Pharmacotherapy Review: Calcium Channel Blockers

Abstract

As a drug class, calcium channel blockers encompass a heterogeneous group of compounds with distinctive structures and pharmacologic characteristics. These agents are widely used in the treatment of hypertension, chronic coronary ischemia, and/or supraventricular arrhythmias. Much of the early debate alluding to increased cardiovascular risk associated with calcium channel blocker use has been silenced by an array of outcomes trials that show these drugs to be both safe and effective in reducing hard cardiovascular end points. The most common side effects associated with calcium channel blockers are vasodilatory in nature and include a non‐volume‐dependent form of peripheral edema, flushing, and headache. Despite the sometimes discomforting side effects seen with calcium channel blocker therapy, their robust blood pressure‐lowering effect makes them an important component of most multidrug regimens used for blood pressure control.

Ten calcium channel blockers (CCBs) are now marketed in the United States. These agents are used for the treatment of a host of cardiovascular diseases, including hypertension, angina, and/or supraventricular arrhythmias. Nimodipine is approved for short‐term use in patients having experienced a subarachnoid hemorrhage and is the only CCB not indicated for the treatment of hypertension. Diltiazem, nicardipine, and verapamil are the only CCBs currently offered in intravenous formulations and that provide short‐term options for blood pressure (BP) and rate control in the hospitalized patient. The chronic treatment of hypertension with a CCB generally occurs with long‐acting compounds. Short‐acting, immediate‐release CCBs are useful therapies in the special circumstance patient, such as the patient with labile hypertension or the patient who requires pill crushing before ingestion (Table).

Table.

Considerations for Calcium Channel Blocker (CCB) Use in Hypertension and End‐Organ Disease

In most patients, the upward dose titration of a CCB can be expected to provide a recognizable reduction in blood pressure.

The antihypertensive response to a CCB improves with the addition of all antihypertensive drug classes including diuretics.

In the United States, the only fixed‐dose combinations available with a CCB contain an angiotensin‐converting enzyme (ACE) inhibitor. Beta‐blocker and CCB fixed‐dose combinations are available outside the United States.

CCBs are a useful component of multidrug regimens for patients with otherwise resistant hypertension, such as patients with diabetes or renovascular disease.

In hypertensive patients with metabolic abnormalities, including insulin resistance and/or hypercholesterolemia, glycemic or lipid control is not adversely affected by drugs in this class.

Black hypertensives as a group respond particularly well to monotherapy with a CCB, whereas they may respond less predictably to monotherapy with drug classes such as β blockers, ACE inhibitors, or angiotensin receptor blockers.

CCBs should not be used as monotherapy in patients with type 2 diabetic nephropathy and are to be avoided in patients with systolic forms of heart failure.

The side‐effect profile with CCBs is an important element in dose titration and adherence to therapy. Vasodilator side effects such as flushing and peripheral edema are common with dose titration of drugs in this class. CCB‐related peripheral edema is attenuated by coadministration of an ACE inhibitor.

GUIDELINES

The Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and numerous other international guideline‐promulgating groups currently endorse CCBs as an initial therapy option in patients with essential hypertension. A surfeit of drugs in this class has led most formularies to include several CCB options; however, a price hierarchy often exists, with cheaper drugs in this class often having a preferred formulary status.

CLASS HETEROGENEITY

CCBs are a heterogeneous group of compounds with distinctive structures and pharmacologic effects, which explains the differing responses noted with these agents. There are three distinct subclasses of CCBs: phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), and dihydropyridines (e.g., nifedipine, amlodipine, isradipine). All CCBs are vasodilators, and therein lies their capacity to decrease BR The vasodilator potency of CCBs varies according to subclass, with dihydropyridine‐type compounds being comparably more potent than the phenylalkylamine and benzothiazepines groupings.

Dihydropyridine CCBs have variable effects on heart rate. Acutely, these drugs tend to induce a reflex tachycardia, but long‐term studies show similar heart rates before and during therapy. Higher doses of these drugs are generally associated with an increase in heart rate. Dihydropyridine CCBs are less likely than nondihydropyridine CCBs to reduce cardiac output. Nondihydropyridine CCBs may decrease pulse rate by as much as 10% and can have a negative inotropic effect.

These intraclass differences amongst CCBs can be exploited in the course of BP management; hence, using CCBs from different groups results in additive effects in the treatment of hypertension. A pharmacokinetic interaction is an important contributing feature to the complementary response of different CCB subclasses. CCBs, such as diltiazem and verapamil, are known inhibitors of the cytochrome P₄₅₀ system and will slow the metabolism of dihydropyridine CCBs (drugs biotransformed by CYP3A4), leading to higher‐than‐expected blood levels at any specific dose.

