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Most forms of hypertension require life-long treatment; thus, it is important to determine the continuing effectiveness and safety of any new therapeutic agent. While participating in various investigational studies, 7103 hypertensive patients received captopril, of whom 4397 were treated for 3 months to 4 years. The 4-year patients included 2498 with mild or moderate essential hypertension (diastolic pressure less than 120 mm Hg), 893 with severe essential hypertension, and 517 with renovascular hypertension. Repeated examinations of these long-term therapy patients, the majority of whom also were receiving a diuretic, indicated no drug tolerance to the combination, i.e., there was continuing control of the blood pressure without significant increases in dosage or addition of other drugs.Side-effects occurring during the first few months of captopril administration (rash, taste disturbances, and, rarely, neutropenia) were not a problem during prolonged therapy. A few patients (70/ 7,103, or 1.0%) developed proteinuria, usually reversible and seldom associated with any deterioration of renal function. The proteinuria occurred most often in patients who had preexisting renal disease and were receiving high doses of the drug. There were no significant changes in key biochemical parameters. A total of 230 patients discontinued treatment for failure to maintain adequate blood pressure reduction, and 397 for side-effects. The estimated 4-year cumulative frequency of drug discontinuance for side-effects was 11.6% (life table method), which compares favorably with other classes of antihypertensive drugs. The frequency of such side-effects was further reduced, without compromising efficacy, by adding a diuretic to the regimen if 150 mg captopril daily did not produce normotension. It is concluded that captopril provides sustained blood pressure control with minimal side-effects during long-term therapy for hypertension. (

Nadolol, a nonselective beta adrenoceptor antagonist, was evaluated in 9 normal sybjects with essential hypertension for ability to inhibit exercise-induced changes in double-product (systolic pressure x heart rate). Propranolol and placebo were included as positive and negative controls. The beta antagonists were administered orally in single doses at 10, 20, 40, and 80 mg on a crossover basis. Both nadolol and propranolol induced comparable dose-related inhibition of double-product. Duration of beta receptor blockade was greater with nadolol than with propranolol; significant inhibition of double-product occurred 24 hr after a single 80-mg dose of nadolol. The antihypertensive effect of nadolol was evaluated in another series of 46 subjects with essential hypertension. The dose of nadolol ranged from 80 to 320 mg once daily. Consistent decreases in supine heart rate (20%) and diastolic blood pressure (9%) from baseline were observed. During steady state, the oral daily dose of nadolol was proportional to the minimum steady-state serum concentration (Cmin) of nadolol (r = 0.75, p less than 0.001) obtained just before the next dose of nadolol. Statistically significant correlation was observed between the antihypertensive effect and the Cmin for nadolol (r = 0.45, p less than 0.05).

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