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Myocardial infarction (MI). Following a myocardial infarction, the left ventricle may fail acutely from the loss of functional tissue or in the long-term from a process of 'remodelling' due to thinning and enlargement of the scarred ventricular wall. Angiotensin II plays a key role in both of these processes and an ACE inhibitor given after an MI markedly reduces the incidence of heart failure. The effect is seen even in patients without overt signs of failure, but who have low left ventricular ejection fractions during the convalescent phase (3-10 days) following their MI. Patients such as this receiving captopril in the SAVE trial,11 had a 37% reduction in progressive heart failure over the 60-month follow-up period compared to placebo. The benefits of ACE inhibition after MI are additional to those conferred by thrombolysis, aspirin and |3-blockers.

Cautions. Certain constraints apply to the use of ACE.

• Heart failure: severe hypotension may result in patients taking diuretics, or who are hypovolaemic, hyponatraemic, elderly, have renal impairment or with systolic blood pressure < 100 mmHg. A test dose of captopril 6.25 mg by mouth may be given because its effect lasts only 4-6 h. If tolerated, the preferred long-acting ACE inhibitor may then be initiated in low dose.

• Renal artery stenosis (whether unilateral, bilateral renal or suspected from the presence of generalised atherosclerosis): an ACE inhibitor may cause renal failure and is contraindicated.

• Aortic stenosisAeft ventricular outflow tract obstruction: an ACE inhibitor may cause severe, sudden hypotension and, depending on severity, is relatively or absolutely contraindicated.

• Pregnancy represents a contraindication (see below).

Angioedema may result (see below). Adverse effects

ACE inhibitors cause persistent dry cough in 10-15% of patients. Urticaria and angioedema (< 1

11 Swedberg K P et al 1992 New England Journal of Medicine 327: 669-677.

in 100 patients) are much rarer, occurring usually in the first weeks of treatment. The angioedema varies from mild swelling of the tongue to life-threatening tracheal obstruction, when s.c. adrenaline (epinephrine) should be given. The basis of the reaction is probably pharmacological rather than allergic, due to reduced breakdown of bradykinin.

Impaired renal function may result from reduced glomerular filling pressure, systemic hypotension or glomerulonephritis, and plasma creatinine should be checked before and during treatment. Hypo-natraemia may develop, especially where a diuretic is also given; clinically significant hyperkalaemia (see effect on aldosterone above) is confined to patients with impaired renal function. ACE inhibitors are fetotoxic in the second trimester, causing reduced renal perfusion, hypotension, oligohydramnios and fetal death. Neutropenia and other blood dyscrasias occur. Other reported reactions include rashes, taste disturbance (dysguesia), musculoskeletal pain, proteinuria, liver injury and pancreatitis.

ATj receptor blockers are contraindicated in pregnancy, but avoid most other complications — particularly the cough and angioedema. They are the only antihypertensive drugs for which there is no 'typical' side effect.

Interactions. Hyperkalaemia can result from use with potassium-sparing diuretics. Renal clearance of lithium is reduced and toxic concentrations of plasma lithium may follow. Severe hypotension can occur with diuretics (above), and with chlorpro-mazine, and possibly other phenothiazines.

Individual drugs

Captopril (Capoten) has a t\ of 2 h and is partly metabolised and partly excreted unchanged; adverse effects are more common if renal function is impaired; it is given twice or thrice daily. Captopril is the shortest-acting of the ACE inhibitors, one of the few where the oral drug is itself active, not requiring de-esterification after absorption.

Enalapril (Innovace) is a prodrug (tV2 35 h) that is converted to the active enalaprilat (t'/2 10 h). Effective 24-h control of blood pressure may require twice daily administration.

Other members include cilazapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. Of these, lisinopril has a marginally longer Xx/2 than enalapril, probably justifying its popularity as a once-daily ACE inhibitor. Some of the others are longer-acting, with quinapril and ramipril having also a higher degree of binding to ACE in vascular tissue. The clinical significance of these differences is disputed. In the Heart Outcomes Prevention Evaluation (HOPE) Study of 9297 patients, ramipril reduced, by 20-30%, the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who were not known to have a low ejection fraction or heart failure.12 The authors considered that the results could not be explained entirely by blood pressure reduction.

