High Blood Pressure / Hypertension

Calcium channel blockers

By Cardiologist on July 7th, 2011

Pharmacology and mechanism of action

Sustained contraction of blood vessels is a major determinant of peripheral vascular resistance. Because the intracellular concentration of calcium is critical in determining the extent of vascular smooth muscle contraction, it is not surprising that drugs that inhibit calcium entry into vascular smooth muscle cells can play an important role in the treatment of hypertension. Although the mechanisms of action are not completely understood, these drugs inhibit the entry of calcium ions into smooth muscle cells by blocking voltage-gated L-type (i.e., late) calcium channels (also simply called L channels). In addition, some of these drugs antagonize entry of calcium into cardiac myocytes and cells in the conduction system of the heart; these actions contribute to negative inotropic effects and alterations in cardiac conductance. See Table Calcium Channel Entry Blockers for general properties of many available calcium-entry blockers.

The first clinically available calcium-entry blocker, namely verapamil, is a congener of papaverine. Many other calcium-entry blockers are now available and have a wide range of structures. The largest group, which includes amlodipine, felodipine, isradipine, nicardipine, and nifedipine, is called dihydropyridines.Interestingly, these different structures lead to differences in their sites and modes of action on calcium entry for reasons that are not well understood. Intracellular calcium flux is a final common path for a spectrum of cellular responses to a variety of stimuli. Given that the molecular basis of calcium channels is quite heterogeneous, coupled with the chemical heterogeneity of available calcium channel blockers, the pharmacologic similarities of presently available compounds may be more apparent than real (see clinical use and adverse effects below). The latest addition to the calcium channel blocker class acts mainly on so-called T-type (i.e., transient) calcium channels (also simply called T channels), which are distinct from the L channels blocked by other agents described below. The index T-channel blocker is mibefradil, a compound that is structurally unrelated to the other three major groupings typified by verapamil, nifedipine, and diltiazem.

Verapamil can have marked negative inotropic (contractility), chronotropic (heart rate), and dromotropic (atrioventricular node conduction) actions compared with many other calcium-entry blockers. Nifedipine is a relatively selective peripheral smooth muscle dilator. On the other hand, diltiazem lies somewhere in between these two drugs in terms of balance of effects on the heart versus peripheral vasculature. These differences can be exploited by choosing the most appropriate calcium channel antagonist for individual patients. Calcium-entry blockers typically dilate renal arteries, increasing renal blood flow, glomerular filtration rate, and filtration fraction. This combination of effects contributes to a mild diuretic and natriuretic effect. Mibefradil acts predominantly as a vasodilator, but the reflex tachycardia observed with dihydropyridines is blunted by the ancillary property of blocking T channels on the adrenal that blunts sympatho-adrenal activation and by T-channel blockade on the atria that prevents reflex tachycardia. There is usually mild bradycardia, slowing heart rate by 2–5 beats per minute. At usual doses, mibefradil has minimal impact on the L channels on ventricular myocardium, and the usual cardiodepressant effect of L-channel blockers is not observed. However, mibefradil has been withdrawn from the market because of liver toxicity.

For some calcium channel blockers such as nifedipine, prompt-release formulations lead to rapid increases in drug concentration that have relatively short durations. The peak in concentration has been associated with prompt reductions in peripheral vascular resistance and blood pressure that may be associated with reflex tachycardia. There is epidemiological evidence suggesting that use of this type of formulation of nifedipine is associated with potentially adverse outcomes, especially in patients with coexisting ischemic heart disease. In any event, short-acting calcium-entry blockers used in rapid-release formulations require multiple doses (three or more) per day to provide relatively stable control of blood pressure. Based on available evidence, there does not appear to be a role for short-acting formulations of calcium-entry blockers in the treatment of hypertension. Rather, either long-acting (extended or sustained release) formulations or drugs with intrinsic long half-lives, such as amlodipine, are more efficacious and probably safer for treating primary hypertension. Interestingly, the bioavailability of some dihydropyridines may be potentiated by the consumption of grapefruit juice. The interaction is most striking when the calcium channel blocker, such as felodipine, undergoes substantial first-pass metabolism in the small intestine by cytochrome P450 metabolism (CYP3A4) that is impaired by as yet unidentified substances in the grapefruit juice.

Clinical use and adverse effects of calcium channel antagonists

In comparison with other classes of drugs used as monotherapy for hypertension, calcium-entry blockers have similar capacities as antihypertensive agents. Calcium channel blockers are effective when combined with β-adrenergic antagonists and Angiotensin-converting enzyme inhibitors. Verapamil combined with a β-adrenergic antagonist therapy is more effective in lowering blood pressure than either drug alone. However, as might be expected, the two drugs may have additive effects on the progesterone receptor interval seen on the electrocardiogram. As a consequence, this combination should generally be avoided. Because calcium channel blockers have other clinical uses, they are ideal in certain two-for-one situations.

Many of the adverse effects caused by calcium channel blockers can be predicted from the differences in pharmacologic effects of the different chemical entities. Because nifedipine acts rapidly, especially when given as liquid-containing capsules, symptomatic hypotension and/or orthostatic hypotension can occur and can be associated with rapid heart rate. The practice of breaking nifedipine capsules to speed drug delivery may exacerbate these adverse effects. Indeed, there is no evidence that this approach to administering nifedipine has efficacy in preventing clinically significant endpoints but may increase the risks of adverse events and unpredictable reductions in blood pressure, especially in patients with severe hypertension or coronary artery disease. Bradyarrhythmias and conduction disturbances are more common with verapamil and to a lesser degree with diltiazem. The arrhythmias are particularly prominent when verapamil is taken in combination with other negative chronotropic and dromotropic agents such as β-adrenergic antagonists, quinidine, or digitalis.

Some calcium-entry blockers (e.g., verapamil) may worsen heart failure by virtue of their adverse effects on systolic myocardial function. However, other members of this class, such as amlodipine and felodipine, have small or negligible negative inotropic effects (see Table Calcium Channel Entry Blockers). Although these drugs seem to preferentially relax vascular smooth muscle, relaxation of smooth muscle in other organs can lead to esophageal reflux or urinary retention. Constipation is especially common with verapamil and is unusually most prominent in patients with an underlying tendency toward constipation. Ankle edema can occur, especially with nifedipine. This may be secondary to hemodynamic alterations across the capillary, changing Starling forces to favor movement of fluid from the capillary into the interstitium. Because the edema is local and not associated with renal salt and water retention, diuretics are of little use. The adverse effect of ankle edema should not be clinically confused with the development of congestive heart failure. These drugs tend to be neutral in their effect on lipid profiles. In fact, an antiatherosclerotic effect has been reported in animal models, although the significance of these findings for human disease is unclear.

Recommendations

Calcium channel blockers are effective as first-line therapy, especially in patients for whom diuretics and β-adrenergic antagonists are contraindicated. Calcium channel blockers are useful for hypertensives with other associated conditions (e.g., angina pectoris, atrial tachyarrhythmias) in which the two-for-one concept can be exploited. They are very useful as alternatives for β-adrenergic antagonists in patients for whom those agents are contraindicated (e.g., patients with asthma), especially patients with angina.

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