TRAINING MANUL NEUROLOGY
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- TRAINING MANUL NEUROLOGY
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TRAINING iM : *. i I ’ .4 I
Neurology
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Module 1 - Epilepsy
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- Definition
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Epilepsy is defined as ia chronic
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neurological disorder characterized by recurrent seizures.
Seizure or convulsion is a surge in the brain-'s electrical activity (abnormal and excessive),
which manifests as a disturbance in body movements or consciousness or behavior.
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Types of Epilepsy
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Classifying epilepsies is a difficult task. It is useful for neurologists to group epilepsies into
different types, but the reality is more complex. Each epilepsy is a malfunction of a particular
area of the brain and is different for each patient.
Epilepsy
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Partial
epilepsy
Generalized
epilepsy
Unclassified
Simple partial
b. Complex partial
a. Generalized tonic clonic
b. Absence
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a. Neonatal
b. Infantile
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c. Partial with secondary
generalization
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c. Atonic
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d. Myoclonic
e. Tonic
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f. Clonic
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Partial Epilepsy
These are epilepsies with a clearly defined focal area within the brain.
Simple partial seizures
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The person is fully conscious and rmay
“ exhibit symptoms depending upon the area of
brain involved, like disturbances in the
.'.e motor cortex can cause motor disturbances in the
face, limbs or other parts of the body; those in the
sensory regions of brain can produce
auditory, olfactory or visual hallucinations.
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Complex partial seizures
Complex partial seizures are one of the most common forms of seizure. They always
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involve impairment of consciousness. The attack may begin as a partial seizure, which
may act as an 'aura' that warns the patient of the impending seizure. During the seizure,
there may be altered behavior or automatisms, in which the patient engages in repetitive
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movements such as lip-smacking or chewing, facial grimacing, plucking at clothing, or
wanders aimlessly or even undresses.
Partial with secondary generalization
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7116 se'zure starts as partial seizure (localized to one part of brain), but gradually spreads
to both side* of brain.
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Generalized Epilepsy
Generalized epilepsies are those, which have
defined focal area within the brain- as a'
result they have generalized symptoms as ide whole brain becomes affected,
The most
common types of generalized seizures are -
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Clinical features of the main types of generalized epileptic seizures
Tonic-clonic seizures
(Grand mal)
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The patient falls suddenly to the ground. There is
continuous forceful contraction and relaxation of
muscles
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Tonic phase: stiffness (the tongue may be bitten),
increased heart rate and blood pressure, sweating
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Clonic phase: clonic movements, labored breathing,
excessive salivation. pATT
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Deep sleep often follows the attack.
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Most common in children.
Short intervals of loss of consciousness; look of
blankness and staring.
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Absence seizures
(Petit mal)
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Last only a few seconds and may not be recognized
until other problems (e.g. learning difficulties) arise
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Sudden, brief muscle contractions (jerky movements)
occurring singly or in clusters, involve peripheral parts
of limbs
Myoclonic seizures
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Atonic seizures
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Sudden loss of body tone followed by falling to the
ground.(drop attack)
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Severe injury often occurs.
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Tonic seizures
More contractions of muscles
Clonic seizures
More relaxation of muscles
Unclassified Epilepsy
This, of course, is the grouping for epilepsies, which do not fit the classification.
Neonatal seizures: Brief episodes of eye deviation, eye blinking, repetitive movements
of arms, legs
Infantile seizures: Sudden jerky movements of different body parts, like sudden flexion
of neck etc.
Febrile fits: A common trigger factor for seizures in young children (up to 5 years of age)
is high fever (38°C and above). About 4-5% of children have 'febrile seizures' or 'febrile
convulsions
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Epilepsy Syndromes
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Syndrome consists of cluster of symptoms.
Lennox-Gastaut syndrome:
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Age group 1-8 years
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Multiple types of seizures
Mental retardation
IVesf syndrome (Infantile spasm)
Age group <1 year
Multiple types of seizures
Juvenile myoclonic epilepsy
Appears in early adolescence
Predominantly myoclonic seizures, GTC or absence are also seen
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Causes of Epilepsy
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Seizures are a result of a shift in the normal balance of excitation and inhibition within
the Central Nervous System.
Brain injury to the fetus during pregnancy
Birth trauma, such as a lack of ox\/gcn
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Poisoning from substance abuse or environmental contaminants, eg lead poisoning
Aftermath of infection, e.g. meningitis
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Head trauma, e.g. car accident
Metabolic disorders- e.g. hypoglycemia, hepatic failure
Brain tumour or stroke
Genetic defect
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Idiopathic: unknown cause
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Basic Pathophysiology
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Initiation Of Seizure
A]
Sodium channels:
Action potential burst
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Open of (Nat voltage dependent channels
Excess Na+ entry, l^+ exit across the cell
Depolarization of cell membrane
B]
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Other channels thought to be involved in the development of seizures:
1.
High voltage calcium channels
2.
Potassium channels
Spread Of Seizure
The abnormal discharge may remain localized around the epileptic focus, or spread to
adjacent areas or generalize throughout the brain via cortical or subcortical routes including
callosal and thalamocortical pathways. Spread of discharge occur via
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Excess of K+ outside the cell - depolarizes the neighbouring neurons
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Accumulation of Ca++ in presynaptic terminal lead to release of glutamate.
Neurotransmitters
Gamma-amino-butyric Add (GABA)
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GABA is the most important known inhibitory neurotransmitter. Experiments at a cellular
level have indicated that decreased GABA inhibition can result in electrical activity typical
of epilepsy in experimental foci. It has also been shown that some people with epilepsy
have low levels of GABA in their brains, and that drugs that increase the concentration of
GABA in the brain can control some types of epilepsy.
Glutamate
There is some evidence that excessive activity or increased sensitivity in the excitatory
amino acid neurotransmitter systems imay be involved in the genesis of epileptic seizures.
Substances to block the release of the
...j amino acid neurotransmitters, glutamate, have
been another focus of research on drug treatments for epilepsy.
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Summary of Pathogenesis of Epilepsy
1.
2.
3.
Excess Na+ entry
Increase Glutamate
Decrease GABA
Electro-encephalography (EEG)
An electroencephalograph (EEG) measures the electrical activity occurring in the cerebral
cortex.
A set of electrodes is attached to the scalp. The electrodes pick up the electrical discharges
in the cortex, amplify and then record them. The whole procedure usually takes about 30
to 40 minutes.