Losartan was the first AT., receptor antagonist licensed in the UK. It is a competitive blocker with a noncompetitive active metabolite. The drug has a short t'/2 (2 h) but the metabolite is much longer lived (tl/2 10 h) permitting once daily dosing. Other ATj receptor antagonists in clinical use include candesartan, eprosartan, irbesartan, telmisartan and valsartan. Some of these appear more effective than losartan, which is generally used in combination with hydrochlorothiazide. In a landmark study this combination was 25% more effective than atenolol plus hydrochlorothiazide in preventing stroke.13

This class of drug is very well tolerated; in clinical trials their side effect profiles are indistinguishable or even better than placebo. Unlike the ACE inhibitors they do not produce cough, and are a valuable alternative for the 10-15% of patients who discontinue their ACE inhibitor for this reason. ATt receptor antagonists are used to treat hypertension but any role in cardiac failure or after myocardial infarction (as have ACE inhibitors) remains to be established.

The cautions listed for the use of ACE inhibitors (above) apply also to ATj receptor blockers.

12 Yusuf S, Sleight P, Pogue J et al 2000 Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. New England Journal of Medicine 342:145-53.

13 Dahlof B et al 2002 Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:995-1010.

Other vasodilators

Several older drugs are powerfully vasodilating, but precluded from routine use in hypertension by their adverse effects. Minoxidil and nitroprusside still have special indications.

Minoxidil is a vasodilator selective for arterioles rather than for veins, similar to diazoxide and hydralazine. Like the former, it acts through its sulphate metabolite as an ATP-dependent potassium channel opener. It is highly effective in severe hypertension, but causes increased cardiac output, tachycardia, fluid retention and hypertrichosis. The hair growth is generalised and although a cosmetic problem in women, it has been exploited as a topical solution for the treatment of baldness in men.

Sodium nitroprusside is a highly effective antihypertensive agent when given i.v. Its effect is almost immediate and lasts for 1-5 min. Therefore it must be given by a precisely controllable infusion. It dilates both arterioles and veins, which would cause collapse if the patient stands up, e.g. for toilet purposes. There is a compensatory sympathetic discharge with tachycardia and tachyphylaxis to the drug. The action of nitroprusside is terminated by metabolism within erythrocytes. Specifically, electron transfer from haemoglobin iron to nitroprusside yields methaemoglobin and an unstable nitroprusside radical. This breaks down, liberating cyanide radicals capable of inhibiting cytochrome oxidase (and thus cellular respiration). Fortunately most of the cyanide remains bound within erythrocytes but a small fraction does diffuse out into the plasma and is converted to thiocyanate. Hence, monitoring plasma thiocyanate concentrations during prolonged (days) nitroprusside infusion is a useful marker of impending systemic cyanide toxicity. Poisoning may be obvious as a progressive metabolic acidosis or manifest as delirium or psychotic symptoms. Toxic subjects are also reputed to emit the characteristic bitter almond smell of hydrogen cyanide. Clearly nitroprusside infusion should not be undertaken without meticulous regard for the manufacturer's recommendations and precautions; outside specialist units it may be safer overall to choose another more familiar drug.

Sodium nitroprusside is used in hypertensive emergencies, refractory heart failure and for controlled hypotension in surgery. An infusion14 may begin at 0.3-1.0 micrograms/kg/min and control of blood pressure is likely to be established at 0.5-6.0 micrograms/kg/min; close monitoring of blood pressure is mandatory usually with direct arterial monitoring of blood pressure; rate changes of infusion may be made every 5-10 min.

Diazoxide is chemically a thiazide but has no appreciable diuretic effect; indeed, like other potent arterial vasodilators it causes salt and water retention. It reduces peripheral arteriolar resistance through activation of the ATP-dependent potassium channel (c.f. nicorandil and minoxidil), with little effect on veins. The is 36 h.

The principal use of diazoxide has been in the emergency treatment of severe hypertension. The maximum effect after an i.v. bolus occurs within 5 min and lasts for at least 4 h. The dangers from excessive hypotension are now recognised to outweigh the benefit, and emergency use of diazoxide is almost obsolete.

Because it stimulates the same potassium channel in the pancreatic islet cells as is blocked by sulphonylureas, diazoxide causes hyperglycaemia. This effect renders diazoxide unsuitable for chronic use in hypertension, but a useful drug to treat insulinoma. Long-term oral administration causes the same problem of hair growth seen with minoxidil (see below and 'alopecia').

