Drug Combinations in the Treatment of Hypertension

Abstract

Not uncommonly, to effectively treat hypertension, multiple drugs must be given. Multidrug combinations that dominate clinical practice typically include a thiazide-type diuretic together with either an angiotensin-converting enzyme inhibitor, an angiotensin-receptor blocker, or less so a β-blocker. On the other hand, there are several approaches that can also incrementally reduce blood pressure (BP) but are used less regularly and, as such, go underappreciated as to their effectiveness. Such approaches may include within-class switching of diuretics, combining a thiazide-type diuretic with a calcium-channel blocker (CCB), using 2 CCBs from different subclasses, adding a peripheral α-blocker to an angiotensin-converting enzyme inhibitor, or tacking on an aldosterone receptor antagonist or nitrate therapy to any of several other drug classes. All of these presumably novel approaches offer useful options for treatment in the otherwise difficult-to-control hypertensive patient.1 These aforementioned fresh therapeutic approaches succeed in lowering BP based on the nature of the pharmacokinetic and pharmacodynamic interplay between select drug classes. A pharmacokinetic interaction that can be exploited clinically in the patient with difficult-to-treat hypertension is that of combining a dihydropyridine CCB, such as nifedipine, with a nondihydropyridine CCB, such as diltiazem or verapamil. The latter 2 compounds are known inhibitors of the cytochrome CYP3A4 isozyme. The dihydropyridine CCB nifedipine, as is the case for all CCBs, is extensively metabolized by CYP3A4 with little inhibitory effect on this isozyme itself. When nifedipine is combined with diltiazem or verapamil, the latter dose-dependently inhibits the clearance of nifedipine. This interaction occurs quickly, relates to the relatively steep dose-response relationship for nifedipine plasma levels and BP reduction when nifedipine is given in submaximal doses, and is nearly optimized within 3 days of …