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DEBATES
IN
MEDICINE
Professor P. Sleight
Professor R. Campbell
BETA BLOCKADE IN HYPERTENSION;
DOES THE MOLECULE MATTER?
DEC.1992
COMMUNITY HEALTH /'c'l
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BETA BLOCKADE IN HYPERTENSION;
DOES THE MOLECULE MATTER?
“Low-dose thiazides and [or] beta blockers should be accepted universally as
suitable first-line therapy for die vast majority of hypertensive patients.”
(Editorial, Lancet 1991:338;1300).
Professor P. Sleight
Field Marshal Alexander Professor of
Cardiovascular Medicine,'University of Oxford,
and Department of Cardiology, John Radcliffe
Hospital, Oxford, UK
Professor R. Campbell
Professor of Cardiology, Department of
Academic Cardiology, University ofNewcastle
upon Tyne, and University Department of
Cardiolog)', Freeman Hospital, Newcastle upon
CONTENTS
Introduction
5
Properties of Beta Blockers
7
Pharmacological Effects
8
Cardioselectivity
8
ISA
12
Hydrophilicity
13
Co-existing Alpha Blockade..
17
Back to Basics
18
3
INTRODUCTION
The relationship of elevated resting blood pressure to an increased risk of
cerebrovascular and cardiovascular events is well accepted [1,2]. The value of
intervention aimed at reducing abnormally high blood pressure - whether by
drugs, diet, change in lifestyle, or by a combination of these - to reduce the risk of
coronary heart disease (CHD) and stroke has also been established [3,4]. Indeed, a
fairly modest (5-6mmHg) reduction in diastolic blood pressure (DBP) (which is
actually the mean effect of treatment in the randomised trials [5]) produces a
significant reduction in risk of stroke and CHD [5] (Fig 1).
2p-value:
<0.0001
<0.01
<0.0002
‘ Includes any deaths bom unknown causes
Fig 1. Crudely summated results ofthe unconfounded randomised trials ofantihypertensive drug therapy.
(Reproducedfrom ref 5 by hind permission ofthe publishers ofthe Lancet.)
There are many effective antihypertensive agents - beta blockers, diuretics,
angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, and alpha
blockers - but not all have been shown to reduce morbidity and mortality. In fact,
data on ‘hard’ cardiac and cerebrovascular end-points are available only for beta
blockers and diuretics. Beta blockers reduce the incidence both of stroke [6-11 ] in
all ages of patient, and of myocardial infarction (Ml) in the middle-aged
5
hypertensive [12,13]. This is evident from an analysis of two primary prevention
studies [10,14], where there were significantly fewer (p<0.05) coronary events in
men in the beta blocker group, compared to the diuretic group. In the
peri-infarction period, beta blockers reduce vascular death, reduce infarct size, and
prevent a threatening infarct from proceeding to myocardial necrosis [15,16]. In
infarct survivors, beta blockers are accredited as reducing morbidity and mortality,
particularly sudden death (Fig 2) [17].
Overall mortality
Mode of death:
Sudden
Other
Non-fatal reinfarction —h—
Illi
0
0.2
0.4
0.6
■lii........
0.8
1.0
I
I
I
I
I
1.2
1.4
1.6
1.8
2.0
Odds ratio (active: control)
Fig 2. Sudden death, other death, and non-fatal reinfarction in long-term beta blocker trials that
reported these end-points separately. (Reproducedfrom ref. 17 by kind permission ofthe publishers of
Progress in Cardiovascular Diseases.)
There is thus much to commend the use of beta blockers, and it is therefore
appropriate to review their effects in the treatment of hypertension. Of particular
relevance are the effects of their differing pharmacological profiles on efficacy,
tolerability and ‘cardioprotection’.
6
PROPERTIES OF BETA BLOCKERS
Originally, beta blockers were classified by their relative specificity for beta,
adrenergic receptors (beta, selective or cardioselective) and/or by their ability to
mimic sympathetic stimulation (intrinsic sympathomimetic activity - ISA).
