Antihypertensive drugs
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It is now well-established that hypertension confers an increased risk of
heart attacks and strokes and that treatment of high blood pressure reduces
this risk. We now have a wide variety of antihypertensive agents, although
most can be classified into one of five major classes (see Panel 1). Each of
these classes has merits and disadvantages, as well as ancillary properties
that influence the choice for a particular patient. In addition, many
patients require more than one agent to control their blood pressure and
thus, the choice of combination therapy, with appropriate synergistic effects
of the drugs, becomes similarly important
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Panel 1: main classes of antihypertensive drugs
Diuretics
beta-blockers
Calcium channel blockers
ACE inhibitors
alpha1-blockers
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Choice of drug
With the wide variety of antihypertensive agents available, which is the
ideal drug to use? The cynic would argue that the ideal antihypertensive drug
does not really exist. However, when assessing those that are available to us,
it is important to bear in mind the properties that make up an ideal drug for
the control of hypertension. The ideal drug should have a predictable
dose-response curve, as well as an acceptable, recognised side effect profile.
Blood pressure tends to be highest first thing in the morning and this is when
the majority of cardiac events occur and, therefore, 24-hour control has been
recognised as important. A short-acting drug, even if taken the evening before,
may have worn off by the time the patient rises in the morning, whereas a drug
with a longer half-life would still be protecting the patient. A drug with a
long half-life also has the advantage of only being taken once daily. This may
improve compliance, since up to 30 per cent of patients miss a dose at least
weekly.
As the purpose of treating hypertension is to reduce the incidence of
hypertensive complications (particularly coronary heart disease and stroke),
the ideal drug should have trial evidence to prove that it achieves these ends,
as well as simply lowering blood pressure. This is not to say that other drugs
do not prevent complications but simply that the evidence from large-scale
trials is not there. Advocates of other drugs can point to reductions in
surrogate markers, such as left ventricular hypertrophy (LVH) or reduction of microproteinuria,
to indicate their effectiveness. Large scale trials, such as ALLHAT
(Antihypertensive and Lipid Lowering Heart Attack Trial) and ASCOT
(Anglo-Scandinavian Outcomes Trial), which compare newer drugs, such as calcium
channel blockers and the ACE inhibitors, with the well-established ß-blockers
and diuretics, are currently in progress.
Diuretics
Thiazide diuretics Thiazide diuretics reduce the reabsorption
of sodium and chloride in the early part of the distal convoluted tubule of the
kidney. This results in the delivery of increased amounts of sodium to the
distal tubule, where some of it is exchanged for potassium. The net result is
increased excretion of sodium, potassium and water. Circulating volume is
diminished, reducing preload on the heart and, thus, cardiac output and blood
pressure. With long-term therapy, autoregulation by the body’s own compensatory
mechanisms results in vasodilatation, reduction of peripheral vascular
resistance and return of the cardiac output to normal. Thiazides also have some
direct vasodilatory properties.
Thiazides are rapidly absorbed orally and produce a prolonged diuresis. They
tend to produce a maximal response at relatively low doses, such as 12.5mg
hydro-chlorothiazide or 1.25mg bendrofluazide. Further increases in dose simply
increase side effects with little further effect on blood pressure. On the
whole, standard doses of thiazides lower blood pressure as much as other
first-line antihypertensives. In some patient groups, such as blacks and the
elderly, the thiazides are particularly efficacious. However, they tend to be
less effective in younger, white patients.
Thiazides are one of the classes of antihypertensive that have been extensively
tested in large clinical trials. In early trials, thiazides reduced the
incidence of stroke by 40 per cent, although the reduction in coronary heart
disease was disappointing. This may have been due to the adverse metabolic
effects of the large doses used. More recent trials, using lower doses, have
demonstrated impressive reductions in both stroke and coronary heart disease,
especially in the elderly.
There is little to choose between the various thiazides, although it seems
prudent to use agents, such as hydrochlorothiazide and bendrofluazide, that
have been proved to be effective at low doses in clinical trials. Newer agents,
such as indapamide, have fewer metabolic side effects, and may even regress
hypertensive LVH on echocardiography. Adverse effects The main concerns
about thiazide diuretics are their metabolic side effects, although, at low
doses, these are less likely to be a problem. They may cause hypokalaemia due
to renal potassium wasting. Hypokalaemia may give rise to ventricular
arrhythmias and cause adverse drug effects in patients taking digoxin or drugs
that prolong the QT interval on the ECG (eg, class I antiarrhythmics, tricyclic
antidepressants, antihistamines).
Acute gout is another common side effect of thiazides, even in low doses.