Hydralazine now has little use long-term for hypertension, but it may have a role as a vasodilator (plus nitrates) in heart failure. It reduces peripheral resistance by directly relaxing arterioles, with negligible effect on veins. In common with all potent arterial vasodilators, its hypotensive action is accompanied by a compensatory baroreceptor-mediated sympathetic discharge, causing tachycardia and increased cardiac output. There is also renin release with secondary salt and water retention,

14 Light causes sodium nitroprusside in solution to decompose; hence solutions should be made fresh and immediately protected by an opaque cover, e.g. metal foil. The fresh solution has a faint brown colour; if the colour is strong it should be discarded.

which antagonises the hypotensive effect (so-called 'tolerance' on long-term use). Therefore, hydralazine, when used, is combined with a (3-blocker and diuretic. The tl/2 is 1 h.

In most hypertensive emergencies (except for dissecting aneurysm) hydralazine 5-20 mg i.v. may be given over 20 min, when the maximum effect will be seen in 10-80 min; it can be repeated according to need and the patient transferred to oral therapy within 1-2 days.

Prolonged use of hydralazine at doses above 50mg/day may cause a systemic lupus-like syndrome, more commonly in white than in black races, and in those with the slow acetylator phenotype.

Three other vasodilators find a role outside hypertension.

Nicorandil is an effective vasodilator through two actions. It acts as a nitrate by activating cyclic GMP (see above) but also opens the ATP-dependent potassium channel to allow potassium efflux and hyperpolarisation of the membrane which reduces calcium ion entry and induces muscular relaxation. It is indicated for use in angina, where it has similar efficacy to (J-blockade, nitrates or calcium channel blockade. It is administered orally and is an alternative to nitrates when tolerance to these is a problem, or to the other classes when these are contraindicated by asthma or cardiac failure. Adverse effects to nicorandil are similar to those of nitrates, with headache reported in 35% of patients. It is the only antianginal drug for which at least one trial has demonstrated a beneficial influence upon outcome.15

Papaverine is an alkaloid present in opium, but is structurally unrelated to morphine. It inhibits phosphodiesterase and its principal action is to relax smooth muscle throughout the body, especially in the vascular system. It is occasionally injected into an area where local vasodilatation is desired,

15 The Impact Of Nicorandil in Angina (IONA) study was a double-blind, randomized, placebo-controlled trial conducted in the United Kingdom in which high-risk patients with stable angina were assigned placebo or nicorandil 10-20 mg. Over a mean follow-up of 1.6 years, significantly more placebo-treated patients suffered an acute coronary syndrome or coronary death (15.5% vs 13.1%, P = 0.01).

especially into and around arteries and veins to relieve spasm during vascular surgery and when setting up i.v. infusions. It is also used to treat male erectile dysfunction (see p. 546).

Alprostadil is a stable form of prostaglandin Er It is effective in psychogenic and neuropathic penile erectile dysfunction by direct intracorporeal injection (see p. 545) and is used i.v. to maintain patency of the ductus arteriosus in the newborn with congenital heart disease.

Vasodilators in heart failure (see p. 517)

Vasodilators in peripheral vascular disease

The aim has been to produce peripheral arteriolar vasodilatation without a concurrent significant drop in blood pressure, so that an increased blood flow in the limbs will result. Drugs are naturally more useful in patients in whom the decreased flow of blood is due to spasm of the vessels (Raynaud's phenomenon) than where it is due to organic obstructive changes that may make dilatation in response to drugs impossible (arteriosclerosis, intermittent claudication, Buerger's disease).

Vasodilators such as naftidrofuryl (Praxilene) and oxpentifylline (pentoxifylline) (Trental) increase blood flow to skin rather than muscle; they have also been successfully used in the treatment of venous leg ulcers (varicose and traumatic).

