MECHANISM OF ACTION

Calcium movement into cells is mediated by several mechanisms. Albrecht Fleckenstein showed that the calcium channels can be selectively blocked by a class of agents. He called these agents calcium antagonists. Calcium movement into the cells is mediated by several mechanisms. Calcium antagonists act at the plasma membrane to inhibit calcium entry into cells by blocking voltage-dependent calcium channels.

Calcium ions play an important role in the contraction of cardiac, skeletal, and smooth muscle. Myoplasmic calcium depends on calcium entry into the cell. Calcium binds to the regulatory protein troponin, removing the inhibitory action of tropomyosin. In the presence of adenosine triphosphate this allows the interaction between myosin and actin with consequent contraction of the muscle cell.

There are at least three different types of calcium channels designated as L, T, and N types. The L-type channels, once activated, remain for a long period of time and have a large calcium-carrying capacity. The T channels have a brief opening time and N channels have characteristics that are neither of the L nor T type. Only the L-type channels are sensitive to the action of calcium antagonists. The effect of the calcium antagonists is to restrict calcium entry, and over a given period of time fewer calcium ions are available for participation in intracellular events such as muscle contraction and neuronal activity. Thus some have labeled these compounds calcium channel blockers, calcium channel antagonists, calcium entry blockers, and slow calcium blockers. Calcium antagonists differ from one another in terms of their potency, tissue selectivity, and duration of action. The calcium antagonists available for clinical use are mainly L-type channel blockers. The T channel appears at more negative potentials and seems to play a role in the initial depolarization of the sinus node and atrioventricular (AV) node tissue. Mibefradil, a T channel blocker, caused bradycardia and a host of adverse effects that caused the drug’s premature withdrawal from the market.

The three major calcium antagonists include nifedipine, diltiazem, and verapamil. Dihydropyridine, the prototype of which is nifedipine, appears to act by plugging the calcium channels. These agents cause dilation of coronary arteries and marked peripheral arteriolar dilatation resulting in a profound fall in blood pressure. There is little or no action on the sinoatrial (SA) node and conducting tissue. Verapamil and diltiazem are phenylalkylamines and benzothiazepines. They cause distortion of calcium channels and coronary artery dilation, but there are additional effects on the SA and AV nodes. These agents also have a negative inotropic effect and decrease myocardial contractility. Thus, the dihydropyridines, phenylalkylamines, and benzodiazepines have vastly different actions. For example, only amlodipine and felodipine, of the dihydropyridine family, have proved relatively safe in patients with left ventricular dysfunction and heart failure. Other agents may precipitate heart failure.

AVAILABLE CALCIUM ANTAGONISTS

Dihydropyridines
These agents cause dilation of arteries throughout the body including mild dilatation of coronary arteries. They also cause a variable decrease in myocardial contractility that may lead to heart failure in susceptible individuals. Dihydropyridines include amlodipine, felodipine, and, nifedipine. They are indicated for the management of hypertension. They may also be used for the treatment of stable angina, but only in combination with a betablocking drug that prevents an increase in heart rate and the increase in cardiac workload that may be caused by dihydropyridines. The common adverse effects include edema of the ankles, flushing, headaches, and rarely, hypertrophy of the gums. Other dihydropyridines include isradipine, nicardipine, nimodipine, nitrendipine, and niludipine.

1. Amlodipine (Norvasc)
This dihydropyridine has a long half-life of 35–50 h and peak blood levels are reached after 6–12 h. Amlodipine is an effective antihypertensive agent that is used worldwide. It has a good safety profile but pulmonary edema (heart failure) may be precipitated in patients with severe left ventricular dysfunction and ejection fraction of less than 30%. Edema of the ankles, feet, and lower leg may be bothersome in about 10% of treated patients. This drug is often combined with a beta-blocker in the management of angina. The dose for angina or hypertension is 5–10 mg once daily.

2. Felodipine (Plendil)
This dihydropyridine has actions, effects, and indications that are similar to amlodipine. The dose for hypertension is 2.5–5 mg daily with a maximum dose of 10 mg.