Hyperuricaemia can be present in about 30 per cent of all hypertensives but it
is a poor predictor of acute gout. Impotence may occasionally be a problem.
Thiazides can increase serum LDL-cholesterol and triglyceride levels but this
is much less of a problem with modern low doses. There is also some evidence
that diuretics impair glucose tolerance and increase insulin resistance.
However, reports of frank diabetes are rare. Although thiazides probably should
be avoided as first-line drugs in patients with diabetes and those with
hyperlipidaemia, there should be no anxiety about adding them in where
necessary. Rarer side effects include nausea, headache, rashes,
photosensitivity and blood dyscrasias.
Other diuretics Loop diuretics act on the ascending limb of the
loop of Henle and inhibit the reabsorption of chloride, sodium and potassium.
They produce a brisk but short-lived diuresis and are thus unsuitable as
first-line agents for hypertension, as they do not provide 24-hour control.
However, they do have a role in patients with impaired renal function in whom
thiazides are ineffective, and in patients with hypertension resistant to
multiple drug therapy, who are often fluid overloaded. Furthermore, they may be
synergistic with agents such as the ACE inhibitors.
Potassium-sparing diuretics, such as amiloride and triamterene, produce little
reduction in blood pressure themselves. They may be useful in combination with
other diuretics to prevent hypokalaemia. Spironolactone is a specific
aldosterone antagonist, with a particular role in primary hyperaldosteronism or
Conn’s syndrome.
Beta-blockers
Beta-blockers act by blocking the action of noradrenaline at b adrenoceptors
throughout the circulatory system and elsewhere. Their major effect is to slow
the heart rate and reduce its force of contraction. beta-blockers also cause
some reduction in renin release and central sympathetic tone.
Beta-blockers may be subdivided according to their ancillary properties. For
example, b1 or cardioselective agents, such as atenolol, have less action on b2
receptors in the bronchi and peripheral vessels compared with non-selective
agents, such as propranolol. This reduces (but does not abolish) b2
receptor-mediated side effects. Lipid-soluble agents, such as propranolol and
metoprolol, cross the blood-brain barrier more readily and are associated with
a higher incidence of central side effects. Some beta-blockers, such as
pindolol, have intrinsic sympathomimetic activity (ie, they stimulate b
receptors when background sympathetic nervous activity is low and block them
when background sympathetic nervous activity is high). They, therefore, cause
less bradycardia and possibly fewer problems with cold extremities than
conventional beta-blockers. However, in practice, they are little used in the
treatment of hypertension.
Labetalol and carvedilol have both a- and b1-blocking properties, causing a
reduction in peripheral vascular resistance, as well as slowing the heart rate.
In addition to its b1-blocking properties, carvedilol also has antioxidant
effects, which give it theoretical advantages in reducing endothelial damage
and lowering levels of highly atherogenic oxidised LDL-cholesterol. However,
both labetalol and carvedilol have the disadvantage of possessing the side
effects of both classes of drug.
Beta-blockers are useful as first-line antihypertensive agents, although they
tend to be less effective in the elderly and in black hypertensives. For the
treatment of hypertension it is best to choose a beta-blocker with high
cardioselectivity and low lipid solubility to reduce side effects. A long
half-life also allows once daily dosing.
Adverse effects Most of the side effects of beta-blockers are
predictable from their mode of action. For example, they slow the rate of
conduction at the atrio-ventricular node and are thus contraindicated in
patients with second- and third-degree heart block. Sinus bradycardia is common
and is not a reason to stop beta-blockers unless the patient is symptomatic or
the heart rate falls below 40 beats/minute.
Even small doses of ß-blockers can cause bronchospasm due to blockade of
pulmonary b2 receptors, although the problem is less common with
cardioselective agents. Even so, all beta-blockers are contraindicated in
asthma. Blockade of b receptors in the peripheral circulation causes
vasoconstriction, at least in the immediate term, and the drugs are, therefore,
contraindicated in patients with rest ischaemia of the legs. Nevertheless, they
are reasonably tolerated in those with lesser degrees of peripheral vascular
disease. Lipid-soluble agents can cause central nervous system side effects of
insomnia, nightmares and fatigue. Exercise capacity may be reduced by
beta-blockers and patients may experience tiredness and fatigue. As with most
antihypertensives, impotence has been reported, although rates are little
higher than with placebo.
Like diuretics, ß-blockers can worsen glucose intolerance and hyperlipidaemia.
In diabetic patients prone to hypoglycaemia, beta-blockers may, theoretically,
reduce the awareness of low blood glucose. Nevertheless, many diabetic
hypertensives have good reasons, such as a previous myocardial infarction, to
be on a beta-blocker and should not be denied them because of concerns about
metabolic side effects.