Intermittent claudication. Patients should 'stop smoking and keep walking' — i.e. take frequent exercise within their capacity. Other risk factors should be treated vigorously, especially hyper-lipidaemia, and patients should also receive aspirin 75-150 mg daily as an antiplatelet agent. Most patients with intermittent claudication succumb to ischaemic or cerebrovascular disease, and therefore a major objective of treatment should be prevention of such outcomes. Naftidrofuryl or oxpentifylline (pentoxifylline) may be tried but should be withdrawn if there is no benefit in a few weeks. Naftidrofuryl has several actions. It is classed as a metabolic enhancer since it activates the enzyme succinate dehydrogenase, increasing the supply of ATP and reducing lactate levels in muscle. It also blocks 5HT2-receptors and inhibits serotonin-

induced vasoconstriction and platelet aggregation. Oxpentifylline is thought to improve oxygen supply to ischaemic tissue by improving erythrocyte deformability and reducing blood viscosity, in part by reducing plasma fibrinogen. Neither of these drugs is a direct vasodilator, as is the third drug used for intermittent claudication, inositol nicotinate. The evidence in favour of any benefit is stronger for the first two, for which meta-analyses provide some evidence of efficacy (increase in walking distance). Most vasodilators act selectively on healthy blood vessels, causing a 'steal' of blood from atheromatous vessels.

Night cramps occur in the disease and quinine has a somewhat controversial reputation in their prevention. Nevertheless, meta-analysis of six doubleblind trials of nocturnal cramps (not necessarily associated with peripheral vascular disease) shows that the number, but not severity or duration of episodes, is reduced by a night-time dose.16 The benefit may not be seen for 4 weeks (see ticlopidine).

Raynaud's phenomenon may be helped by nifedipine, reserpine (an a-adrenoceptor blocker, in low doses) and also by topical glyceryl trinitrate; indeed any vasodilator is worth trying in resistant cases; enalapril (ACE inhibitor) seems to lack efficacy. In severe cases, especially patients with ulceration, intermittent infusions over several hours of the endogenous vasodilator, prostacyclin (epoprostenol), achieves long-lasting improvements in symptoms.

p-adrenoceptor blockers exacerbate peripheral vascular disease and Raynaud's phenomenon by reducing perfusion of a circulation that is already compromised. Switching to a pj-selective blocker is unhelpful, since the adverse effect is due to reduced cardiac output rather than unopposed rx-receptor induced vasoconstriction.

Adrenoceptor blocking drugs

Adrenoceptor blocking drugs occupy the adreno-

16 Man-Son-Hing M, Wells G 1995 Meta-analysis of efficacy of quinine for treatment of nocturnal cramps in elderly people. British Medical Journal 310: 13-17.

ceptor in competition with adrenaline (epinephrine) and noradrenaline (norepinephrine) (and other sympathomimetic amines) whether released in the body or injected; circulating adrenaline and noradrenaline are antagonised more readily than are the effects of adrenergic nerve stimulation.

There are two principal classes of adrenoceptor, a and P: for details of receptor effects see Table 22.1.

«•ADRENOCEPTOR BLOCKING DRUGS

There are two main subtypes of a-adrenoceptor, defined by their relative affinity for the drugs which occupy them:

• Classic a3-adrenoceptors, on the effector organ (postsynaptic), mediate vasoconstriction

• «^adrenoceptors are present both on some effector tissues (postsynaptic), and on the nerve ending (presynaptic). The presynaptic receptors (or autoreceptors) mediate a reduction of release of chemotransmitter (noradrenaline), i.e. they provide a negative feedback control of transmitter release. They are also present in the CNS.

The first generation of a-adrenoceptor blockers were nonselective, blocking both a^- and o^-receptors. When subjects taking such a drug rise from supine to erect posture or take exercise, the sympathetic system is physiologically activated (via baroreceptors). The normal vasoconstrictive (a,) effect (to maintain blood pressure) is blocked by the drug and the failure of this response causes the sympathetic system to be further activated and to release more and more transmitter. This increase in transmitter would normally be reduced by negative feedback via the a2-autoreceptors; but these are blocked too.

The p-adrenoceptors however are not blocked and the excess transmitter released at adrenergic endings is free to act on them, causing a tachycardia that may be unpleasant. It is for this reason that nonselective a-adrenoceptor blockers are not used alone in hypertension.

An a-adrenoceptor blocker that spares the a2-receptor so that negative feedback inhibition of noradrenaline release is maintained, is more useful in hypertension (less tachycardia and postural and exercise hypotension); prazosin is such a drug (below).

For use in prostatic hypertrophy, see page 548.

