Pharmacokinetics

The nitrates are generally well absorbed across skin and the mucosal surface of the mouth or gut wall. Nitrates absorbed from the gut are subject to extensive first-pass metabolism in the liver, as shown by the substantially higher doses required by that route compared with sublingual application (and explains why swallowing a sublingual tablet of glyceryl trinitrate terminates its effect). They are first de-nitrated and then conjugated with glucuronic acid. The t_½ periods vary (see below), but for glyceryl trinitrate (GTN) it is 1–4 min. The de-nitration of GTN is in fact genetically determined as the enzyme responsible, a mitochondrial alcohol dehydrogenase, ALDH2, is polymorphic and in subjects carrying a common coding variant (E504K) sublingual GTN has reduced efficacy.²

Tolerance

to the characteristic vasodilator headache comes and goes quickly (hours).³ Ensuring that a continuous steady-state plasma concentration is avoided prevents tolerance. This is easy with occasional use of GTN, but with nitrates having longer t_½ (see below) and sustained-release formulations it is necessary to plan the dosing to allow a low plasma concentration for 4–8 h, e.g. overnight; alternatively, transdermal patches may be removed for a few hours if tolerance is suspected.

Uses

Nitrates are chiefly used to relieve angina pectoris and sometimes left ventricular failure. An excessive fall in blood pressure will reduce coronary flow as well as cause fainting due to reduced cerebral blood flow, so it is important to avoid accidental overdosing. Patients with angina should be instructed on the signs of overdose – palpitations, dizziness, blurred vision, headache and flushing followed by pallor – and what to do about it (see below).

The discovery that coronary artery occlusion by thrombosis is itself ‘stuttering’ – developing gradually over hours – and associated with vasospasm in other parts of the coronary tree has made the use of isosorbide dinitrate (Isoket) by continuous intravenous infusion adjusted to the degree of pain, a logical, and effective, form of analgesia for unstable angina.

Transient relief of pain due to spasm of other smooth muscle (colic) can sometimes be obtained, so that relief of chest pain by nitrates does not prove the diagnosis of angina pectoris.

Nitrates are contraindicated in angina due to anaemia.

Adverse effects

Collapse due to fall in blood pressure resulting from overdose is the commonest side-effect. The patient should remain supine with the legs raised above the head to restore venous return to the heart. The patient should also spit out or swallow the remainder of the tablet.

Nitrate headache, which may be severe, is probably due to the stretching of pain-sensitive tissues around the meningeal arteries resulting from the increased pulsation that accompanies the local vasodilatation. If headache is severe the dose should be halved. Methaemoglobinaemia can occur with heavy dosage.

Interactions

An important footnote to the use of nitrates (and NO dilators generally) has been the marked potentiation of their vasodilator effects observed in patients taking phosphodiesterase (PDE) inhibitors, such as sildenafil (Viagra) and tadalafil (Cialis). These agents target an isoform of PDE (PDE-5) expressed in the blood vessel wall. Other methylaxanthine PDE inhibitors, such as theophylline, do not cause a similar interaction because they are rather weak inhibitors of PDE-5, even at the doses effective in asthma. A number of pericoital deaths reported in patients taking sildenafil have been attributed to the substantial fall in blood pressure that occurs when used with a nitrate. This is an ironic twist for an agent in first-line use in erectile dysfunction that was originally developed as a drug to treat angina.⁴

For prophylaxis,

GTN can be given as an oral (buccal, or to swallow, Sustac) sustained-release formulation or via the skin as a patch (or ointment); these formulations can be useful for sufferers from nocturnal angina.⁵

Venepuncture

The ointment can assist difficult venepuncture and a transdermal patch adjacent to an intravenous infusion site can prevent extravasation and phlebitis, and prolong infusion survival.

Isosorbide dinitrate

(Cedocard) (t_½ 20 min) is used for prophylaxis of angina pectoris and for congestive heart failure (tablets sublingual, and to swallow). An intravenous formulation, 500 micrograms/mL (Isoket), is available for use in left ventricular failure and unstable angina.

Isosorbide mononitrate

(Elantan) (t_½ 4 h) is used for prophylaxis of angina (tablets to swallow). Hepatic first-pass metabolism is much less than for the dinitrate so that systemic bio-availability is more reliable.

