterid + Antifungal agents likem hydroxiquinoline is
a weak antifungal agent and imparts yellow, colour to the
skin.
Miconazole Econazole Clotrimazole
Should be used where
chances of candidiasis and dermatophytosis are there, e.g.
Eczema in perianal region, axilla, groin, diaper dermatitis,
(Candida plays important role in diaper deranatitis)
Cortico Steroid + salicylic acid turea as a additive increases
penetration of cortico steroid. Salicylic acid has antimicrobj~1
antimycotic and keratolytic properties. Urea has keratolytic
popular brand of urea and diprosalic keratin that of salicylic
acid,) Coteryl H increases hydration - and so it is useful in
day conditions.
Other topical agents s
Calamine lotion
Zinc paste (emollient ) popular brand name is siloderm.
Tar. Popular brand neme is Pregmatar.
Patient should not add any substance or should not try
to dilute the preparations#
Systemic_therapy •
1.
Corticosteroid
Should be used in actite eczema and generalized subacute
eczema. D© not give systemic cortico steroids in chronic
eczema.
depot preparations Depomedrol Kenacort, are
also available. Kenacort contains 40 mg/ipl of the steroid
Triamecenolone It should be given deep intramuscularly and
is effective for 3-4 weeks.
2. Antihistaminics: As the cause drowsiness and sedation
So occupation of the patient must be kept in mind, while
prescribing.
3. Antibacterial ? Avoid injection pencillin in atopies.
Tab. co. trimoxazole is routinely prescribed these day and
is found effective.
□>
LOCOST
Xi. P. 0. Box No.
Baroda = 390 001.
No;
Malaria, Antimalarial drugs and Chemot.hprany
of Malaria
---------------- Sagun Desai
Introduction
Malaria is still a common. major public health problem
in India.
It is caused by parasitic protozoa - plasmodia and
is characterised by fever with figors,z anaemia and
spleenomegaly.
Once nearly eradicated,- malaria has staged a come-back
because ofresistance developed by plasmodia to
resistance developed by mosquito to insecticides,
bad sanitation and lack of vaccination.
Life cycle of Malarial Parasite and Malarial Infection
nara Jbot^P2Uant.t0 understand the life cycle of malarial
p asites briefly, since the efficacy of drugs in prevention
and treatment
off malaria
depends on species of infecting
^arA^
atmeat-?
malarla Spends
parasite and its stage of development.
Plasmodic infecting malaria are of four types s
(1) Plasmodium Falciparum : causes malignant tertian
malaria, a fulminating infection which proves fatal if
untreated. Delay in treatment may lead to irreversible
shock and death. Early treatment leads to cure without
relapses.
(2) Plasmodium vivax sc
causes^
benign tertian malaria. The
clinical attacks are milder than the falciparum1 attacks
associated with low mortality ceven when untreated but is
characterised by high incidence
---- j of relapse,
(3) Plasmodium Malariae °e causes benign quartan malaria.
relapse occurs at lower frequency.
(4) Plasmodium ovale o oenign tertian malaria like vivax
but milder and more readily cured.
Mosquito - serves as a ]host during sexual phase (vector)
Man - serves as a host duringj ... a sexual development stage.
Infected Female
Anopheles --Mos, Bite
--•
Blood transfusion
J
with infected blood J
5 * * *
Tsporozoites )
! Placental
! transfer
c (mother to
! foetus)
;
j
J
J
•••
•o
Use of contaminated
“
needle by drug abusers
Disappear rapidly from a circulation, Localise in
parenchymal cells of liver, grow, segment
.-and
sporulate. This is 'preerythrocytic stage'' of
infection. Subject remains symptomfree duringJ this stage.
Sporozoites mature to Merozoites in liver
Merozoites rare released in the circulation,
enter the
RBC and start
rt ’Blood cycle’.
-2-
I C : 18
•/
2
Note: Except in cases of P,falciparum, in rest varieties
a few of these merozoites infect more tisaue cells. This
leads to 1 Exoerythrocytic circle1 whicin may continue for
several years. This is responsible for relapses,
o
Merozoites mature, grow and segment in RBC, young
parasites in RBC are called ‘trophozoites’. This is
’stage of schizogony1 and RBC with these trophozoites
is called ’Schizont*.
|
Rupture of schizont
.... liberation of
merozoites ...... infection of more RBC
starting...of new cycle.
......
Note : Periodic breaking of RBC is responsible for
chills of malaria, followed by fever due to liberated
foreign proteins and cell products.
•• Male
microgameto
cytes
* I.Female
microgameto
cytes
N°te : No further development of gametocytes in human
occurs unless the blood is ingested by a female mosquito
G-oino ffiArozoi t.es in kbc -j-4-^^eren
tiate
Gameto
cytes
j
In the gut of the mosquito, <exflagellation of male
gametocytes occurs mkking it motile, followed by
fertilization of the female gametocytes ......
formation of 1 zygote1 in gut wall
Oocyst which
develops**•
contains thousands of infective sporoqoites. Oocyst
develops in the salivary gland of mosquito. The cycle repeats.
Chemotherapy of Malaria in relation to the biology of the infection
There are six categories s
1* Causal prophylaxis — is an agent that prevents
demonstrable infection by exerting a lethal effect on the
malarial parasites during their pre-erythrocytic stages.
Because man is his own reservoir of infection, causal
prophylaxis also prevents further transmission of malaria
to mosquitoes. To be effective, such therapy must continue
as long as the individual is in endemic zone. There is
no true causal prophylaxis as it should kill sporozoites
before they infect RE cells of liver.
Agdnts - Primaquine ( most effective against P.Falci.)
clinically impracticable for this purpose because of
toxicity.
Chloroquanide and pyrimethamine - marketed activity against
P. F&lci. but partially effective against vivax.
-3-
3
2O Suppressive treatment - because of lack of an
ideal causal prophylaxis we need suppressive drug
therapy. Suppression means inhibition of the erythrocytic
stage of development of parasites, so that the infected
individual is kept free of clinical manifestations of
the disease. Infection is not prevented by
suppressive drug. Exoerythrocytic stage persists and
therefore relapse occurs when suppressive' drugs are
discontinued - particularly in vivax.
Agents s chloroquine, chloroquanide, pyrimethamine
Continued suppressive treatment is required to prevent
clinical attacks in vivax. Falciparum infection cured
by such treatment. Suppressives given during periods of
exposure to infected mosquitoes and for a few weeks
thereafter.
3» Clinical cure-- agents in this category interrupt
erythrocytic schizogony of malarial parasite and thus
terminate the clinical attack. Such agents are also called
1schizontocides1.
Agents s chloroquine, amodiaquine (drugs of choice in
vivax and falciparum).
Chloroquanide and Pyrimethamine - effective but
have slower action
Quinine - in resistant cases.
4. Radical cure - means eradicating not only the
erythrocytic but also the exoerythrocytic parasites of an
established infection. Radical cure in vivax malaria
possible only by 8 aminoquinolines (primaquine) given
alongwith chloroquine, persons in endemic areas are not
suitable for this therapy because of the risk of
reinfection (for this reason in India, presently use of
primaquine is not recommended). Because there is no
exoerythrocyticstage in falciparum malaria, proper
treatment of clinical attack is all that necessary and
primaquine is not required.
5. Suppressive cure - means complete elimination of
malarial parasites from the body by continued suppressive
therapythe effect of which is longer than the life span
of the infection. Continue administration of pyrimethamine
for 10 weeks after leaving a malarious area — suppressive
cure of certain vivax infection.
6. Gametocytocidal therapy — drugs in this category
destroy the sexual forms of malarial parasites in human
blood and thereby eliminate the reservoir from which
mosquitoes are reinfected, causal prophylaxis, suppressive
therapy and prompt and adequate treatment of acute
clinical attacks all prevent the development of
persistence of vivax and falciparum gametocytes.
Chloroquanide and pyrimethamine do not destroy gametocytes
but prevent their growth in mosquitoes.
Primaquine in small doses eliminate gametocytes of vivax
and falciparum in 3 days.
Remaining antimilarials are effective against gameto
cytes of vivax but not of falciparum.
4
Antimalarial
I.
II .
Ill
(chemical classification)
Cinchona alkaloids - Quinine
4—aminoquinolines — chloroquine, amodiaquine
8-aminoquinolines — primaquine, pentaquine,
pamaquine
Acridines .- Mepacrine
'■
(quinacrine)
SSojiSl'
■clloSSianll
IV
V
VI
VII
- Pyrimethamine
Miscellaneous - sulfonamides, sulfones.
/ mefloquine etc*
Mechanism of action of antimalariaIs
Antimalarials ) ---- Older agents (chloroquine,
primaquine,quinine, mefloquine)
)
)“
)
--- iPhibito-rs of folate metabolism
(Pyrimelhumine, chloroquanide, "
)
sulfonamides. sulfones, etc.)
sulfonamides,
)"■
Older agents
‘j’x
( if!
schiqontocidal action
scbiqontocidal
difffcSr development
deVelopment of resistance
relatively
unknown. also not
mefloquine.
P^-rmaqum^ and quinine but not with
causes much less change
V-l -?
____ t J
• .
stages of parasite is due to its effectiveness at a ve?71ow
concentration which do not affect host cells. at e
Inhibitors of folate metabolism ;
(
i) schizontocidal action slow in <--- *
onset and depends on
the stage of multiplication
---- ^*1 of parasite.
( ii) resistance develops readily due
and really exists in the fields. to their slower action
a^d
of folic
or folinic
Pyrimetha^iSe and'^JlJ^anidl)^1101'336 lnhibitors ~
Acquired resistance to_Antimalarial drugs
Resistance readily develops to i
’
pyrimidines
and biguanides
but less readily to clinchone alkaloids
""
4-aminoquinolines
and 8—aminoquinolines.
z
5
Resistance develops by selection
of resistant anJ/^3' °CCUrS during massand
v over growth
underdosage and/or malabsorption of drug".prophylaxis due to
Strains resistant to
olerance to other drugs. one drug may aiso exhibit cross
Due to
the value as
has lost
ln many parts
of world have
Pyrimethamine
as a
Of mass suppression. Same
'
a icaulr
result nr
of p
found in vivax
aJaS Zro^-P-falClpan”’S^ ■
developed resistance
of a long actino XU"’ ™°al“quine. However,
effective UZaSZoToX8 ?“lfaao>=lne) o'r a combination
dapsone is
resistance of even multi resisSS":^™^ pyrimethamine
of P.falciparum.
Sc infa ?aSP®as®0i°ht'’i0£SaconelitJit“ proDlem- Resistance is
+-hp
--- - grave problem.
“g,J?lectea "fth malaria naLXU" SX? oopoclty of the
affinity binding sites foCit.
d chsnUes in high
J thin9 is £:«-“-z:.
Many strains of
. also resistant to othe^i^iAo^nn?-^ tO chlOT°quine are
°^>-nolines, mepacrine,
strains. oinlZthounHesJT? ?S
face resistance.'
effective'druZ L^UiZ
SlXXSSiSe
ZS.a9alnst
and Cl
discriminate use of
combination (i.
use
™etakelfin) and
will lead to J lunting of these useful
-- l making
- it a gravely serious
In resistant milaria,
r has been
useful regimens are s
/ . a) Quinine alone —
/. r? Pyrime th amine t still very effective
(m) Quinine + a tet«Z£lne/SU“a‘iiaZlns!/a»Psone
( iv) Mefioqulne
/intima la rials a n d Immunity
of malaria
the a5ZZZZZZe;.°
Onfet Partlal immunity and
Unfortunately
immunity has yet to^rdtiXeranHne tO C°nfer active
drugs and on casually a^SeiSi?jrenti°n dependS on
proPhyJac?tr(sayYch™qu!nI?1%9enerally not take
a
absence of the red cell cvX' \l°r owing to the resulting
immunity so that ahoda they ihZWil1
thei?
ft hl9hV vulnerable ?o SV" USe the Prophylactic
y take a prophylaxis in the fonowlngUU^^^shoula
6
(
(i) If it is virtually certain that they will never stop
it. (ii) if they go to another malarious area where the
strains of parasite may differ or (iii) during the last months
of pregnancy in^s areas of p.falciparum to avert the risk of
miscarriage.
The non immune should receive continuous prophylaxis in
malarious areas. Drugs should be chosen in the light of local
knowledge of drug resistant strains.
Immune antibodies cross the placental barrier and confer
passive immunity on the foetus. The latter, therefore is
protected for some months after birth.
Individual drugs (only common, imp. drugs)
£-• aminoquinolines ? chloroquine, amodiaquine - mainstay of
suppressive therapy.
Antimalarial actions
No action on exoerythrocytic forms therefore not a
causal prophylactic.
Highly effective against the asexual erythrocytic forms
vivax and falciparum and gametocytes of vivax.
A good suppressant. In acute malaria, rapidly controls
parasitemia and clinical symptoms. Patients become symptom free
in 24-48 hours after therapeutic doses and amear negative in
48-72 hours.
Does not prevent relapses of vivax.
Mechanism of action
(
i) interference with DNA synthesis of parasites.
( ii) intereferes with the parasite's ability to digest
haemoglobin, which deprives it of essential amino acids
for DNA synthesis and
(iii) preferential accumulation in parasitized RBC (mechanism
unknown).
Pharmacokinetics
Rapidly and almost completely absorbed from gut.
Slowly Excreted in urine, excretion can be enhanced by
acidification of urine.
Concentrates in liver by several hundred times.
Because of the diversion into tissues and the plasma
protein binding, a priming dose is used in order to achieve
adequate free plasma concentration in the treatment of the
acute attack.
Preparations
Tabs of chloroquine phosphate - 250 mg. (=150 mg.base)
Tabs of chloroquine sulfate - 200 mg.
(
-do)
Tnj. of chloroquine
(40 mg. base/ml.
phosphate or sulfate
)ampoules of 5 ml.
o
o-
7
Toxicity and side effects
Usually well tolerated.
Commen ; mild and transient headache.
visual disturbances
GIT upsets
pruritis
Nausea and vomiting.
Others : skin
‘ rashes,t bleaching of hair, rethinopathy
(on prolonged +treatment
with large doses) cardiac
-nt with
arrhythmias (on i.v. injc.)
Note s (Other 4 aminoquinolines - Hydroxychloroquine
and amodiaquine are similar to chloroquine.
8-aminoquinolines (primaquine)
Antimalarial actions
Highly active against primary exoerythrocytic forms
of vivax and falciparum.
Can act as .causal prophylaxis but no practical
value due to toxicity.
Active against asexual blood forms of vivax but
erratic effect and therefore^ not useful as a suppressant.
Gametocytocidal activity against all species more
^gainst that ef p. falciparum.
Useful for radical cure of vivax malaria.
Supplement to chloroquine when alone is not effective
for suppression.
Resistance has n«t been absenced so far.
M/A acts by Interfering with plasmodial mitochondria
and also binds to DNA like chloroquine
s rapid absorption from gut, moderate concen—
tration in tissues, rapid metabolism.
