Calcium Channel Blockers

Calcium is involved in the initiation of smooth muscle and cardiac cell contraction and in the propagation of the cardiac impulse. Actions on cardiac pacemaker cells and conducting tissue are described in Chapter 24.

Vascular smooth muscle cells. Contraction of these cells requires an influx of calcium across the cell membrane. This occurs through ion channels

4 Useful, but not always safe. Defibrillator paddles and nitrate patches make an explosive combination, and it is not always in the patient's interest to have the patch as unobtrusive as possible (Canadian Medical Association Journal 1993 148: 790).

that are largely specific for calcium and are called 'slow calcium channels' to distinguish them from 'fast' channels that allow the rapid influx and efflux of sodium.

Activation of calcium channels by an action potential allows calcium to enter the cells. There follows a sequence of events which 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, as it cannot be stored in the cell, it passes out again through the channel. Calcium channel (also called calcium entry) blockers inhibit the passage of calcium through the voltage-dependent L- (for 'long-opening') class membrane channels in cardiac muscle and conducting tissue, and vascular smooth muscle, reduce available intracellular calcium and cause the muscle to relax.5

There are three structurally distinct classes of calcium channel blocker:

• Dihydropyridines (the most numerous)

• Phenylalkylamines (principally verapamil)

• Benzothiazepine (diltiazem).

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 cardiac inotropic action and negative chronotropic effect via pacemaker cells and depress 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 bioavailability depends on the extent of first-pass metabolism in the gut wall and liver, which varies between the drugs. All

5 Several calcium-selective channels have been described in different tisues, e.g. the N (present in neuronal tissue) and T (transient, found in brain, neuronal and cardiovascular tissue); the drugs discussed here selectively target the L channel for its cardiovascular importance.

undergo metabolism to less active products, predominantly by cytochrome P-450 CYP3A, 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.

Indications for use

• Hypertension: amlodipine, isradipine, nicardipine, nifedipine, verapamil

• Angina: amlodipine, diltiazem, nicardipine, nifedipine, verapamil

• Cardiac arrhythmia: verapamil

• Raynaud's disease: nifedipine

• Prevention of ischaemic neurological damage following subarachnoid haemorrhage: nimodipine.

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. In theory the oedema should also be attenuated by combining the calcium blocker with another vasodilator which is more effective (than calcium blockers) at relaxing the postcapillary venules, e.g. a nitrate or an ACE inhibitor. Bradycardia and arrhythmia may occur. Gastrointestinal effects include constipation, nausea and vomiting; palpitation and lethargy may be felt.

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.6

Interactions are quite numerous. The drugs in this group in general are extensively metabolised, and there is risk of decreased effect with enzyme inducers, e.g. rifampicin, and increased effect with enzyme inhibitors, e.g. 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. Beta-adreno-ceptor blockers may exacerbate atrioventricular block and cardiac failure. Grapefruit juice raises the plasma concentration of dihydropyridines (except amlodipine) and verapamil.

Individual calcium blockers

Nifedipine (t1/, 2h) is the prototype dihydro-pyridine. 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 with minimal peaks and troughs in plasma concentration so that adverse effects due to rapid fluctuation of concentrations are also lessened. Various methods have been used to prolong, and smooth, drug delivery, and bioequivalence 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

6 Both the NORDIL and INSIGHT trials (Lancet 2000 356: 359-365,366-372) confirmed that a calcium channel blocker (diltiazem and nifedipine respectively) had the same efficacy as older therapies (diuretics and/or p-blockers) in hypertension with no evidence of increased sudden death.

manoeuvre; 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. 492).

Amlodipine has a t'/2 (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 PRAISE7 Study).

Verapamil (t'/2 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 (t1/, 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.

Isradipine (tl/z 8 h) is given once or twice daily (it is similar to nifedipine).

7 PRAISE = Prospective Randomised Amlodipine Survival Evaluation (see Packer M et al 1996 The effect of amlodipine on morbidity and mortality in severe chronic heart failure. New England Journal of Medicine 335: 1107-1114).