Pentaerithrityl tetranitrate (Peritrate) (t_½ 8 h) is less efficacious than its metabolite pentaerithrityl trinitrate (t_½ 11 h).

Vascular smooth muscle cells

Contraction of these cells requires an influx of calcium across the cell membrane. This occurs through voltage-operated ion channels (VOCs) and this influx is able to trigger further release of calcium from intracellular stores in the sarcoplasmic reticulum. The VOCs have relatively long opening times and carry large fluxes; hence they are usually referred to as L-type channels.⁶ The rise in intracellular free calcium results in activation of the contractile proteins, myosin and actin, with shortening of the myofibril and contraction of smooth muscle. During relaxation calcium is released from the myofibril and either pumped back into the sarcoplasm or lost through Na/Ca exchange at the cell surface.

There are three structurally distinct classes of calcium channel blocker:

The differences between their clinical effects can be explained in part by their binding to different parts of the L-type calcium channel. All members of the group are vasodilators, and some have negative inotropic and negative chronotropic effects on the heart via effects on pacemaker cells in the conducting tissue. The attributes of individual drugs are described below.

The therapeutic benefit of the calcium blockers in hypertension and angina is due mainly to their action as vasodilators. Their action on the heart gives non-dihydropyridines an additional role as class 4 antiarrhythmics.

Pharmacokinetics

Calcium channel blockers in general are well absorbed from the gastrointestinal tract and their systemic bio-availability depends on the extent of first-pass metabolism in the gut wall and liver, which varies between the drugs. All undergo metabolism to less active products, predominantly by cytochrome P450 CYP3A4, which is the source of interactions with other drugs by enzyme induction and inhibition. As their action is terminated by metabolism, dose adjustments for patients with impaired renal function are therefore either minor or unnecessary.

Adverse effects

Headache, flushing, dizziness, palpitations and hypotension may occur during the first few hours after dosing, as the plasma concentration is increasing, particularly if the initial dose is too high or increased too rapidly. Ankle oedema may also develop. This is probably due to a rise in intracapillary pressure as a result of the selective dilatation by calcium blockers of the precapillary arterioles. Thus the oedema is not a sign of sodium retention. It is not relieved by a diuretic but disappears after lying flat, e.g. overnight. Bradycardia and arrhythmia may occur, especially with the non-dihydropyridines. Gastrointestinal effects include constipation, nausea and vomiting; palpitation and lethargy may be experienced.

There has been some concern that the shorter-acting calcium channel blockers may adversely affect the risk of myocardial infarction and cardiac death. The evidence is based on case–control studies which cannot escape the possibility that sicker patients, i.e. with worse hypertension or angina, received calcium channel blockade. The safety and efficacy of the class has been strengthened by the recent findings of two prospective comparisons with other antihypertensives.⁷

Interactions

are numerous. Generally, the drugs in this group are extensively metabolised, and there is risk of decreased effect with enzyme inducers, e.g. rifampicin, and increased effect with enzyme inhibitors, e.g. ketoconazole or cimetidine. Conversely, calcium channel blockers decrease the plasma clearance of several other drugs by mechanisms that include delaying their metabolic breakdown. The consequence, for example, is that diltiazem and verapamil cause increased exposure to carbamazepine, quinidine, statins, ciclosporin, metoprolol, theophylline and (HIV) protease inhibitors. Verapamil increases plasma concentration of digoxin, possibly by interfering with its biliary excretion. β-Adrenoceptor blockers may exacerbate atrioventricular (AV) block and cardiac failure. Grapefruit juice raises the plasma concentration of dihydropyridines (except amlodipine) and verapamil, while St John’s wort, as an inducer of CYP3A4, can reduce bio-availability of verapamil and dihydropyridines.

