Tenoretic

Physicians in the 1950s and 1960s frequently treated hypertensive patients with combination therapy--reserpine and a diuretic (Hydropres, Diupres) or reserpine, hydralazine and hydrochlorothiazide (Ser-Ap-Es), among others. Goal blood pressure was achieved in a high percentage of patients with these regimens, and, if not, other medicines such as a ganglionic blocking agent or guanethidine (Ismelin) were added.[1] Although the dosages in the combination tablets were high by today's standards, most patients tolerated this approach to initial therapy without too much difficulty.

Since the 1970s and 1980s, however, an emphasis has been placed on monotherapy and "individualization of treatment." Some objections to initial combination therapy included increased cost, more side effects, loss of dosing flexibility and unsuitable pharmacokinetics.[2] Most pharmacology textbooks have discouraged fixed-dose combination therapy.[3] Many of the stated objections, however, have proved to be more theoretic than real. It is time to re-examine the fixed-dose combination approach to the treatment of hypertension.

Possible Advantages of Fixed-Dose Combinations

In most cases, the exact initial dosages of the drugs used in the management of hypertension are not critical, because the therapeutic and toxic dosages are quite different.[4] For example, the effectiveness and toxicity of a dose of 12.5 mg of hydrochlorothiazide (Esidrix, Hydrodiuril) or 5 mg of enalapril (Vasotec) differs little from 15 mg or 7 mg of each drug, respectively. Thus, the exact dose of each component in a combination need not be carefully defined. A higher percentage of patients responds to combination medication than to higher-dose monotherapy with any of the available antihypertensive agents. Fewer pills are necessary to produce the desired results; cost is generally not increased and actually may be reduced. Fewer office visits are necessary for dosage titration. Psychologically, patients feel better taking one or two pills per day than taking three or four. If relatively small doses of each component are incorporated in the combination, side effects may actually be decreased when compared with medium- or high-dose monotherapy.[5]

Recently, fixed-dose combinations of a low-dose bisoprolol-hydrochlorothiazide (Ziac) and betaxolol-chlorthalidone (Kerledex) were approved as initial once-a-day therapy for hypertension.[6] This approval by the U.S. Food and Drug Administration was based on studies demonstrating that the effects of the components of these drugs were additive, that side effects of the combinations were lower and that the percentage of responders was greater than with larger dosages of the individual components of the combination.[7] This approval of a combination as initial antihypertensive therapy may signal a new era in the management of hypertension (the betaxolol-chlorthalidone combination has not yet been marketed). A combination of an angiotensin-converting enzyme (ACE) inhibitor, captopril, and hydrochlorothiazide (Capozide) has also been approved for initial therapy primarily because the addition of the diuretic greatly extended the duration of action of the ACE inhibitor.

Effective Combinations of Antihypertensive Agents

Numerous combination therapies are effective (Figure 1), and many are now available or in research. Examples include the following:

[Figure 1 ILLUSTRATION OMITTED]

(1) ACE inhibitor-diuretic combinations such as captopril-hydrochlorothiazide, enalapril-hydrochlorothiazide (Vaseretic), lisinopril-hydrochlorothiazide (Prinzide), and benazepril-hydrochlorothiazide (Lotensin HCT);

(2) beta blocker-diuretic combinations such as propranolol-hydrochlorothiazide (Inderide), atenolol-chlorthalidone (Tenoretic), or bisoprolol-hydrochlorothiazide;

(3) an alpha blocker-diuretic combination (prazosin-polythiazide [Minizide]);

(4) calcium antagonist-ACE inhibitor combinations such as benazepril-amlodipine (Lotrel), felodipine-enalapril (Lexxel), diltiazem-enalapril (Teczem), and

(5) an angiotensin-II receptor antagonist ([AT.sub.1] blocker) and diuretic combination (losartan-hydrochlorothiazide [Hyzaar]).

All of these combinations make good physiologic sense, because the component medications act on different mechanisms important in the pathogenesis of hypertension.

Some combinations may be especially useful when hypertension coexists with other diseases. When cardiac function is depressed (congestive heart failure with a decreased ejection fraction), then the combination of an ACE inhibitor and a diuretic might be preferable. If diabetes mellitus is present, then the combination of a calcium antagonist and an ACE inhibitor may offer some added benefit, although other combinations, such as an ACE inhibitor and a diuretic, might also be used. If persistent angina is present, then adding a long-acting dihydropyridine calcium antagonist to beta-blocker therapy is logical (such a fixed-dose combination is not as yet available).