PREDICTORS OF RESPONSE

All patient groups are to some degree responsive to CCB monotherapy; however, there are no reliable predictors of the magnitude of the BP reduction to a CCB. Diabetic and black hypertensives who are low renin, salt‐sensitive, and volume‐expanded are more often responsive to a CCB than to an angiotensin‐converting enzyme (ACE) inhibitor or a β blocker. CCBs differ from ACE inhibitors and angiotensin receptor blockers (ARBs) in that their BP‐lowering effect is not enhanced with sodium restriction. Although gender has not been viewed as an important factor in the response to antihypertensive agents, oral verapamil is not as well cleared in women and plasma concentrations (and effect) are higher in women at comparable doses.

The elderly generally respond well to CCBs, although not necessarily any more so than younger hypertensives. The prior belief that elderly hypertensives were more responsive to CCB monotherapy than were young hypertensives was more perception than reality. A recognized feature of the response to a CCB is that the higher the BP at initiation, the greater the reduction in BP with CCB treatment; thus, the greater systolic BP elevations typically seen in the elderly (compared with the young) provided a higher starting point for treatment and an opportunity for larger reductions in BP. Aging, secondary to the age‐related decrease in hepatic blood flow, slows the metabolism of several CCBs; therefore, at the same medication dose, older hypertensives may see higher plasma levels (with a greater effect) than younger individuals.

MONOTHERAPY DOSING CONSIDERATIONS

CCBs are considered an appropriate first‐step option in a variety of hypertensive types. The underpinnings of support for drugs in this drug class reside in their strong BP‐lowering ability. Response rates with CCBs are in excess of 50% in stage I or II hypertension. Ethnicity and the level of sodium intake have little bearing on the overall effect of CCBs. There is little, if any, difference in BP‐lowering potency between the various CCBs, provided that comparable doses are given. Although sudden discontinuation of a CCB does not result in rebound hypertension, occasionally a patient may experience an exacerbation of ischemic heart disease symptoms with rapid drug withdrawal.

Since most patients are responsive to CCB monotherapy, the dosing questions that arise with their use include how high to titrate the dose before adding a second antihypertensive drug class and whether drugs in this class work better when given twice daily. The response to increasing the dose of a CCB is generally that of significant additional BP reduction, which separates this drug class from both ACE inhibitors and ARBs; however, such dose titration comes with a greater number of side effects. CCB‐related side effects often serve as the trigger for drug discontinuation, dosage reduction, and/or addition of a second drug class. Split dosing of a CCB does not necessarily ensure a better overall response or less prominent side effects than full‐dose, once‐daily administration.

An additional question with CCB therapy is how specific delivery systems influence the observed BP‐lowering response. CCBs are available in immediate‐, sustained‐, and delayed‐/sustained‐release formulations. Immediate‐release dihydropyridine CCB use has all but stopped owing to serious dose‐dependent adverse hemodynamic effects. Immediate‐release forms of verapamil, and more so diltiazem, are still used occasionally, but compliance suffers with their use because multiple daily doses are required for the treatment of hypertension or chronic angina. However, immediate‐release forms of verapamil and diltiazem are useful for the occasional patient who requires carefully titrated doses of either compound.

CCBs are available in various sustained‐release delivery systems. Understanding the uniqueness of specific delivery systems is important if a patient is to maximally benefit from the chosen therapy. For example, the gastrointestinal therapeutic system used for nifedipine is rigid. If bitten into, it can chip teeth and possibly obstruct the gastrointestinal tract if it lodges at an intestinal stricture. The coat‐core system used with nisoldipine has a hydrophilic gel surrounding the active drug. It must be swallowed whole since crushing the tablet acutely dose dumps, giving rise to immediate drug exposure with the potential for overly rapid vasodilation.

Another type of CCB formulation employs a delayed‐ and sustained‐release chronotherapeutic delivery system. These products have been developed for nocturnal administration and have a several‐hour delay before drug absorption begins. These systems synchronize the delivery of the BP drug to coincide with the morning rise in BP and have also shown the ability to maintain adequate BP levels during the trough period which, in this case, occurs at bedtime.

CCB COMBINATION THERAPY

CCBs complement the BP‐lowering ability of all drug classes and work in salt‐sensitive as well as salt‐resistant forms of hypertension. For example, adding a peripheral α antagonist, a β blocker, an aldosterone receptor antagonist, a thiazide‐type diuretic, and/or an ACE inhibitor (or ARB) to a CCB regimen can further reduce BP. Also, the combination of two different CCB subclasses additively reduces BP.

Beta blockers and CCBs interact by complementary hemodynamic mechanisms, with the CCB lessening the α‐adrenergic reflex vasoconstriction induced by β blockers and the β blocker at least, in part, acting through a reduction in cardiac output. In addition, particularly in the instance of the dihydropyridine CCBs, the β‐blocker component of such a fixed‐dose combination product will minimize the adverse hemodynamic effects of CCB‐related activation of the sympathetic and renin‐angiotensin axes. Combinations utilizing these two drug classes generally have not employed nondihydropyridine CCBs because of concern for an excessive effect on sinus and atrioventricular nodal function.