Nifedipine

(t_½ 2 h) is the prototype dihydropyridine. It selectively dilates arteries with little effect on veins; its negative myocardial inotropic and chronotropic effects are much less than those of verapamil. There are sustained-release formulations of nifedipine that permit once-daily dosing, minimising peaks and troughs in plasma concentration so that adverse effects due to rapid fluctuation of concentrations are lessened. Various methods have been used to prolong, and smooth, drug delivery, and bio-equivalence between these formulations cannot be assumed; prescribers should specify the brand to be dispensed. The adverse effects of calcium blockers with a short duration of action may include the hazards of activating the sympathetic system each time a dose is taken. The dose range for nifedipine is 30–90 mg daily. In addition to the adverse effects listed above, gum hypertrophy may occur. Nifedipine can be taken ‘sublingually’, by biting a capsule and squeezing the contents under the tongue. In point of fact, absorption is still largely from the stomach after this manoeuvre, and it should not be used in a hypertensive emergency because the blood pressure reduction is unpredictable and sometimes large enough to cause cerebral ischaemia (see p. 417).

Amlodipine

has a t_½ (40 h) sufficient to permit the same benefits as the longest-acting formulations of nifedipine without requiring a special formulation. Its slow association with L-channels and long duration of action render it unsuitable for emergency reduction of blood pressure where frequent dose adjustment is needed. On the other hand, an occasional missed dose is of little consequence. Amlodipine differs from all other dihydropyridines listed in this chapter in being safe to use in patients with cardiac failure (the PRAISE study).⁸

Verapamil

(t_½ 4 h) is an arterial vasodilator with some venodilator effect; it also has marked negative myocardial inotropic and chronotropic actions. It is given thrice daily as a conventional tablet or daily as a sustained-release formulation. Because of its negative effects on myocardial conducting and contracting cells it should not be given to patients with bradycardia, second- or third-degree heart block, or patients with Wolff–Parkinson–White syndrome to relieve atrial flutter or fibrillation. Amiodarone and digoxin increase the AV block. Verapamil increases plasma quinidine concentration and this interaction may cause dangerous hypotension.

Diltiazem

(t_½ 5 h) is given thrice daily, or once or twice daily if a slow-release formulation is prescribed. It causes less myocardial depression and prolongation of AV conduction than does verapamil but should not be used where there is bradycardia, second- or third-degree heart block or sick sinus syndrome.

Nimodipine

has a moderate cerebral vasodilating action. Cerebral ischaemia after subarachnoid haemorrhage may be partly due to vasospasm; clinical trial evidence indicates that nimodipine given after subarachnoid haemorrhage reduces cerebral infarction (incidence and extent). Although the benefit is small, the absence of any more effective options has led to the routine administration of nimodipine (60 mg every 4 h) to all patients for the first few days after subarachnoid haemorrhage. No benefit has been found in similar trials following other forms of stroke.

Other members

include felodipine, isradipine, lacidipine, lercanidipine, nisoldipine.

Hypertension

The antihypertensive effect of ACE inhibitors, ARBs and renin inhibitors results primarily from vasodilatation (reduction of peripheral resistance) with little change in cardiac output or rate; renal blood flow may increase (desirable). A fall in aldosterone production may also contribute to the blood-pressure-lowering action of ACE inhibitors. Both classes slow progression of glomerulopathy. Whether the long-term benefit of these drugs in hypertension exceeds that to be expected from blood pressure reduction alone remains controversial.

ACE inhibitors, ARBs and renin inhibitors are most useful in hypertension when the raised blood pressure results from excess renin production, e.g. renovascular hypertension, or where concurrent use of another drug (diuretic or calcium blocker) renders the blood pressure renin dependent. The fall in blood pressure can be rapid, especially with short-acting ACE inhibitors, and low initial doses of these should be used in patients at risk: those with impaired renal function or suspected cerebrovascular disease. These patients may be advised to omit any concurrent diuretic treatment for a few days before the first dose. The antihypertensive effect increases progressively over weeks with continued administration (as with other antihypertensives) and the dose may be increased at intervals of 2 weeks.

Cardiac failure

(see p. 406). ACE inhibitors have a useful vasodilator and diuretic-sparing (but not diuretic-substitute) action that is critical to the treatment of all grades of heart failure. Mortality reduction here may result from their being the only vasodilator that does not reflexly activate the sympathetic system.