EEG Recordings
ISiEBOi; focai motor seizure, left arm
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EEG is useful to Confirm the clinical diagnosis of epilepsy
Support classification of partial-onset or generalized seizures
Monitoring drug therapy
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Discontinuing drug therapy
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Management of Epilepsy
Therapy for a patient with a seizure disorder is almost always multimodal.
7.
2.
Treatment of underlying conditions
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Metabolic disturbance such as an abnormality of serum electrolytes or glucose,
then treatment is aimed at reversing the metabolic problem and preventing its
recurrence.
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Seizures caused by a structural CNS lesion such as a brain tumor or blood vessels
abnormality or brain abscess may not recur after appropriate treatment of the
underlying lesion.
Avoidance of precipitating factors
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Precipitants such as stress, sleep deprivations, exposure to toxic substances and
certain medications, should be avoided.
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3.
Anti-epileptic drug therapy (AED)
Goals of anti-epileptic drug therapy
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To prevent the occurrence of seizures
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To help the patient accept his / her disease state & improve the quality of life
Antiepileptic Drugs
Conventional Antiepileptic Drugs
Carbamazepine, phenytoin, valproic acid, phenobarbitone
Newer Antiepileptic Drugs
Lamotrigine, topiramate, oxcarbazepine, gabapentinw, clobazam, clonazepam, vigabatrin
lhe limitations of the conventional anti-epileptic drugs
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These drugs are not effective in the treatment of all types of epilepsy and hence are
said to have narrow therapeutic indices.
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Despite their efficacy, the agents fail to produce complete seizure control in about
30% of treated cases
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Short half-lives pose problems for some AEDS sirice it may be difficult to maintain a
stable concentration of the drug in the blood over 24 hours which is essential for
the efficacy of some AEDs e.g. carbamazepine. Due to this, the increase in number
of daily doses would however, adversely affect compliance
Enzyme induction and inhibition
Enzyme Inducers: Carbamazepine, phenytoin and phenobarbitone induce the
cytochrome P450 isoenzymes hence; the concomitant drugs are metabolised
faster.
Enzyme Inhibitor: Sodium valproate is an enzyme inhibitor hence, concomitant
drugs are slowly metabolised and remain in circulation for long time causing
side-effects.
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Close monitoring of plasma concentrations is generally necessary.
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The pharmacokinetics of Phenytoin are non-linear (serum-concentration increases
disproportionately to an increase in the dose) and carbamazepine induces its own
metabolism (auto induction).
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Adverse effects caused by the traditional AEDs limits their use in many situations.
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Limitations of conventional antiepileptic agents
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Limitations
Carbamazepine
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Neurological: Carbamazepine affects cognition, sedation, ataxia,
vertigo
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Systemic: Aplastic anemia, bone marrow suppression,
neutropenia
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Allergic rash
Drug-drug interactions
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Pharmacokinetic disadvantages, like enzyme induction and auto
induction
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3-4 times daily dosing due to autoinduction, decreased patient
compliance
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Phenytoin
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Long term phenytoin therapy can caufie gum hyperplasia,
hirsutism (hairy face), acne, hypertrophy of subcutaneous facial
tissue
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Osteoporosis
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Teratogenic - 30% of infants exposed to phenytoin in utero
can develop severe anomalies such as cleft lip, cleft palate,
microcephaly, heart defect known as 'fetal anticonvulsant
. syndrome'
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Drug-drug interactions due to interference with cytochrome
P450 liver enzymes. Increases clearance of oral contraceptives
and can lead to oral contraceptive failure
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Vitamin K depletion in foetus leading to bleeding disorders
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Hyperactivity in children
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Sedation in adults, megaloblastic anaemia, osteopenia
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Increases chances of developing tolerance due to sedation
Doubled risk of congenital malformations in foetus
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GI side-effects
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Transient Alopecia
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Hepatotoxicity
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2% of children develop spina bifida / before birth exposed to
valproic acid
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Weight gain
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Initially it is highly effective, but within a few days to few
weeks efficacy decreases in approximately one third of patients
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Cannot be used for long term therapy
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Increased risk of breakthrough seizures
Phenobarbital /
Phenobarbitone
Sodium Valproate
Clobazam
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Clonazepam
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Patients develop tolerance to therapeutic effects of
benzodiazepines
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Not good choices for long term treatment
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Increase risk of seizure recurrence
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Sudden withdrawal leads to status epilepticus
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SELF-ASSESSMENT 1
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Define
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Epilepsy
Seizure
2)
Types of partial seizures are
a)
b)
c)
3)
4)
Match the following
Absence seizure
Patient falls down on the ground
GTC
Staring at one point
Atonic seizure
Brief contraction at peripheral parts of limbs
Myoclonic seizure
Forceful contraction or relaxation of muscles
throughout the body
Name the 3 important reasons in pathogenesis of epilepsy
a)
b)
c)
5)
Match the following
Phenobarbitone
Allergic rash
Phenytoin
Weight gain
Sodium valproate
Cleft lip and cleft palate
Carbamazepine
Osteopenia
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Module 2 - Antiepileptics drugs
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Valtec / Valtec CR
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Valtec / Valtec CR
Brand Name
:
Molecule
Sodium Valproate
Class
Conventional anti-epileptic drug
Mechanism of action
Reduces Na+ entry, improves GABA synthesis B release
Valtec is our brand of sodium valproate. Valtec is available as Valtec 200, Valtec 300,
Valtec 500 containing sodium valproate 200 mg, 300 mg and 500 mg respectively.
Valtec CR is our brand of controlled release sodium valproate. Valtec CR is combination
of sodium valproate and valproic acid. Valtec CR is available as Valtec CR 200, Valtec CR
300 and Valtec CR 500.
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Advantages of Valtec CR
Feature
Benefit
1.
Valtec CR is a combination of sodium
valproate plus valproic acid
Results in greater amount of
valproic acid to be available for
action
2.
Sustained release preparation
Ensures sustained
concentrations of valproic acid.
No wide fluctuations
3.
Long elimination half-life
Convenient daily dosing hence
better patient compliance
4.
Sustained release of valproic
acid in GI tract
Less gastrointestinal
side effects hence better
tolerability profile
Sr. No.
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Indications
I.
Epilepsy
Valtec/Valtec CR is indicated as monotherapy and add-on therapy in adults and
children for the treatment of all types of seizures.
