Combination Calcium Channel Blocker Therapy in the Treatment of Hypertension

In This Article

Abstract and Introduction

Effective control of blood pressure is usually achieved only with the use of two or more antihypertensive medications. The treatment options for hypertension are numerous, and the number of possible combinations large. The selection of a specific combination drug regimen has often been linked to the perceived need for diuretic therapy as first- or second-step therapy; thus, the popularity of such drug combinations as an angiotensin-converting enzyme (ACE) inhibitor/diuretic, an angiotensin-receptor blocker/diuretic, or a b blocker/diuretic. Rational alternatives exist, including an ACE inhibitor/calcium channel blocker (CCB) or a dihydropyridine CCB/b blocker combination. Traditionally, recommendations have advised against the use of combination therapy with two drugs from the same therapeutic class. However, because of the different binding and pharmacologic characteristics of CCBs, a rationale exists for combining different agents in this class in the management of hypertension and/or symptomatic coronary artery disease. In the treatment of either hypertension or angina, combination CCB therapy can prove uniquely successful.

Ten calcium channel blockers (CCBs) are currently marketed in the United States. These agents are employed in the treatment of hypertension, angina, and/or supraventricular arrhythmias. Nimodipine is approved for short-term use in patients who have suffered a subarachnoid hemorrhage. Diltiazem, nicardipine, and verapamil are the only CCBs currently available in intravenous formulations. Long-term treatment with CCBs is typically by the oral route. Long-acting CCBs are now the preferred mode of therapy in the treatment of hypertension and/or angina when a CCB is opted for (Table 1).[1]

CCBs are a heterogeneous group of compounds, with distinctive structures and pharmacologic properties. There are three distinct subclasses of CCBs, which explains the differences observed with these agents. These subclasses are the phenylalkylamines (e.g., verapamil), the benzothiazepines (e.g., diltiazem) and the dihydropyridines (e.g., nifedipine, amlodipine, felodipine). All currently available CCBs are vasodilators and thereby reduce blood pressure. The relative potency of CCBs as vasodilators varies, with dihydropyridine-type compounds, such as nifedipine, regarded as the most potent subclass, and verapamil, diltiazem, and bepridil as somewhat less potent.

In vitro, several calcium antagonists (e.g., nifedipine, nisoldipine, and isradipine) bind with some selectivity to the L-type calcium channel present in blood vessels, whereas verapamil binds equally well to cardiac and vascular L-type calcium channels.[2,3] The applicability of these in vitro findings to treatment response in humans remains ill-defined. In vitro, all CCB subclasses both depress sinus node activity and slow atrioventricular conduction. Only verapamil and diltiazem delay atrioventricular conduction or cause sinus node depression at doses in common use clinically.[1] Similarly, all CCB subclasses exhibit a concentration-dependent negative inotropic effect in vitro, but only verapamil and diltiazem do so in vivo. The disparities between the in vitro and in vivo effects may relate, in part, to the sympathetic activation triggered by dihydropyridine-induced vasodilation, which blunts any direct negative chronotropic and inotropic effects.