Short- and long-term efficacy of a calcium-antagonistic agent (nifedipine) combined with methyldopa in the treatment of severe hypertension.

Abstract

Nifedipine induces a potent vasodilating and antihypertensive effect in man through a calciumantagonistic action. The drug was tested alone and in combination with methyidopa in 23 subjects with uncomplicated primary severe hypertension (diastolic pressure > 120 mm Hg) in a short-and long-term therapeutic trial. Hourly pressure readings during the short-term period showed that the antihypertensive response to nifedipine (10 mg orally) is maximal within 40 minutes and lasts for 8-12 hours. When nifedipine is administered every 6 hours the tendency of blood pressure to rise after each dose is repressed by the next dose, so that pressure remains significantly reduced throughout the 24 hours; when methyidopa is combined (250 mg four times daily) blood pressure is further reduced toward normal, without significant fluctuations during the day. After 10 days of drug combination, the antihypertensive response was mediated through reduction of peripheral vascular resistance associated with increase in cardiac output. Renal function was unchanged or improved and sodium retention and plasma volume expansion were not promoted. In six patients with very severe hypertension (diastolic pressure > 140 mm Hg) complicated by cardiac failure, a dosing regimen every 4 hours of the two compounds promptly relieved dyspnea and lung congestion and, within 2-3 days, stabilized blood pressure to an average of 150/98 mm Hg. Persistence of the antihypertensive efficacy of this drug combination in a dosing regimen every 6 hours and its beneficial effects on heart size, ECG and fundi were documented in 22 subjects (four of whom belonged to the decompensated group) who completed a 12-month follow-up. A tendency in seven cases to ankle pitting or edema was the major side effect of nifedipine; the cause of this effect remains obscure. NIFEDIPINE specifically inhibits the penetration of extracellular calcium through the cell membrane and the inflow of Ca++ ions from the binding sites of the sarcoplasmic reticulum into the cell plasma where ATPase of the myofibrils is located. This effect prevents splitting of ATP for the energy-delivering process of smooth-muscle contraction. One of the consequences in man of this pharmacologic property is systemic vasodilatation, which generally induces profound blood pressure fall when pressure is excessively elevated. On this basis, several investigators have explored the use of nifedipine in the acute and chronic management of hypertension.'-' A short-term therapeutic trial carried out by our group3 showed that in primary hypertensive subjects the hypotensive response to a 10-mg oral dose is maximal within less than 1 hour and proportional to the baseline level of systemic vascular resistance; after maximal fall, pressure tends to recover and approaches the control levels in the subsequent 8-12 hours; a dosing regimen every 6 hours significantly reduces blood pressure over the 24 hours, although some fluctuation occurs owing to the rate of decay of the vasodilating effect; the hemodynamics of the pressure fal...

Calcium Channel Blockers in Systemic Hypertension

“…In one study of 27 hypertensive patients, a single 10-mg oral dose of nifedipine reduced mean arterial pressure by 21 % from control with an average fall of 28 mm Hg [15]. This hemodynamic response to nifedipine was characterized by a reduction in peripheral vascular resistance and a concomitant rise in cardiac output.…”

“…Following the intravenous injec tion of technetium-99m-labeled human albumin, the in vestigators performed a total body scan and found that no shift in fluid volume from the limbs to the trunk occurred after nifedipine administration. The tendency of a small subset of patients to develop edema with nife dipine use has been attributed to arteriolar vasodilation without venous vasodilation, effects that could increase capillary hydrostatic blood pressure and result in edema [15].…”

The management of hypertension.

“…The combination of nifedipine and methyldopa has also been found to be additive (Guazzi et al, 1980). Similarly, nifedipine added to a combination of a diuretic plus a P-adrenoceptor blocking drug is useful in more resistant patients (Dean & Kendall, 1983;Murphy et al, 1983;Sloan & Beevers, 1983).…”

Nifedipine in the treatment of hypertension: report of a double‐blind controlled trial.

“…In the remaining seven patients in whom the change of preparation necessitated an increase of 10 mg in the total daily dose, arterial pressure fell after transfer to the slow release tablet so that there was a significant reduction in pressure in the group as a whole ( (Guazzi et al, 1977) and it has also been reported to be effective in more prolonged therapy when given either alone or in combination with a-methyldopa (Olivari et al, 1979;Guazzi et al, 1980). When given alone, nifedipine induces a greater proportional reduction in arterial pressure in patients with hypertension than it does in normal subjects (MacGregor et al, 1981).…”

“…In the majority who did respond, however, the fall in arterial pressure that was achieved was comparable to that reported with hydralazine (Zacest & Koch-Weser, 1972) and one patient who was almost entirely resistant to hydralazine responded well to nifedipine. The direct pharmacological effects of nifedipine are of relatively (Guazzi et al, 1980). In the present trial, measurements of arterial pressure were made 2 to 3 h after the morning dose of capsules and no information on the duration of action is available.…”