II.
Bipolar disorder
III. Migraine Prophylaxis
Dosage
In Epilepsy
Monotherapy (initial therapy)
Patients should initiate therapy at 10 to 15mg/kg/day. The dose should be increased by 5
to lOmg/kg/week to achieve optimal clinical response.
No recommendation regarding the safety of sodium valproate for use at doses above
60mg/kg/day can be made.
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Conversion to gjonotherapy
Patients should initiate therapy at 10 to 15mg/kg/day. The dosage should be increased by
5 to Wmg/kg/week to achieve optimal clinical response. No recommendation regarding
the safety of sodium valproate for use at dose above 60mg/kg/day can be made.
If satisfactory clinical response has not been achieved, plasma levels should be measured
to determine whether or not they are in the usually accepted therapeutic range (50WOmcg/mL).
Concomitant anti-epileptic drug (AED) dosage can ordinarily be reduced by approximately
25% every 2 weeks. This reduction may be started at initiation of Valtec therapy, or
delayed by 1 or 2 weeks if there is concern that seizures are likely to occur with a
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reduction.
Adjunctiyejherapy
Valtec/Valtec CR may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/
day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical
response. If the total daily dose exceeds 250 mg, it should be given in divided doses.
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Migraine
The recommended starting dose is 250mg twice daily. Some patients may benefit from
doses up to WOOmg/day.
Highlights
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Valtec/Valtec CR is recognized as a broad-spectrum anti-epileptic drug highly effective
against all types of seizures.
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Lamotrigine and valproate show synergism in clinical studies. This is due to multiple
reasons
Different mechanisms of action
Well documented combination in epilepsy
Less drug interactions
Greater efficacy
Minimal side_effeets
Cost effective
Effective in childhood epilepsy
lessjncidence of allergy rash than carbamazepine
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Lametec
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Brand Name
Lametec
Molecule
Lamotrigine
Class
Newer antiepileptic drug
Mechanism of action
Reduces excess Na+ entl
reduces glutamate release
Z “'g-ne and available as Lametec 5 DT containing lamotrigine
5 mg in dispersible tabiet form, Lametec 25 containing lamotrigine 25 mg, Lametec 50
contammg 50 mg lamotrigine and Lametec too containing W0 mg iamotrigine
Indications
As <add-on therapy in the treatment of all types of epilepsy. In UK it is recommended
as a□ monotherapy in the treatment of epilepsy
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As add-on therapy in Lennox-Gastaut Syndrome
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Neuralgias
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Childhood epilepsy
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Dosage
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Dose recommendations for Lametec (mg/day) for adults (over
AEDs
Weeks 1 and 2
Week 3 and 4
16 years)
Usual
Maintenance Dose
Phenytoin,
With
<50carbamazepin^
mg/day
2^00 mg/day
(once a da-y
(two divided
(two divided). To achieve
doses)
maintenance, doses may
Phenobarbitone
with or without
300-500 mg/day
K
sodium valproate
Valproic acid with
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25mg every other day
be increased by
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100 mg/day every
1 or 2 weeks
25mg (once a day)
or without other
100-400mg/day (two
divided doses). To achieve
AEDs
maintenance, doses may
be increased by
25-50 mg/day every
lor 2 weeks.
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Anti-epilepti
drugs (AEDs)
Weeks 1 and 2
With carbamazapine,
0.6mg/kg/day in -r—^>J.2mg/kg/day in
5 to 15mg/kg/day
phenytoin,
two divided doses
Week 3 and 4
Maintenance Dose
two divided doses,
(maximum 400 mg/
phenobarbitone
rounded down to
day in two divided
with or without
the nearest 5 mg
doses).
sodium valproate
, Increments every
1 to 2 weeks as follows:
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Calculate 1.2mg/kg/day
round this amount down
to the nearest 5mg and
add this amount to the
previously administered
daily dose.
Valproic acid with
0.15mg/kg.day in
0.3mg/kg/day in one
or without other
one or two divided
or two divided doses, (maximum 200 mg/day
AEDs
doses, rounded down
rounded down to
to the nearest 5mg.
the nearest 5mg.
1 to 5mg/kg/day
in one or two divided
doses).
Increments every 1 to 2
weeks as follows:
calculate 0.3 mg/kg/day,
round this amount down
to the nearest 5 mgand
add this amount to the
■previously administered
daily dose.
Highlights
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Pharmacokinetics
98% oral bioavailability
Linear pharmacokinetics in adults as well as children
No enzyme inducing or inhibiting properties
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Routine therapeutic monitoring of plasma concentration? not required
Convenient dosing due to long elimination half life
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Efficacy & Tolerability
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Effective against all types of seizures and syndromes
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and secondarily generalised tonic-
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In UK approved additionally as monotherapy
Highly effective against a wide range of seizures
in children and in Lennox Gastaut
Syndrome
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< 4
No interaction with oral contraceptive drugs
Lower withdrawal rates
As effective as Carbamazepine but displays superior tolerability profile
Treatment withdrawal due to CNS related effects
was lower In patients receiving
lamotrigine (2.5%) as compared to CBZ (7.7%) or
PHE (7.4%)
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Lametec is ideal antiepileptic drug for use in epilepsy in females.
Does not alter steroid hormones, hence less menstrual abnormalities
Does not interfere with effectiveness of hormonal contraceptives
Does not lead to appreciable weight gain, hair loss
or gum disorders
Prevents development of PCOS symptoms in epilepsy patients & improves fertility
rates in patients with epilepsy & PCOS. p-x
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Less chances of teratogenicity
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Topamate
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Topamate
Brand Name
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Molecule
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Topiramate
Class
Newer antiepileptic drug
Mechanism of action
Reduces excess Na entry, blocks glutamate receptors and
increases release of GABA
Topamate is our brand of topiramate. Available as Topamate 25, Topamate 100 containing
topiramate 25 mg and 100 mg respectively
Indications
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As adjunctive treatment for adults with partial onset and primary generalized tonicclonic seizures
Dosage
Initiate therapy with Topamate (Topiramate) at 25-50mg/day followed by titration to an
effective dose in increments of 25-50mg/week. The recommended total daily dose of
Topamate Oopiramate) as adjunctive therapy is 400mg/day in two divided doses. Daily
doses above 1600 mg have not been studied. "The recommended titration rate for
Topiramate is:
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AM Dose
-----PM Dose
Week 1
None
25-50 mg
Week 2
25-50 mg
25-50 mg
Week 3
25-50 mg
50-100 mg
Week 4
50-100 mg
50-100 mg
Week 5
50-100 mg
100-150 mg
Week 6
100-150 mg
100-150 mg
Week 7
100-150 mg
150-200 mg
Week 8
150-200 mg
150-200 mg
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Highlights
Multidimensional approach to seizure control attributed to multiple mechanisms of
action
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Blocks Na+ channels, enhances GABA activity, antagonizes glutamate receptors
Topamate has a high neuroprotective index. Due to multiple modes of action,
Topamate effectively controls imbalance of ions and chemicals in epilepsy and protects
against the neuronal damage secondary to ion-chemical imbalance and antioxidants.