It has been suggested that thiazide‐type diuretics have an additive effect on BP reduction with all drug classes other than CCBs. It was first believed that the natriuretic effect of CCB therapy effectively substituted for that of a thiazide‐type diuretic; thus, if both drug classes were given together, the volume/vasodilator axis might be redundantly interrupted. This has not proved to be the case, and a significant number of trials have shown that thiazide‐type diuretics complement the antihypertensive effect of both dihydropyridine and nondihydropyridine CCBs. In assessing the additivity of a thiazide‐type diuretic with a CCB, a sequence effect may exist. When a CCB is added to a diuretic, the antihypertensive effect is clearly greater; conversely, when the order of administration is reversed, the potentiation is less evident.

A CCB and ACE inhibitor combination is generally more effective at controlling hypertension than either component given as monotherapy and is as effective as a number of other fixed‐dose combination therapies. Typically, the CCB component of these fixed‐dose combinations is more long‐acting and is the main determinant of duration of effect. Also, CCBs are intrinsically natriuretic and will induce a state of negative sodium balance, which can further enhance the antihypertensive effect of an ACE inhibitor.

The CCB combined with an ACE inhibitor may interpose a different mechanistic basis for the observed antihypertensive effect. As such, when a dihydropyridine CCB is given together with an ACE inhibitor, the latter may attenuate the dose‐dependent sympathetic activation that occurs with a dihydropyridine CCB (Table). Alternatively, when a nondihydropyridine CCB is combined with an ACE inhibitor, the observed response does not involve any such reciprocating actions.

Several fixed dose antihypertensive combination products, which contain an ACE inhibitor and a CCB, are available worldwide with only three such combinations available in the United States. Of these three products, two contain a dihydropyridine CCB (amlodipine/benazepril and felodipine/enalapril) and the other, a nondihydropyridine CCB (verapamil/trandolapril). There have been limited head‐to‐head comparisons of these combination products.

OUTCOMES CONSIDERATIONS

Where do CCBs now stand from an outcomes perspective? A recent analysis of data from nine randomized trials comparing different treatment approaches in 62,605 hypertensive patients found that CCBs afforded comparable degrees of cardiovascular protection as diuretics and β blockers. In addition, a recent meta‐analysis published by the Blood Pressure Lowering Treatment Trialists' Collaboration group ⁵ observed that a CCB‐based treatment regimen lowered the rate of stroke by 7% (compared with diuretic‐/β blocker‐based regimens) and 12% in contrast with ACE inhibitor‐based regimens; however, it was also shown that CCBs were less beneficial than diuretics, β blockers, or ACE inhibitors in the prevention of heart failure.

Dihydropyridine CCBs should not be used as monotherapy in patients with hypertension and proteinuria. It remains to be determined to what extent the detrimental renal effects of dihydropyridine CCBs are blocked when combined with either an ACE inhibitor or an ARB. Thus, CCBs are far from being optimal antihypertensive drugs, but they are important tools in continuing the efforts to control hypertension. After a decade of largescale studies, these drugs now exhibit extensive efficacy and an improved safety profile and have properly come of age.

SIDE EFFECTS

CCB use can be associated with vasodilator side effects as well as other troubling side effects such as polyuria, gastroesophageal reflux, and/or gingival hyperplasia. Peripheral edema, however, is the CCB‐related side effect that most commonly has an impact on the continued use of these drugs. Its etiology relates to a disproportionate change in arteriolar resistance whereby precapillary hydrostatic pressures increase, which then favors fluid shifting into the interstitial compartment. CCB‐related edema is more common in women and relates to upright posture, age, and the choice and dose of the CCB. Once present, it can be slow to resolve without intervention.

A number of strategies exist to treat CCB‐related edema including switching CCB classes, dosage reduction, and/or addition of a known venodilator such as a nitrate, an ACE inhibitor, or an ARB to the treatment regimen. ACE inhibitors have been best studied in this regard. Diuretics may alter the edematous state somewhat, but at the expense of reducing plasma volume. Finally, traditional measures, such as limiting the amount of time that a patient is upright and/or consideration of graduated compression stockings, are useful adjunctive therapies. When all else fails, CCB therapy can be discontinued and an alternative antihypertensive therapy given.

CONCLUSIONS

CCB therapy has an established role in the management of hypertension either as monotherapy or in combination with other antihypertensive drug classes. CCBs generally reduce BP more so than other drug classes. Among CCBs, there appears to be some difference in relative efficacy of the compounds making up this class which, for the most part, relates to half‐life and drug delivery system characteristics. Monotherapy with a dihydropyridine CCB does not provide optimal protection against heart failure and/or chronic kidney disease. Alternatively, use of compounds in this class favorably impact both stroke and coronary artery disease‐related events.