Recendy, sub-groups have been identified having either beta, selectivity with beta2
ISA, or possessing both alpha and beta blocking properties.
Thus, beta blockers can be regarded as belonging to one of six sub-groups:
• Beta, selective (cardioselective) without ISA (e.g. atenolol, metoprolol)
• Beta] selective (cardioselective) with ISA (e.g. acebutolol)
• Beta! selective (cardioselective) widt beta, ISA (e.g. celiprolol)
• Non-selective without ISA (e.g. propranolol)
• Non-selective with ISA (e.g. oxprenolol)
• Alpha/beta blockers (e.g. labetalol).
Beta blockers can also be categorised by their relative degree of lipophilicity, i.e.
their ability to partition between octanol and water and hence cross cellular
membranes. In this regard, atenolol is regarded as water soluble (i.e. hydrophilic)
while propranolol and metoprolol are lipid soluble (i.e. lipophilic).
SUMMARYPOINTS
• Beta blockers vary:
(i) In beta-adrenoreceptor selectivity
(ii) In ISA
(iii) In lipid solubility.
• Some agents possess alpha and beta blocking properties.
7
PHARMACOLOGICAL EFFECTS
Cardioselectivity
The advantage of cardioselective beta blockers over non-selective agents can be
demonstrated in at least six areas:
(a)
(b)
(c)
(d)
(e)
(f)
(a)
Relative blood pressure lowering effects
In airways disease
In insulin-dependent diabetic hypertension
In smokers
During exercise
On serum lipids.
Bloodpressure lowering
An analysis of published clinical trials [18] suggests that, at the recommended
doses, cardioselective beta blockers, such as atenolol, are more effective hypotensive
agents. T hey reduce resting DBP by about 4mmHg more than their non-selective
counterparts, such as propranolol. The explanation may be that cardioselective
agents exert little effect on the peripheral beta, receptors, whereas non-selective
agents can give rise to unopposed alpha vasoconstriction due to blockade of the
peripheral beta, receptor.
(b)
Airways
Figure 3 shows the comparative effects on FEV, of a variety of beta blockers, before
and after isoprenaline [19]. AU doses produced adequate beta blockade as shown by
their effect on heart rate. Placebo caused a small fall in FEV,, as did atenolol, but all
other beta blockers induced a fall of over 25%, with the non-selective agents having
most effect. After isoprenaline, atenolol was the only beta blocker to increase FEV,
above baseline. Thus atenolol was the most cardioselective agent of those studied
and, like other cardioselective agents, may be used with caution in patients with
underlying airways disease, since any increase in airways resistance which may
occur can be reversed bv bronchodilator therapy. Non-selective agents, however,
are contra-indicated.
(c)
Diabetes
Following the i.m. administration of insulin to subjects receiving placebo, a
non-selective beta blocker, or a cardioselective beta blocker [20] (Fig 4), the blood
sugar concentration falls to the same degree. However, recovery' from
hypoglycaemia was similar in the placebo and atenolol groups, but was significantly
delayed in the propranolol group. Other work [21,22] supports the preferential use
8
Fig 3. Effect ofbeta blockers on pulse rate and FEV, before and after isoprenaline. (Reproducedfrom
ref. 19 by kind permission ofthe publishers ofthe British Heart Journal.)
Fig 4. Insulin-induced hypoglycaemia and beta blockers. (Data from ref 20 by kind permission ofthe
publishers ofthe British MedicalJournal.)
of a cardioselective agent when a beta blocker is used in insulin-dependent diabetic
hypertensives. It may, however, modify the tachycardia of hypoglycaemia, and
both the patient and physician must be aware of the risk of masking this feature.
(d)
Smoking
Smoking is a major risk factor for CHD and stroke. Stopping smoking is
important first advice given to hypertensive patients. Not all patients can comply,
9
however, and for them, their continued smoking may have implications for the
choice of hypotensive therapy, and for rhe success of that therapy.