Preparations : Tabs, of primaquine phosphate 13 17 mg
= 7.5 mg. *f base,o
Toxicity and side effects z Most impt. : intravascular
hemolysis m persons with G-6-PD deficiency, methaemoglobinemia.
Others s gastro intestinal upsets, haematological
dyscrasias, rarely b.p. cardiac arrhythmias.
Pyrimethamine
Antimalarial action
Exerts causal prophylactic and suppressive activity in
falciparum malaria, adequately controls acute clinical attack
and usually eradicates the infection.
Suppressive activity against p. vivax, controls acute
attack put slower action compared to chloroquine. No effect
on exoerythrocytic forms therefore, relapses are common.
Gametocytes are not destroyed but development of
gametocytes aflcysted in the gut wall of mosquito is
prevented.
Resistance is very common.
M/A. • inhibits dihydrofolase reductase specifically
(in very small doses) in malarial parasites. This inhibits
conversion of folic acid to folinic acid which is important
tor metabolism and survival of parasite.
8
Combination of pyrimethamine with sulfonamide —
supraadditive.(synergistic) effect because of
supraadditive
ci ’*sequential
blockade
This prevents
prevents development
development ®f
®f resistance
resistance on
----- --- ’ ’„. This
advantage.
Kinetics g 1weH ^sorbed after oral administration;
long biological half life
= /4 days)
“
; suppressive
concentration maintained in blood---for*
--2 weeks
--- .j following a
single oral dose.
Preparations
Tabs, of 25 mg.(daraprim)
Pyri 4- dapsone (maloprim)
Pyri + sulfadoxin (metakelfin)
( for prophylaxis
( and treatment of
( multiresistant
( infections.
Adverse effects ; No significant toxicity,
large doses - megaloblastic anaemia.
Quinine s Oldest antimalarial drug, became absolete because
of its toxicity and availability of safer and more effective
drugs (chloroquine) but has staged a comeback. Valuable in
treatment of multiresistant falciparum malaria either alone >or
in combination with dapsone/sulfonamide - injection useful
in emergency/cerebral malaria.
Tab. of 300 mg. Inj. 300 mg./ml.
Mefloquine s Structurally similar to quinine developed to
overcome the problem of multi resistant falciparum malaria.
Effective in single d^se - radical cure m/a - not well known
t?*
250 mg. each. Indicated only in treatmenb/prevention
of chloroquine resistant malaria. Not br be used in routine.
Management of malaria ? Prophylaxis g pne of the following i) Two tablets of chloroquine phosphate (0.5 g or 300 mg.
base) once a week <>n fixed day after meals or with milk) .
ii) Two tabs, of amodiaquine HC1 (0.5 g or 400 mq. base)
once a.week as above.
iii) Pyrimethamine (25 mg.
mg. +
+ long
long acting,
acting, sulfa
sulfa 500
5 00 mg.)
mg.) One
One
tablet once a week or two tablets
--- -.
once in two weeks - only
for prevention of malaria due to resistant strains.
Treatment of acute attack g One of the following g
17 Tab. chloroquine 4 Ci.e . 600 mg. base) straight + 2 tabs,
(300 mg.) after ax 6 hrs. Tnen
Then two tabs.
tabs, on day 2 and 3 each
in morning ad a single dnse. Total 10 tabs. (= 1.5 g base) in
3 days. Given with food or milk.
ii) Tab. amodiaquine - 3 tabs.(600 mg. base) followed by
1 tab. (200 mg. on day one and then 2 tabs. 400 mg. each on
day 2 and 3.
iii) Tab. quinine 2 tabs, on day
day 11 and
and 22 and
and then-9
then-9 22 tabs,
tabs.
bd for 5-10 days (only for resistant malaria).
NOTES g
1.
Give oral tablets only as far as possible. Injection of
chloroquine is absolutely unnecessary (except in unconcious
patient or in cerebral malaria) is painful, more costly and
may cause abscesses.
2.
To avoid nausea and vomiting give tablets with food or
milk. If necessary give antiemetic tab. half an hour before
each dose.
3.
After completion of treatment put the patient on weekly
prophylaxis. Attempting radical cure with primaquine is useless
m India at present because of fear of reinfection.
Issues for discussion g (1)Improper choice of antimalarials
inadequatetherapy (2) Variable regiments with chloroquine by
fdoctors (3) Use of chloroquine injection by G.P.S.
(4) se of metaikelfin by doctors.(5) Problem of resistance.
i
14;!?.
r
A SiTRygY OF COUGH JYRUPg.
Objective :
and similar products
proofs usca
various
cough
s
y
ru
Pf
nut
the
or th^ir
rationality
To study the
find
outa one
x
^-.ivqis ox
of the
of
cough
t
to
'
Of
detailed
analysis
in the treatment
for cough, by doing and also finding <out
■-- the cost/
usage in therapy
of
the
mixtures
various ingredients
day’s treatment.
,
(June *86)
expecto •
;^u=ts r
were
rants, cough suppressants, mucolytic
included in the survey.
■ ’ : rationality from ther'They were analysed according to the
as laid
various categories AzB,C..-•
peutic point of' view under
down in the summary part.
-3 of U particular cough mixture
To judge the effectiveness
considered.
£oiio:xrir;x:x i
■; which
(a) ifthe unproduc •
is proven
tivez dry
9 as single constituent.
codeine, etc.z
is to h. expectorated^brough^out).
(b)
If tbe sputum
• i iodide as
x. ectorant and administration
contain an expectorant like Pota|*b
■; expectorant
..... However
for the
j-0 he more oiiic.iCiove
c—
tuent.
other
compounds
.is
nor
of <-expectorant action.
hrnnchitis where? aim is to
(c) In patients of
.^loar°them of excess
j-- , ;--secretions
J^coJl^contain^ronchodilaLors like Ilbutamol, ephedrine, etc
as single constitutent ingredien
guff^
.
cient^Ss^hS ioXd^X^penSodny efficacious.
For therapeutic effeU t eb lets^?
; --- ; liquid
soothing effect
”, one ecu L •
imple sugar
oot for alternatives like drinKing
svrups or sucking a sugar cuoe, etc.
— r to see 111. t
n-inlo ingredients
it other's
is necessary
in case of multiple
X 3
■actions
---in any
the ingredients do not ..ntagonisc
form.
be combined with a cough
bronchodilator with an antie.
hUtmihh or » cough suppressant.. etc.
l advised
with a’ particular formulation
the
The cost of therapy
low
as possible for -■— desired
1
e
e
z
as
—
should be reasonable, . '
action - the tnercipeucxC benefit.
In any case, one has to make' sure
whatever
formulation
is being
iS-hetion
’S
i"t
is
4-v.o nnt-ion for Which it
fiummarv_of ^th^surve^findipj.3 ’
exo la ined > '>e low
The formulations are categorised as
SUP^ ““?hors“hShLtSnrr
Category
A .
B
C
the cough refl'x)
Only Antitussive (can suppress
. bringing out to
•Only expectorant (which help in
s utum)
Only rnucol/tics (which is
contd
2/-
/V
Category
E
Only •bronchodilator (which dilates the bronchi)
Only Antihistamine. (anti-allergic compounds)
F
Expectorant !•
intitussive
G
Expectorant
Broncho 'l i la tor
H
I
Expectorant ;• Mucolytics
Expectorant > \ntihistamines
J
Having more 11ian 2 of the a/B/C/DzE.
K
Bronchodilator
Bron ohodi la tor
D
L
.-intihistamine
Hue o ly t ic s
1
T able
Category
Break uo yaf
Total No. of formulations
80 Irrational
Rational
Formulation
Formulation
A
5
B
2
4
C
2
D
E
6
F
2
G
H
I
7
J
47
K
3
11 (13.75%)
69
(86.25%)
2
Table
Type of f ormu1a ti on
Tablets/capsules
19
Liguids/Syrups
56
5
Other forms
TOT’LL
30
70.00%
6^2.5%^^
100 %
contd. o . . . 3/-
I
3
Table
No. of
B’orinulations
NO. of
Ingredients
%
9
11.25
2
11
13.75
3
20
25.00
4
11
13.75
13
16.25
7
8.75
2
2.50
1
5
'
6
7
6.25
8
1
9
1.25
0
10
0
11
1
1.25
30
100.00
12
Table - 4
------------
—
W.
No. of
Forum latioa's^
~Cost/day for an
Adult
Below Re. 0.50
Re. 0.50 - below 0.95
1-95
Rs. 2.00 and above
Re. 1.00- R- .
TOTAL
1
. 1.36
5
6.84
23
31.50
41
60. 27
73
99.97
Conclusion :
--l to the
raise the basic
-5 in cough
when compared to
irl llexly
liekiy to
to have.
have.
*
I £>: 26
Based on the Essential Drug List of World Health Organisation
and also learning from other experiences# the present lists of drugs
required at Primary/ Secondary and Tertiary health organisations
have been prepared. Initially the lists were worked out to indicate
priority for manufacture/avail ability of thd drugs at any health
organisation. But later on it was felt that the scope be widened
to facilitate a debate on rationality of usage of the drugs.
Certain modifications are made accordingly. The first draft of
the lists was circulated in December# 1986. In the subsequent
meetings of the Rational Therapy Cell of Locost after much deli
berations# the present lists have been prepared. They are typed
and retyped again and again and somewhat final draft has been put
in your hands.
We request you to go through them/ apply in practice and partici
pate in the process of working out the ideal lists of rational
drugs in various health institutions.
RATIONAL THERAPY CELL
L
0
C
0
S
T
1st Floor/ Premanand Sahitya Sabha
Dandia Bazar
Baroda 390 001
OBJECTIVES
!•
To enable the voluntary health projects/private dispen
saries and hospitals to draw their own essential drug lists,
suitable to their own requirements and thus suggest a policy for
their availability to the patients.
2.
To ascertain and draw a list of the minimum drugs required
and give an idea of minimum level of competence and facilities that
may be required to deal with the illness at a given health set up.
3.
To provide a reference list of drugs to ‘the doctor for
making a rational;choice of drugs in the given condition.
4.
To provide a prioritised reference list for stepwise avail
ability of essential drugs in a given health set up.
THE LISTS
List - A z :List of drugs required at a health set up equi
valent to
primary health centre. It may be a small community
health project with not enough diagnostic facilities.
List - B ? In addition to the drugs in List-A, List B
drugs are required at secondary health organisations which has at
least a qualified Medical Officer with some diagnostic facilities
such as a ’ small pathological laboratory, This may be a referal
centre at town or taluka level.
List- C 2 7In addition to the List A and List B, drugs, these
drugs are required to be used at
-3 a tertiary level health set up i.e.
a district level hospital, medical college and teaching.
List - D s These drugs
"
can be handled by the para medical
workers with adequate training.
List - D s All the deviations from the Essential Drugs
list of WHO, as published vide their Technical Report series No.722
are included here alongwith the reasons for the deviation,r in case
of each of them.
PRIORITIES
The drugs in every list are divided into two Priority I
drugs and Priority II drugs. This is from the view point that if
the priority I drugs are made available at each set up, then they
will meet the need for drugs most of the conditions,
The priority II
drugs serve as supplementary to the priority I list, It also
indicates the.priority for usage e.g. Aspirin & Paracetamol^clasLfiod as Priority I drugs at primary health organisation as
analgesic and antiinflammatory drugs, - meaning thereby that in
majority of the cases these -two drags should be able to take
care of the need. Only a few cases ma y need Ibuprofen.
FORMULATIONS
An attempt is also made to suggest the strengths and forms
of each drug to avoid the dilemma of choosing from hundreds of
formulations for each drug.
LIMITATIONS OF THE LIST
!•
The list does not suggest all alternative rational drugs
which may be used in given condition, This implies that the drugs
outside this list are not necessarily "non-essential” or
"irrationals” T^-J
This li: t gives only the list of minimum priority
drugs which have to be made available at particular health set up>
2
2*
It is possible that it may be necessary to use the drugs
outside this list in individual patients. A proper record of
such cases may be kept. It should contain the detailed history/
reasons why the present drugs cannot take care of the condition
and what is the additional advantage of the other drug being
chosen. Such a record will help in the improvisation of the list
after proper review.
APPLICABILITY OF THE LIST
1.
You may be a general practitioner or at a village level
dispensary or in a hospital. These lists will give you a reference
guide to examine the utility of the many drugs being stored or
used at your institution.
2*
Some institutions are faced with a situation where donors
supply a big chunk of drugs/ and the physician in charge is under
pressure to use them even if he/she thinks such drugs as
unnecessary. These lists can be used to act as a reference for
both the donors and the administrators.
3.
A LARGE NUMBER OF DOCTORS BELIEVE THAT THE LIMITED DRUG
LIST WILL HARM THE PATIENTS’ BEST INTERESTS. THESE LISTS CAN BE
A STARTING POINT FOR CONCRETE EXPERIMENTATION IN THIS REGARD. A
FEW CATEGORIES OF DRUGS CAN BE SELECTED AND AN ATTEMPT BE MADE
TO PRESCRIBE THE DRUGS IN THESE CATEGORIES FROM THIS LIST. THE
EXPERIENCES MAY BE RECORDED SYSTEMATICALLY AND OVER A PERIOD OF
TIME - SAY ONE YEAR - A REVIEW CAN BE DONE WITH THE TEACHERS IN
PHARMACOLOGY, COMMUNITY PHYSICIANS AND EXPERTS IN VARIOUS
DISCIPLINE. THS RESULTS OF SUCH A REVIEW BE GIVEN WIDE PUBLICITY
TO START HEALTH AND DRUG ACTION BY SO MANY CONCERNED INDIVIDUALS
AND INSTITUTIONS.
4The Govt* and a large number of public & private sector
companies are giving health benefits to their eipployees* This
list can serve as a guiding list to them and will help them
to formulate their rational drug policy and other health benefits#
•V »• *1
LIST
A
DRUGS REQUIRED AT PRIMARY HEALTH CARS ORGANISATION
Cate
gory
"■
Name of Medicines
Priority 1
■ ^Priority 2
Sr.
No.
Formulation
No,
•i
Anae site tics
1.1
General Anae sthe tic s and Oxygen
Oxygen
1.2
Local Anaesthetics
2.
Analgesics, Antipyretics, Non
steroidal Anti Inflamatory Drugs
and Drugs to treat Gout, „
2.1
Non Opioids
Acetylsalicylic
' acid.
Tab.
3.
Paracetamol
Tab. 500 mg.
Syp, 125 mg/5 ml.
Ibuprofen
Tab,
Tab.
200 mg
400 mg.
Tab.
30 mg.
Opioids analgesies
5,
3.
300 mg.
2.
4,
2,2
Inhalation (Gas)
Codeine
A n ti a 1 le rg i c s
Tab. 4 mg.
Syp. 4 mg./5ml
Inj. 10 mg /ml
Ch"orpheniramine
Maleate.
6
4.
Antidotes, and other substances^used in poisoning
4.1
Genera].
7.