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Wide spectrum of antiseizure activity hence effective against all types of seizures and
syndromes in adultsjjs well as children
Linear kinetics in adults as well as'children
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Routine monitoring of plasma concentrations not required
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Convenient twice daily dosing due to long elimination half-life of 21 hours
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Favourable safety and tolerability profile
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Topiramate causes weight loss unlike some conventional antiepileptic drugs like Sodium
Valproate
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Oxcarb
Brand Name
Oxcarb
Molecule
Oxcarbazepine
Class
Newer antiepileptic drug
Mechanism of action
Blocks voltage-sensitive sodium channels, increases potassium
conductance, modulates high-voltage activated calcium channel
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Oxcarb is our brand of oxcarbazepine and available as Oxcarb 150, Oxcarb 300, Oxcarb
600 containing oxcarbazepine 150 mg, 300 mg and 600 mg respectively
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Pharmacokinetics
Superior Pharmacokinetics Over Carbamazepine
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OXCARBAZEPINE------------REDUCTION
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No auiQinduction
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Less enzyme induction (Cyt P 450) - Less drug-drug interactions
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Less side effects
CARBAMAZEPINE ----------- 10, 11 EPOXIDE
OXIDATION
3
Autoinduction
Enzyme induction (Cyt P 450) - More drug- drug interactions
More side effects
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Indications
7.
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Epilepsy
Oxcarbazepine is indicated for use as monotherapy or adjunctrye_therapy in the
treatment of partial seizures in adults with epilepsy and as adjunctive therapy in the
treatment of partial seizures in children ages 4-16 with epilepsy. In clinical studies,
Oxcarbazepine has~beeffproven to control partial and generalized tonic clonic seizures.
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Trigeminal neuralgia
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Oxcarbazepine may be a useful alternative to carbamazepine in the management of
trigeminal neuralgia. In clinical studies, Oxcarbazepine appears to have equivalent
analgesic effects compared with carbamazepine.
3.
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Acute mania of bipolar disorder
Dosage & Administration
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Monotherapy and adjunctive therapy with Oxcarbazepine
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Start with 600 mg/day given 300 mg BID
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Add 600 mg/day in approximately one week
Effective daily dose: 1200 mg/day
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If needed, continue further titration at weekly intervals (600 mg/day increments) to a
maximum daily dose of 2400 mg/day
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A lower starting dose and slower titration may be considered for more sensitive
patients
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For pediatric patients aged 4 to 16 as an Adjunctive therapy with Oxcarbazepine
Start Oxcarbazepine at 8 to 10 mg/kg given BID (not to exceed 600 mg/day)
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Titrate to target dose over two weeks
Recommended daily dose according to weight
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20-29 kg - 900 mg/day
29.1-39 kg - 1200 mg/day
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Over 39 kg - 1800 mg/day
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Highlights
Highlights of Oxcarb
Pharmacokinetic Highlights
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OXCARB is not oxidatively metabolized, therefore causing minimal induction of hepatic
enzymes.
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OXCARB does not undergo autoinduction.
Oxcarbazepine exhibits linear pharmacokinetics.
The plasma concentration half-life of the active metabolite (monohydroxy derivative:
MHD) makes it possible to administer OXCARB twice daily.
Highlights In Efficacy
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OXCARB has similar efficacy to carbamazepine in patients with partial seizures with
or without secondary generalization, or tonic-clonic seizures
•
OXCARB has similar efficacy to other^ conventional drugs like valproate or phenytoin.
Many patients who are hypersensitive to carbamazepine can be treated with OXCARB.
The usually administered dosage of OXCARB is approximately 50% higher than that
of carbamazepine. However, betterjolerability of OXCARBjnakes it possible to give
higher dosage.
In patients with refractory seizures, substitution of oxcarbazepine for carbamazepine
may be associated with reduced "seizure frequency and an improved mental state.
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No changes in dosage are necessary in patients with impaired renal function unless
creatinine clearance is below 30 ml/min.
Oxcarb is easy to start, titrate, and manage - important for patients and physicians
*
Highlights In Tolerability
Rash leading to discontinuation of OXCARB seems to be less frequent than with CBZ,
but resolution of carbamazepine-associated skin rashes after substitution with
oxcarbazepine has also been reported.
Oxcarbazapine cause less ocular side effects as compared to carbamazepine.
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OXCARB may be less sedating and may cause less cognitive impairment and other
CNS side effects (e.g.headache) than most marketed AEDs.
Less drug-drug interactions with concomitant medications than most marketed
antiepileptic drugs.
No drug interaction with warferin
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No need of monitoring of WBC count
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Fill the columns
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Valtec CR
1.
Composition
2.
Class
3.
Mechanism of action
4.
Indication & dosage
5.
Highlights
Lametec
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9
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1.
Composition
2.
Class
3.
Mechanism of action
4.
Indication 8- dosage
Oxcarb
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Highlights
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Module 3 - Alzheimer's disease and
Acetylcholinesterase Inhibitor
9
9
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Dementia
3
•
3
Dementia is an acquired complex of intellectual deterioratiorL which affects areasjjf
cognitive functions.
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The cognitive functions can be memory, orientation (time and place), ability to speak
and understand language,, ability of proper judgement (to differentiate between right
and wrong, good or bad), perception (of any of the 5 senses), attention, ability to
perform simple tasks, etc.