Figure 5 shows the results of treatment with cardioselective or non-sclective beta
blockers under such circumstances [23]. Smoking stimulates catecholamine release,
with resultant alphai-mediated arteriolar constriction plus beta;-mediated
dilatation. A non-selective beta blocker will block beta, receptors, will allow
unopposed alpha-mediated vasoconstriction, and will result in a greater rise in
DBP. A cardioselective beta blocker minimises this effect in the patient who
continues to smoke.
■ Placebo
□ Propranolol
□ Atenolol
A Heart rate
(beats/min)
£
A Systolic
blood pressure
(mmHg)
p<0.05
p<0.05
Hn
A Diastolic
blood pressure
(mmHg)
A Forearm
blood flow
(ml/100g.min)
-1.0
Fig 5. Haemodynamic effects ofsmoking. (Reproducedfrom ref 23 by kind permission ofthe publishers
ofthe European Journal of Clinical Investigation.)
(e)
Exercise
Control of exercise blood pressure [24] is an important measure of the effectiveness
of any antihypertensive agent. Figure 6 shows that exercise performance is
unchanged with a cardioselective agent, while a non-selective agent clearly impairs
performance by a presumed beta, receptor mechanism in the peripheral
musculature [25]. An additional advantage is the fact that beta blockers are known
to inhibit the catecholamine-stimulated rise in free fatty acids during stress [26],
10
3?
2 8?
+15"| ■ Placebo
+10Propranolol
Atenolol
Fig 6. Effect ofexercise conditioning on work performance. (Reproducedfrom ref 25 by kind permission
ofthe publishers ofthe American Journal of Cardiology.)
and by doing so decrease myocardial oxygen consumption. However, these
metabolic effects of beta blockade may hamper the performance of athletes and
heavy manual labourers.
(fl Lipids
Beta blockers cause little change in total serum cholesterol but may lower serum
HDL cholesterol and raise serum LDL cholesterol and triglycerides [27-31].
Cardioselective agents without ISA exert lesser effects on these parameters than
non-cardioselective agents without ISA [29]. Furthermore, at low doses,
cardioselective agents can control blood pressure, in which case these changes are
minimal [28].
The timing of the role of lipids in atherogenesis is controversial. Endothelial
damage may precede lipid deposition. Thus rhe intimal effects of hypertension,
smoking, stress (increased adrenergic drive), and increased blood flow velocity may
be early features. These insults may be followed by adhesion of platelets to the
damaged wall and deposition of lipids, particularly LDL [32]. Beta blockers lower
blood pressure, reduce adrenergic drive, and reduce peak blood velocity [33]. In
addition, in animal studies, cardioselective agents protect against endothelial
damage induced by chloralose anaesthesia [34], Recent work suggests that
cardioselective agents reduce the binding affinity between proteoglycans in the
vessel wall and serum LDL [32]. Thus, despite effects on lipid levels, beta blockers,
particularly cardioselective agents, may mitigate against the development of
atherosclerosis. This is supported by an animal model (Table 1) in which, despite
serum lipid changes, a non-selective beta blocker was highly effective in preventing
coronary atheroma [35-37]. These observations may explain the apparent paradox
whereby beta blockers raise serum lipid levels but reduce morbidity and mortality
from ischaemic heart disease.
COMMUNITY HEALTH CELk
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Koramangala
Bangalore-560034
1 able I. Effect of beta blockers on coronary atherosclerosis in cholesterol-fed animals.
Study
Animal
Drug
Scrum
lipids
Amount of
coronary
atherosclerosis
irrespective of
lipid levels
Reinis et al., 1976 [35]
Pick and Glick, 1977 [36]
Kaplan ct al.. 1987 [37]
Cocks
Monkeys
Monkeys
(stressed)
Propranolol
Propranolol
Propranolol
T
T
T
l (60%,)
l (60%)
I (60%)
Nine more studies show that various beta blockers retard aortic atherosclerosis.
SUMMARY POINTS
• Cardioselecrive beta blockers reduce resting DBP to a greater degree than
non-selective agents.