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).8 Although the benefit is small, the absence of any more effective alternatives has led to the routine administration of nimodipine (60 mg every 4 hours) to all patients for the first few days following subarachnoid haemorrhage. No benefit has been found in similar trials following other forms of stroke.

Other members include felodipine, isradipine, laci-dipine, lercanidipine, nisoldipine.

ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS AND ANGIOTENSIN (AT) II RECEPTOR ANTAGONISTS

Renin is an enzyme produced by the kidney in response to a number of factors including adrenergic activity (Pj -receptor) and sodium depletion. Renin converts a circulating glycoprotein (angiotensinogen) into the biologically inert angiotensin I, which is then changed by angiotensin converting enzyme (ACE or kininase II) into the highly potent vasoconstrictor angiotensin II. ACE is located on the luminal surface of capillary endothelial cells, particularly in the lungs; and there are also renin-angiotensin systems in many organs, e.g. brain, heart, the relevance of which is uncertain.

Angiotensin II acts on two G-protein coupled receptors, of which the angiotensin 'Aiy subtype accounts for all the classic actions of angiotensin. As well as vasoconstriction these include stimulation of aldosterone (the sodium-retaining hormone) production by the adrenal cortex. It is evident that angiotensin II can have an important effect on blood pressure. In addition, it stimulates cardiac and vascular smooth muscle cell growth, contributing probably to the progressive amplification in hypertension once the process is initiated. The AT2 receptor subtype is coupled to inhibition of muscle growth or proliferation, but appears of minor importance in the adult cardiovascular system. The

8 Packard J D et al 1989 British Medical Journal 289: 636.

recognition that the ATj-receptor subtype is the important target for drugs antagonising angiotensin II has led, a little confusingly, to two alternative nomenclatures for these drugs: either ATj-receptor blockers, or angiotensin II receptor antagonists (AURA).

Bradykinin (an endogenous vasodilator occurring in blood vessel walls) is also a substrate for ACE. Potentiation of bradykinin contributes to the blood pressure lowering action of ACE inhibitors in patients with low-renin causes of hypertension. Either bradykinin or one of the neurokinin substrates of ACE (such as substance P) may stimulate cough (below). The ATj blockers differ from the ACE inhibitors in having no effect on bradykinin and do not cause cough. Those that achieve complete blockade of the receptor are slightly more effective than ACE inhibitors at preventing angiotensin II vasoconstriction. ACE inhibitors are more effective at suppressing aldosterone production in patients with normal or low plasma renin.

Uses

Hypertension. The antihypertensive effect of ACE inhibitors and AT receptor blockers 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 and ATj-receptor blockers 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 adminis tration (as with other antihypertensives) and the dose may be increased at intervals of 2 weeks.

Cardiac failure (see p. 517). ACE inhibitors have a useful vasodilator and diuretic-sparing (but not diuretic-substitute) action in all grades of heart failure. Their reduction of mortality in this condition, due possibly to their being the only vasodilator which does not reflexly activate the sympathetic system, has made the ACE inhibitors more critical to the treatment of heart failure than of hypertension, where they are not usually an essential part of management. The ATj blockers have not yet been introduced for the treatment of cardiac failure. This may only be a matter of time, but the establishment of new drugs for cardiac failure encounters the problem of demonstrating efficacy against a background of existing ACE inhibitor therapy, where a placebo control is no longer ethically acceptable.

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, possibly because of the role of angiotensin II in driving the underlying glomerular hyperfiltration in these patients.9 These drugs are now considered first-line treatment for hypertensive type I diabetics, although most patients will need a second or third agent to reach the new BP targets for these patients (see below). There is also evidence that ACE inhibitors have a proteinuria-sparing effect in type I diabetics with 'normal' BP, but here it is less clear whether this effect extends beyond just a BP-lowering effect.10 For hypertensive type 2 diabetics with nephropathy, there are better data to support use of ATj-receptor blockers than ACE inhibitors for a renoprotective effect independent of the blood pressure lowering effect.

9 For a review, see: Cooper M E 1998 Pathogenesis, prevention and treatment of diabetic nephropathy. Lancet 352:213-219.

10 The EUCLID study group 1997 The EUCLID study. Randomised, placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbiminuria. Lancet 349:

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