9
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Types of Dementia
Reversible dementia: those types of dementias, which can be reversed or which can be
4
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corrected
CTy
Toxicity due to drugs like anti-epileptics,, anti-psychotics, etc
Infections of the blood or Central Nervous System
Metabolic disorders like thyroid disorders, Chronic kidney or liver failure
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Brain tumors or brain injury
Alzheimer’s Disease
i
4%.
i
Causes of
Dementia
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6%. Otho-r Causes
114% Vascular Causes or
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12% Multiple Causes
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Irreversible dementia: those types of dementias, which can't be reversed or which can
be corrected
Alzheimer's disease
Multi-infarct dementia (vascular dementia)
Parkinson's disease
Lewy body dementia
AIDS - dementia complex
Alzheimer's disease
Type of irreversible dementia
It is the most common cause of the loss of mental function known broadly as
dementia
^e-c\-
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11 is a neurodegenerative disease (Neurodegenerative: Where the nerve cells / neurons
degenerate or get destroyed)
•
It proceeds in stages (slow progression) gradually destroys the memory, reasoning
ability, judgement, language skills
•
In the last stages, a patient of AD becomes totally dependent on the family members
(care-givers / care-providers) to do even the simplest of tasks
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ABCs of Alzheimer's Disease
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A.
Activities of daily living
B.
Behaviour
C.
Cognition
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Stages of AD
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To define the various stages of AD, a standard was set, using two scales: CDR (Clinical '—
Dementia Rating), GDR (Global Dementia Rating)
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Early Stage
Middle Stage (Self-Care difficulty)
• Routine loss of 'recent' memory
• Chronic loss of 'recent' memory
(working memory / immediate memory)
• Mild aphasia (word-finding difficulty)
•
• Seeks the familiar (people, objects, places)
• May get lost at times, even inside the
9
9
9
9
Moderate aphasia
home
• Avoids the unfamiliar
•
Repetitive actions (forgotten theyjiad
9
done the same thing before -
9
e.g.: Combing of hair)
9
>
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• Some difficulty in writing and using objects
(pen, spoon, comb)
i
• Apathy (no emotions expressed or
l
inappropriate emotions), depression
I
• Needs reminder with some Activities of
>
• Apraxia (Difficulty or inability of movement)
•
Possible mood and behavioral disturbances
(aggression, violence, shouting, agitation)
•
Need reminders and help with most ADLs
Daily Living (ADLs)
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>
Last Stage
I*
(Completely dependent)
9
9
)
Terminal Stage
• Mixes up past and present
•
No link to past or present
• Expressive aphasia
•
Remains mute (doesn't speak) or speaks
senselessly
(inability to express in words)
• Misidentifies familiar persons and places
•
Very little spontaneous movement
• Bradykinesia (slowing down of movement)
■:
Unaware of surroundings
• At risk for falls
• Complete?/ passive mood and behavior
• Greater incidence of mood and
• Can't swallow food or drink
behavioral disturbances
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• Need reminders with all ADLs
•
Lose control over bladder and
spincter muscles
• Urinary incontinence, defecation
• Co-existing medical problems can aggravate
symptoms and hasten decline
•
29
Death from Pneumonia or sepsis
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Inside the brain in Alzhiemer's disease
i)
Neurotransmitters
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ACh is responsible for learning and memory. ACh is found abundantly in
Hippocampus (memory store) and cerebral cortex
0
2)
It was thought at that time that AD might disrupt the synthesis of ACh
Or
AD might tqgger the over-production of the enzyme that destroys ACh
Acetylcholinesterase Enzyme
Neurofibrillary Tangles
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Loss of tau protein
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Loss of microtubules (give shape to neuron)
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Neurones shrink and die
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A-Beta protein
J, In AD
Insoluble
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Neuritic Plaques
Amyloid precursor proteins
4
Fibrils formation
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Neuritic plaques
Strategies for medical treatment of AD
a)
Prevention of disease (e.g. with a vaccine)
b)
Delay onset of symptoms for 5-W years
c)
Slow down progression of the disease - thus maintaining individual at their highest
possible level of functioning
d)
Treat the secondary symptoms (behavioral) symptoms of AD - like agitation
aggression, hallucinations, delusions, insomnia.
30
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Donecept
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Brand
Donecept
Molecule
Donepezil
Class
Acetylcholinesterases inhibitor
Mechanism of action
Non-competitive, reversible inhibitor of acetylcholinesterase and
thereby increase Ach levels, at synapse
i
9
9
Donecept is our brand of Donepezil and available as Donecept-5, Donecept-10 containing
Donepezil Smg, Wmg respectively
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Indications
'v
Alzheimer's disease
Vascular dementia
•
I
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i
Lewy-body dementia
Dosage
Starting dose : 5 mg/day
Can be increased to 10 mg/day after 6 weeks
OD as compared to QID of Tacrine and BID of Rivastigmine
>
Highlights
Donepezil is considered as a first - line therapy for mild to moderate AD
Improves symptoms of cognition and global clinical function
>
Significantly delays loss of function and disease deterioration
Reduces care-giver stress
Well-tolerated
Once-daily dosing convenience
>
>
I
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Effect of Donepezil in moderate to severe AD - Evidences support that Donepezil is
effective in moderate-severe AD. Donepezil improves cognitive measures and day-today function in persons with moderate to severe AD.
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What is ABC of Alzheimer's disease
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3)
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a)
Serotonin
b)
Noradrenaline
c)
Aspartate
d)
Acetylcholine
What happens to memory, speech and activities of daily living in all stages of
Alzheimer's disease
>
Middle stage
Early stage
I
Last stage
Memory
>
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Speech
Activities of
)
daily living
4)
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Match the following
Reversible dementia.
Insoluble A-beta protein
Irreversible dementia
‘ Loss of TAU-protein
Neurofibrillary tangles
"
Neuritic plaques
>
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a
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Which neurotransmitter is reduced in Alzheimer's disease?
5)
Lewy-body dementia
Dementia due to renal failure
Primary line of treatment for AD is
33
Terminal stage
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Donecept
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Class
3.
Mechanism of action
4.
Indication & dosage
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5.
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Module 5 - Migraine, Parkinson's disease,
haemorrheogical disorders
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Migraine
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Definition
Migraine is defined as a familial disorder characterized by recurrent attacks of throbbing
headache, generally felt on one side of the headusually followed by pain_freejnteryals
and often provoked by stereo-typed stimuli.
Clinically, migraine can be defined as a syndrome (group of symptoms that occur together
in a similar pattern, time after time) characterized by periodic, throbbing headache affecting
one side of the head (unilateral) accompanied with nausea and sometimes vomiting.