• Cardioselecrive beta blockers have advantages for patients with
insulin-dependent diabetes, with airways disease, and for those who cannot
stop smoking. Additionally, the)- do not interfere with exercise
performance.
• Bera blockers do not affect total cholesterol bur lower serum HDL
cholesterol and raise LDL cholesterol and triglycerides. With cardioselecrive
agents these changes are minimised.
• Cardioselectivity opposes some of the fundamental pathological processes
involved in atherosclerosis.
• The potentially adverse effects of beta blockers on serum lipids are offset by
their benefits in patients with ischaemic heart disease.
Intrinsic sympathomimetic activity (ISA)
Beta blockers van- widely in the degree to which they possess ISA. it has been
claimed that agents with pronounced ISA provide ‘cardiac support’ and have a
better lipid profile than other class members.
An analysis of all the published trials [18], however, has shown that beta blockers
without ISA, such as atenolol, reduce DBP by about 4mmHg more than agents
with ISA, such as oxprenolol and pindolol. This is likely to arise because the
cardioselecrive agent without ISA reduces cardiac output to a greater degree than a
similar agent with ISA.
Furthermore, agents with ISA, such as pindolol, are less well tolerated; they cause
a significantly greater incidence of muscle cramp than do their cardioselecrive
counterparts [38].
12
50
40
O
30
©
20
10
s
o Alprenolol
o Timolol
Metoprolol
n Propranolol
0 Practolol
s Sotalol
* Oxprenolol
a Pindolol
▲
A
0
4
▲
8
12
16
20
Reduction in heart rate (beatstmin)
Fig 7. Correlation between mortality reduction and heart rate reduction tn post-infarct beta blocker
trials. (Reproducedfont ref. 39 by kind permission ofthe publishers ofthe American Journal of
Cardiology.)
Beta blockers with non-selective ISA have proved relatively ineffective in
reducing morbidity and mortality for infarct survivors [17], although those with
betai-selective ISA, such as aceburolol, have shown significant benefit [39].
Kjekshus [40] has suggested that this is because those agents have little or no effect
on resting heart rate due to the presence of their non-selective ISA (Fig 7).
SUMMARY POINTS
• Cardioselectivc beta blockers reduce resting DBP to a greater degree than
non-selective agents with ISA.
• Non-selective agents with high ISA have had little success when used as
secondary preventative agents post-MI, despite their ‘beneficial’ effects on
serum lipids.
Hycb -ophilicity
There is a wide range in the lipid or water solubility of beta blockers [41 ] (Fig 8).
What are the implications of this aspect for their antihypertensive efficacy and
tolerability?
(a) Half-life
Hydrophilic drugs usually are not metabolised and are excreted unchanged by the
kidney. As a consequence, they tend to have long plasma and pharmacodynamic
half-lives. This would be expected to give predictable pharmacodynamic actions,
and might be an explanation for the results in a 24-hour ambulator}- monitoring
13
Fig 8. Distribution coefficients in octanollaqucous bufferfor several beta blockers. (Adaptedfrom
ref. 41.)
trial, in which hydrophilic atenolol was more effective over 24 hours in lowering
mean arterial pressure than the more lipophilic agents, metoprolol and pindolol
[42] (Fig 9).
(b)
Dosingfrequency
A long half-life allows once-daily dosing, thus encouraging a higher level of patient
convenience and compliance [43]. Multiple daily dosing is required with many
lipophilic beta blockers unless they are specially formulated.
(c)
Interactions
Hydrophilic agents are relatively insensitive to alterations in hepatic enzyme
activity. Pharmacokinetic interactions based on this action are therefore unlikely.
Combination therapy with other agents is simplified and safer [41].
(d)
CNS effects
Lipophilic beta blockers, because they are more likely to cross the blood-brain
barrier than hydrophilic agents, may cause CNS disturbances. A comprehensive
review [44] has shown that a hydrophilic agent has a lower incidence of
CNS-related side effects than lipophilic agents (Table 2; [45]).
