Calcium channel antagonists

What are calcium channel antagonists?
There are 3 different classes of clinically useful calcium channel antagonists; the members of each class bind to a different receptor site within the calcium channel. The 3 classes are represented by verapamil, diltiazem and the dihydropyridines: nifedipine, felodipine and amlodipine. Calcium channels at different sites throughout the body have variable concentrations of the 3 receptor sites, thus conferring a different pharmacological profile on each of the classes.

What are the effects of calcium channel antagonists?
The calcium channel antagonists inhibit calcium uptake into cells through a channel in the cell membrane which is specific for the entry of divalent cations particularly calcium. The result of this inhibition is to reduce the availability of intracellular calcium and thus interfere with the cellular processes dependent on calcium.

All of the calcium channel antagonists have their predominant effects on arteriolar smooth muscle, the myocardium and cardiac conducting tissue. The profile of effects is characteristic for each class. Other tissues which are 'calcium-dependent', e.g. skeletal muscle, secretory cells, nervous tissue, are not affected by the available calcium channel antagonists, either because they are dependent on intracellular calcium stores (skeletal muscle) or they have different types of calcium channels. All calcium channel antagonists have an intrinsic natriuretic effect.

Verapamil
Verapamil relaxes arteriolar smooth muscle resulting in vasodilatation, reduced peripheral resistance and reduced arterial pressure. At therapeutic concentrations, verapamil also depresses myocardial contractility, sinus node firing rate and AV conduction. These cardiac effects may be sufficient to precipitate cardiac failure, heart block or sinus arrest in susceptible patients, particularly when verapamil is given with beta blockers. The direct negative chronotropic and inotropic effects of verapamil oppose any reflex-mediated sympathetic stimulation resulting from reducing the blood pressure, so there is no increase in heart rate and sometimes heart rate is slowed. As all calcium channel antagonists including verapamil have no significant effect on venous tone, they do not interfere with the circulatory response to orthostasis, so they do not cause postural hypotension. Verapamil's intrinsic natriuretic effect balances any tendency for salt and water retention resulting from blood pressure reduction. Verapamil has a more profound effect on gut smooth muscle than the other calcium channel antagonists. It reduces gut motility and causes constipation.

Diltiazem
Like verapamil, diltiazem is an arteriolar dilator which reduces peripheral resistance and thus blood pressure, but it is less cardio depressant. The less marked cardio depressant effects are still sufficient to oppose the reflex-mediated cardiac stimulation arising from the reduction of blood pressure and thus there is no accompanying increase in heart rate. Although it may precipitate cardiac failure in susceptible patients and also interfere with AV conduction, diltiazem can be used safely in combination with a beta blocker for the treatment of hypertension without causing unacceptable cardio depression.

Dihydropyridines
Nifedipine, felodipine, amlodipine and nimodipine are available in Australia. Nimodipine is marketed only for the treatment of cerebrovascular spasm following subarachnoid haemorrhage. The dihydropyridines are selective for blood vessels as therapeutic doses relax arteriolar smooth muscle without detectable cardio depression. In general, they cause a more profound reduction in peripheral resistance and thus blood pressure than verapamil or diltiazem. Although in vitro the dihydropyridines can depress myocardial contractility, the usual clinically observed effect on the heart is one of reflex- mediated sympathetic stimulation of both heart rate and contractility. This cardiac stimulation has been associated with the precipitation or worsening of angina or even the occurrence of myocardial infarction or sudden death. Reflex-mediated cardiac stimulation is less likely with the longer-acting and slow-release preparations because their slower onset of effect allows baroreflex resetting. It is also effectively blocked by the concomitant administration of a beta blocker.

Despite having an intrinsic diuretic effect, the dihydropyridines cause peripheral oedema. The oedema represents a redistribution of extra cellular fluid rather than a net retention of salt and water and hence does not respond to diuretics.