Recent Studies with Fixed-Dose Combinations

A recent study with one of the beta blocker-diuretic combinations (bisoprolol-hydrochlorothiazide) demonstrated that response rates (diastolic blood pressure of 90 mm HG or less or a decrease of 10 mm HG or more) were equal to or higher than with monotherapy with a calcium channel blocker, amlodipine (Norvasc), or an ACE inhibitor, enalapril (Figure 2).[8] In addition, side effects were significantly less, and systolic blood pressure lowering as well as diastolic blood pressure lowering was greater than with enalapril alone. This combination was effective in young and elderly, black and nonblack patients.[7,9] Studies have also shown that the combination of a diuretic with an ACE inhibitor[10] or angiotensin-II receptor antagonist[11] and the combination of an ACE inhibitor with a calcium antagonist all yield higher response rates and greater decreases in blood pressure than monotherapy.

[Figure 2 ILLUSTRATION OMITTED]

Not all combinations are safe or additive, however. The combination of a beta blocker and an alpha adrenoceptor agonist such as clonidine (Catapres) may not be additive and has the potential for a paradoxical increase in blood pressure and rebound hypertension on withdrawal. The combination of a beta blocker and an ACE inhibitor or of an alpha adrenoceptor agonist and an alpha blocker is not additive. There is some controversy as to whether the effects of a diuretic and a calcium antagonist are additive,[12,13] but our experience suggests that they are. One should be cautious about adding a beta blocker to verapamil (Calan) or diltiazem (Cardizem) because of the risk of bradycardia, heart block or heart failure. The combination of a calcium antagonist and an alpha blocker may cause excessive hypotension.

Is It Time for a Change in Strategy in Initiating Therapy?

All of the available combination therapies are effective on a once-a-day basis. Although the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC) has traditionally suggested one medication as initial monotherapy, the JNC V in 1993 did note that combinations are appropriate after specific dosages of individual drugs are determined.[14] Based on new studies with low-dose combination therapy, we may have reached a point where this approach might be considered appropriate initial treatment in many individuals with stage I hypertension, especially those with target organ involvement or in subjects with stage II or higher levels of blood pressure. The FDA has clearly defined why this approach might be suitable even in patients with less severe hypertension.[6] This is not an anti-academic approach and makes sense from a practical point of view. Recent data suggest that fewer than 50 percent of hypertensive patients who receive therapy have achieved good blood pressure control (systolic blood pressure of 140 mm Hg or less/diastolic blood pressure of less than 90 mm Hg).[14] The use of low-dose combination therapy should help to increase this number.

REFERENCES

[1.] Moser M, Mattingly TW. Critical evaluation of drug therapy of hypertension. Postgrad Med 1955;17:351.

[2.] Oster JR, Epstein M. Fixed-dose combination medications for the treatment of hypertension: a critical review. J Clin Hypertens 1987;3:278-93.

[3.] Fingl E, Woodbury DM. General principles. In: Goodman LS, Gilman A, eds. The pharmacological basis of therapeutics. New York: Macmillan, 1970:24-5.

[4.] Moser M. Low-dose diuretic therapy for hypertension. Clin Ther 1986;8:554-62.

[5.] Fagan TC. Remembering the lessons of basic pharmacology Arch Intern Med 1994;154:1430-1.

[6.] Fenichel RR, Lipicky RJ. Combination products as first-time pharmacotherapy. Arch Intern Med 1994; 154:1429-30.

[7.] Frishman WH, Bryzinski BS, Coulson LR, DeQuattro VL, Vlachakis ND, Mroczek WJ, et al. A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Arch Intern Med 1994; 154:1461-8 [published erratum appears in Arch Intern Med 1995;155:709].

[8.] Prisant LM, Weir MR, Papademetriou V, Weber MA, Adegbile IA, Alemayehu D, et al. Low-dose drug combination therapy: an alternative first-line approach to hypertension treatment. Am Heart J 1995;130:359-66.

[9.] Frishman WH, Burris JF, Mroczek WJ, Weir MR, Alemayehu D, Simon JS, et al. First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension. J Clin Pharmacol 1995;35:182-8.

[10.] Chrysant SG. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group. Arch Intern Med 1994;154:737-43.

[11.] MacKay JH, Arcuri KE, Goldberg AI, Snapinn SM, Sweet CS. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components. Arch Intern Med 1996;156:278-85.

[12.] Nicholson JP, Resnick LM, Laragh JH. Hydrochlorothiazide is not additive to verapamil in treating essential hypertension. Arch Intern Med 1989; 149:125-8.

[13.] Prisant ML, Carr AA. Calcium channel blockers as second-line therapy in thiazide-resistant hypertension [Letter]. Arch Intern Med 1990;150:1755.

[14.] The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993;153:154-83.

MARVIN MOSER, M.D. Yale University School of Medicine New Haven, Connecticut

L. MICHAEL PRISANT, M.D. Medical College of Georgia Augusta, Georgia

Dr. Moser is clinical professor of medicine at Yale University School of Medicine, New Haven, Conn., and senior medical consultant to the National High Blood Pressure Education Program of the National Heart, Lung, and Blood Institute. He was chairman of the first Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure and a member of the JNC in 1980, 1988, 1993 and 1997. Dr. Prisant is professor of medicine in the Section of Cardiology, Medical College of Georgia, Augusta, Ga.

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