(e)
Quality oflife
Hypertension is an asymptomatic condition and, as such, drug therapy designed to
reduce blood pressure and, hopefully, increase survival, should cause minimal
14
Comparison of each pair of hourly means
’ P<0.05
•* p<0.01
Mean arterial pressure (mmHg)
— Control
Beta blockade
Time of day
Fig 9. Antihypertensive control during 24 hours. Between-patient comparison forfour beta blockers.
(Reproducedfrom ref. 41 by kind permission ofthe publishers ofthe British MedicalJournal)
Table 2. Beta blockers and CNS side effects during
antihypertensive therapy. (Data from ref. 45.)
Beta blocker
Incidence of
vivid drcams
Incidence of
sleep disturbance
Atenolol
Pindolol
Propranolol
4/48 (8%)
9/39(23%)],
10/25 (40%)\
9/48 (19%)
15/39 (38.5%)],,
10/25(40%) J
'p<0.01
”p<0.1
15
interference in the patients’ enjoyment of normal daily life. A review [46] of studies
using beta blockers and reporting quality of life indices has shown that hydrophilic,
cardioselecrive atenolol produced similar effects to the ACE inhibitors enalapril and
captopril. By contrast, the lipophilic, non-selective beta blocker propranolol was
judged inferior to the ACE inhibitors. Atenolol, but not propranolol, has been
shown to be similar in terms of quality' of life to the calcium antagonist verapamil.
These differences between atenolol and propranolol in quality of life almost
certainly arise from their differing pharmacological profiles.
(f)
Mortality
There has been a suggestion [47] that lipophilic, but not hydrophilic, beta blockers
can reduce the incidence of sudden death in hypertensive patients and patients
with ischaemia. This was first proposed when work in rabbits indicated the
possibility' that metoprolol (lipophilic), but not atenolol (hydrophilic), could cross
the blood-brain barrier, ‘switch on’ vagal activity, and raise the threshold for
ventricular fibrillation under acutely ischaemic conditions [48]. Meesmann,
however, has been unable to confirm these observations [49].
In man, a hy'drophilic beta blocker has been shown to greatly' increase
parasy'mpathetic activity [50], to ‘electrically stabilise’ the heart [50], to increase
sinus arrhythmia [51], to significantlv suppress life-threatening ventricular
arrhythmias in the acute post-MI period [52], and to significantly reduce mortality
when given within 12 hours of MI [15]. Although atenolol has been assessed in
only' one small trial of late intervention after Ml [53], the results were similar to
those of propranolol (and hydrophilic acebutolol [39]) in that mortality was
reduced by' over 50% in those who continued receiving treatment. In a very recent
publication of a statistical analysis of the post-infarction beta blocker data, Lewis
[54] has shown no difference in cardioprotection between hy'drophilic and
lipophilic agents.
With regard to primary prevention of MI in hypertensive patients, there is
evidence [10,12] that lipophilic propranolol has a modest benefit in middle-aged
subjects (particularly non-smoking men). However, the Heart Attack Primary
Prevention in Hypertension (HAPPHY) Study Steering Committee [55]
concluded that any apparent differences in benefit between hydrophilic atenolol
and lipophilic metoprolol could be due to chance. Death rates in the HAPPHY
study were lower in patients receiving the hydrophilic agent than in patients
receiving the lipophilic agent (6.93 vs. 7.89 deaths per 1000 patient-years).
In elderly patients with mild to moderate hypertension, it is now established that
diuretics should be first-line therapy' [56]. If, however, the patient has had a recent
MI or has angina, a beta blocker may' be more appropriate. Hy'drophilic
atenolol-based therapy prevents strokes, but seems not to prevent MI in elderly
hypertensive patients. Both are probably class effects of beta blockers, since in the
16
Swedish STOP-HT trial of elderly patients with hypertension [8], the incidence ol
MI was unaffected by three different beta blockers with widely differing degrees of
lipophilicity, i.e. pindolol, metoprolol, and atenolol. This trial, however, was of
short duration, and effects on cardiovascular events may take longer to show (as
seen with cholesterol lowering in the POSCH trial; [57]).