Migraine usually begins in early childhood, adolescence or young adult life.
)
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Prodrome
Aura
Migraine
Prodrome - The prodrome refers to vague yawning, excitation, or depression and
lethargy, sometimes with a craving or distaste for various foods, in the 24 hours
before the headache and lasts for 15 to 20 mins.
Aura - The aura is usually yjsual. Flashing lights, zig-zag lines or balls of light may
appear in the visual field peripherally and spread centrally or start centrally and
spread to the periphery. There may be loss of one half of visual field (scotoma) or
35
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appearance of bright, simmering stars in front of the eyes. The aura typically lasts
for 30 minutes and is succeeded by headache. The change in vision is often followed
by numbness and tingling of the lips, hands and face.
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Migraine - Unilateral headache
Types
Migraine is classified as follows:
1.
Common Migraine (Migraine without aura)
2.
Classic Migraine (Migraine with aura)
' ' 1
Causes
Aetiology of Migraine includes stress, emotions, hormonal changes, dietary factors,
medications, disturbances in sleep pattern, hunger, atmospheric conditions and
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hypoglycemia.
The various migraine triggers
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9
1.
Food Items: Cheese dairy products, citrus fruits, chocolates, seafood, onions
2.
Food additives: Aspartame, nitrates, caffeine
3.
Alcohol: Red wine, beer
4.
Hormonal changes: Menstruation, pregnancy, ovulation
5.
Medications: Nitroglycerin, oral contraceptive, H2 -receptor antagonist
6.
Physical Exertion : Excessive exercise, fatigue
f
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7.
Visual stimuli: Bright lights, glare
r
8.
Auditory stimuli: Loud noise or music
9.
t\
Olfactory stimuli: Perfumes and certain odours
Weather
12.
Hunger
13.
Stress and Anxiety
9
9
9
9
9
9
9
9
9
10. Sleep: Too much or too little
11.
f
36
9
9
9
^2
Pathogenesis of Migraine
The brain is supplied by the paired carotid and vertebral arteries, through an extensive
system of branches. The carotid arteries further branch out into the cerebral arteries,
which supply the cerebrum. The vertebral arteries unite at the base of the brain to form
basilar artery, which supplies the brain stem cerebellum and spinal cord. The vascular
theory proposes that the constriction of blood vessels supplying the cerebrum (intracerebral)
accounts for aura / prodrome of migraine and dilation of blood vessels inside the skull
(intracranial) and those, which are outside the skull (extracranial) are probably responsible
for headache. This constriction occurs due to excessive calcium entry, which may be
triggered by any of the migraine trigger factors.
Management
Acute migraine
Acute migraine: Treatment (Abortive therapy) to treat isolated mild to moderate migraine
attacks, an analgesic together with an anti-nauseant may be adequate.
Analgesics - Aspirin, Paracetamol , Ibuprofen , Diclofenac, Naproxen, Acetaminophen +
Caffeine, Acetaminophen + Aspirin + Caffeine
Anti-nauseant drugs - Antiemetics, Promethazine, Chlorpromazine, Metoclopramide,
Domperidone
Analgesic is to be given along with anti-nauseant drugs 15-20 minutes before onset of
headache or during the headache. Anti-nauseant drugs can be repeated 4-6 hourly as per
the patient's response.
Other drugs used in acute migraine are :
Ergotamine and Sumtatriptan
Prophylactic therapy
This is employed to lessen the frequency and severity of migraine attacks.
Preventive therapy is indicated in the following situations
1.
When attacks occur at a frequency of more than 2 per month
2.
When attacks are refractory to abortive therapy.
3.
When their pattern is predictable like a Menstrual Migraine.
37
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Preventive Therapy for Migraine
1
II
II!
IV
V
VI
VII
Drugs
Dose (mg)
Beta-blockers
Propranolol
Atenolol
40-320mg/day
50-120mg/day
Calcium Channel Blockers
Flunarizine
Verapamil
Nimodipine
Diltiazem
10-20mg/day
120-480mg/day
60-120mg/day
120-360mg/day
Serotonin antagonist
Methysergide
4-8mg/day
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Tricyclic Antidepressant
Amitriptyline
W-20mg/day
Serotonin reuptake inhibitors
Fluoxetine
20-60 mg/day
Anticonvulsant
Sodium valproate
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600-1200 mg/day
Adrenergic Blocker
Clonidine
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0.2-03 mg/day
VIII Anti-histaminics
Cypropheptadine
4-8 mg/day
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Introduction
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The Triad of Hypokinesia, Tremor and Rigidity producing a typical syndrome was first
described by James Parkinsons in 1871.
This disease is also called as 'Paralysis Agitans' a disorder of the extrapyramidal system
that becomes evident in the fifth and sixth decades of life.
I
Epidemiology
PD usually occurs in the middle or late life between 50 and 70 years, though it rarely is
seen in young people. The prevalence of this disease is estimated to be between 59 and
353 cases per 1,00,000.
Clinical symptoms
Tremor
Rigidity
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Parkinson's disease
*
*
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Gait hesitation
Diminished levels of Dopamine causes unnecessary skeletal muscle movements, that often
interfere with voluntary movement therefore causing TREMOR, the most common symptom
of PD. Some muscles may contract continuously causing RIGIDITY of the involved body
part. Rigidity of the facial muscles gives the face a mask like appearance (the expression
is characterized by a wide unblinking stare and a slightly open mouth with uncontrolled
drooling). As the disease progresses patient develops GAIT HESITATION (Freeze on initiating
gait-start hesitation or when approaching a target terminal hesitation).
Some more signs are: decreased swallowing resulting in drooling of saliva, soft voice
(hypophonia), loss of speech modulation, impaired handwriting with micrographia, decreased
amplitude in performing repetitive movements (such as opening and closing the hand or
tapping the foot). The cause of these abnormal motor effects is almost unknown.
Etiology
PD results from relative imbalance between the neurotransmitters as a result of depletion
of dopamine in the presence of normal amount of acetylcholine. In effect, in PD there is
degeneration of dopamine-producing neurons in the substantia nigra and thus severe
reduction of dopamine in the basal ganglia, which bring about most of the symptoms of
PD.
