Nifedipine in Combination Therapy for Chronic Hypertension

A Review

LARS-G&AN EKELUND, M.D. Durham, North Carolina

Results are presented from a study conducted in twelve male pa- tients with hypertension who were treated during alternating one- month periods with a calcium channel blocker, a beta blocker, or a combination of both drugs. After one month of placebo therapy, the patients received 10 mg of nifedipine three times daily, 100 mg of metoprolol twice daily plus 10 mg of nifedipine three times daily, or 100 mg of metoprolol twice daily during successive periods. Nifedi- pine monotherapy resulted in a significant decrease in both systolic and diastolic blood pressures at rest and in systolic blood pressure during exercise. Monotherapy with metoprolol also significantly reduced systolic blood pressure during exercise. Combination ther- apy with the calcium channel blocker and the beta blocker produced a significantly greater decrease in both resting and exercise blood pressures than with either drug alone, with achievement of ade- quate blood pressure control in all patients.

Calcium channel blockers, notably nifedipine, have been used success- fully in combination with other antihypertensive drugs as second-line agents in the treatment of hypertension, or as third-step agents in refrac- tory cases of hypertension [l-4]. Why combine a calcium channel blocker with another antihypertensive agent? Theoretically, it would ap- pear to be easier to increase the dose of the calcium channel blocker since there is a linear relationship between dose and blood pressure re- duction with these agents.

One reason to combine nifedipine with a beta blocker is because of the compensatory reflex increase in sympathetic tone induced by the drop in blood pressure. This increase in sympathetic tone will produce an in- crease in both heart rate and plasma renin activity. Even if the reflex increase in heart rate is decreased during chronic treatment, it still could diminish the reduction in blood pressure. Additionally, tachycardia experi- enced by patients in the form of palpitations could be easily controlled by the concomitant administration of a beta blocker. Calcium channel block- ers, in turn, will counteract some of the adverse effects induced by beta blockade, particularly vasoconstriction.

CALCIUM BLOCKERS AND BETA BLOCKERS

From the Department of Medicine, Duke Univer- sity, Durham, North Carolina. Requests for reprints should be addressed to Dr. Lars-G&an Ekelund, University of North Carolina at Chapel Hill, Suite 203, NCNB Plaza 322A, Chapel Hill, North Caro- lina 27514.

To illustrate the effects of combined therapy with nifedipine and a beta blocker, results from a study [5] conducted at Karolinska Hospital, Stock- helm, Sweden, are presented herein. Twelve male patients were studied; in seven, essential hypertension had been diagnosed two to 10 years earlier and in five, the condition was newly diagnosed. The seven patients in whom the condition had previously been diagnosed were referred be-

October 11, 1985 The American Journal of Medicine Volume 79 (suppl 4A) 41

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-EKELUND

I Figure 1. Mean resting systolic and diastolic blood pres-

sures (k SD) in 12 male patients with hypertension who re- ceived placebo, nifedipine, nifedipine plus metoproiol, and metoprolol alone. Adapted with permission from [5].

ZOO-

Systolic l!iO- blood pressure

during exercise (mm Hg) loo-

50 0 1

7

igure 2. Mean systolic blood pressure (t- SD) after six minutes of standardized submaximal exercise in 72 male patients with hypertension who received placebo, nifedi- pine, nifedipine plus metoprolol, and metoprolol alone. Adapted with permission from 151.

cause they had unsatisfactory therapeutic responses. Four of the seven patients had been treated with various doses of beta blockers, two with thiazides, and one with clonidine. Secondary hypertension was ruled out through clinical and laboratory evaluations. At the time of entry into the study, all patients had been without antihypertensive medication for more than one month, except for the two patients with the highest blood pressures who had contin- ued to receive treatment with a low, constant dose of a thiazide. The study design was single-blind, consisting of four consecutive one-month periods. Placebo was admin- istered during the first month; 10 mg of nifedipine three times daily during the second month; 10 mg of nifedipine three times daily plus 100 mg of metoprolol twice daily during the third month; and 100 mg of metoprolol twice daily during the fourth month. Blood pressure and side effects were assessed in the middle of each month; rest- ing electrocardiography was performed at the same time.