4.2
Specific
Inj. 0.5 mg/ml.
Atropine
0
5.
50 gm sachets
powder.
Activated Charcoal
Antiepileptic s
0,
6.
Antiinfective Drugs s
6.1
Anthelminthic Drugs
10, 11.
Tab. 30 mg.
Tab. 60 mg.
Phenobarbital
Mebendazole
Pyrantel Pamoate-
Tab. 100 mg,
Tab. 500 mg.
Suspension 50 mg/ml.
... 2
O
Z 2
o o
Q
O
List A Contd.
_____ Name of Medicines____
Friotity 1
Priority *2
Cate
gory
No.
Sr.No.
6.2
Antiamoebic Drugs
1:2.
Metronidazole
13.
Chloroquine Phosphate
6. 3
Antibacterial Drugs
6. 3.1
Penicillins
14;
6 .3.3
Procaine benzyl
pencillin.
Benzathine benzyl Inj. 12 lac IU
16.
Penicillin
0 ther antibac terial drugs
* s ter ate or Ethyl
succinate-^
Tab. 250 mg. (as
Erythromycin
17Oral susp. 125 mg/
5 ml.
Tab. 500 mg
15. Sulphadimidine
Tab. 400 mg 4Sulphamethoxazole
80 mg.
+ Trime th oprim
20 a
Tetracycline
21e
Doxycycline
22.
Amcxyciline
Cap. 250 mg (hydroch
loride) .
Cap. 100 mg ( as hydrochloride)
250 mg (as trihydra to)
125 mg /5 ml ^’powder
for oral susp.
Antileprosy Drugs
Rifampicin
Dapsone
Clofazimine
23.
24. -*
25
6.3.4
Cap. 150 mg/ 300 mg.
Tabs. 50 mgy 100 mg.
50 mg. 100 mg.
Cap.
Anti tuberculosis Drugs
26
Ethambutol
27.
Isoniazid
Thiacetazone t
Isoniazid
Antifilarial Drugs
28.
6.4
Tab. 200 mg./ 400 mg,
Susp. 200 mg/5 ml.
Tab. 150 mg/Base
50 mg/5 mil base)
Syp,
Inj. 10 lac IU (sodium/
Inj. 50 lac IU P?ttasium)
inj.
3 lac IU
Benzyl Penicillin
15 ?
6.3.2
Formulation
29.
Diethyl Carbamazine
Tab. 200 mg, 400 mg
800 mg.
Liquid 100 mg /5 ml.
Tab. 100 mg'/ 300 mg<>
Tab. 150 mg + 300 mg
Oral Liquid = 50 mg_/
5 ml.
Tab. 50 mg/ 100 mgm.
' citrate)
... 3
3 ?s
s?
List ’A1 Contd.
Name of Medicines t
priority i
Priority 2
Cate
gory
No.
Sr.
No.
6.5
Antifungal Drug
Pessary of One lakh
unit.
Nystatin
30
6.6
Antilei shmaniasis Drugs,
6.7’
Antimalaerial Drugs
Chloroquine
31
Primaquine
32
6.8
Antischistoscmal Drugs
6.9
Antipanqsomal. Drugs
7.
Antimigraine Drugs
8.
A n ti neopl a stic & Immuno suppreasive drugs.
9. .
An tiparkinsoni sm Drugs
10.
Blood Drugs Affecting the
10.1
Anti Anaemia Drugs
33e
34.
3 5.
Ferrous Sulphate
Folic acid
Ferrous sulphate +
Folic Acid.
10.2
Anticoagulants andAntagonists
11.
Blood products and Blood Sub^
s titute s.
11.1
Plasma substitute
11.2
Plasma Fractions for Specifictuses.
12.
Cardiovascular Drugs
12.1
Antianginal Drugs
12.2
Antidysrhythmic Drug s
12.3
Antihypertensive Drug s
12.4
12.5
Cardiac Glycosides
Drugs used in Shock - Anaphylaxis
3 5-
Epinephrine
Formulation
Tab. tPhOBphate#
Sulphate) 150 mg
(Base) .
Syp. (phosphate/
Sulphate) 50 mg/5 ml.
Tab. (as PhO-'sphate)
7.5 mg.
Tab. 200 mg
Tab. 1 mg.
Tab. 200 mg + 200
micrograms.
Inj. 1 mg/ml (hydro
chloride)
4
:s .4 s s
List ’A1 contd.
-----
Cate
gory
No.
■- Sr ,
Name of Medicines_____
Priority 1
Priority 2
No.
F-o.unulation
-T----
De rm a toloqic al Drug s
13.1
An \J. fungal D rug s
37.
13.2
°int*/Cream 6% + 3%
Benzoic Acid +
Salicylic Acid
3 3^
Nystatin
39,
Miconazole
Anti Infective Drugs
Neomycin"' +
Bacitracin
13.3 '
°int. 5 mg neomycin
sulphate + 500 IU
bacitracin zinc/gm.
Anti inflammatory and
Antipruritic Drugs
4'1.
42-
Calamine lotion
Lotion
°int. /Cream 1%
(acetate)
Hydrocorti s one
Betametho sone
Oint./Cream
(Valerate) 0.1%.
13.4
Astringent Drugs
13.5
Keratoplastic and Keratolytic Agents.
Topical Soln. 20%
«
■
<
Coal tar
13.6
Oint./Cream, 1 lac
IU/gm
Oint/Cream, 2%
Scabicides and Pediculicides
45.
/46.
Benzyl Benzoate
Lotion, 25%
Lindane (BHC)
Lotion, 1%
14.
Diagnostic Agents.
15.
Disinfectants
47.
48^
Solution, 5%
Tincture,2% and 7%
Topical Solution, 1%
Chlorhexidine
Iodine
Gentian Violet
..Im*
16.
Diuretics
17.
Gastrointestinal Drugs
17.1
Antacids and other antiulcer
Drug So
Aluminium Hydroxide +
Magnesium (Trisilicate
Tab. 2 50 mg.-I- 125 mg
Oral Susp. 320 mg/
5 ml.
Oral suspension
equivalent 550 mg
of MgO/10 ml.
... 5
© O
© o
Sr,
No.
17.2
Antiemetic Drus
17.3
Antihaemorrhoidal Drugs
Local anaesthetic,
astringent and
anti inflammatory
drug combination.
Cathartic Drugs
Bisecodyl
17.6
Diarrhoea
17.6.1
Antidiarrhoeal ( Symptomatic) Drugs
17.6.2
55. Loperamide
Fluid Replacement Solution
56,
'
Tab. 1 mg.
Atropine
54.
18i
Ointment.
Anti spasmodic drugs
53.,
17.5
Formulation
Tab. 10 mg, 25 mg.
Promethazine -
52.
17.4
© o
© o
_____Name of Medicines
Priority 1
Priority 2
Cat.
No.
51•
C
Oral Rehydration
Salt
Tab. 5.0 mg.
Tab. 1 or 2 mg.
Sodium Chloride 3.5 gm
+ Trisodium citrate
dihydrate 2.9 gm
+ Potassium chloride
1.5 gm
+ Glucose 20 gm for
1 litre solution.
18.1
Hormones
Adrenal Hormones and synthetic substitutes?
18.2
Androgens
18.3
C on traceptive s
57<
Oral Contraceptive
pills.
18.4
Estrogens
18,5
Insulins and other AntiDiabetic Agents
18.6
0vu1ation Inducers
18.7
Progestogens.
18.8
Thyroid Hormones and Antithyroid Drugs,
19.
Immunologicals
Ethyl Estradiol +
Norethas terale 30 microgram + 1 mgm.
... 6
o
©
o
o
9
List ’A’ Contd.
Cat.
No.
Name of Medicines
Priority”
Priority 2
Sra
. . No.
19.1
Dj^gnostic. Agents
19.2
Sera and Immunoglobulins
19.3
yaccines
19.3.1
For Universal Immunisation.
Inj.
5a
BCG Vaccine
59.
DPT Vaccine
DT Vaccine
Measels Vaccine
Poliomyelitis Vaccine
60.
61..
62.
63-.
Formulation
Inj.
Inj.
inj.
Solution
Inj.
Tetanus Vaccine
NOTE : All vaccines should comply with
for biological
WHO reouirements
J
substances.
19.3.2
For specific groups of Individuals.
20.
Mu sc le Re 1 ax anys. and Cholinesterase Inhibitors
21. •
Ophthalmologic al Preparations,
21.1
Antiinfectiye Agents.
64e
6? >
21.2
Antiinflammatory Agents
21.3
Local Anaesthetics
56
Drops 10%
Eye Oint. 1%
Sulfacetamide
Tetracycline
Solution 0.5%
Tetracaine
21.4
Miotics and Antiglaucoma Drugs
21.5
Mydriatic s
22.
Oxytocics
_________ ,
M.W.. U. Wl 1^ •
Ergometrine
6723.
24.
P.eritonea 1 Dia 1 ysi s Sj^lution
P sych other apeu^tj^Drugs
63.
25.
. Tab. 0.2 mg
(Maleate)
Diazepam
. Tab. 5 mg^
Re spiratory Tract/ Drugs Acting on the
... 7
s s 7 s:
List ’A’ Contd.
Cat,
No.
Sr.
No,
25.1
Anti Asthmatic Drugs
71.
Aminophylline
Ephedrine
Salbutamol
72<
Adrenaline
69.
7Q,
25.2
Name of Medicines_______
Priority 1
Priority 2
Formulation
Tab, 100 mg
Tab.
30 mg.
Tab. 2pasr, , 4 r.xf
Liquid 2 mg /5 ml.
Inj. 1 mg/ml.
Anti tussive s
73.
Tab. 10 mg.
Codeine
26.
Solutions Correcting water Electrolyte, and acid base distur
bance^" . 3
_ __ - ... - - ■ —
r—
26.1
Oral
26,2
Parenteral
26.3
Miscellaneous
7a.
27.
Water for injection
in 2 ml, 5 ml, 10 ml.
ampoules.
Vitamins and Minerals
75.
Ergocalciferol
76.
Retinol (Vit. A)
Tab/Cap. 50000 IU
Cap./Tab. 25,000 In
Oral Soln. - 1 lakly'ml.
Ascorbic acid
Tab, 50 mg.
LIST
B
DRUGS REQUIRED AT SECONDARY HEALTH CARS ORGANISATION
(The drugs in List - A should also be available)•
Name of Medicine ,
P ri o rl ty
Priority 2
Cate
gory
No.
Sr.,
No.
1
Anaesthetics
1.1
General Anaesthetics and Oxygen
Thiopental
1.
1.2
Powder for Inj. 0; 5
gm, 1.0 gm in amp.
Inj. 1%, 2% in vial
of 30 ml.
Inj. 1% 2% + Epine
phrine 1:1 lac in
vial, topical forms
2-4% (hydrochloride) .
Local Anaesthetics
Lidocaine
2.
Formulation
2.
Analgesics^ Antipyretics, Non-ystoroidal Anti inflamatory
‘yx^g^s/ahd^drugs to treat Gout.
2.1
Non Opioids
Allopurinol
Indomethacin
3.
4.
2.2
3.
Tab. 100 mg*
C ap• 25 mg•
Opioids
5.
Morphine
Inj. 100 mg/ml.
6.
Pe ttiidine
Inj. 50 mg/ml.
Anti allergies
7.
Dexamethasone
8.
Epinephrine
. 9.
Prednisolone
Tab. 0.5 mg, 4 mg.
Inj. 4 mg (Sodium
Phosphate) in 1 ml.
ampoule.
Inj. 1 mg. (hydx>chloride) in 1 ml.
ampoule.
Tab. 5' nrg.
4.
Antidotes and other substances
used in Poisoning.
4ul
General
4.2
Specific
Sodium tliiosulfate
10.
11.
12.
Atropine
Pralidoxime
(PAM)
Inj. 250 mg/ml in
50 ml amp.
Inj. 1 mg/ml.
10 ml amp / vial.
Inj. 1 gm. powder.
o c
Q c
Q
• o
•
Q
List ’B' Contd.
i
Cate
gory
Nd.
5<
Sr.
No.
____Name of Medicine______
Priority 1
Priority 2
Antiepileptics
13.
Diazepam
Inj. 5 mg/ml»
2 ml. Amp.
14.
Phenytoin
Cap. 25 mg, 100 mg.
Syp. 100 mg/5 ml.
Ethosuximide
Carbamazepine
15»
16.
17.
Valproic Acid
6.
Antiinfectiye Drugs
6.1
Anthelminthic Drugs
6.2
Antiamoebic Drugs
18.
Antibacterial Drugs
6.3.1
Penicillins
19.
Gentamicin
21.
Phenoxy Methyl
Pencillin
22.
Ampicillin
Cap. 250 mg. 500 mg.
Powder for susp.
125 mg/5 ml.
Inj. 500 mg/vial.
Tab. 100 mg.
Syp. 25 mg/5 ml.
Nitrofurantoin
Antileprosy Drugs
24.
25.
6. 3. 4
Inj. 10 mg, 40 mg/ml.
2 ml. vial.
Susp. 125 mg/5 ml.
Tab. 250 mg.
Other antibacterial Drugs
23.
6.3.3
250 mg.
200 mg.
200 mg.
200 mg/5ml.
C^> . 250 mg.
Syp. 125 mg/5 ml.
Inj. 1 gm powder/vial.
Ch1oramph e nic o1
20.
Cap.
Tab.
Tab.
Syp.
Tab. 500 mg.
Dilcxanide Furoate
6.3
6.3.2
Formulation
Ethionamide
Protionamide
Tab. 125 mg, 250 mg.
Tab. 125 mg.
Pyrazinamide
Streptomycin
Tab. 500 mg.
Powder for inj.
0.75 gm and
1 gm/vial•
Antituberculosis Drugs
26.
27.
3
? 2
3 ss
List 1B1 contd.
. °f medicines
Priority 2
Priority 1
Cat.
No.
Sr.
No.
6.4
Antifilarial Drugs
6.5
Antifungal Drv.gs
28.
Tab, 125 mg.
Griseofulvin
Nystatin
29.
6.6
Antileishmaniasis Drugs
6.7
Antimal arj. aJ- D rugs
30.
Formulation
Tab, 5 lac IU
Tab.
Quinine
250 mg.
300 mg.
31.
Chloroquine
Inj. 200 mg/ 5ml.
32.
Sulphadoxine
Pyrimethamine
Tab, 500 mg t 25 mg.
Ergotamine
Tab. 2 mg (as tar
trate) .
6.8
Antischistosomal Drugs
6,9
Anti pario soma 1 Drugs
7.
Antimigraine Drugs
3;3.
8.
Antineoplastic and_Immuno
suppressive Du. gs.
9.
Antiparkinsoni sm Drugs,
10.
Blood, Drugs effecting the
10. 1
Anti anae.m_ia_ Drugs
Inj. equivalent to
50 mg. iron/ml.
2 ml. inj. or 10 ml.
amp.
34
Iron Dextran
35.