39
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Management
Commonly used drugs for the management of PD are
D
Levodopa
2)
Levodopa + Carbidopa
3)
Bromcriptine
4)
Anticholinergic Drugs
5)
Amantidine
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Levodopa
Levodopa remains the most effective drug in Parkinsons disease. Unfortunately the side
effects associated with long-term levodopa treatment constitute an important cause of
c
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functional disability.
i
Side effects of levodopa:
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Involuntary movements
•
Psychiatric disorders, which result from increase in dopamine levels
•
Other important side effects of levodopa are agranulocytosis and postural hypotension.
•
Another problem with levodopa is fluctuations in clinical response with passage of
time. More than 50% of patients experience these fluctuations which is called as on
and off phenomenon where certain doses fail to cause a response and there is
increasing variation in the latency period for taking the drug to clinical response.
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Haemorrheological Disorders
Haemorrheology
Haemorrheology is the study of behaviour of blood flow.
e
Haemorrheological disorders
Haemorheological disorders include
•
Peripheral vascular disease (diseases of arteries / veins)
i
t
t
Diabetic vascular disease (diabetic neuropathy, diabetic nephropathy)
Bl'.:
•
Cerebral vascular disease
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
Peripheral vascular disease (PVD)
PVD is usually classified as vasospastic or occlusive. In vasospastic disorder, such as
Raynaud's disease, blood flow to the skin is reduced by reversible vasoconstriction and
there is little or no organic involvement in chronic occlusive peripheral vascular disorders,
blood flow is reduced by organic obstruction.
I.
Diseases of Arteries
a.
Chronic arterial occlusive diseases
These are slowly progressive disorders characterized by chronic ischaemia of the
limb. Risk factors include smoking, diabetes, mellitus, hyperlipidaemia, hypertension,
obesity and atherosclerosis
a
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Clinical manifestation
iv
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a.
Men: women = 5:1
b.
Intermittent claudication: This consists of a cramp-like pain in the calf-muscles
produced by a constant amount of exercise and relieved by rest. As the disease
progresses, effort pain is characteristically brought on by diminishing amounts
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of exercise.
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c.
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Rest pain: It is a continuous pain affecting the distal portion of the feet and
toes. The pain is severe, usually occurring at night when the patient is in bed.
Relief is obtained by handing the foot off the bed.
d.
Colour changes such as pallor or cyanosis
(
I|
e.
Absence of pulse
I
f.
Trophic changes
b.
Burger's Disease (Thromboangitis Obliterans)
(
This is an uncommon disease of unknown origin, which usually affects young
men. It is confined to males who smokes heavily and usually begins after the
age of 40. Clinical signs and symptoms are similar to (a) above. There is no
specific treatment, but it is imperative that they stop smoking at once.
i
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c.
Acute (sudden) arterial occlusion
The two most common causes of sudden obstruction of a peripheral artery are
thrombosis and embolism, the other causes being trauma or spasm of the vessel
secondary to inadvertent intra-arterial injection of drugs.
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II. Diseases of The Veins
<
/.
Deep vein thrombosis
Thrombosis of the deep veins of the lower extremities. The predisposing factors
are stasis of blood flow, injury to the vein wall and hypercoagulability of the
blood.
The common underlying conditions responsible are bed rest, surgical procedures,
obesity, pregnancy, C.C.F., oral contraceptives etc.
i.
The symptoms are variable, complications mainly being pulmonary embolism
and chronic venous hypertension.
7
6
42
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5
5
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ii.
Varicose veins
These are defined as abnormally dilated, tortuous, superficial veins of the lower
Hi.
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Superficial Thrombophlebitis
It is a self-limiting disease of the superficial veins most commonly caused by
indwelling catheters / needles.
Cerebrovascular Diseases
II
II
11 ■'
Transient ischemic attacks (TIA):
»
This is a temporary period during which blood supply to the brain is reduced either due
to block of an artery or rupture of blood vessel.
¥
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Clotting of blood is called thrombosis, which occurs inside a blood vessel.
Embolism:
Embolus is a mass of bacteria or blood clot, which is carried by blood flow to a blood
vessel and blocks the blood vessel.
Subarachnoid haemorrhage/bleeding
Rupture of blood vessel in the subarachnoid space (space below arachnoid layer of brain).
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Diabetic Vascular Disease
Diabetes presents with multiple microvascular and macrovascular complications.
• *
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43
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Thrombosis:
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SELF ASSESSMENT 4
D
Migraine is characterized by
(Say yes / no)
I I Bilateral headache
I I Unilateral headache
9
9
9
9
9
9
3
3
3
3
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9
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3
>
)
>
3
3
3
>
3
>
3
3
O Nausea, vomiting
I I Diarrhoea
2)
3)
4)
Match the following
Common migraine
Lethargy and yawning
Classic migraine
Flashing lights
Prodrome
Migraine with aura
Aura
Migraine without aura
Vascular theory of migraine consists of
Vaso
of intraceretral and
Vaso
of exracrenial blood vessel
Prophylactic therapy of migraine is necessary in
a)
b)
c)
5)
Drugs used for prophylaxis of miraine are
Pl Propranolol
9
9
9
9
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Fl Venlafaxine
I | Sodium Valproate
|—| Azithromycin
45
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Key features of Parkinson's disease are
6)
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8)
neurotransmitter is reduced in Parkinson's disease in basal ganglion.
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Define Haemorrheology
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Module 5 - Anti-migraine drugs,
Anti-Parkinsonian drug, Haemorrheological gent
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Migarid
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Brand
Migarid
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Molecule
Flunarizine
Class
Selective calcium entry blocker
Mechanism of action
Selective class IV calcium entry blocker.
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Dosage and Administration
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Migraid is our brand of flunarizine and available as migarid 5, migarid 10 containing
flunarizine 5mg and Wmg
Indications
1.
Prophylaxis of classic (with aura) or common (without aura) migraine
2.
Treatment of vertigo
3.
'Add-On' therapy in the treatment of epilepsy resistant to conventional antilepileptic
medication.
The recommended maximum daily dose of Flunarizine in the prophylaxis of migraine,
and treatment of vertigo is Wmg/day in adults and 5mg/day in children weighing less
than 40kg.
An optimal therapeutic dosage in epileptic patients receiving other anti-epileptic drugs is
15 to 20mg/day in adults and 5 to Wmg/day in children.
47
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Highlight
Flunarizine is a 'selective' calcium antagonist. It appears to selectively block calcium
entry when calcium is stimulated to enter cells in excess and thus prevents
vasoconstriction. Thus it prevents cell damage caused by 'calcium overload' in various
tissues.