At the end of each treatment period, blood pressure was measured after ten minutes of rest in the supine position, after eight minutes in a standing position, and during standardized submaximal exercise for six minutes on a bicycle ergometer. The exercise work loads were selected to produce a heart rate of about 130 beats per minute during the placebo period. At least two measurements were made in rapid succession on each occasion, and the mean value was used in the statistical analysis.

Nifedipine monotherapy produced a significant de- crease of 20 mm Hg in the resting systolic blood pressure and 11 mm Hg in the resting diastolic blood pressure (Fig- ure 1); the heart rate increased significantly by five beats per minute. During exercise, the systolic blood pressure decreased significantly by 14 mm Hg (Figure 2). The ad- dition of metoprolol to the nifedipine regimen resulted in a further decrease of 17 mm Hg in the resting systolic blood pressure and of 4 mm Hg in the diastolic blood pressure (Figure 1). Combination therapy induced significantly greater decreases in both the resting and exercise blood pressures; adequate blood pressure control was achieved in all patients. During treatment with nifedipine alone, two patients reported feeling flushed and warm. However, these symptoms disappeared completely during the com- bination period. The P-Q interval was unchanged during both nifedipine alone and combination therapy.

The alleviation of minor side effects when a beta blocker was added to nifedipine was also found in a study comparing nifedipine alone or in combination with a beta blocker in the treatment of patients with angina pectoris [6]. Results from that study produced similar data in re- spect to blood pressure reduction at rest and during exer- cise (Table I). The blood pressures of patients in that study were mostly within the normal range, although some patients had mild hypertension.

The additive effects of nifedipine and a beta blocker have been reported by several investigators [7-131. The magnitude of the decrease in blood pressure after the addition of a beta blocker was similar to that obtained in this study, namely a 16 to 19 mm Hg decline in systolic pressure and an 8 to 12 mm Hg decline in diastolic pres- sure. However, most of these investigators measured resting blood pressure only. The evaluation of the effects of antihypertensive drugs on blood pressure during exer- cise is perhaps more important than measuring changes in resting blood pressure, since patients spend most of each day involved in some type of activity.

NIFEDIPINE IN COMBINATION WITH OTHER DRUGS

Nifedipine has been combined with diuretics [14], methyl- dopa [15], and captopril [16,17] in the treatment of pa- tients with hypertension. In all combinations, nifedipine has produced a significant and clinically important de- crease in blood pressure. To date, other calcium channel blockers, e.g., verapamil and diltiazem, have mainly been

42 October 11, 1985 The American Journal of Medicine Volume 79 (suppl 4A)

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-EKELUND

TABLE I Comparison of the Effects of Nifedipine, Nifedipine and a Beta Blocker, and Placebo on Selected Cardiovascular Variables in Patients with Angina Pectoris or Hypertension

Mean Values Reference Placebo Nifedipine Nifedipine plus Beta-Blocker

Heart rate at rest (beats per minute) [51 77 82 61 161 72 77 67

Heart rate during exercise (beats per minute) [51 123 128 92 El 110 113 90

Systolic blood pressure at rest (mm Hg) El 178 158 141 f ‘31 147 130 118

Systolic blood pressure during exercise (mm Hg) 151 230 216 177 IsI 170 152 133

Exercise tolerance, total work (watts minute) PI 770 925 1,088

used as monotherapy in patients with hypertension, al- though there are some preliminary data showing an addi- tive effect if a beta blocker is added. However, because of the adverse effect on atrioventricular conduction resulting from the administration of either of these two drugs, most notably verapamil, the addition of a beta blocker could induce bradyarrhythmia. Calcium channel blockers similar to nifedipine, such as others in the dihydropyridine class, should be more suitable for combined therapy with beta blockers in treating patients with hypertension.