• Hypertension

— essential: doxazosin, labetaloi phaeochromocytoma: phenoxy benzathine: phentolamine (for crises)

• Peripheral vascular disease

• Benign prostatic hypertrophy (to relax capsular smooth muscle that may contribute to urinary obstruction)

Adverse effects. The converse of the benefit in the treatment of prostatism is the adverse effect of micturition incontinence in women. Other adverse effects of a-adrenoceptor blockade are postural hypotension, nasal stuffiness, red sclerae and, in the male, failure of ejaculation. Effects peculiar to each drug are mentioned below.

Notes on individual drugs

Prazosin blocks postsynaptic aj-receptors but not presynaptic a2-autoreceptors. It has a curious adverse 'first-dose effect'; within 2h of the first (rarely after another) dose there may be a brisk hypotension sufficient to cause loss of consciousness. Hence the first dose should be small (0.5 mg) and given before going to bed. This side effect together with a rather short duration of action (tV2 3 h) has meant that newer longer-acting drugs have largely replaced it.

Doxazosin (tl/2 8h) was the first a-adrenoceptor blocker suitable for once daily prescribing. The first dose effect is also much less marked, although it is still advisable to start patients at a lower dose than is intended for maintenance. It is convenient, for instance, to prescribe 1 mg daily, increasing after 1 week to twice this dose without repeating the blood pressure measurement at this stage. A slow-release formulation, Cardura XL, can be started at the maintenance dose of 4 mg daily.

Other a blockers are alfuzosin and terazosin.

Indoramin is an older otj-blocker, which is a less useful antihypertensive, but still used for prostatic symptoms.17 It is taken twice or thrice daily.

Phentolamine is a nonselective a-adrenoceptor blocker. It is given i.v. for brief effect in adrenergic hypertensive crises, e.g. phaeochromocytoma or the MAOI-sympathomimetic interaction. In addition to a-receptor block it has direct vasodilator and cardiac inotropic actions. The dose for hypertensive crisis is 2-5 mg i.v. repeated as necessary (in minutes to hours). The use of phentolamine as a diagnostic test for phaeochromocytoma is appropriate only when biochemical measurements are impracticable, since it is less reliable.

Phenoxybenzamine is an irreversible nonselective a-adrenoceptor blocking drug whose effects may last 2 days or longer. The daily dose must therefore be increased slowly. It is impossible to reverse the circulatory effects by secreting noradrenaline (norepinephrine) or other sympathomimetic drugs because its effects are insurmountable. This makes it the preferred a-blocker for treating phaeochromocytoma (see p. 495).

It is wise to observe the effects of a single test dose closely before starting regular administration.

Indigestion and nausea can occur with oral therapy, which is best given with food.

Thymoxamine (moxisylyte) is a nonselective ablocker for which Raynaud's phenomenon is the only extant indication.

Labetaloi has both a- and p-receptor blocking actions that are due to different isomers (see under (3-adrenoceptor block, below). Its parenteral preparation is valuable in the treatment of hypertension emergencies (see p. 491).

Ergot alkaloids. The naturally occurring alkaloids with effective a-adrenoceptor blocking actions are also powerful a-adrenoceptor agonists, i.e. they are

17 It can be the reflex sympathetic activation, as much as hypotension itself, which causes problems. Many cardiologists have had their efforts at controlling angina in elderly patients sabotaged when the patient visits a urologist for his prostatic symptoms, and is treated with one of the newer, more powerful ocj-blockers.

partial agonists; the latter action obscures the vasodilatation that is characteristic of a-adrenoceptor blocking drugs.

Chlorpromazine has many actions of which a-adrenoceptor block is a minor one, but sufficient to cause hypotension, and to be clinically useful in amphetamine overdose.

^-ADRENOCEPTOR BLOCKING DRUGS

Actions

These drugs selectively block the P-adrenoceptor effects of noradrenaline (norepinephrine) and adrenaline (epinephrine). They may be pure antagonists or may have some agonist activity in addition (when they are described as partial agonists).

Intrinsic heart rate. Sympathetic activity (through Pj-adrenoceptors) accelerates, and parasympathetic activity (through muscarinic M2-receptors) slows the heart. If the sympathetic and the parasympathetic drives to the heart are simultaneously and adequately blocked by a P-adrenoceptor blocker plus atropine, the heart will beat at its 'intrinsic' rate. The intrinsic rate at rest is usually about 100/min, as opposed to the usual rate of 80/min, i.e. normally there is parasympathetic vagal dominance, which decreases with age.