Hydroxocobalamine Inj.. 1 mg/ml. amp.
10.2
Anticaogulants and Antagonists
11.
Blood products and Blood substitutes.
11.1
P1 a sm a Sub s ti tu te s
11.2
Plasma fractions for specific uses,.
12,
Cardiovascular Drugs
12.1
Anti anginal D -ug s
36.
37.
38.
39.
Propranolol
Glyceryl Trinitrate
Isosorbide dinitrate
Verapamil
Tab. 10 mg<
40 mg.
Tab. 0^5 mg.
Tab. 5 mgi sublingual)
Tab. 40 mg# 80 mg,
4
9 » <
4 ss
List. ’.B.C.Qntd.-_
Cat.
No.
Sr.
No.
12.2
An tidy srhy thmi c Drug s
40
12.3
12 .4
_____ Name of Medicines
’ Priori ty 1
Priority 2“
Propranolol
4
Isoprenaline
424
43 -
Procainamide
Quinidine
44 ‘
Propranolol
45 o
Reserpine
Tab. 40 mgz 80 mg
(Hydrochloride)
Tab. 0.1 mg, 0.25 mg.
46. c
Clonidine
Tab. 100 microgram
4.7
4G-.,
49
Methyldopa
Hydralazine
Hydroch1oro th i azide
Tab. 250 mg.
Tab. 50 mg.
Tab. 50 mg.
C ard i ac G1yc o sides
Digorrin
12 ,5
Tab. 0.25 mg.
Oral Soln. 0.05 mg/ml.
Shock - Anaphylaxis
13.
Dermatological Drugs
13.1
A ntifunca 1 Drug s
13.2
An ti inf ec tivo Drugs
13.3
Anti inflammatory and
13.4
Astringent Drugs
13.5
Ke ra topi a stic and Keratolytic Agents
£1
antipruritic, drugs
P od ophy 1 line
13.6
Scabicides and Pediculicides
14
Diagnostic Agents
15.
Di, si n £ ec tanus
16
Diuretics
52,
535
54.
17>
17.1
Tab. 10 mg. 40 mg.
Tab. 10 mg. 15 mg.
Tab. 250 mg, 500 mg.
Tab. 200 mg.
An tihvoor tonsive Drugs
SO’.
O
Formulation
Hydrochlorthiazide
Furosemide
Chlortalidone
Solution 10—25%
Tab. 50 mg.
Tab. 40 mg.
Tab. 25 mg.
Gastrointestinc1 Drugs
Antacids and other antiulcer Drugs
55.
Ranitidine
Tab. 150 mg.
r
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o
9
cr
—J
o •
•
<>
List ’B1 Contd
Cat.
No.
' 17*2
Sr.
No,
_ Name of Medicines
__
Priority 1
Priority 2
An tiemo tic Drucis
Promethazine
17. 3
A n tihaemprrhoida.1 D rugs
17.4
Anti_ _spasinpdic Drugs
17.5
Cathartic Drugs
17.6
Diarrhoea s
17t7
Fluid Replacement Solution
18,
Hormones
18., 1
Ad renal H cirmone s and Synthetic,
58S
59 .
Antidiarrhoeals ( Symptomatic Drugs)
Substitutes
D cxame th a s one
Predhisolc ne
Tab. 0.5 mg.
Tab. 5 mg
Powder for Inj.
100 mg/vial.
60 <-
Hydrocorti sone
61^
Dexame th a sone
4 mg/mlf
Norethisterone
Tab • 0., 35 mg.
18<2
Androgens
18*3
Con trac ep tive s
18.5
Tab. 10 mg, 25 mg
Inj. 25 mg/ml 12 in
2 ml amp.
Oral liquid 5 mg/5 ml.
Tab. 10 mg.
Inj. 5 mg. /ml in
2 ml amp.
' Metoclopramide
18i4
Formulation
oge n s.
Insulins and other Anti Diabetic agents
Lente Insulin
6? ’
64.
Insulin Soluble
65,
Glibenclamide
18.6
Thyroid Hormones and Anti-Thyroid' drugs
19 o
Immunologicals
19.1
19,2
Diagnostic Agents.
Sera and Immunoglobuling.
Inj. 40 lU/ml in 10 mlInj, 40 lU/ml in
10 ml.
Tabs. 5 mg.
6
i
0 o
o o
0
0
Q
O
List ’3’ Contd,
Cat.,
No.
—— —
_ _
Name of Medicines
~ Priority 1
Priority 2
Sr.,
Srt,
No.
P w BU,
MW
Formulation
—
Tetanus Antitoxin Inj . 50/000 IU in
vial.
(Human)
Inj. 500 lU/vial.
666
Diphtheria
Antitoxin
Inj. 10/000 IU
tl
r- ------- - ----------20/000 IU in
vial#
68
Inj. 1000 IU in 5 ml.
Anti Rabies
hyperimmune serum
69.
Anti Snake Venom
Anti-D Immuno
globulin (Human)
19.3
Vaccine s
19(,3„1
For Universal Immunisation s
19.3.2
For specific croups of Individuals s
Inj.
Inj. 0.25 mg/ml.
71.
Typhoid Vaccine
Inj.
ry /->
Rabies Vaccine
Inj.
Note s All vagclnes should comply with WHO requirements of
Biological substances.
Muscle Relaxant and Cholinesterase inhibitors
20.
21,
Oohtlialmplogacal Preparations
21*1
21.2
Anti.rnfc ctive Agents.
Anti-inflammatory Agents
73'
Eye oint. 1%
Hydrocortisone
21.3
iocal Anaes the tics
21.4
Miotics and Anti-glucoma Drugs
21.5
Mvd ria tics.
22.
Inj. 0.2 mg/ml
(Maleate) in 1 ml
ampoule.
Ergometrine
Dialysis Solution.
23.
Peritoneal
4.
P s veto th erapeutic Drugs.
•~i r~
/ U
.
Chlorpromazine
Tab. 50 mg, 100 mg.
Syp. 25 mg/5 ml.
(as hydrochloride).
• •• 7
o o
o Q
/
O •
Q «
List 1B1 Contd.
Cat.
No.
Sr.
no.
25.
Respiratory Tract/ Drugs acting on the
25.1
Anti Asthmatic Drugs
_____ Name of Medicines____
Priority 1
Priority 2
Aminophylline
Formulation
Inj. 2 5 mg/ml.
77.
Cromoglycic acid
(Cromolyn)
Oral Inhalation
(Cartridges)
20 mg/dose (Sodium
salt) .
7&
B ac 1 ome tna s one
Oral Inhalation
0.05 mg/dose,
Inj. 1 mg/ml in 1 ml
ampoule (as hydro
chloride) ,
7^
Epinephrine
25.2
. Antitussives
26.
Solutions correcting water Electrolyte and acid base
distgrbancQs
2 6.1
Oral
26.2
Parenteral
80.
Potassium Chloride
Oral Soln. 0 5 CV5ml
8- .
Glucose
82.
Glucose +
Chloride
Inj. Solution 5%
Isotonic.
500 ml/ 1000 ml.
50% in 25 ml amp.
Inj. Soln. 4% +
0.18%.
83,
Sodium Chloride
Sod.
2 6.3
Mi scellaneous
27.
Vitamins and Minerals
84*
r
Inj. Soln. 0.9%
isotonics.
Pyridoxine
Riboflavin
Thamine
8T*
Tab. 25 mg.
Tab. 5 mg. -
Tab; 50 mg^
Calcium Gluconate Inj. 100 mg/ml.
in 10 ml. amp.
LIST
C
DRUGS REQUIRED AT TERTIARY HEALTH CARE ORGANISATION
(The Drugs in List ‘A1 and List ‘B1 should also be available).
Cate
gory
No.
!•
1.1
Sr.
No.
Name of medicines_______
Priority 1
Priority 2
Anae s the tic s
General Anaesthetics and Oxygen.
1,
2.
. 3.
1.2
Formulation
Anesthetic Ether
Halothane
Nitrous Oxide
Inhalation (gas)
Bupivacaine
Inj. 0.25% and 0.5%
in 10 ml amp.
ii
it
H
ii
Local Anaesthetics
4.
2.
Analgesics^ Antipyretics/ Non steroidal
Anti Inflamatory Drugs and drugs to
treat Gout.
_____________________
2*1
Non Opioids
5.
6.
Colchicine
Tab. 0.5 mg.
Probenecid
Tab. 500 mg.
2.2
Opioids
3.
Anti alle rgic s
4.
Antidotes and other substances
used in Poisoning.
4.1
General
4.2
Specific
7
Sodium Nitrate
Inj. 30 mg/ml in
10 ml amp,
8.
Sodium Thiosulfate
Inj. 2 50 mg/ml
in 50 ml amp.
ae
De f e rox amine
Inj. 500 mg in vial.
10.
Dimercaprol
Inj. 50 mg/ml in
oil/ 2 ml amp.
11.
12.
Protamine Sulphate Inj. 10
mg/ml.
Inje 200 mg/ml.
Sodium Calcium
Edetate
5 ml/amp.
D-Pencillamine
Cap. 250 mg.
Nalexone
Inj, 0.4 mg/ml.
13.
14.
5.
Antiepileptics
6.
Antiinfective Drugs - Anthelmintic Drugs
15.
16.
Tiabendazole
Niclosamide
Chewable Tab.500 mg.
Tab. 500 mg.
s ?
2 ::
List C Contde
Sr.
No.
6.2
Antiamoebic Drugs
Dehydro emetine
17.
6.3
Antibacterial Drugs
6.3.1
Penicillins
■ 11
wii
to
Cap. 500 mg.
Inj. 500 mg in vial
Inj.
Syp. 125 mg/5ml
O ther a.ntiloac terial drugs
20.
Salazosulphapyridine
21.
Erythromycin or
Lactobionate
Cephalosporin
22.
Antileprosy Drugs.
6.3.4
Antituberculosis Drugs.
6.4
An ti f .1 lar ia L B rugs
6.5
Antjjungal Drugs
23.
24
6. 6
An ti 1 e i shmani a s i s
Drugs,^
6.7
j^ntimalarial Drugs
25
Flucytosine
Cap. 2 50 mg. Infusion
2.5 g in 250 ml.
Amphotericin-B
Inj. 50 mg in vial.-
Quinine
Inj. 300 mg/ml
in 2 ml amps.
6.8
Anti schistosomal Drugs
6.9
Antipanosomal Drugs
7.
Antimigraine Drugs
8.1
Antineoplastic and Immunosuppressive Drugs
Immunosuppressive drugs
26.
8.2
Tab. 500 mg.
Inj. 500 mg in vial.
Syp. 125 mg/5ml.
500 mg.
Cap. 250/ 5?''
"I
6.3.3
8
60 mg in- 1 ml
amp.
*
Cloxacillin
19.
Inj.
Inj.500 mg in 100 ml
Metronida.zo^e
18.
6.3.2
Formulation
Name of Medicines
_ _ 7T
Priority
Priority 2
Cat.
No.
Azathioprine
Cytotoxic Drugs
27.
Blgomycm
28.
Bu sulf an.
Tab. 500 mg.
inj. 100 mg as
sodium salt in vial:.
Inj. 15 nig as sulph
in vial.
Tab.
2 mg .
:s
3 :s
List C Contd»
Cat.
No.
Sr.
No.
Name of Medicines
Priority 1
Priority 2
Formulation
29
Calcium folinate
Tab. 15 mg.
Inj, 3 mg/ml in
16 ml amp.
3'0.
31,
Chlorambucil
Tab. 2 mg* ,
C yc 1 oph o sph amide
Tab. 25 mg.
Inj. 500 mg. in vial.
32-
Cytarabine
Inj. 100 mg in vial o
3 3,
Doxorubicin
Inj. 10 mg and
50 mg in (as hydro
chloride) vial.
9.
3 4,
Fluorouracil
Inj. 50 mg/ml. in
5 ml amp.
3 5-
M e th o trex a te
Tab. 2.5 mg.
Inj. 50 mg as sodium
in vial.
3 6.
Proc arbazi ne
Cap, 50 mg (as
hydrochloride) .
3 7c
Vincristine
Inj, 1 mg and 5 mg
in vial.
Anti pa rk i nsoni sm D rug s
3 8.
Levodopa
39.
Levodapa t
Carbidopa
Th rihexyphenydyl
40.
10.
Blood/ Prigs affecting the
10.1
Anti
10.2
Anti coagulants and Antiagonists
Anaemia Drugs
41,
Warfarin
Tab. 5 Mg.(Sodium
salt)
42.
Pin r tome n ad i o ne
Inj, 10 mg/ml
1 & 5 ml amp.
43.
Heparin
44
Protamine
Inj. 1000 IU ;
5000 iu ; 1 ml
amp.
20000 IU !
Inj. 10 mg/ml in
5 ml amp.
Sulfate
11.
Blood Products and Blood Substitutes,
11.1
P1 a sma Sub s ti tu te
4 5*
11.2
Tab.. 2 50 mg.
Tab. 150 mg + 10 mg.
Tab. 250 mg t 25 mg.
2 mg. tabs.
Dextran
Plasma Fractions for
Specific uses,
A Ibu min* hum an •
4 6’
Inj.
6%
500 ml.
Inj. solution^ 25%
(dried) .
... 4
o o
C
CJ
4 s ?
List C contd.
Cat.
No*
Name of Medicine
Priority- 1
Priority 2
•Sr>
.No.
Factor VIII
Concentrate
Factor IX
complex
(Coagulation
factors II/VII,
IX, X) concentrate
(dried)
12.
C ardi ovascuiar
12.1
Antianainal Drugs
w
-wm-, ■ ■
47i
I
Bl
I ■ *
12.4
Verapamil
ig in 1 ml amp.
fajJHCir
2^5 mg/ml in
Inj. r.
2 ml Amp.
Anfidvsrhythmic Drugs
d9-L-
Propranolol
5 0-
Lidocaine
Inj. 1 mg in 1 ml
ampoule.
Procainamide
Inj. 20 mg/ml in
5 ml Amp.
Ini. 100 mg/ml in
10 ml amp.
jx ntihyperten sive Ds
52
Propranolol
5'3.
Sodium Nitroprusside
Inj. 1 mg in 1 ml
Ampoule.
Inj. 50 mg in Amp.
Cardiac Glycosidss
54«
12,5
-
Propranolol
51’
12,3
All plasma fractions
should comply with
WHO Requirements of
collection processing
and Quality control
of human blood and
blood products>
• •*
48*
12.2
Formulation
Inj< 0.25 mg/ml in
2 ml amp.
Digoxin
Drugs used in Shock - Anaphylaxis.
55
Inj. (as hydrochlo
ride) 40 mg/ml in
5 ml vial.
Dopamine
13.
13.1
Dermatological Drugs
Antifungal Drugs
13.2
13.3
Antiinf 1<mmatory and Antipruritic Pni£S
13.4
A s tri ngen t pr;g s
13,5
VAratnnlastic and Keratolytic Agents
13,6
Scabicides ano Pediculicides
lp
ve p
5
... 5
• •
O
V
K
Cl
o ©
•
•
List C Contd.