Based on the results of these studies and reports in the

literature, nifedipine may be safely administered concomi- tantly with other antihypertensive agents. In a majority of cases, combination therapy results in greater decreases in blood pressure, both at rest and during exercise, in comparison with the levels achieved with single-agent therapy. Combination therapy with the calcium channel blocker nifedipine and a beta blocker is a particularly at- tractive therapeutic modality for patients requiring two- drug therapy, since the positive actions of these two classes of drugs can often counteract the other’s adverse effects.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

Murphy MB, Striven AJI, Dollery GT: Efficacy of nifedipine as a step 3 antihypertensive drug. Hypertension 1983; 5 (suppl2): 118-121.

Mimran A, Ribstein J: Effect of chronic nifedipine in patients in- adequately controlled by a converting enzyme inhibitor and a diuretic. J Cardiovasc Pharmacol 1985; 7: S92-S95.

Brennan FN, Blake S: The use of nifedipine as a third-step agent in the treatment of refractory hypertension. Ir Med J 1982; 75: 29-30.

Dean S, Kendall MJ: Nifedipine in the treatment of difficult hy- pertensives. Eur J Clin Pharmacol 1982; 25: l-5.

Ekelund L-G, Ekelund C, Rossner S: Antihypertensive effects at rest and during exercise of a calcium blocker, nifedipine, alone and in combination with metoprolol. Acta Med Stand 1982; 212: 71-75.

Ekelund L-G, Oro L: Antianginal efficiency of nifedipine with and without a beta-blocker, studied with exercise test. A double- blind, randomized subacute study. Clin Cardiol 1979; 2: 203- 211.

Aoki K, Kondo S, Mochizuki A, et al: Antihypertensive effect of cardiovascular Ca+ antagonist in hypertensive patients in the absence and presence of beta-adrenergic blockade. Am Heart J 1978; 96: 218-226.

Lederballe Pedersen 0, Christensen CK, Mikkelsen E, Ramsch KD: Relationship between the antihypertensive effect and steady-state plasma concentration of nifedipine given alone or in combination with a beta-adrenoceptor blocking agent. Eur J Clin Pharmacol 1980; 18: 287-293.

Murphy MB, Striven AJI, Dollery GT: Role of nifedipine in treat- ment of hypertension. Brit Med J 1983; 287: 257-259.

10.

11.

12.

13.

14.

15.

16.

17.

Yagil Y, Leibel B, Kobrin I, Stessman J, lshay DB: The combina- tion of propranolol and nifedipine in the treatment of hyperten- sion: acute and long-term effects. Postgrad Med J 1983; 59 (suppl 2): 114-l 18.

Bayley S, Dobbs RJ, Robinson BF: Nifedipine in the treatment of hypertension: report of a double-blind controlled trial. Br J Clin Pharmacol 1982; 14: 508-512.

Lejeune PH, Gunselman W, Hennies L, et al: Effects of BAY I 5240, a fixed combination of low-dose nifedipine and acebutolol on hypertension: comparison with standard-dose nifedipine. Eur J Clin Pharmacol 1985; 28: 17-21.

Tsukiyama H, Otsuku K, Yamamoto Y: Effect of pindolol and nifedipine alone and in combination on haemodynamic pa- rameters/variables in essential hypertension. J Int Med Res 1984; 12: 154-162.

Hallin L, Andren L, Hansson L: Controlled trial of nifedipine and bendroflumethiazide in hypertension. J Cardiovasc Pharma- col 1983; 5: 1083-1085.

Guazzi M, Fiorentini C, Olivari MT, Barterelli A, Necchi G, Polese A: Short- and long-term efficacy of a calcium-antago- nist agent (nifedipine) combined with methyldopa in the treat- ment of severe hypertension. Circulation 1980; 61: 913-919.

Brouwer RML, Bolli P, Erne P, Conen D, Kiowski W, Buhler FR: Antihypertensive treatment using calcium antagonists in com- bination with captopril rather than diuretics. J Cardiovasc Pharmacol 1985; 7: S88-S91.

MacGregor GA, Markanda ND, Smith SJ, Sagnella GA: Capto- pril: contrasting effects of adding hydrochlorothiazide, pro- pranolol, or nifedipine. J Cardiovasc Pharmacoll985; 7: S82- S87.

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