The cardiovascular effects of P-adrenoceptor block depend on the amount of sympathetic tone present. The chief cardiac effects result from reduction of sympathetic drive:

• Reduced automaticity (heart rate)

• Reduced myocardial contractility (rate of rise of pressure in the ventricle)

• Reduced renin secretion from the juxtaglomerular apparatus in the renal cortex.

With reduced rate the cardiac output/min is reduced and the overall cardiac oxygen consumption falls. The results are more evident on the response to exercise than at rest. With acute administration of a pure p-adrenoceptor blocker (i.e. one without any instrinsic sympathomimetic activity, ISA), peripheral vascular resistance tends to rise. This is probably a reflex response to the reduced cardiac output, but also because the a-adrenoceptor (vaso constrictor) effects are no longer partially opposed by p2-adrenoceptor (dilator) effects; peripheral flow is reduced. With chronic use peripheral resistance returns to about pretreatment levels or a little below, varying according to presence or absence of ISA. But peripheral blood flow remains reduced. The cold extremities that accompany chronic therapy are probably due chiefly to reduced cardiac output with reduced peripheral blood flow, rather than to the blocking of peripheral (p2) dilator receptors.

Hepatic blood flow may be reduced by as much as 30% which prolongs the t'/2 of the lipid-soluble members whose metabolism is dependent on hepatic flow (i.e. whose first-pass metabolism is extensive and actually dependent on the rate of delivery of blood to the liver), including propranolol itself; also lignocaine (lidocaine), which is liable to be used concomitantly for cardiac arrhythmias.

Effects

Within hours of starting treatment with a P-blocker, blood pressure starts to fall. The mechanism(s) remain uncertain, and the consistency of antihypertensive response in many different types of hypertension may reflect a contribution from a variety of mechanisms. P-blockers are most effective in patients who respond also to ACE inhibitors; blockade of renin secretion is likely therefore to be the main cause of blood pressure reduction. An additional contributor may be the 2-3-fold increase in natriuretic peptide secretion caused by P-blockade.

Most of the blood pressure effect occurs quickly (hours, days) but there is often a modest further decrease over several weeks.

A substantial advantage of p-blockade in hypertension is that physiological stresses such as exercise, upright posture and high environmental temperature are not accompanied by hypotension, as they are with agents that interfere with a-adrenoceptor-mediated homeostatic mechanisms. With P-blockade these necessary adaptive a-receptor constrictor mechanisms remain intact.

At first sight the cardiac effects might seem likely to be disadvantageous rather than advantageous, and indeed maximum exercise capacity is reduced. But the heart has substantial functional reserves so that use may be made of the desired properties in the diseases listed below, e.g. angina, without inducing heart failure. Indeed, p-blockade is now becoming routine practice in patients with established mild-to-moderate heart failure. But heart failure due to the drug does occur in patients with seriously diminished cardiac reserve.

Effect on plasma potassium concentration, see page 517.

^-Adrenoceptor selectivity

Some p-adrenoceptor blockers have higher affinity for cardiac -receptors than for cardiac and peripheral p2-receptors (see Table 23.1). The ratio of the amount of drug required to block the two receptor subtypes is a measure of the selectivity of the drug. (See the note to Table 22.1, p. 449, regarding use of the terms [i, selective and cardioselective.) The question is whether the differences between selective and nonselective (J-blockers constitute clinical advantages. In theory pj-blockers are less likely to cause bronchoconstriction, but in practice few available

P, -blockers are sufficiently selective to be safely recommended in asthma. Bisoprolol and nebivolol may be exceptions that can be tried at low doses in patients with mild asthma and a strong indication for P-blockade. There are unlikely ever to be satisfactory safety data to support such use. The main practical use of Pj-selective blockade is in diabetics where P2-receptors mediate both the symptoms of hypoglycaemia and the counter-regulatory metabolic responses that reverse the hypoglycaemia.

Some P-blockers (antagonists) also have agonist action or ISA, i.e. they are partial agonists. These agents cause less fall in resting heart rate than do the pure antagonists and as a result may be less effective in severe angina pectoris in which reduction of heart rate is particularly important. There is also less fall in cardiac output and possibly fewer patients experience unpleasantly cold extremities. Intermittent claudication, however, may be worsened by p-blockade whether or not there is partial agonist

TABLE 23,1

^-adrenoceptor blocking drugs: properties at therapeutic doses

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