Name of Medicine
Priority 1
Pariority 2
Cat.
No.
Sr.
No.
14.
Diagonistic Agents
14.1
Ophthalmic Drugs
Flurescein
14.2
Eye drops 1%
(Sodium salt)
Radio Contrast Media
Meglumine Amido trizoate
Sodium amidotrizoate
Barium Sulphate
lopanoic Acid
Pro pyliodone
lohexol
lotroxate
15.
D i s in f e c tan t s
16.
Diuretics
Formulation
Inj. 60% in 20 ml
ampoule.
"
50% in 20 ml,
amp.
Powder.
Tab/ 500 mg.
Inj. 600 gify/1 in 20
ml. ampoule.
Inj. 300 mg in 5 or
16 ml ampoule.
Solution 8 gm (as
iodine) in 100-250
ml.
56,
Furosemide
57.
Spironolactone
58,
Mannitol
Inj. 10 mg/ml in
2 ml amp.
Tab, 25 mg.
Inj „ 10% & 20%
59,
Triamterene
Tab. 50 mg.
17.
Gastrointestinal Drugs
17,1
Antacids and other Antiulcer drugs
60-
Cime tidine.
17.2
An tierne tic Drug s
17.3
Antihaemorrhoidal Drugs
17.4
Anti spasmodic Drugs
17. 5
Cathartic Drugs
17.6
Diarrhoea
Inj. 100 mg/ml in
2 ml amp.
17.6.1 Antidiarrhoeals (symptomatic) Drugs.
17.6.2 Fluid Replacement Solution
... 6
o
o
o
o
fC
kJ
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co
¥ ,
List C Contdo
Cat.
No.
Name o f medicine
.
Priority 1
Priority 2
Sr.
No,
Formulation
18
18 hl ’ _Aclnena 1_Ho-rmones and Synthetic Substitutes*
61,
18e2
Tab. 0,1 mg
(acetate)
Testosterone
Inj. 200 mg (as
enantate) in 1 ml
amp. and 25 mg (as
propionate) in 1 ml
amp.
Androgens
62.,
18,3
Fludrocortisone
C on trad ey tive s
63,
Depot Med roxy Pro
de s te rone ac e tate.
Inj. 150 mg in 3 ml
64.
Nore thi s terone
i'na'ntate
Inj. 200 mg in vial.
’ -
vial.
18.4
18.6
Tab. 0.05 mg<
E thinyle s tradi ol
65
Ovulation Tn Au .r rs
Tab. 50 mg (citrate)
Cion .if eno
66 n
18. 7
?r2.'lS§i222.25.
18.8
Th*vrsid. hormones and Antithyroid drugs.
mi.
■
■ ■—
-
■
i
-
-
—
-
•- t
r-
Levo -th vr o>: i n e
68
Potassium Iodide
Tab, 0,05 mg, 1 mg
( sodium salt)
Tab. 60 mg.
69.
P ropy1th i ouvaci1
Tab. 50 mg.
Ircmu nolog ica.l_s-
19,1
pj, agnostic: Agent s
Tuberculin purified
Protein derivative (PPP)
70
Injection
Sera and Immunoglobulins
, - -tj
1
/a
72
F—»
19.3
■■
67
19.
19.2
X.. i
.
-...—I
—
‘
■ .■>■>1—Ml W • —■ ■■ —» ■»
•.« *
«■■■
-r •'
Anti-D immunoglobulin (numan)
Tmmu:-.og 1 ooulin, bxuman
normal.
Inj-. 0.25 mg/ml.
Injection.
V accinns
19.3.1 For universal 1mmunisatiqn•
19.3.2 For specific grcaps of individuals.
... 7
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•
^7
/
° 9°
0
List C contd.
Name of Medicine
Priority 1
Priority 2
Formulation
Cat.
No.
Sr.
No.
20.
•Muscle Relaxants and ChblinesterasooInhibitors
Neostigmine
Tab. 15 mg Bromide.
Inj. 0.5 mg (Metilsu
lfate in 1 ml amp.)
Gallamine
Suxamethonium
Inj. 20 mgm/ml.
Inj. 50mg/ml in2ml
Amp. (Chloride)
Tab. (bromide) 60 mg.
Inj. (bromide) 1 mg.
1 ml. amp.
74.
75.
Pyridostigmine
21
Ophthalmological Pre--parations
»l|l^ I
■
I
■!
* WH" •
21>1
Antiinfactive Agents
21.2
A nti i nf1ammatory Agents
21.3
Local Anaesthetics
21.4
Miotics and Antiglaucoma Drugs
Acetazolamide
77 •
78o
21,5
Inj. 10 IU in 1 ml
amp.
Oxytocin
Peritoneal Dialysis Solution
In trape ri tone al
dialysis solution
81
24
Solution (hydrobromide)
2%
Homatropine
Oxytocic s
80.
23
Solution (hydrochlo
ride or nitrate) .
2%, 4%
Pilocarpine
Mydriatics
7-0 <
22
Tab. 250 mg.
Parenteral solution.
Psychotherapeutic Drugs
82,
Ami tryp ti line
Tab. 25 mg» (Hydro
chloride) .
S3.
Haloperidol
Tab. 2 mg.
Inj. 5 mg in 1 ml amp.
84/-.
Irnipramine
8^
Lithium carbonate
Chlorpromazine
(hydroch1oride)
Tab 10 mg/ 25 mg.
(hydroch 1 or i de)
Cap. or Tab 300 mg.
Inj. 25 mg/ml in
2 ml amp* 78
:s 8 ss
List C contd.
___________
Cat.
"4.
Sr.
No.
97.
Name of Medicine <
Priority- 1
Priority z
Fluphenazine
Formulation
Inj. 25 me /ml amp.
(decanoate or enan—
tate) .
25.
Respiratory Tract/ Drugs. acting on the
25.1
&nti Asthamatic Drugs
25.2
Antituss ive s
26.
Solutions correcting watery electrolyte acid base
disturbances.
26.1
Oral
26.2
Parenteral
8 8.
Sodium bicarbonate
26*3
Miscellaneous
27<
Vitamins,
and Minerals
Inj. solution/ 1.4%
:
isotonic.
(Na+ 167 mmol/1
HCO^ 167 mmol/1)
LIST D.
List of Drugs which can be used by the Village Level
Workers with adequate training.
W II
1
II I"
■■■ ■ ■■■■■■ I I
■ ■
■ !■
I
—I
.1. .■■■.■
■■
—
IM
■ ■■
II ■!■■■■■
■!
■Hill
BI ■
■■l— — ■■■■■
■ ■■• emilM ■■■■ ■
!■■■
F ormu .1 a ti on s
Drugs
1.
Acetylsalicylic Acid
Tab 300 mg.
2.
Powder 50 gm. sachets.
3.
Activated Charcoal
Antacid
(Aluminium Hydroxide +
Magnesium Hydroxide).
4.
5.
6.
An Antihaemerrhoidal drug.
Atropine
Aminophylline
Tab. 1 mg (as Sulfate)
Tab, 100 mg*
7.
8.
9.
Benzoic Acid + Salicylic Acid
Be tame th a s o ne
Benzyl Benzoate
Oint. (Benzcqc Acid 6%.+
Solicylic Acid 3%)
Oint.0.1%
Lotion./ 25?4
10.
Bisecodyl
11.
12.
Calamine
Chlorhexidine
13.
Chloroquine
-ab. z 5 mg
Lotion. 1% (Acetate)
Solution z 5% (diqluconate
for dilution)
Tab. 2 50 mg
14.
15.
Chlorpheniramine Maleate
Clofazimine *
16.
Coal Tar
Codeine (As anti’tussive)
Dap sone
17.
18.
Phosphate
Tab 125 mg.
Tab., 4 mg.
Caps/ 50 mg/ 100 mg.
Solution, Topical 20%
Tab,. 15 mg. z sjrp. 12 mg/ml
Syp. 12 mg/ml.
19.
20.
21.
Diethyl Carbamezine *
22-
Ergometrine (for post parturn
Haemorrhage)
23.
Ethyabutol
Tab/ 200 mg/400 mg/800mg
24.
25.
26.
Folic Acid
Gentian Violet
Glycerine Suppository
Tab 5 mg
Solutioni2
27.
28a
29a
Iodine
Iron
Iron ’b Folic Acid
Isoniazid
Isoniazid + Thiacetazone
Lindane
Loperamide
Mebendazole
Metronidazole
Solution/ 2.5%
30.
31.
32.
33.
34.
35*
36.
Diazepam
Ephedrine
Myconazole
Tab.50 mg(c i trate)
Tab. 2 mg.
Tab. 30 mg.
Tab. 0.2 mg(Mal^ate)
Solution
Tab200 mg. (as sulphate)
Tab.
Tab., 200 mg + 0.2 mg.
Tab.100 mg, 300 mg.
Lotion 75 mg + 150 mg,
150 mg + 300 mg.
Tab.2 mg.
‘
Tab-. 100 mg*
Tab. 200 mg.
Oint. or cream 2%
(Nitrate) .
v o O u ©
O
O
K
List D continued.,.
Formulations
Druqs
37»
Neomycin + Bacitracin
38.
39.
40.
Nystatin *
Oral Rehydration Salt
Oral contraceptive pills
(Ethynylestradiol +
Levonorgestrel )
41.
Paracetamol
42.
Promethazine
43.
44.
45<
Rifampicin *
Salbutamol
Sulphace tamide
4 6.
Tetracycline
47.
48.
Vitamin A
Vaccines t
Note :
Ointment 5 mg neomycin
sulphate + 500 IU
bacitracin Zinc/gm.
Pessary 1 lac I.U.
W.Ii.O. Formula.
J
Tab* 0.0 3 mg t 0.15 mg.
Tab. 500 mg.
Syp. 125 mg/5 ml.
Tab. 25 mg (hydrochloride)
Syp. 5 mg/5 ml ( -do)
Cap-150 mg, 300 mg.
Tab. 4 mg.
Eye drops 10% (sodium
salt) .
Eye Oint<. 1 % (H yd roca 1 o ride) .»
Capsule 2 lac I.U.
These drugs could be given under supervision
and periodic monitoring by the doctor.
+
They should be easily accessible all round
the year either at the centre or in the
village.
VARIATIONS FROM WHO ^E .D . ^LI ST
Sr.
no.
Category No.
1
4.2
2
It
3
6.1
4
ti
Locost
list
C
Name of- Drag
Reasons for inclusion/
exclusion
Protamine Sulphate
Included because this
is a specific antidote
for heparin which is
widely used at Tertiaoy
health care level
eg. heart surgery.
Meth y1 thianinium
Chloride
Piperafeine
Excluded because broader
coverage as an anthel
mintic drug can be had
by use of Mebendazole
and Pyrantel Pamoate
Praziquental
Excluded because this
drug j s used against
Schistosomiasis which
does not occur in our
country at present.
5
6.3.2
Spec tinomyc in
Excluded because this
is useful for gonorrhoea
in multiple resistant
cases which are still
not common in India.
6.
6.4
Suramin Sodium
Excluded because the
specific parasite is
not reported to be
occuring in India.
7
6.6
Penta midine
Sodium Stiboglu
conate „
Excluded because
Leishmaniasis does not
occur in India.
8
6.7
Amodiaquine
Excluded because
Amodiaquine and
Chloroquine belong to
the same category of
chemical group, sharing
same actions, adverse
effects, etc.
9
9
Thrihexyphenydyl
Included because it is
more’ easily available
in India.
Biperidin
Excluded because W.H.O.
has suggested Biperi
dine or any substitute
drug of same group.
Thrihexyphenydyl is
suggested in this list.
C
... 2
o o
o •
Q
Z.
© •
o •
Variation from WHO E.D. List Contd.
Sr.
no.
Category No.
Locost
list
Name of Drug
Reasons for inclusion/
exclusion
Clonidine
Included because it is
easily available in
India and cheap anti
hypertensive drug - a
substitute for Methyldr
opa.
12.4
Digitoxin
Excluded because not
available in India.
12.
13.4
Aluminium Acetate
13.
13.5
Salicylic Acid
14.
14
C
Edrophonium
15.
16
C
Triamterene
Included as a substi
tute for Amiloride,.
Amiloride
Triamterene as its
substitute included*
Calcium Carbonate
Excluded because other
agents are available,
and possibility of its
adverse effects.
10.
12.3
11.
B
Excluded because the
combination of Benxoic
acid and salicylic acid
will suffice the use.
16.
17.1
17.
17.1
A
Ranitidine
Included because of its
advantages such as less
incidence of adverse
reaction and less dos
age frequency, there
fore seibcted as a
substitute for
cimetidine.
18.
17.6.1
A
Loperamide Tab.
Included because of
its symptoma tic u sc
in emergency situa
tion for adults c.
19.
19.3.2
Influenza vaccine
J
Meningococcal
vaccine.
Yellow fever
vaccine
Excluded because of
their non-feasibility
in Indian context.
20.
21.1
Silver Nitrate
Solution.
Excluded from Locost
List because better
antibacterials are
available.
//
-
3
3.
Concise, accurate and comprehensive drug information should
be prepared to accompany the list of essential drugs.
4.
Quality, including stability and bioavailability, should be
assured through vesting or regulation.
5.
The success of the entire essential drugs programme is
dependent upon the efficient administration of supply,
storage and distribution at every point from the manufactu
rer to the end user. Government interventions may be
necessary to ensure the availability of same drugs in the
formulations listed, and special arrangements may need to
be instituted for the storage and distribution of drugs
that have a short shelf-life or require refrigeration.
6.
Efficient management of stocks is necessary to eliminate
waste and to ensure continuity of supplies. Procurement
policy should he based upon detailed records of turnover.
In some instances, drug utilization studies may contribute
to a better understanding of true requirements.
7.
Research, both clinical and pharmaceutical, is sometimes
required to settle the choice of a particular drug product
under local cond.itions.
II. (b)
^jErs't Expert Comini't'tee on ~thc Selection of Essential Dtui^s?
(i).
From the preliminary reports it became clear that for the
optimal use of limited financial resources the available drugs must
be restricted to those ]proven to be the rape nt ic ally effective, to
have acceptable safely and to satisfy the health needs of
__ the populat ion. The selected drugs are here called ’’essential” drugs,
indicating
theyare of the utmost importance, and are basic,
- that
*
indispensable and necessary for the health needs of the population.
Drugs included in such a list would differ from Country to
Country depending on many conditions, such as the pattern of prevailent diseases, the type of health personnel available, financial
resources, and generic, demographic and environmental factors. The
basic principle (dichem) is:
’’Because of great differences between countries, the prepara
tion of a drug list of uniform, general applicability and acceptibility
is not feasible or possible. Therefore, each country has the direct
responsibility of evaluating and adopting a list of essential drugs,
according to its own policy in the firld of health".
’’The list of essential drugs based on tile guidelines put
forward in this report is a model which can furnish a basis for
countries to identify their own priorities and. to make their own
select ion.”