The ARBs are at least as effective as ACE inhibitors in patients with heart failure and they can be substituted if patients are intolerant of an ACE inhibitor. Based on the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trial, they may also benefit patients with heart failure and a low ejection fraction when added to treatment with a β-blocker and ACE inhibitor.⁹

Diabetic nephropathy

In patients with type I (insulin-dependent) diabetes, hypertension often accompanies the diagnosis of frank nephropathy, and aggressive blood pressure control is essential to slow the otherwise inexorable decline in renal function that follows. ACE inhibitors appear to have a specific renoprotective effect, probably because of the role of angiotensin II in driving the underlying glomerular hyperfiltration.¹⁰ These drugs are now first-line treatment for hypertensive type I diabetics, although most patients will need a second or third agent to reach the rigorous blood pressure targets for this condition (see below). Their role in preventing the progression of the earliest manifestation of renal damage, microalbuminuria, is more complicated. Here the evidence suggests that ACE inhibitors do not slow the incidence of microalbuminuria in type I diabetics and an ARB may actually substantially increase it.¹⁰ In contrast, an ACE inhibitor halves the incidence of microalbuminuria in type 2 diabetics with hypertension and normal renal function on follow-up. A parallel group on verapamil did not show any protection confirming that inhibition of the renin–angiotensin–aldosterone (RAAS) axis is required for this effect, not simply lowering the blood pressure.¹¹ For hypertensive type 2 diabetics with established nephropathy, both ARBs and ACE inhibitors protect against a decline in renal function and reduce macroproteinuria.¹⁰ The evidence suggests they are interchangeable in this respect. Whether combining the two classes of drugs (‘dual block’) confers further protection of renal function is not yet resolved, although ‘dual block’ does produce substantially better urine protein sparing than either agent alone.¹⁰

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 (see p. 425). Angiotensin II plays a key role in both of these processes and an ACE inhibitor given after MI markedly reduces the incidence of heart failure. The effect is seen even in patients without overt signs of cardiac failure, but who have low left ventricular ejection fractions (< 40%) during the convalescent phase (3–10 days) following the MI. Such patients receiving captopril in the SAVE trial,¹² had a 37% reduction in progressive heart failure over the 60-month follow-up period compared with placebo. The benefits of ACE inhibition after MI are additional to those conferred by thrombolysis, aspirin and β-blockers. ARBs also prevent remodelling and heart failure in post-MI patients, but there is no additional benefit from ‘dual blockade’.¹³

ACE inhibitors:

ARBs

are contraindicated in pregnancy as are ACE inhibitors, but avoid the other complications of these drugs – especially the cough and angioedema. They are, in fact, the only antihypertensive drug class 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 chlorpromazine, and possibly other phenothiazines.

Captopril

(Capoten) has a t_½ of 2 h and is partly metabolised and partly excreted unchanged; adverse effects are more common when renal function is impaired; it is given twice or thrice daily. Captopril is the shortest acting of the ACE inhibitors, one of the few that is itself active by mouth, not requiring de-esterification after absorption.

Enalapril

(Innovace) is a prodrug (t_½ 35 h) that is converted to the active enalaprilat (t_½ 10 h). Effective 24-h control of blood pressure probably requires twice-daily administration.

Other members

include cilazapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril. Of these, lisinopril has a marginally longer t_½ than enalapril (it is the lysine analogue of enalaprilat), probably justifying its popularity as a once-daily ACE inhibitor. Some of the others are longer acting, with quinapril and ramipril also having 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.¹⁴ The authors considered (probably erroneously) that the results could not be explained entirely by blood pressure reduction.

Losartan

was the first ARB to be licensed in the UK. It is a competitive blocker with a non-competitive active metabolite. The drug has a short t_½ (2 h) but the metabolite is much longer lived (t_½ 10 h), permitting once-daily dosing.

Other ARBs

in clinical use include candesartan, eprosartan, irbesartan, telmisartan, valsartan and olmesartan. Some of these may be marginally more effective than losartan at lowering blood pressure, but few if any comparisons have been performed at maximal dose of each drug. Losartan is generally used in combination with hydrochlorothiazide. In a landmark study this combination was 25% more effective than atenolol plus hydrochlorothiazide in preventing stroke.¹⁵

This class of drug is very well tolerated; in clinical trials the side-effect profiles are indistinguishable or even better than those of placebo. Unlike the ACE inhibitors they do not produce cough, and are a valuable alternative for the 10–15% of patients who thereby discontinue their ACE inhibitor. ARBs are used to treat hypertension, left ventricular (LV) failure after MI and established heart failure. With the possible exception of chronic heart failure, they do not appear to be superior to ACE inhibitors.