3. Nifedipine (Procardia, Adalat XL)
Nifedipine is the first calcium antagonist used in clinical practice. It was introduced during the early 1980s for the management of hypertension, angina, and particularly coronary artery spasm (variant angina) and is still used worldwide. The drug is an excellent antihypertensive agent. Headache, edema of the ankles, and facial flushing occur in about 15% of patients. Although introduced for the management of angina, like other dihydropyridines, the drug should be used only for stable angina in patients who are also administered a beta-blocker. For the management of coronary artery spasm (Prinzmetal variant angina), the drug can be used without beta-blockers, which are contraindicated in this condition. Short-acting capsule or tablet formulations of nifedipine are no longer recommended because an increase in morbidity and mortality has been reported in patients with coronary artery disease. The slow-release once daily formulation is now used worldwide at a dose of 30–60mg once daily. The maximum dose of 90 mg shoul be used with caution.

Benzothiazepines
Diltiazem
Diltiazem is a mild arteriolar vasodilator. It is a widely used calcium antagonist because its safety profile is good. The blood pressure lowering effect of this benzothiazepine is not as powerful as the dihydropyridines, and a large dose is usually required to obtain a satisfactory antihypertensive
effect. Diltiazem has a milder action than the dihydropyridines and causes less vasodilatation of arteries; thus it is a week antihypertensive agent. The drug causes some decrease in myocardial contractility and heart failure may be precipitated in patients with left ventricular dysfunction or in patients who are administered a beta-blocking drug concomitantly.

Most important, the drug inhibits electrical conduction through the AV node. It is useful for the management of supraventricular tachycardias by slowing rapid heart rates that may occur with atrial fibrillation. Unfortunately, this drug causes some suppression of the sinus node and normal pacemaker activity and may cause bradycardia. It should be avoided in patients with sick sinus syndrome and heart failure. Adverse effects include increased liver function tests, increased transaminases, and constipation, but headache and edema of the ankles are less common than with the dihydropyridines.

Important interactions occur with digoxin, and digoxin levels may be increased by about 33%. Diltiazem combined with amiodarone may produce deleterious effects on the sinus pacemaker causing arrest and hypotension. Interactions have been noted with cyclosporine, cimetidine, and carbamazepine.

The short-acting tablet formulation of diltiazem is not recommended. Long-acting and slow-release formulations are administered 180 mg to a maximum of 300 mg once daily.

Phenylalkylamines
Verapamil
Verapamil is a moderately potent vasodilator. Two major differences between the actions of verapamil and the dihydropyridines include a major depressant effect on the AV node and a mild depressant effect on the SA node. Also, depression of myocardial contractility for verapamil is considerably more than the maximum effect observed for dihydropyridines. This marked negative inotropic effect may precipitate heart failure in patients with left ventricular dysfunction and an ejection fraction less than 40%. Because of this effect, verapamil should not be combined with a beta-blocking agent.

The electrophysiologic effect of mild depression of conduction through the AV node makes the drug effective in the management of supraventricular tachycardia. Given intravenously, verapamil was used worldwide for the management of this condition from 1984 to 1996 and has now been relegated to second choice behind adenosine. Verapamil is indicated for the management of hypertension and for angina, particularly when beta-blockers
are contraindicated. It is also used for the management of coronary artery spasm. The intravenous preparation is indicated for supraventricular tachycardia. Doses of 120–240 mg sustained-release, long-acting preparations are advised once daily.

Verapamil is contraindicated in patients with bradycardia (a heart rate of <60) and those with disease of the from baseline. These agents may precipitate pulmonary edema in patients with left ventricular dysfunction. Next generation agents include lercanidipine, lacidipine, and manidipine. These dihydropyridines have important and subtle differences when compared with second and third generation dihydropyridine calcium antagonists. Lercanidipine has been shown to have major advantages over amlodipine. Because the drug dilates both afferent and efferent arterioles, the high incidence of peripheral edema caused by older calcium antagonists is reduced more than 50%. The balanced effect of lercanidipine and manidipine on efferent and afferent arterioles is important in renal protection. The older calcium antagonists listed above dilate only afferent arterioles. The COHORT study of elderly hypertensive patients concluded that lercanidipine and lacidipine are much better tolerated than amlodipine.

Recent investigations indicate that lercanidipine administered to hypertensive diabetic patients is more effective than the angiotensin receptor blocker, losartan, in reducing left ventricular hypertrophy and left ventricular mass. These third generation dihydropyridines represent an important addition to the therapeutic armamentarium. Their place in clinical practice will increase further if they are shown to be devoid of the major adverse effect of all calcium antagonists — the precipitation of heart failure in patients with significant left ventricular dysfunction.