It was stressed in the First Report that VfflO list is a
’’model” or "guiding list" which is meant to serve as a basis for
countries to identify their own priorities and to make their own
selection. A list of essential drugs can take care of the majority
(80 - 9($) of health problems amenable to any treatment. It does,
however, not mean that other drugs are not useful, but simply that
in a given situation these essential drugs are the most needed for
the health care of the majority of the population, and therefore
diould be available in ad_equate amounts, and in the proper dosage
forms.
The nation thJ: tl
of necessary drugs is relatively
small is supported hy experience, Several developing countries that
have adopted limited drug lists report good acceptance as well as
...4.
4
favourable medical and economic results. Lists and formulations with
Gr °
rUgs arG also successfully used in mary developed
eounuries.
Limited drug lists have several advantages:
1.
Reduction in the number cof~ pharmaceutical products to be
purchased, stored analysed1, and distributed.
2.
Dnprovement in the quality of drug utilization, management
information and monitoring.
5.
Stimulation of local pharmaceutical industries.
4.
Assistance to the least developed countries in urgent need of
care problems drUSS pro6r?-'nmes io serve their primary health
An effective programme of drug selection coupled with appropriate
^^^ucation may help to improve attitudes
regarding the role of drugs ’ in he
alt h& disease.
-------------(ii)
General Principles .for establishing a list of Essential Drugs:
The following principles were c_.
~.i a list of Essential drugs:
considered by the Expert Committee
to be a foundation on which to establish
1.
2.
hea£hOpolfcy/i--°f•e.S'-ntial
°f a
This implies that priority is given to achieving the widest possible
‘
_j c"
coverage
of the population with drugs
of proven effcacy and safety in order to meet the needs for
prevention and treatment of the most prevailent diseases.
/■ru&s for yhich adequate scientific data are
available from controlled studies
-------- j should be selected.
3.
Each selected pharmaceutical product must meet adequate
standards of quality, including when necessary bioavailabilitv
4.
Concise, ?accurate
and comprehensive drug information drawn
from unbiased
------ sources should accompany each list of essential
drugs.
(iix)
.Criteria for the Selection of Essential Drugs:
First Expert Committee Report, it was emphasized that
criteria
for
the
selection
+
~ T of essential
--------- ^ru^s a-370 intended to ensure
that
that the process of sole
selection
nt inn W
will
4ii be unbiased
-u
...
-- and based on the best
available scientific information 9 yet allow for a degree of variation
to take into account local needs and requirements. Guidelines
recommended that:
1.
ac country should appoint a Committee to establish a list
of essential drugs. The Committee should include individuals
competent in the fields of clinical medicine, pharmacology
and pharmacy, as well as peripheral health workers.
2.
Drug selection should be based on the results of benefit and
safely evaluations obtained in clinical trials and/or
e pi.dem 1 crogic dl w L act It? s .
3.
i
1
rna
non-PTOprietary (generic) names for drugs
A crSs-inde/of nTtanCeS
USed
available.
initi!!iv be
Zr°Pfdtaly aM
names should
initially be provided to the prescribers.
5
5
4.
Regulations and facilities should be available to ensure that
the quality of selected pharmaceutical products meets adequate
quality control standards, including stability and when necessary
bioavailability where national resources are not available for
this type of control, the suppliers should provide documentation
of the products compliance with the requested specifications.
5.
Cost represents a major selection criterion. In cost comparisons
between drugs, the cost of the total treatment, and not only the
unit cost, must be considered. In addition, the cost of non
pharma ceutic al therapentic modalities should be taken into account.
6.
Local health authorities should decide the level of expertise
required to prescribe single drugs or a group of drugs in a
therapentic category. Cons ide rat ion should also be given to the
competence of the personnel to make- a correct diagnosis. In
some instances, while individuals with advanced treaining are
necessary to prescribe initial theraphy, individuals with less
treaining could be responsible for maintenance theraphy.
7.
The influence of local diseases or conditions on pharmaceu
ticals and pharmacodynamic parameters should be eondidered in
making the selections i.e. malnulrition, liver disease.
8.
When several drugs are available for the s ame ind icat ion 9
select the drug, pharmaceutical products and dosage form that
provide the highest benefit/risk ratio.
9.
When two or more drugs are therapeutic ally equivalent 9 preference
should be given to:
10.
(i)
the drug which has been most thoroughly investigated.
(ii)
the drug with the most favourable pharmacokinetic proper
ties, i.e. to improve compliance, to minimize risk in
Various patho-physiological states;
(iii)
drugs for which local, reliable, ma,nufacturing facilities
for pharmaceutical products exist;
(iv)
drugs 9 pharmaceutical products and dosage forms with
favourable st ab il ity , or for which storage facilities
ex ist.
Fixed ratio combinations arc only acceptable if following
criteria-are mets
(i)
Clinical documentation justifies the concernitant use
, of more than one drug.
(ii)
the therapeutic effect is greater than the sum of the
effect of each.
(iii)
the cost of the combination product is less than the
sum of the individual products.
(iv)
Compliance is improved.
(v)
Sufficient drug ratios are provided to allow dosage
adjustments satisfaction dor the majority of the popula~
t ion.
6
11.
The list should be reviewed atleast once a year and whenever
necessary. Bew drugs should be introduced only if they offer
distinct advantages over drugs previously selected. If new
information becomes available on drugs already in the list which
alearly shows that they no longer have a favourable benefit/risk
ratio, they should oe deleted and replaced by a safer drug. It
should be remembered that for the treatment of certain conditions,
non-pharmaco logic al forms of therapy, or no therapy at all, may be
preferable.
(iv)
Sgug. selection- what does it mean and where does it take place. ?
At a national level, it is generally a country
countiy’s drug laws and
medical economic conditions which determine the selection of the drug
products to be approved by the authorities for marketing. There are
countries where new drugs products quality for registration only if they
satisfy a defined mectical need in addition to approved standards of quality 9
efficacy and safety. At the other end of the spectrum, most developing
countries have no registration standards or evaluation procedures at all,
nor do the authorities know what drugs are available in the countly.
Therapentic Committees and formularies have been introduced in
hospitals in many developed countries, not only for economic hut also
for medical reasons, namely to monitor and evaluate several aspects of
drug use. In these developed countries drug formularies recommend or
guide in selection, in developing countries, where economic constraints
are much more severe , access to drugs more difficult and drug supply
systems in adequate, the drug lists or formularies may have to play a
stricter role.
In the selection or choice of drugs, the ultimate decision lies
with the Doctor.
------ The most important element in his/her decision to
prescribe is the disease to be treated in a given patient. Beyond this $
however
—
factors such as
the prescriber is influenced by a variety of factors,
(i)
his/her medical training
(ii)
the selling of the medical practice (whether it is private- or
in a hospital)
(iii)
local prescribing traditions and habits.
(iv)
economic conditions
(v)
the country’s health policy (reimbursement scheme, information,
distribution etc.
(vi)
the influence of the drug industry (advert ising, compendia etc.)
Which drugs should be selected ?
Further to criteria mention in Il(t>)(iii) the following criteria
should be considered for selection of drugs.
(i)
relevance to diseases treated at different levels of health
care or facility.
(if)
medic al import ance/ne ed
(iii)
therapeutic effectiveness
(iv)
(v)
relevance to the level of trainir^ of the health workers
safety of the drugs
(vi)
cost of treatment
7.
7
(vii)
Safety in dispensing (i.e. administration: tablet versus
inject able)
(viii)
drug expiry date
(ix)
usability against more thaji one disease/condition
(x)
how easy for patient to take
(xi)
how easy for the staff to dispense
(xii)
whether it is locally produced
In the application of its guidelines, the first expert
Committee gave some examples of drugs -which had been either excluded
or included in the model list. A drug like chloramphenicol was
included in spite of being capable of causing severe adverse effects,
whereas others such as phenulbutazene were exluded. The concensus was
that the benefit of chloramphenicol when properly used, outweighed its
risks, whereas the same was not true for phenulbut az one since other
drugs were available with a better benefit/risk ratio. Clioquinol and
noramidopyrine were excluded for similar reasons.
*
Guidelines for the selection of pharmaceutical dosage forms:
The purpose , of selecting dosage forms and strengms for the
drugs in the model list is to be provide guidance to countries wishing
to standardize or minimize the number of preparations in their , own
drug lists. As a general mere, pharmaceutical forms are selected
on the basis of their general utility and their wide availability
■ internationally. In many instances, a choice of preparations is
provided, particularly in relation to solid dosage forms, Tablets are usually
less expensive than capsules, but while the cost factor should be taken
into account, the selection should also be based on a consideration of
pharmacuukinetics, bioavailability, stability under ambient climatic
conditions, availability of excipients, and established local preference.
Scored tablets more useful when precise dose is not mandatory
simple method of macking dosage more flexible, also convenient for
paediabic dose. Specific paediabic dosages and formulations are
included in the list only when indicated by special circumstances.
* Pruff Information and Education ActivitiGs
Information about drugs and pharmaceutical products is a
pre-requisite at all health case levels to ensure proper utilisation
and promote rational prescribir^. These levels include: regulatory
authorities, doctors, pharmacists5 nurses and other paramedical
personnel, and the consumer. The types of information required can be
classified as chemical and pharmaceutical, pharmacological, clinical and
economic.
extneit to which each type of information is reqiijred' at
different levels will vary. For example, regulatory authorities should
have all existing data about a drug. In developing countries, however
such information is often not available. In addition, adequate manpower
and expertise to evaluate the information are often lacking.
Accurate and objective information must be supplied for each
drug in the essential list in a manner that is understandable to each
level of prescriber. For each indication, diagnostic criteria should
be provided whenever appropriate. The use. of any drug without adequate
knowledge may be dangerous. The inclusion of adjuate and concise informa
tion with each product should allow the piescriber to obtain optimal
effects while minimizing harmful effects. Since self-medication by the
pu ic is increasing, it is imperative that the information be available
in a form which is understandable by individual users.
...8.
8
begin
begin early
early ln
in the?f ^^ining^ddrUgS Shoulti
SS fS^SnXSdX^d0^---n^ted^
-^XXXls
distributed by the Committee which"
L*
Edition to that included
could be disseminated through sSh " nJ
Ettere
seminars particles
Jatteys. FOy the consumer wh-r
can be used
4..
*
Tr m-sw-
•
■?
rUgS for the essential
Pr°duct > formation
education by
3 al J°urnals and news-
Psinphlets, the mssej mr/Uo
10 minimize bias it win
to be
aucat”“ eff°rt’ >»
V
j
mass media and posters
sxi* ;r’s”y r”
ft is f
important that those with the greater tr • •
the. knowledge of^sT.
•
—“J with
lesser training
tralnih? upgrade
should continually
infom
, . ----- J consumer about the m+• eXaraPle’ Pharmacists
as they are ?being dispensed.
the Clonal use of products
Education about
a* well
the consumers
Persuaded that, when there
products are as effective ;
products. Education of the cwST^ 1hGalth Care ^vel where’
will be by self medication,
aggarated fears of adverse
unjustified expectations.
prescribers
the cheaper
^particularly important L'
—-i proportion of drug u
consumers should relieve
rugs as well as prevent
3 ~J&J
^^agijiformat ion Sheet:
Various types of
consumers to ohtalToptlJ?uSSS^
by P^^riteys and
& sample which
sh^ni^ k
■>.
fization
p^erffier.
1011 Stald
to tte of drugs. Th^ -r^n
1.
subI^ceOnandNrecPr°Prietary K™e
^°e, and recommended dosage form.
of each active
2.
3.
inf0™^ion: brief
description of pharmacological effects and mechanism of
action.
Clinical Information
5.1
indications: Whenever appropyiate
criteria should
-- - be provided.
3.2
Dosage regimen and. relevant
3.2.1
3.2.2
Pharmacokinetic d.ata;
Average dosage and
rai¥<e fey adjuIts &
children.
Dosing interval
Average duration <Of treatment
•J o.g. renal,
which
or
4oew
<■■«>■»
3.5.5
3.2.4
3.3
3.4
3.5
’ simple diagnostic
Coni raindic at ions
3.6
Precautions (reference to r
pregnancy, laot ?,t ion etc.)
Adverse effects (quantitate
J
c^te-ory, if possible)
Drug interactions (to be
relevant, drugs used for ^tioned only if clinically
sc If medication should be
included).
3.7
Overdossage;
3.7.1
5.7.2
3.7.3
—
Brief c'clinical description of symptons.
Non-rlrug treatment and
support ive th&rapy
Specific
~ -J antidotes.
------- — U.I^O
9
4.
Biamnceut ic o 1 Sif ormat ion
4.1
4.2
4.5
4.4
4.5
4.6
4.7
4.8
Excipients.
Dosage- forms available
Strength of dosage forms
Storage conditions nnH shelf-life (expiration date)
racka^ing sizes
.description of the. product and package
Leftal c-tcjory (Nareotic, prescription or non-pro script ion)
Maine and address of manufacturcr(s) and importer(s).
It was reco/jnised^that
r* *
* ’ •
this formul?.iy9 once product, will
need to he updated pr .’inptly
j as occasion demands if it is to he of
optimal value and a*an appropriate consultative procedure will need
to he estahlished to
to permit this.
c omniun xty he xlt h workc rs •
tn +Ha- Ir
dfcT; increasingly evident that drugs are not used
LntlTf
pot®n'tia1’ nor according to generally accepted criteria.
Little is known about the clinical consquences of the major differences
ha. ex^st
Prescribing patterns between countries and between
Z™nql1
countries. The problem is complicated in
general, in uhat drug utilization is not followed up systematically
and comprehensively after the drugs have been marketed. Drug
utilizacion dataare required for selection committees to function
optimally.
hrug utilization rcan and’ should
'
-----be studied, at various levels
5
depending on the purpose and facilities available,
------------- ‘, generally,
generally, the
the ”
value of such studies may be considerably enhanced if they• are
are made
made
comparable by applying uniform methods. (Common drug classification
system ano. units of measurement) in investigation in different regions
and countries. The common method should provide data on all relevant
drugs in the particular therapeutic class, given in either cost
or quantity parameters, and taking differences in therapentic practice
into consideration, 'The methods could be designed to quantitate the
drug inventoiy only or to evaluate drug* utilizationo
+ UQ
Ih+ °^2Cti^e Of a drue' utHization survey is to quantitate
the present state, developmental trends and time course profiles
U!afe;
type of <iata can then he used! (1 ) to measure the
effects of informational and. regulater measures, price policy etc.,
def“® areas for further investigation on the absolute and
relative eliicacy and. safely of drug therapy, (5) to aid in the
dtermination of benefit/risk and cost/effectiveness and (4) when
properly interpreted, to indicate the overuse, underuse, or misuse
of single drugs or "the rape nt ic classes,.
•^Quality Assurance
TO. J_.
d ty assurance of drugs, as embodied in good far manufacturing
practice and subsequent monitoring of quality through to utilization
is a critical element in any essential drugs programme.