The cautions listed for the use of ACE inhibitors (above) apply also to AT₁-receptor blockers.

Renin inhibitors

share the benefit of ARBs over ACE inhibitors in terms of cough and angioedema. By implication with other agents targeting the RAAS they should not be used in pregnancy.

Interactions

Hyperkalaemia can result from use with potassium-sparing diuretics. Severe hypotension can occur on first dosing if given after agents that increase circulating renin levels such as diuretics (especially loop diuretics) and potent vasodilators.

Aliskiren

is the only orally active non-peptide renin inhibitor licensed (t_½ 40 h). The agent is well tolerated apart from dose-dependent diarrhoea; it is not clear if this is a class side-effect. It produces additive effects on blood pressure with ACE inhibitors, ARBs, calcium channel blockers and thiazide diuretics. There are currently no outcome data in terms of preventing hypertension-related cardiovascular events, so it should be reserved for inhibiting the RAAS where an ACE inhibitor or ARB is not tolerated.¹⁶

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 adenosine triphosphate (ATP)-dependent potassium channel opener. It is highly effective in severe hypertension, but 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, which antagonises the hypotensive effect (so-called ‘tolerance’ on long-term use). Therefore, it is used in combination with a β-blocker and loop diuretic (as is hydralazine; see below). Hypertrichosis is perhaps the most notorious side-effect of minoxidil. The hair growth is generalised when taken orally and, although a cosmetic problem in women, it has been exploited as a 2–5% topical solution for the treatment of male-pattern baldness (Regaine).

Sodium nitroprusside

is a highly effective antihypertensive agent when given intravenously. 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 were the patient to stand 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 may manifest as delirium or psychotic symptoms. Intoxicated subjects are also reputed to have the characteristic bitter almond smell of hydrogen cyanide. Clearly nitroprusside infusion must be used with caution, and 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 infusion¹⁷ 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 by direct arterial monitoring; rate changes of infusion may be made every 5–10 min.

Diazoxide

mimics the actions of other ATP-dependent potassium channel openers or KCOs. The t_½ is 36 h. Diazoxide was used as an intravenous bolus for the emergency treatment of severe hypertension, but this use is now obsolete.

During its use as an antihypertensive it was noted that it caused hyperglycaemia because, unlike other KCOs, it can activate the sulphonylurea-sensitive form of the ATP-potassium channel in the pancreatic islet cells switching off insulin release. Hence it is used in patients with chronic hypoglycaemia from excess endogenous insulin secretion, either from an islet cell tumour or islet cell hyperplasia. Long-term use can cause the same problems of hair growth seen with minoxidil, albeit less consistently.

Hydralazine

is now little used for hypertension except for that related to pregnancy (owing to its established lack of teratogenicity), 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; the mechanism of vasorelaxation is unclear. The t_½ 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 50 mg/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 effective 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 β-blockade, nitrates or calcium channel blockade. It is administered orally and is an alternative to nitrates when tolerance 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 on outcome.¹⁸

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, especially into and around arteries and veins to relieve spasm during vascular surgery and when setting up intravenous infusions. It is also used to treat male erectile dysfunction (see p. 465).

Alprostadil

is a stable form of prostaglandin E₁. It is effective in psychogenic and neuropathic penile erectile dysfunction by direct intracorporeal injection (see p. 465) and is used intravenously to maintain patency of the ductus arteriosus in the newborn with congenital heart disease.

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 hypertension and hyperlipidaemia. Patients should also receive low-dose aspirin (75 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. Vasodilators such as naftidrofuryl (Praxilene) and pentoxifylline (Trental) increase blood flow to skin rather than muscle; they have been used successfully in the treatment of venous leg ulcers (varicose and traumatic). A trial of these drugs for intermittent claudication is worthwhile but they should be withdrawn if there is no benefit within a few weeks.

