Drug Combinations in the Treatment of Hypertension

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 -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 -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 dosing.2 Another such pharmacokinetic interaction of some clinical use is that of combining verapamil with eplerenone, with the former inhibiting the CYP3A4-mediated metabolism of eplerenone.3 This can be viewed as the “poor man’s” way of reaching higher plasma levels of eplerenone without incurring the substantial cost of higher prescribed doses of the “pricey” eplerenone. Drug-drug interactions that display pharmacodynamic additivity for BP lowering most typically rely on 1 drug blocking counterregulatory responses prompted by the other; this has been the basis for the development of a number of fixed-dose antihypertensive combinations.4 Acute and chronic BP reductions often activate an interlinked series of mechanisms designed to restore BP. Reflex increases in cardiac output, peripheral vasoconstriction, and salt/water retention can result from baroreflex-mediated activation of the sympathetic nervous and renin-angiotensin systems (RASs). This pattern of response is illustrated by the greater reduction in BP when a vasodilating drug, such as hydralazine or minoxidil, is coadministered with a pulse ratecontrolling compound, such as a -blocker or a diuretic. An additional and very popular drug-drug interplay, used to good effect in the treatment of hypertension, is that of combining a volume-depleting drug, such as a thiazide-type diuretic, with a compound that interferes with RAS activity. The mechanism by which a diuretic enhances the BP-reducing effect of a RAS inhibitor relates to the induced volume changes and thereby the creation of a system sensitized to RAS inhibition. A final consideration in how a patient with difficult-to-treat hypertension is brought to goal BP relates to the guesswork in choosing the first 1 or 2 medications in a treatment regimen. In that regard, the common failure of the first or second medication selected for the treatment of hypertension relates to the fact that many patients have their hypertension mediated by excess activity of the -adrenergic system or the aldosterone axis. Because drugs that block the -adrenergic system, such as doxazosin, and the aldosterone system, such as spironolactone or eplerenone, are viewed as fourthor fifth-line therapies, the truly effective therapy for a patient’s hypertension is often added only as a last resort.5 In point of fact, either of these drug classes might have been the primary hypertension therapy in such patients if chosen initially. In uncovering the effectiveness of either of these drug classes, other minimally effective compounds in an existing regimen can be removed and the patient’s designation as being “resistant” or “difficult to treat now dropped. It is into this cluttered therapeutic arena for resistant or difficult to treat hypertension that the combination of a nitrate and a phosphodiesterase type 5 inhibitor tries to gain entry. Oliver et al6 are to be commended for the cleverness with which they deploy an established adverse drug-drug interaction in a proof-of-concept study to show that BP can be lowered in treatment-resistant hypertensives. The authors are quite careful to point out the many issues that remain to be The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Nephrology, Virginia Commonwealth University Health System, Richmond, Va. Correspondence to Domenic A. Sica, Clinical Pharmacology and Hypertension, Virginia Commonwealth University Health System, Richmond, VA 23298-0160. E-mail [email protected] (Hypertension. 2010;56:22-23.) © 2010 American Heart Association, Inc.