WO
Scheme ^11
on the qualin of
. . has setn up a "Certification
---------- v—
pharmaceutical products in international commerce"
commerce which provides
valuable safeguards in relation to imported products, particularly for
countries lacking* adequate laboratory facilities for drug analyses’.
Bioavailability is a specific problem that is of particular
importance with products with law solubility or a narrow therapentic
index. In addition, unsatisfactory formulation can result in therapentic
-ailure due to lack of absorption,
10
Research and. Peyejlopfner±_
If the establishment of a list of essential drugs is to succeed
°YhenDth and reducing costs of drugs in developing countries,
utilization of the list should be either preceded by or developed
together with^supply and distribution systems and procurement procedures.
To hasten self reliance research and development should be undertaken
in the followirg1 areas;
jin
(a)
Haa^rnaceut ical°.
1.
Develop local or :regional quality control facilities in
order to ensure the quality of drugs> on a continuing bais.
(b)
2.
Establish procurement procedure to take advantage
advantage of
of
the benefits of purchasing in large quantities.
5.
Develop research capabilities to study dosage forms,
particularly for vaccines and other heat sensitive drugs.
4.
Develop facilities for processing simple dosage forms as
s'fceD towards later manufacturing of raw materials
is will enable countries to optimize drug expenditure
by reducing the cost of drugs and to be less dependant on
imports of dosage forms.
5
Develop.and efficient country-wide distribution system
with suitable trained personnel. This is to ensure
that drugs of adequate quality are available at all
times in sufficient quantity at appropriate places.
6.
Develop packaging of essential drugs to improve patient
compliance and product stability.
Clinical
Develop the capabilities and expertise to cariy out therapeutic
trials in order to assess;
(c)
1.
The relative efficacy and safety of new as compared,
to essential drugs.
2.
The benefits and safety of traditional medicines
9
including medicinal plants.
3.
The effects of genetic nutritional and environmental diffe
rences among populations on pharmacokinetics, pharmaco
dynamic and. the rape nt ic parameters.
4.
Exploration of the value of non-medicinal forms of
treatment.
5.
Dose-response studies should be conducted where there
appear to be differences in therape nt ic response or
incidence of adverse reactions in specific populations
Educational
1.
Develop simple , concise labels for each dosage form.
2.
Develop appropriate public education and information
programmes in dia/mosis and self-medication for those
conditions in which early recognision of symptons and
prompt sell medication are life saving.
11.
11
5.
Develop progr^ee for the training of personnel for
Pharmaceutical activities in ‘■-«uch fields as euality
control, or.Tulation of policies, develop-*ent of pharmacon real information systems, procurement, Production,
storage and distribution proceedures.
1.
Develop control of ph=uwceutic?l orofuct advertising
m both the loy >*nd scientific press.
(d) .
SgseiliaUh-Mgs.ffealth ,Carej_
Tn a mrntoer o: countl ies, large segments of the copulation do
reeby access to h alth facilities ^ich tend to be oriented
hospitals and urban areas. In sn attempt to
svrenjhhen the healrh care system anc1 achieve maximum ponulation
ZXJUVW'COSt
effecttie
efficient hZaS sS^s,
attention xs being focused increasingly on the develop ent of primer
„n+ v ,
he.ah c;.„. iyv,,„010h 1;wolve8 t;„ usa of
„OISX-’S^
'iiniwum .. ormal training to Perform limited tasks as the community level.
J x ^?e firs'fc
Committee had visualised that there was a
need to identify the widest range o? drugs that can ’be safely and
adecuat€$.y handled by this type <f zv-alth workers
Howevez ? no list was
prepared, at that time.
(a)
Rotors atfe<rting; th-, selection„of dru^_ for
Cajre.
Jbrsuant to above , after road consultation, and. having regard
to situations in which t.a traoivioral healer of CH I rather ihan a
qualified doctor is the Patients* firsf point of reference, the third.
Sxpert Committee has selected 22 subsbances or typos of substance
from the main list tha- might be considered for this
---- j purpose. It goes
wiohout sayiny that, in practice 9 the selection must be determined"
nationally since the training ?and respons. ibilrt ips o? these workers
was within wide limits. However,2 the foilo • ing cons iderat ion- (guide~
lines) would inevitably in:! luonce the
cont . nt of th<> list.
1.
Exist inf' systems of medicine: lhe establishment of prinazy
health care services should not result in about disruption7of
such a way as to ensure that innovation is successfully integrated into existing system-s of caxe.
2W
Tne national Moalth infrastzrjcture* ■fhe type of P. H. C. se rv i oe
that a countxy requires is dependent upon the prcKimity and
nature of the first referral facilities, It is still not
unusual in so'-?e countries for the nearest permanently manned
health pas?; to be one or no re <'days’ travelling; time: from
isolated villages in its Cc-t cline nt area.
5.
Training and Supplies: The scope and. limitations of -.H.C
system are determined by the number of trained pers-onnel, °the
facilities placed at their disposal and the supplies entrusted
to tnem. Little can be sccomnlishec!. unleer: continuity of
essential supplies & information is assured.
.0.12.
12
4.
The pattern of endemic disease:
The prevalence of major endemic
within101®
Msitic diseases
witnm a. count ly in <confirmity wit^lSS^^pVicar^0'
typographical, social
economic and occupational factors. ’careful
planning and in some cases
ensure that the most
i„
ef-fecti vo d ruxrs
•
are reauired to
full benefit, from
n limited.
iMM
*” Pr0™ea’ •“ *•
A model list ._Qf drugs
Xfr—I2i_imgry_ hc-s.lt h _CA.ro s
Acetylsalicylic acid
Activated charcoal
an antacid
an antihaemonhcidal drusr
atropine (antispasmedic)
bc^0^014 & Salicyclic acid
benzyl benzoate
calamine lotion
Chlcrhesidine solution
chloroquine
Chlorpheniramine
Ephedrine (astuma)
IodineblRe P°St ~ Pa-stum heamowhage)
Ipecacuanha
Iron/Folic acid (nutritional supplement
Lindane
during pregnancy)
Inebondazole
Oral rehydration salts
Paracetamal
Piperazine
Tetracycline eye ointment
Tilese selected drugs can be used e " “
effectively and safely by
re s pons ib le ind iv id uaIs
with little formal
imedical knowledge. The
instructions for using the
drugs
<
~5 can be based
---- 1 upon the recognition of
a few basic clinical
------- signs and sympions.
Highly v/ained workers might
to their diagnostic skills
^ilir^h^eSi^A^
°f
with ? -
«Priate
the availability of snecifir ri-m-. safely, Decisions regardins’
specific
drugs
to o^'th^
c-~ taken only when all the
re levant
§fact
7 health w°rkers can be
been taken into account.
factors that operate locally heave
used only by individuals Sth Avmced
instanC1- should be
access to appropriate microbuZica! faAvA*0 Ski^s
with
f0J uhese dTO®S is
However» the need
is as great in isolated A11!
and health administrators have a
communitieasrr as elsewhere
a prime r—
as far as possible, basic mediCpl
to ensure that,
—
services are brought within-the reach
of the whole population.
services
13
-Oonc lusion?
Since its first
essential drugs has^coS^d1977’ the WH0
concept of
useful tool towards rationalTO and acccPted as a very
whose rresources
---and trained
Usa-2* ^evclopir^ countries
—
. .
rained manpower are scarrn
to spend -their
cannot afford
"»»>y on nows„rtiej dJL
through their
and should 9 therefore
that r
— suitable for
are
-J select ]more drugs
^herapentic needs. In doing
WHO model H
s
t
---- J Of essential drugs
J so, the
continues to serve as guidance
and reference.
: ro“»^ -«Ssts
°m !
essential drug
developing
Reduction in the number of
. r
*
:
r"
•••?
I^rcha-sed
Analyzed
Stoned
distributed
products to be
((in other words
(
case in logistics)
Improvement in the standards
of:
Use of drugs
Management
Mo nit or i:•ng of drug usage (t
o know Which drugs are used
where and how)
improve me nt of
Information of drugs
draining
Easier recognition of:
Adverse Reactions in
populations using relatively few drugs.
All these W±11 helP
bUild a r°ad t0 bcttGr therapy.
Vaceines focuses
And■ iodeed, unless a limited number of thoT® ^imry health care,
to rural areas and tn tn-, r, •
01 “tem can be reoularlv rioi,-.,, j
strate,7y of health for All by the7 S1UmS’ WH0’s whose'’ambit ions
Partial or even total disastere^
200° Wil1 face Purt-iell
The important
hing to note is that the ’
companies cr?
are partners in this
-—; venture. The big Ig Pharmaceutical
WHO that they arc truly ready
companies assured
to
-J shoulder what can be termed their
social responsibilities in
respect of the have
not of the Third. World.
Riysician and other health workers who prescribe drugs
workers who
2SionOj5iSPenSin4? ?harmacists
9 are obvious partners too in the
am w
when
prescribed
and with due attention to the
)solutt-’ly nocessaiy
patient
’s understandinga}how
to use them9
are wal1 within the bounds
ol good medical
—pract ice.
T~
loom t^Vati£ntS’ too>
supported
information, must
icarn to take more req-nma-rh-jn
••
o by
v better
---own drugs use. Consumer arouno
—
°1‘t their
own
healthrol
and,?. their
groups can play ■’’* ln]
portant
.n lr
educating the Rahlie in tke
-e- correct use of pharmaceutical products.
.
Finally to t
Dr. Ernst Laundsen, ---Action Programme on quote
Programme Manager ? TVHO
Essential Drugs and. Vaccines^
14.
14
"I believe that history i
will judge us honestly - some 10 to
20 years from now if w have such
-i
wonderful drugs and vaccines, but
fail to put our best talents to work on finding
new ways of making them
them" 16 tO the raany hunr?r '(3s of minions who'so
desparately need
LOCCST andi Essential Drugs -Programme?
though
Action Lines
(A)
Es t ah 1 ishmc-nt o£_l.ist__of Essential .Drugs (LOCOST)
„
„ LOCOST has already identified
72 essential drugs from WO list,
Hat hi Commission Report a.
and Pune Workshop - We feel that the list
iS
biased for primary health care level in rural
most essential 5 tne scope should be enlarged area. 'Though this is
We may review the drug
list and PIW mXD6 Wh6rf;in h;
wherc in h alth caD, at three tier systemi can
be incorporated 9 xAGuiit- ly •
(i)
(ii)
(ill)
Rural primary 1- health care (Village & HV level)
Primary Health Centres and referral centres
Large and teaching' hospitals
- —' and consultants level.
From above lists,9 in the
same priority, drugs can be chosen
for manufacturing, procuring
and. supplying under LOCOST banner.
Por —
preparing this list a small g
*
group from
our present committee
can be entrusted the work o
After preparing the listsJ, they can be
sent to experts ccommittees from above three levels
9
for their critical
review, suggestions etc.
(B)
Druj .Information
ife have already begun in this
direction we have started
preparing Package inserts for the use of partners.
Ve should complete
d^
ThX thF earliest by propping packa^’
t ,' “
of present
V11 1986inserts
- ^ercaftfr
also 50
Thereafter
also
information for other
— essential drugs (even not
should be collected 9 analysed and stored to be produced by L0CC6T)
re le as ed on inqu ixy
to the partners.
The present format for information sheet
is enclosed for your
review a.nd comments,
(C)
gclucati ona 1 AP.t lv it jes;
Educational activities should be taken
up at various levels.
(i)
. Concept of essential drugs .
and their use should be propagated
to medical profession by publishing
•4-u
’ ar^lcles in the scientific journals,
arranging talks and discussion
with
professional groups, sending
pamphelets tc.
(ii)
Writing articles
m simple and. vernacular language in lay press
to provide information
savins
y di^nosis
self medication which may
become life < a mg (demysci-ication)
warning against indiscriminate use
of drugs etc.
(35)
felieX-SOlince^
To work as a pressure group for entering
St at e trove rnmo nt to prepare, essential drug lists, guard against substandard drugs. Hanning harmful drugs, etc.
? 6 *. Z 2LOCOST
GPO BOX2 134
BARODA - 390001
Management & Treatment of TB
Phone : 63962
Part II
Childhood Tuberculosis
By Dr. Anita Srivastava
Tuberculosis is one of the major health problens in developing
countries. Over the last few years it has been increasingly obvious
that it is not sufficient to see a case of tuberculosis as an isolated
clinical problem, but it must be viewed in the context of the patients
community and against the background of health policies and heqlth
resources of the nation. Like Sholera or Smallpox tuberculosis is
became a "tropical” disease during the twentieth century, not through
receiving an ecological advantage from a warm or humid climate,
but because it was largely eliminated from those countries, grasped
in the temperate zone whose affluence and organisation afforded
them the opportunity to apply effective preventive measures, and
whose general standard of living rose.
Prevalance of Tuberculosis
t
It has been estimated that where 60% of the population are
infected at the age 15 years, one
. should expect 30 new cases
of T.B. meningitis annually in children aged 0-4 years, and 360
new smear positive cases (all ages).
These estimates are useful
because direct results of surveys in childhood are unsatisfactory childhood disease being often extrapulmonary, and the demonstration
of the T.B. bacilli are / elusive.
^more
The adult cases are the sources of ..infection in children.
The extra-thoracic type of tuberculosis (mairily CNS tuberculosis,
miliary disease and disseminated
tuberculosis) is responsible for
nearly 10% of death in children, while 30% of death are due to
intrathoracic type. In a childrens’ hospital in a developing country,
TB is among the five major causes^in children, ^of death
Countries / 1high prevalence are those where more than 10% ^with
of children are""infected by 10 - 14 years of age.
Natural History of Tuberculosis
Untreated Primary TB
Infection is usually through droplet infection and the primary
sit of infection is in the lung. Infection is followed by a
symptomless incubation period of 6-8 weefe until sensitivity develops.
Sensitivity is marked by the conversion of the tuberculin skin tests,
which become positive and usually remains positive. Sensitivity
has both advantages and disadvantages. The advantage is that it is
accompanied by an immune response which in most children overcomes
the primary infection without any di.sease being apparent or with
onjy transitory fever and malaise. The development of sensitivity
£Sa sa vantageojis in
may itself cause symptoms and initiate
anrl ex dative reaction and further spread of the infection ( via caseaand . Rupture of a gland).
tion
The sto^y of a tuberculous infection is therefore largely
dependent upon the balance between the immune response arid the
acquired sensitivity. Factors such as concurent infection or mal
nutrition which reduce the immune response, will favour rapid spread
of the disease from its initial site. A primary infection with
development of a complex can precipitate kwashioker in a child already
suffering from malnutrition because tuberculosis increases protein
requirements particularly when the child is febrile.
The.clinical picture which may follow if the primary infection
is not quickly
_ ’ n \ overcome
j are s
(a)
extension of the primary focus
(b)
involvement of regional lymph glands
(c)
blood spread.