Naftidrofuryl has several actions. It is classed as a metabolic enhancer because it activates the enzyme succinate dehydrogenase, increasing the supply of ATP and reducing lactate concentrations in muscle. It also blocks 5HT₂ receptors and inhibits serotonin-induced vasoconstriction and platelet aggregation.

Pentoxifylline 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 diversion (‘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 double-blind 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.¹⁹ The benefit may not be seen for 4 weeks.

Raynaud’s phenomenon

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

β-Adrenoceptor blockers exacerbate peripheral vascular disease and Raynaud’s phenomenon by reducing perfusion of a circulation that is already compromised. Switching to a β₁-selective blocker is unhelpful, because the adverse effect is due to reduced cardiac output rather than unopposed α-receptor-induced vasoconstriction.

Adverse effects

The converse of the benefit in the treatment of prostatism is the adverse effect of urinary incontinence in women. Other adverse effects of α-adrenoceptor blockade are postural hypotension, nasal stuffiness, red sclerae and, in the male, failure of ejaculation. They may also exacerbate symptoms of angina.²⁰ Effects peculiar to each drug are mentioned below.

Prazosin

blocks postsynaptic α₁ receptors but not presynaptic α₂ autoreceptors. It has a curious adverse ‘first-dose effect’: within 2 h of the first dose (rarely after another) there may be a brisk fall in blood pressure sufficient to cause loss of consciousness. Hence the first dose should be small (0.5 mg) and given before going to bed. This unwanted effect, together with a rather short duration of action (t_½ 3 h) has led to a sharp decline in its use.

Doxazosin

(t_½ 8 h) was the first α-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 double this dose without repeating the blood pressure measurement at this stage. A slow-release formulation, doxazosin XL, can be started at the maintenance dose of 4 mg daily.

Other α-adrenoceptor blockers used for prostatic symptoms are alfuzosin and terazosin.

Indoramin

is an older α₁-blocker, which is a less useful antihypertensive but still used for prostatic symptoms. It is taken twice or thrice daily.

Phentolamine

is a non-selective α-adrenoceptor blocker. It is given intravenously for brief effect in adrenergic hypertensive crises, e.g. phaeochromocytoma or the monoamine oxidase inhibitor–sympathomimetic interaction (‘cheese reaction’). In addition to α-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). This is not a reliable diagnostic test for phaeochromocytoma!

Phenoxybenzamine

is an irreversible non-selective α-adrenoceptor-blocking drug whose effects may last for 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 α-blocker for treating phaeochromocytoma (see p. 419).

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.

Moxisylyte

(thymoxamine) is a non-selective α-blocker for which Raynaud’s phenomenon is the only extant indication.

Labetalol

has both α- and β-receptor-blocking actions that are due to different isomers (see β-adrenoceptor block, below). Its parenteral preparation is valuable in the treatment of hypertension emergencies (see p. 416).

Chlorpromazine and amitriptyline,

among their other actions, can both produce clinically significant α-blockade, which may be sufficient to cause postural hypotension and falls in the elderly.

Intrinsic heart rate

Sympathetic activity (through β₁ 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 β-adrenoceptor blocker plus atropine, the heart will beat at its ‘intrinsic’ rate. The intrinsic rate at rest is usually about 100 beats/min, as opposed to the usual rate of 80 beats/min, i.e. normally there is parasympathetic vagal ‘tone’, which decreases with age.

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

With reduced rate the cardiac output per minute 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 β-adrenoceptor blocker, i.e. one with no intrinsic sympathomimetic activity (ISA), peripheral vascular resistance tends to rise. This is probably a reflex response to the reduced cardiac output, but also occurs because the β-adrenoceptor (vasoconstrictor) effects are no longer partially opposed by β₂-adrenoceptor (dilator) effects; peripheral flow is reduced. With chronic use peripheral resistance returns to about pre-treatment 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 (β₂) dilator receptors.

Hepatic blood flow may be reduced by as much as 30%, prolonging the t_½ of the lipid-soluble drugs whose metabolism is limited by hepatic blood flow, i.e. whose first-pass metabolism is so extensive that it is actually limited by the rate of blood delivery to the liver; these include propranolol, verapamil and lidocaine, which may be used concomitantly for cardiac arrhythmias.