Clinical Pharmacology of Pinacidil, A Prototype for Drugs That Affect Potassium Channels

Summary: The clinical pharmacology of potassium channel openers has been reviewed using pinacidil as a prototype drug. When administered acutely or chronically, the hemodynamic and neuroendocrine profile is that of a peripheral arterial vasodilator. The drug produces decreases in peripheral vascular resistance, and subsequent blood pressure decreases are associated with reflex increments in heart rate. When studied, plasma catecholamines increased about twofold during chronic therapy. Plasma renin activity, however, was not increased during chronic therapy with pinacidil monotherapy. When patients were treated with pinacidil doses ranging from 12.5 to 75 mg b.i.d., 66.9% of patients had a decrease in supine diastolic blood pressure to below 91 mm Hg and 10 mm Hg less than baseline, whereas only 23.9% of patients had similar falls during placebo treatment. During maintenance therapy with pinacidil, the average blood pressure during the daytime dosing interval was 137.8 ± 1.2/83.4 ± 0.7 mm Hg (mean ± SEM). Titration of pinacidil as monotherapy resulted in a characteristic adverse event profile dominated by the presence of dose-related edema. Other characteristic events included tachycardia, palpitations and headache. When pinacidil was given to patients unresponsive to hydrochlorothiazide (25 mg b.i.d.), similar efficacy relative to placebo was noted with a change of post-dose supine diastolic blood pressure in the pinacidil group of 13.5 ± 0.8 mm Hg and 7.3 ± 0.9 mm Hg in the placebo group. Under these conditions, the incidence of edema was reduced to 9%. A number of additional effects of pinacidil were noted which may be related to its mechanism of action, including hypertrichosis; transient, asymptomatic changes in the T wave of the electrocardiogram; and favorable trends in serum lipid concentrations. Serum potassium concentration did not appear to be affected by pinacidil given alone. These data suggest that potassium channel openers are effective antihypertensive agents when given alone, at low doses, and when given in combination with diuretic.