What are the clinically relevant pharmacokinetic properties of the calcium channel antagonists?
The drugs are well absorbed from the gut, but their bioavailability varies depending on the extent of first-pass metabolism in the liver (Table 1). The oral bioavailability is affected by endogenous states or drugs which influence hepatic drug metabolism. As metabolism tends to decrease with age, the bioavailability, plasma concentrations and clinical responses for a particular dose are greater in older than in younger patients. Similar effects are observed if these drugs are given to patients with severe liver disease. Drugs which alter hepatic drug metabolism also affect bioavailability. Renal failure has no significant effect on clearance.

The calcium channel antagonists have a range of elimination half-lives which have a considerable impact on their clinical use. Verapamil and diltiazem have short half-lives which require them to be given 3-4 times daily. However, slow-release formulations now allow once-daily dosing.

The original fluid-filled nifedipine capsule releases the drug rapidly in the gut. This causes both a rapid onset and offset of response. Nifedipine capsules are thus prone to produce a rapid drop in blood pressure with adverse reflex cardiac effects. These responses probably account for the adverse outcome with enhanced risk of myocardial infarction which has been associated with the rapidly-acting nifedipine preparation. As a result, the availability of nifedipine capsules in Australia is currently under review. These haemodynamic effects are attenuated when nifedipine is given in hard compressed tablets and not seen with the slow-release osmotically-driven preparation. As absorption occurs from the stomach and small intestine and not from the buccal mucosa, there is no rational basis for the use of nifedipine by the buccal route.

The longer half-life of felodipine was sufficient for the original compressed tablets to be given twice daily, but a once-daily, slow-release formulation of felodipine was also developed and this has become the standard preparation.

The intrinsically much longer half-life of amlodipine makes it suitable for once-daily dosing as a conventional tablet preparation. This long half-life also means that it takes longer for steady-state plasma concentrations to be achieved, causing the clinical response to be delayed for several days until sufficient drug has accumulated. Adverse effects may also take days to resolve.

What are the current clinical uses of calcium channel antagonists?

Verapamil
Verapamil is effective as monotherapy for angina provided that it does not cause cardiac failure.

Verapamil is also used in the treatment of hypertension. It is effective in reducing blood pressure either as monotherapy or in combination with either diuretics or ACE inhibitors. Combination with a beta blocker is not recommended because of additive deleterious myocardial depression. Compared with the other calcium channel antagonists, the limiting factors for the use of verapamil in hypertension are its cardio depression and the almost universal occurrence of constipation.

Verapamil has a unique role among the calcium channel antagonists in the management of supraventricular arrhythmias. Normal conduction through the AV node is dependent on calcium entry into the conducting tissue cells for depolarisation. Verapamil reduces calcium entry and thus slows AV conduction. This action can be beneficial in terminating or preventing paroxysmal supraventricular tachycardia by interfering with AV nodal re-entry and also in controlling ventricular rate in the presence of atrial fibrillation.

Verapamil and diltiazem are sometimes also used to enhance myocardial relaxation either when there is significant diastolic dysfunction or with hypertrophic obstructive cardiomyopathy.

Diltiazem
Diltiazem is suited to the management of angina. Its balance of both coronary and peripheral vasodilatation with mild cardio depression is effective and well tolerated when used as monotherapy.

Although it has been somewhat slow to be accepted, diltiazem has a role in the management of hypertension as a moderately effective arterial vasodilator. It is well tolerated both as monotherapy and in combination with all of the other major classes of antihypertensive drugs.

Dihydropyridines
As more powerful arterial vasodilators, the dihydropyridines are more effective antihypertensive drugs than either verapamil or diltiazem, but they are not as well tolerated because of excessive vasodilator effects and reflex cardiac stimulation. Some patients tolerate a dihydropyridine as monotherapy, but often tolerability and effectiveness are enhanced if lower doses are used in combination with a beta blocker, ACE inhibitor or diuretic. The reflex effects are considerably attenuated with the longer-acting and slow-release formulations which are now the preparations of choice. Amlodipine and slow-release nifedipine have the least variability of plasma concentration and response within a 24-hour dosing interval.

Recently, the long-term safety of treatment has been questioned (see 'Calcium antagonists: the current controversy' Aust Prescr 1996;19:35). It is possible that the adverse outcomes are only related to the shorter-acting preparations. Several major outcome studies using longer-acting calcium channel antagonists are currently in progress and should answer these questions. Calcium channel antagonists as first-line antihypertensive therapy cannot be generally recommended. However, their role is well established in situations where other drugs cannot be used or have been ineffective as monotherapy.