Any of these may occure at the same time and the ris
are all
greater in
:
young children, decreasing gradually with age until
puberty, when the
'’ 5
risk increases again.
The timetable of Tuberculosis
to
Caseation
:is more likely/occure
after infection.
within the first year
Blood spread is more likely in the first few weeks after
primary infection out bone lesions do not often appear until
thjyee or more years later.
Renal & epididymal lesions are uncommon in childhood and
are more often seen at puberty.
Fifteen to twenty per cent children infected in the first
year of life developed TB mening tis or miliary spread
within two years compared with only four per cent of all
children infected under the age of 5 years.
Tuberculin Sensitivity
The object of performing a skin test with tuberculin is to
separate those who have been infected with tubercle bacilli from
those who have not* The most widely used test is the Mantoux
test in which a low dose of 1 T.U» PPD RT23 with Tween
80 is
given intradermally. The test is read 72 hours later and the size
of the indulation of 10 mm or more is generally accepted as
positive with the following gradings*
Grade
Negative (-)
Negative (j;)
1
2
3
4
(+)
(++)
(+++)
(+!-!-+)
Diameter of indulation
below 5 mm
6-9 mm (may indicate infection
by a typical mycobacteria or following
BCG vaccination)
10 - 14 mm
15 - 20 mm
21 - 30 mm
30 mm of necrosis of tissue
A negative reaction excludes TB in the great majority of well
nourished children. Any child with a positive MT who ±s under
2 years of age or malnourished and under 5 years- of age should be
regarded as having active disease requiring treatment. If there is
a close contact with an open case of TB chances of active disease
are extremely high. ’^he stronger the reaction of tuberculin, the
more likely that the disease is active. A child with a positive.
MT without any symptoms may be at a risk of TB meningitis after an
illness like measles or whooping cough, especially in infancy and
early childhood.
In older children and adults a positive MT
means that infection has occured, though in majority there may be
no disease.
contd...o.3
Symptomatic Primary Infection
Clinical features
Children with primary complex may present or mimic the
following clinical pictures,
(a)
irregular pyrexia of one or more weeks' duration, with or
without coryza and cough.
(b)
low grade fever, cough, loss of appetite, loss of weight
and fatigue.
(c)
typhoid like fever
(d)
(£e)
pneumonia
malaria
Fate of the primary Complex
Simple primary complexes heal in the majority of cases, the
pulmonary foci, regress faster: than the hilar nodes. There may be
mild x residual fibrosis or complete resolution,
In a small percentage of cases there is calcification at the site of the focus
and the calcification is more often seen in the hilar nodes where
there are greater chances of caseation.
Progression of the disease is more frequent in infants and
in children below the age of 4—5 years when natural immunity is
low, when the infection is often massive and repeated ' .. ’ derived
from an open contact in the family, and when the child has poor
nutrition and frequent infections. Measles and whooping cough
are important factors which often lead
to ---flarej up
of the old
-----lesions or progression of the existing one.
Diagnosis of TB
(To suspect TB is half way to diagnosis) Suspicion of TB by the
following common clinical features s
Cough with wheeze, pneumonia that fails to resolve, pleural
effusion, painless enlargement of superficial lymph nodes, failure
to gain weight, failure to regain health after illness (e.g. measles,
whooping cough), recurrent abdominal pain, pyrexia o± unknown
origin, head ache or vomitting lasting more than 3 days, pain or
stiffness in a joint, painless hematuria.
Suspicion will be sharpened by :
-
History of contact with an infected adult, family screening
to locate infected persons
a positive MT
radiological changes
Diagnosis is confirmed by . finding A.F.B. usually in the sputum.
because small children swallow their sputum, gastric lavage
is used to obtain material for culture
laryngeal swabs
-
histological examination of a lymph node
examination of pMiral and
peritoneal exudate .
contd..».4
Management of T B
Object of treatment
I
chemotherapy s
(1) To eradicate TB bacilli from various foci
in the body.
(2) to prevent the spread of disease both local
as well as hematogenous.
(3)
To reduce damage caused by
tuberculous toxins and of equal importance, damage caused by
tuberculoprotan in the sensitised tissues.
II
Restoration of normal nutrition - nutritional deficiencies
should be investigated and weight gain used as the best
single guide.
III
Treatment of any other infections or
skin or boils.
IV
Protection against infections - by immunisation.
V
Family & contact rscreening for tuberculosis - case
and their treatment„
infestations
eg
of
detection
Ch emo th e rapy
I*
he most important part of chemotherapy is that the patient
shall take his drugs. Details of chemotherapy are less important
than the cooperation of the parent, and when the treatment fails
it is usually not because of inadequate prescribing but because the
patients family has defaulted. The problem of chemotherapy can best
be discussed by relating treatment to three groups of children while
.linking of simplicity, completness,
the avoidance of toxicity
and cost.
2
Group I
The child without symptoms who is known to have undergone
recent primary infection s: in
In this situation the object is to
removethe danger of hematogenous dissemenation and over time kill
bacilli in the primary complex or any small subclinical lesions which
have already formed. Treatment should be oral and Streptomycin is not
required. In this situation INH should be given once daily for atleast
a year and preferably for 18 months. As the second drug( most authors
feel that it is desirable ), the choice is between PAS, Ethambutol
and Thiacetazone.
in epuntries where cost of a second drug is im
portant thdn ^-hiacetazone can be used.
Group II
Children who have clinical manifestrations of primary infection,
erythma rodosum, pleural effusion etc.,
those with
■ hemotagenous lesions in tissues such as ’bones'’ or joints.
In this situations two drugs given in sufficient dosages regu
regu-
larly for 18 months preferably for two years was sufficient and that
progressive healing was obtained.
o SOme workers have given SM
in addition.
s
Rifampicin can be given but its cost will prevent its use in
many parts of the world, Oral treatment with 2 days is sufficient
if or thisc groups.
Group III
Children seriously ill with acute, or developed milliary disease
extensive pulmonary disease or TB meningitis.
5
t
In these cases speed is most important consideration and the
full weight of*therapy must be brought to bear as quickly as possible.
Therapy must be built around INH as a central drug (dosage
should be sufficient if 15 - 20 mg/kg/day). With INH give Rifampicin
if it is available and SM if it is not, and a third drug chosen
according to circumstances and previous experience from PAS,
Ethambutol or Thiacetazone.
Treatment aimed at elimination of all organisms will take
18 months to 2 years. As a rule if three drugs are being used SM
is the first to be withdrawn at a period of 8 to 12 weeks.
Steroid Therapy
Steriod used as . an adjuvant to chemtotherapy will reduce the
inflamatory reaction of the
host. Since inflamatory response
is correlated with tuberculin sensitivity it is most useful in
these situations when tuberculin sensitivity .is high and when used
at the beginning of of the inflamatory repponse eg. large pleural
effusions or abdominal ascites , T!BM.
Prednisone is the most usual
kg/day in devided doses for a month
preparations by mouth 1-2 mg/
thens reduction over 2 weeks.
In TBM dexamethazone 0.5 mg/kg can be used for relief of
cerebral oedema and headache during the first three days quite
apart from the decisions whether other steroids are to be used for a
larger period.
DRUGS USED FOR TB
Streptomycin
It must be given by injection.
Dose s 20-40 mg/kg/day
INH
It is the most powerful and effective of the first line drugs.
Depending F on the rate of acetylation, children have been
divided into "slow inactivators" and "rapid inactivators". In one
study it was found that 82% of children were "rapid inactivators"
and 18% slow ones.
The dose of INH depends upon the. severity .of the disease and
age of the child. In infancy and early childhood a dose
of“ 20 mg/kg
<
per day should be used while in ©Ider children a dose of 10-15 mg
In miliary disease and TBM the dose may
per kg/day ' is adequate.
be increased to 30 mg/kg/day.
Thiacetazone
(TZ)
May be regarded as a substitute
to take unless bulky.
for PAS, being more pleasant
The dose is 5 mg/kg/day to a maximum of 200 mg.
been introduced in a tablet form combined with INH.
It has also
PAS
It is an unpleasant tasting powder.
Dose s Dose is 200 mg/kg/day to a maximum of 12 gms.
Ethambutol
Dose is 25 mg/kg/day for first 6-8 weeks and then
Rifampicin
Dose is 10-20 mg/kg/day.
15 mg/kg/day.
....6
>
Chemoprophylaxis
The high efficacy, low cost, & low toxicity of isoniazid
have led to its use in preventing progress of TB in infants and
children known to be infected with .TB or heavily exposed to risk
of infection.
A regime for such
chemotherapy (from Lloyd & Jones, 1972)
Clinical State
Asymptomatic primary infection
in children under 5 years
Duration of INH Therapy
I
X
6 months
Asymptomatic infection in children
over 5 years
(a) suffering from malnutrition
6
(b) on steroid therapy
Duration of steroid
therapy
(c) who develop measles
1-2 months
Tuberculin negative contacts of
open cases
Infant of tuberculous mother
I
X
12 months
6 months
6 months (or until
mother’s sputum is
negative)
Isoniazid administration can be coupled with vaccination .
; by
isoniazid resistant BCG strains. but these are expensive and not
readily available.
Control of TB
(1)
(2)
(3)
BCG Vaccination
Case finding programmes
Standard treatment regimens
References
(1)
Diseases of Children in the subtopics and tropics,
^d. D.B. Jelliffe and J.P. Stanfield-. (3rd edition)
(2)
Tuberculosis in children - Evaluation, Epidemiology, Treatment,
Prevention.
F.J.W. Miller.
B.I. Churchill Livingston Pvt. Ltd., New Delhi.
(1st edition 1986'
LocosT
C.P.O. Box 134
Baroda -390 001
COMMITTED TO THf
CORRECT MEDICINE
THE USE QE ESSENTIAL DRUGS
Sagun Desai
Rajul Desai
I.
MoD.
M.D.
INTRODUCTION
Drugs play an important role in protecting, maintaining and
re s t or ir^ .-he alth. In the developed countries, the availability of
drugs is not necessarily governed by
w public health needs.J, rather by
supply and demand. Although we have the technology today to cure
. most human ailments, Ihundreds of millions of people mostly living
in the Third World have no access to the most important medicinal
drugs. The World-wide sales of pharmaceutical products in 1985 was
estimated at IB $ 70 billion and were expected to grow to LB $ 127
billion by 1987. At this rate the sales in 1985 are projected to be
around IB $ 100 billion. The three quarters of the World’s popula
tion living in developing countries use only about 1 % of the Worlds
drug products. On one sid.e the financial resources in those countries
are inadequate to-meet even the basic requirements of majority of
the population while paradoxically dn the other hand many developing
countries have been spending as much as 20 to 5of their national
heaJLth care budgets on pharmaceuticals, and the drug supply situa
tion in those countries tended merely to initiate that in the
industrialized World. In other words - a huge variety of the latest
antibiotics, a vast range of tranquilizers and tonics and a plethora
of anti-dianhocal drugs. In short, the discrepancy between need and
availability in many of the developing countries has become critical
with regard to essential drugs.
The Director General of WHO had reviewed, the main drug
problems facing the developing countries and outlined possible new
drug policies. He pointed out that the selection of these essential
drugs would depend on the health needs and or the structure of and
development of health services of each country and that lists of
. essential drugs should be drawn up locally and periodically updated
with the advice of expert-s in Public Health 9 medicine, pharmacology,
pharmacy and drug manageme nt. He also considered that adequate
information on the properties, indications and use of the drugs
listed should be provided.
To narrow this gap the Twenty Eighth World Health Assembly
in 1'975 passed a resolution in which the WHO Director General was
requested’ ”To develop means by which the Organization case be
greater direct assistance to Member States in advising on the
selection and procurement at reasonable cost, of essential drugs
of established quality corresponding to their national health needs".
Following this the ;VHO in 1977 appointed an Expert Committee
to try to define which drugs were really necessary to deal with.
most health problems. 'The result amounted to a peaceful revolution
in international public health.
K..
The expert Committee concluded that about 200 drugs and vacci
nes could be considered as essential for theraphy in good medical
practice. Most of them were no longer protected by patent rights,
and. could be most marketed as generic (non-brand name) products and
sold at a reasonable price to patients. (A recent study in an African
Country has shown that it requires les^than one U.S,, dollar per
year per person to buy the drugs necessary to meet the most pressing
needs in primary health care).
That original list was met with surprise, indignation and
even open opposition. But it has ‘been revised and updated twice in
1979 and. 1982 and has stood the test of the time. It now contains
about 220 essential drugs anc^ vaccines, and. more than 80 countries Have
adopted the model list to their own requirements. This also led to
establishment in 1981 of the WHO action programme on Essential Drugs
(APED).
o b2 .
y
*
1
2
$
*
Mr
W Mt
OTO
X7 OT C
The provision of essential drugs and vaccines fferms
fdrms one^of^
of
the basic components of primary health care. The regular
.lar supp^r^of
supply o: T"4"
a limited number of essential drugs is also one of the indicaters to
measure progress in attaining the goal of Health for All by the year
2000. .
II.
The Essential Drugs Concept:
In the early seventies, imore and' more complaints were voiced
by health administrators and policy makers of developing countries
ttbout too
a proportion of the health care budget (some times
more than 2>) being spent on drugs. In spite of this, a vast
majority of the people living in rural areas had and have no access
to the most essential drugs. Why ? Reasons....
1.
Selection of drugs for a. country's health services often
has been done arbitrarily with no links between drugs and
health needs. Mary non-essential drugs have been and are
still imported and paid for with scarce foreign exchange.
2.
Hospitals, particularly urban areas, consume much too large
a proportion of the national drug bill compared to health
centres and dispensaries which have to face constant short
age or lack of medicines.
3.
Distribution systems are insufficient, manpower is lacking,
or is not properly trained to prescribe and use drugs due to
inadequate exposure to objective drug information.
4.
A comprehensive national drug policy in support of'dprimaxy
health care based upon a selected number of essential drugs^-^
is. missing in most developing countries.
It is against this background that the concept of essential
drugs was born in 1 975.
U(a)
Guidelines for Establishing a National Programme for
Essential Drugs:
Since the First Report on the Selection of essential drugs
was published in 1977, the concept of essential drugs has become
widely recognized as useful. It has provided a rational basis not
only for drug procurement at national level hut also for establishing
drug requirements at various levels within the health care system.
In fact, maiy developing countries have already selected essential
drugs according to their needs and the related programmes are in
sojjie cases, in an advanced stage of implementation.
In order to ensure that an essential
(
drugs programme is
adequately instituted at national level
------ , several steps are advised:
(
1.
The establishment of a list of essential drugs, based on
the recommendation of a local committee, is the startingpoint of the programme, The Committee should include
individuals competent in the fields of medicine, pharma
cology and pharmacy, as well as peripheral health workers.
Where individuals with adequate training are not available
within the country, assistance from WHO could be sought.
2.
Thu international non-proprietary (generic) napes for drugs
or pharmaceutical substances should, be used whenever
available, and prc-scribers should be provided, with a cross
index of non-proprietary and proprietary names •
...5.
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