2.
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It inhibits contraction of vascular smooth muscle mediated by the entry of extracellular
calcium, and protects.
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a.
endothelial cells against damage from calcium overload
b.
red blood cells from membrane rigidity induced by calcium ion loading, and
c.
brain cells from the effects of hypoxia
3.
It also demonstrates vestibular depressive effects, as well, as antihistaminic and
anticonvulsant properties.
48
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Domcet
Domcet
Brand
Molecule
:
Domperidone + Paracetamol
Class
:
Domperidone is Antiemetic and paracetamol is Analgesic and
Antipyretic
Meeh, of action
:
Domperidone is peripheral dopamine receptor antagonists
while paracetamol is centrally acting analgesic
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Domcet is our brand of domperidone and paracetamol combination available as domcent
tablet containing domperidone 10 mg and paracetamol 500 mg per tablet.
Advantages of domperidone
Domperidone is a very widely used anti-emetic drug, which possesses prokinetic
properties.
Anti-emetic: drug that prevents vomiting.
Prokinetic: enhancing the movement of contents of gastro-intestinal tract Domperidone
has the potential to enhance gastrointestinal tract motility and produce relief from
stagnation of contents in the GIT, which is seen in vomiting
Domperidone enhances the absorption of paracetamol so it can work on the pain
Domperidone does not penetrate well into the central nervous system (CNS), therefore
rarely causes CNS side effects like movement disorders unlike metoclopramide.
Advantages of paracetamol
Paracetamol is an analgesic (it produces relief from pain) and antipyretic agent
(produces relief ffom fever)
Paracetamol is a safe and effective analgesic, widely used for the last 30 years
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The rationale for combining domperidone and paracetamol
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Domperidone is a time tested anti-emetic drug which possesses prokinetic properties
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It has the potential to enhance gastrointestinal motility and produce relief from
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stagnation of contents in the GIT which is seen in vomiting
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Domperidone enhances the absorption of paracetamol so it can work on the pain.
Domperidone does not penetrate well into the central nervous system (CNS), therefore
rarely causes extrapyramidal side effects unlike metoclopromide.
Paracetamol is a time tested analgesic and antipyretic
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Paracetamol is a safe and highly effective analgesic
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Repeated administration of paracetamol does not have any effects on the
cardiovascular and respiratory systems
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It does not produce gastric irritation, erosion or bleeding after administration
No effects on platelets, bleeding time or the excretion of uric acid.
This is an effective combination which produces relief from both headache / other pain /
fever / nausea and vomiting associated with the above conditions.
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Indications of Domcet
This effective combination produces relief from both headache / other pain/ fever / nausea
and vomiting associated with migraine, viral fever, diabetic gastroparesis, post-operative
nausea and vomiting + pain, P1D, Dyspepsia, infections of GIT and the nausea / vomiting
headache associated with oral contraceptives / hormone replacement therapy.
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Dosage of Domcet
1-2 tablets not frequently than every 4 hours upto maximum of 8 tablets in 24 hours.
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Amantrel
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Brand
Amantrel
Molecule
Amantadine
Class
Anti-viral drug
Meeh, of action
:
Augment synthesis and release of dopamine from
dopaminergic presynaptic neurons of the extrapyramidal
system.
Amantrel is our brand of amantadine and available as Amantrel 100 containing amantadine
lOOmg.
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Indications
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Initial therapy of Parkinson's disease
As a Add-on therapy with Levodopa in later stages of Parkinson's Disease
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Amantadine has also been useful in the prophylaxis and treatment of Influenza- A
virus infections.
Dosage and Administration
Amantidine is administered orally. If insomnia occurs the daily last dose should be taken
several hours before retiring.
The usual dosage in all forms of parkinsonian syndrome is IQOmg twice daily. When
patients are receiving other anti-parkinsonian drugs or have other serious illness the
dosage should be started with lOOmg daily for 1 week and then gradually increased
to lOOmg B.D. up to 400mg of Amantadine has been used in divided doses, However
patients, receiving more than 200mg daily, should be supervised closely by their
physicians.
Highlights
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Amantidine, Hydrochloride (Amantrel) is used in the symptomatic treatment of all
types of Parkinsons disease including the post encephalitic, idiopathic types and for
relief from parkinsonian signs and symptoms of carbon-monoxide poisoning and
drug - induced extrapyramidal effects.
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Amantidine may be especially useful in the treatment of drug - induced extrapyramidai
symptoms when drugs with anticholinergic properties should be avoided e.g. in patients
with glaucoma or urinary retention.
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Amantrel produces improvement in all symptoms of akirfesia, rigidity, tremor, salivation,
gait disturbance and total functional disability.
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Subjective responses such as rsense of' all" well being and elevation of mood have
also been reported. Improvement ini cextrapyramidai
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symptoms is apparent within 4080 hours of initiation of therapy. However some
patients experience a reduction in
the benefit which may by regained by increasing the dosage or by discontinuing the
drug for few weeks and then resuming the therapy.
Combined therapy with amantidine (Amantrel) and levodopa has been found to be
more effective than levodopa which will result in less side effects.
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Kinetal
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Brand
Kinetal
Molecule
Pentoxifylline
Class
Haemorrheological agent
Kinetal is our brand of pentoxifylline in sustained form and available as Kinetai-400
containing pentoxifylline 400mg.
The mode of action of Kinetal
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The primary mechanism by which it increases blood flow appears to relate to an overall
improvement in haemorheological characteristics such as:
i.
erythrocytic deformability
ii.
blood viscosity
iii.
platelet aggregation
iv.
plasma fibrinogen concentration
Indications of Kinetal
i.
Peripheral vascular disease
2.
Diabetic vascular disease
3.
Cerebrovascular disorders
Dosage of Kinetal
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The usual adult oral dosage of Kinetal 400 in peripheral vascular disorders is 1200mg/
day in three divided doses. Therapy should be maintained for atleast 8 weeks.
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In cerebrovascular diseases, the currently recommended dosage is 600-1200mg daily in
divided doses.
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The tablets should preferably be taken after meals with some liquid to minimize
gastrointestinal complications.
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SELF ASSESSMENT - 5
Fill the columns
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Migartd
Domcet
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Composition
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2. Class
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3. Mechanism of action
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5. Highlights
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Fill the columns
Kinetal
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1. Composition
2. Class
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3. Mechanism of action
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5. Highlights
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56
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