Calcium channel blockers
Calcium channel blockers, otherwise known as calcium antagonists, act by
interfering with the action of calcium channels in the cell membrane. This
reduces the inflow of calcium, smooth muscle contraction and electrical
conductivity.
Calcium channel blockers may be divided into two classes — the dihydropyridines
and the non-dihydropyridines. The dihydropyridines, such as nifedipine and
amlodipine, act predominantly by causing peripheral vasodilatation. The
non-dihydropyridines, such as verapamil and diltiazem, also slow the heart rate
and atrio-ventricular node conduction. All calcium channel blockers are
efficacious at reducing blood pressure as single agents.
The older drugs, such as nifedipine, have short half-lives and may cause rapid
vasodilatation, a reflex tachycardia and catecholamine surges. This may
increase adverse effects and aggravate myocardial ischaemia. Longer-acting
agents, such as amlodipine or slow-release preparations of nifedipine,
partially overcome these problems.
Until lately, the calcium channel blockers lacked trial evidence to support
their use in hypertension. In the mid-1990s, a series of pharmacosurveillance
case-control studies suggested that the short-acting dihydropyridine drugs
(such as nifedipine capsules) actually increased the risk of heart attacks.1
Recent data from the Syst-Eur trial demonstrated that antihypertensive
treatment of the elderly with the short-acting dihydropyridine calcium channel
blocker, nitrendipine, convincingly reduced strokes and heart attacks, without
an increase in conditions previously attributed to the calcium channel
blockers, such as tumours, bleeding and non-cardiac death.2
Adverse effects The main, and most troublesome, side effect of
calcium channel blockers is ankle oedema. This is caused by vasodilatation,
which also causes headache, flushing and palpitation, especially with
short-acting dihydropyridines. Some of these side effects can be offset by
combining a calcium channel blocker with a b-blocker.
Verapamil reduces intestinal motility and, thus, can cause significant
constipation. More seriously, it can cause heart block, especially in those with
underlying conduction problems. Diltiazem can similarly cause gastrointestinal
and conduction problems, although less frequently than verapamil. Verapamil,
diltiazem and short-acting dihydropyridines are best avoided in patients with
heart failure.
Alpha-blockers
The a1 adrenoceptor blockers produce vasodilatation by blocking the action
of nor-adrenaline at post-synaptic a1 receptors in both arteries and veins.
This results in a fall in peripheral resistance, without a compensatory rise in
cardiac output. The prototype a1-blocker — prazosin — is short acting and tends
to produce precipitous falls in blood pressure, but the longer acting doxazosin
combines the advantage of a more gentle reduction in blood pressure with once
daily dosing.
The a1-blockers produce reductions in blood pressure comparable to first-line
antihypertensive drugs. They seem to be particularly useful as a third drug,
producing good falls in blood pressure where two agents combined have failed.
In contrast to the b-blockers and diuretics, a1-blockers actually produce
modest improvements in serum lipids and glucose tolerance but whether this
translates into improved outcomes is not known, particularly with the paucity
of outcome data with these agents.
Adverse effects a1-blockers are, on the whole, well tolerated.
Their main side effect is postural hypotension, which is more commonly caused
by shorter-acting agents. In women, a1-blockers may cause urinary incontinence.
In men, they may improve the symptoms of benign prostatic hypertrophy. Like
most antihypertensive drugs, a1-blockers can cause headache and fatigue.
ACE inhibitors
Angiotensin converting enzyme (ACE) inhibitors have become increasingly
popular over the past decade. They work by blocking the renin-angiotensin
system, inhibiting the conversion of the inactive angiotensin I to the
powerful vasoconstrictor and stimulator of aldosterone release, angiotensin
II (see Figure 1). This results in decreased peripheral vascular resistance
and also a reduction in the levels of the sodium-retaining hormone —
aldosterone.
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Figure 1: The renin-angiotensin systems and its inhibitors
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ACE inhibitors also reduce the breakdown of the vasodilator bradykinin, which
may enhance their action but is also responsible for their most troublesome
side effect of cough. Furthermore, ACE inhibitors may improve endothelial
function and reduce central adrenergic tone. They also have beneficial effects
on renal haemodynamics, reducing intraglomerular hypertension, resulting in
improvements in proteinuric renal disease. ACE inhibitors are effective as
single agents in hypertension. There is generally little to choose between the
large number of ACE inhibitors available. Recently, the Captopril Prevention
Project (CAPP) study demonstrated that captopril was as effective as
traditional antihypertensive agents (mainly thiazides and b-blockers) in
preventing adverse outcomes in hypertension.3
Other agents, such as fosinopril, have the advantage of hepatic as well as
renal excretion and are (theoretically, at least) less likely to accumulate in
patients with renal failure. Perindopril, ramipril and trandolapril are agents
with long half-lives, which provide good 24-hour antihypertensive coverage.