Some have recommended that hypertensive patients with angina should be
treated with lipophilic beta blockers. This is surprising since the anti-ischaemic
efficacy of hydrophilic atenolol is at least as good as that of lipophilic propranolol
[58].
On current evidence, there is nothing to suggest a difference between lipophilic
and hydrophilic beta blockers in terms of their ‘cardioprotective’ potential.
SUMMARYPOINTS
• Hydrophilic beta blockers have a pharmacokinetic profile which often
allows once-daily dosing, thus aiding patient convenience and compliance.
They are also less likely to have pharmacokinetic interactions with other
co-administered agents.
• Hydrophilic beta blockers, such as atenolol, produce fewer CNS side effects
than lipophilic beta blockers.
• Hydrophilic atenolol produces a quality of life profile similar to ACE
inhibitors but superior to lipophilic propranolol.
• On current evidence, there is nothing to suggest a difference between
lipophilic and hydrophilic beta blockers in terms of their cardioprotective
potential.
Co-existingAlpha Blockade
Published clinical trials [18] show that cardioselective beta blockers, such as
atenolol, reduce resting DBP by about 2mmHg more than those with bodi alpha
and beta blocking properties.
Although beta blockers with co-existing alpha blockade have potential value in
the treatment of hypertension because of their relatively beneficial effects on serum
lipids, there are no long-term studies to assess their value in cardioprotection.
17
BACK TO BASICS
The management of hypertension is a major and difficult clinical challenge. The
need for and the benefits of therapy' are undisputed, but when the condition affects
a major proportion of the population and causes no symptoms, therapy must be
acceptable in the long term, free of adverse effects, and convenient as well as
effective.
There are many hypotensive agents, but there have been few large-scale
comparative studies in the style of the ISIS investigations of MI therapy. Choosing
the best therapy for a given patient must rely in part on scientific evidence and in
part on hopefully logical and apposite inferences. If the fundamental abnormality
in hypertension could be identified (it such exists!), then that might logically be the
optimal focus for therapy. Yet increasingly, it is the secondary effects of
hypertension that seem to dictate management.
There is no consensus on optimal first-line drug therapy' for hypertension; beta
blockers, ACE inhibitors, diuretics and calcium antagonists each have their
protagonists. The purpose of this review is not to prove superiority of one agent vis
a vis another, but radier to draw attention to the proven benefits of cardioselective
beta blockade, as well as the implications of a hydrophilic or lipophilic
pharmacological profile. We should bear in mind that ACE inhibitors and calcium
channel blockers have attractive features but no mortality data to match diuretics
and beta blockers.
Cardioselective beta blockers have an appeal through their precision of action,
their simplicity' of metabolism and distribution, and through their impressive
performance in the management of ischaemic heart disease. We have identified
benefits of such selectivity in the'management of hypertension and have examined
the controversy of how beta blockers may' influence the process of adierogenesis.
Our supportive conclusions for the use of cardioselective beta blockers must, as a
minimum, merit consideration when choosing therapy.
A further consideration is the lipid or water solubility of the beta blockers.
Hydrophilic agents are associated with fewer pharmacological interactions with
co-administered agents and fewer CNS side effects than lipophilic agents, and
therefore have fewer adverse effects than lipophilic agents upon quality of life. In
addition, their long half-lives permit less frequent dosing.
Hopefully' the difficult problems of the management of hypertension may yield
to research — the optimal initial and the subsequent sequential approach may be
revealed by new studies. However, we should not underestimate the very great
difficulty in mounting a trial which will reliably tease out the drug with the best
risk/benefit ratio amongst today’s effective hypotensive agents. In practice, few
patients have isolated hypertension. Many have other problems - angina,
arrhythmia, diabetes, obesity, heart failure. In that case, we do have some
18
reasonable clinical grounds for choosing one drug over another. In the case of
symptomless mild hypertension, we would make a strong plea for the use of
cardioselective beta blockade and/or thiazide diuretics.
19
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