Classification Of Drugs

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Drugs may be classified as producing: Reduction of preload

Diuretics increase salt and water loss, reduce blood volume and lower excessive venous filling pressure (see Ch. 26). The congestive features of oedema, in the lungs and periphery, are alleviated; when the heart is grossly enlarged, cardiac output will also increase (see discussion of Starling curve, above).

Nitrates (see also Ch. 23) dilate the smooth muscle in venous capacitance vessels, increase the volume of the venous vascular bed (which normally may comprise 80% of the whole vascular system), reduce ventricular filling pressure, thus decreasing heart wall stretch, and reduce myocardial oxygen requirements. Their arteriolar dilating action is relatively slight. Glyceryl trinitrate may be given sublingually 0.3-1 mg for acute left ventricular failure and repeated as often as necessary or by i.v. infusion, 10-200 micrograms/min. For chronic left ventricular failure isosorbide dinitrate 40-160 mg/d or isosorbide mononitrate 40-80 mg/d may be given by mouth in divided doses. Exercise capacity is improved but tolerance to nitrates may develop with chronic use. Headache, which tends to limit the dose of nitrate used for angina, is less of a problem in cardiac failure perhaps because of pre-existing vasoconstriction.

Reduction of afterload

Hydralazine (see also Ch. 23) relaxes arterial smooth muscle and reduces peripheral vascular resistance. Reflex tachycardia limits its usefulness and lupus erythematosus may be induced when the dose exceeds 100 mg per day.

Reduction of preload and afterload

Angiotensin converting enzyme (ACE) inhibitors

• reduction of afterload, by preventing the conversion of angiotensin I to the active form, angiotensin II, which is a powerful arterioconstrictor and is present in the plasma in high concentration in cardiac failure

• reduction of preload, because the formation of aldosterone, and thus retention of salt and water (increased blood volume), is prevented by the reduction of angiotensin II.

ACE inhibitors are the only drugs that reduce peripheral resistance (afterload) without causing a reflex activation of the sympathetic system. The CONSENSUS study compared enalapril with placebo in patients with NYHA class IV heart failure; after 6 months 26% of the enalapril group had died, compared with 44% in the control group. The reduction in mortality was found to be among patients with progressive heart failure.13 There is now evidence from numerous long-term studies showing that ACE inhibition improves survival in and reduces hospital admissions for cardiac failure.14

A test dose should be given to patients who are in cardiac failure (or who are already taking a diuretic for another reason, e.g. hypertension). Maintenance of blood pressure in such individuals may depend greatly on an activated renin-angiotensin-aldosterone system and a standard dose of an ACE inhibitor can cause a catastrophic fall in blood pressure. Except for captopril, most ACE inhibitors (including enalapril) are prodrugs, which are inactive for several hours after dosing. This has favoured the use of captopril

13 The CONSENSUS Trial Study Group 1987 New England Journal of Medicine 316:1429-1435.

14 Flather M D et al 2000 Lancet 355:1575-1587.

for the initial dose(s) given under medical supervision; captopril also has the shortest t'/2 so that hypotension will be reversed the most quickly. Alternatively, some of the many ACE inhibitors now available (see p. 469) have a sufficiently long ty2 to suggest that the initial doses would have a cumulative effect on blood pressure over several days; long-acting ACE inhibitors such as lisinopril (t'/212 h) and perindopril (t'/2 31 h) avoid the risk of sudden falls in blood pressure or renal function (glomerular filtration) after the first dose. These can often be initiated outside hospital in patients who are unlikely to have a high plasma renin (absence of gross oedema or widespread atherosclerotic dicease), although it is prudent to arrange for the first dose to be taken just before going to bed.

Beta-adrenoceptor blockers. The realisation that the course of chronic heart failure can be adversely affected by activation of the renin-angiotensin-aldosterone and sympathetic nervous systems led to exploration of possible benefit from [^-adrenoceptors in a condition where, paradoxically, such drugs can have an adverse effect. Clinical trials have, indeed, shown that bisoprolol, carvedilol or metoprolol lower mortality and decrease hospitalisation when added to diuretics, digoxin and an ACE inhibitor (see below).

Spironolactone. Plasma aldosterone is elevated in heart failure. Spironolactone acts as a diuretic by competitively blocking the aldosterone-receptor, but in addition it has a powerful effect on outcome in cardiac failure (see below).

Phentolamine or sodium nitroprusside (see Ch. 23) may rarely be used (by i.v. infusion) when acute cardiac failure is accompanied by a high blood pressure.

Stimulation of the myocardium

Digoxin improves myocardial contractility (positive inotropic effect) most effectively in the dilated, failing heart and in the longer term once an episode of cardiac failure has been brought under control. This effect occurs in patients in sinus rhythm and is separate from its (negative chronotropic) action of reducing ventricular rate and thus improving ventricular filling in atrial fibrillation. Over 200

years after the first use of digitalis for dropsy, the DIG trial has brought some relief for doctors wishing evidence of long-term benefit.15 This was a prospective randomised comparison of digoxin with placebo in 7788 patients in NYHA Class II to III heart failure and sinus rhythm, of whom most also received an ACE inhibitor and a diuretic. Overall mortality did not differ between the groups but patients who took digoxin had fewer episodes of hospitalisation for worsening heart failure; unlike all other positive isotropes, digoxin did not increase overall mortality or arrhythmias.

The phosphodiesterase inhibitors, enoximone and milrinone have positive inotropic effect due to selective myocardial enzyme inhibition and may be used for short-term treatment of severe congestive cardiac failure. Evidence from longer term use indicates that these drugs reduce survival.

Dopamine, dobutamine, dopexamine, xamoterol: see Chapter 22.

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