There is useful synergism between the ACE inhibitors and diuretics and between
ACE inhibitors and calcium channel blockers. The ACE inhibitors are
particularly useful in diabetic hypertensives, in whom they may be
renoprotective, as they slow the progression of diabetic nephropathy.4
Furthermore, these agents have shown some benefits in improving diabetic
retinopathy and even diabetic neuropathy.5,6
However, the ACE inhibitors tend to be less effective as antihypertensive
agents in black/Afro-Caribbean hypertensives and in the elderly, who tend to
have lower renin levels than the general population. Nevertheless, this
relative ineffectiveness can be overcome by using high doses or adding a
diuretic.
Adverse effectsCough, caused by the inhibition of bradykinin
breakdown, is the most common side effect of ACE inhibitors, occurring about
five times more often than with placebo. Cough is more common in women and
older patients.7
The far more serious, but rare, side effect of the ACE inhibitors is
angioedema, which occurs in about 0.1 to 0.2 per cent of patients.
Dramatic deterioration in renal function can occur in patients with bilateral
renal artery stenosis. Serum urea and creatinine should, therefore, be checked
before and a few weeks after starting an ACE inhibitor. This should not prevent
the use of ACE inhibitors in those with other forms of renal disease. In these
patients, ACE inhibitors are often agents of first choice, in view of data
showing that they slow the progression of diabetic and non-diabetic
nephropathy.
The ACE inhibitors can cause hyperkalaemia because they reduce aldosterone and,
thus, potassium excretion. First-dose hypotension is probably an overstated
side effect of ACE inhibitors but large doses of short acting captopril can
cause sudden falls in blood pressure, especially in those with volume
depletion, such as heart failure patients on large doses of diuretics. Rarer
side effects include rash, taste disturbance, blood dyscrasias and a symptom
complex that includes fever and vasculitis.
Angiotensin II antagonists
Like the ACE inhibitors, these drugs act on the renin-angiotensin system,
blocking the action of angiotensin II at its peripheral receptors. As they do
not inhibit the breakdown of bradykinin, they do not cause cough. However, they
may lack the additional physiological benefits that rises in bradykinin levels
may bring. Angiotensin II antagonists have similar physiological effects to ACE
inhibitors and produce similar falls in blood pressure. There is synergism of
antihypertensive effect with thiazide diuretics. There is also evidence that
they may regress LVH and improve proteinuria.8,9
Adverse effects The main advantage of the angiotensin II
antagonists is their apparent lack of side effects. Like the ACE inhibitors,
they may cause hyperkalaemia, renal impairment and hypotension but, otherwise,
they are almost as well tolerated as placebo. Nevertheless, cases of angioedema
have been reported with some of these agents.
Older antihypertensive agents
A number of older antihypertensive drugs still have a role in some special
situations (eg, pregnancy) and in resistant hypertension. These drugs are
popular in countries where hypertensive patients are on low incomes and have to
pay for their own medication, because they are cheap.
Central alpha-blockers These drugs stimulate central a2
adrenoceptors, resulting in a decrease in central sympathetic tone. This leads
to a fall in both cardiac output and peripheral vascular resistance. Examples
of such drugs include methyldopa and clonidine. The drugs cause sedation, dry
mouth and fluid retention. Methyldopa can also cause autoimmune hepatic
derangement and haemolytic anaemia. However, it is safe to use in hypertensive
pregnant women and is commonly used in such patients. A new centrally acting
drug, moxonidine, acts on central imidazoline receptors and is hoped to have
the beneficial effects of centrally-acting drugs, without their side effects.
Direct vasodilators These agents act directly to relax vascular
smooth muscle, thereby reducing peripheral vascular resistance. The resulting
activation of the sympathetic nervous system means that they can only
successfully be used in combination with drugs that block sympathetic activity.
Examples include hydralazine, whose main side effect is a lupus-like syndrome,
and minoxidil. Minoxidil causes hair growth, a side effect welcomed by many
middle aged men but not by their female counterparts.
Adrenergic neurone blockers Such agents are now rarely used in
the
United Kingdom
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Reserpine and guanethidine inhibit the release of noradrenaline from peripheral
nerves. This reduces sympathetic tone, peripheral vascular resistance and
cardiac output. They cause postural hypotension and central nervous system
depression. Small doses of reserpine, combined with a diuretic, form an
effective regimen and are used when low costs are paramount, especially in
developing countries.