The practice of using rapid-release nifedipine to produce acute blood pressure reduction can rarely be justified. The original role of rapid-release nifedipine was in the management of angina. Although it still has marketing approval for this indication, its only real role is in the treatment of proven coronary artery spasm. The tablet and slow-release preparations of nifedipine also have marketing approval for the management of angina. Although the major use of amlodipine is as an antihypertensive, it is approved for the management of angina as it is the least likely of all the dihydropyridines to cause reflex-mediated cardiac stimulation. However, diltiazem would generally be preferred to amlodipine for angina because of its pharmacological profile. Felodipine does not have marketing approval for this indication.

Dihydropyridines can be used to treat peripheral vasospasm. This is useful in patients treated with beta blockers who develop Raynaud's phenomenon.

Are there any particular advantages of calcium channel antagonists?
Calcium channel antagonists may have a particular role in individuals who have conditions such as diabetes, airways disease, peripheral vascular disease and depression which limit treatment with some of the other classes of antihypertensives. The relative contraindications are the use of dihydropyridines as monotherapy in individuals with ischaemic heart disease and the use of verapamil and diltiazem in the presence of impaired myocardial function, impulse generation or cardiac conduction.

Calcium channel antagonists have no adverse metabolic effects on potassium or glucose homeostasis, renal function or lipids. They do produce a small uricosuric effect.

There are potential benefits from calcium channel antagonists which have been claimed on the basis of animal studies, but definitive evidence in humans is lacking. These benefits include reduction of cardiovascular hypertrophy in hypertension, reduction of atherosclerotic lesions, relative reduction of the size of any incident cerebral infarction and myocardial protection from ischaemic damage.

What are the problems with calcium channel antagonists?
Although the calcium channel antagonists can be very effective antihypertensive, antianginal or antiarrhythmic drugs if they are tolerated, their use may be limited by adverse effects which are predictable from their pharmacology (Table 2). The most prominent of these dose-dependent adverse effects are due to arterial dilatation. This can cause flushing, usually of the face but also of the legs, dull or throbbing headache and dependent oedema. While headache and flushing are less marked with the slow-release and longer-acting preparations, oedema is just as prominent. Some individuals complain of lightheadedness and nausea which may be associated with an excessive blood pressure reduction. Although these vasodilator adverse effects are more prominent with the dihydropyridines, they also occur to a variable extent with both verapamil and diltiazem. Treatment should be started with the lowest recommended dose of any calcium channel antagonist to assess tolerability and then gradually increase the dose to achieve the desired effect.

Pregnancy
Dihydropyridines should not be used early in pregnancy as they have been associated with limb bud defects in some animal species. Later in pregnancy they are effective antihypertensives which can be used either as monotherapy or in combination usually with a beta blocker or methyldopa. They do have a potential to prolong labour by relaxing uterine muscle.

Table 2 Adverse effects of calcium channel antagonists
Mechanism	Effects
Vasodilatation (especially dihydropyridines)	headache flushing dependent oedema hypotension dizziness nausea
Reflex cardiac effects (dihydropyridines especially rapid release preparations)	palpitations angina, infarction
Cardiac depression	depressed contractility depressed conduction
(verapamil, diltiazem)	adverse interaction with beta blockers
Other	constipation (verapamil) gum hypertrophy skin rashes hepatotoxicity (rare)

F U R T H E R - R E A D I N G
Katzung BG, Chatterjee K. Calcium channel blocking drugs. In: Katzung BG, editor. Basic and clinical pharmacology. 6th ed. Connecticut: Appleton & Lange, 1995:178-82.

Robertson RM, Robertson D. Drugs used for the treatment of myocardial ischaemia. In: Hardman JG, Limbird LE, editors. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill, 1996:759-79.

Victorian Drug Usage Advisory Committee. Cardiovascular drug guidelines. 2nd ed. Melbourne: Victorian Medical Postgraduate Foundation, 1995.