Sildenafil citrate and blood-pressure-lowering drugs: Results of drug interaction studies with an organic nitrate and a calcium antagonist

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)- specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly ef fective treatment for erectile dysfunction. The mechanism of action of sild enafil depends on activation of the nitric oxide (NO)cGMP pathway during se xual stimulation, which results In corpus cavernosal smooth muscle relaxati on and penile erection. Endogenously derived NO is also involved in blood p ressure regulation through its effect on basal vascular tone, which is medi ated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their p harmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effec ts of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildena fil were also evaluated in a second placebo-controlled crossover study in m en with hypertension who were taking the calcium antagonist amlodipine, whi ch has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40 -minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL i n 5% dextrose at an initial infusion rate of 2.5 mu g/min and doubling ever y 5 minutes to a maximum rate of 40 mu g/min) 1 hour after taking sildenafi l or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 mu g) 1 hour after taking 25 mg of sildenafil or placebo. Durin g sildenafil treatment, the subjects were significantly less tolerant of in travenously administered glyceryl trinitrate than during placebo treatment based on the occurrence of a >25 mm Hg decrease in blood pressure or the in cidence of symptomatic hypotension (p < 0.01). When a sublingual glyceryl t rinitrate tablet was administered on day 5, a 4-fold greater decrease in sy stolic blood pressure was observed for the subjects during the sildenafil t reatment period than during the placebo treatment period. The changes in he art rate were negligible during both glyceryl trinitrate challenges. In con clusion, sildenafil potentiated the hypotensive effects of glyceryl trinitr ate, an organic nitrate. Thus, sildenafil administration to patients who ar e using organic nitrates, either regularly and/or intermittently, in any fo rm is contraindicated. In the second crossover study, men with hypertension , who were taking 5 or 10 mg/day of amlodipine, received a single oral dose of 100 mg sildenafil or placebo. Coadministration of sildenafil did not si gnificantly affect the pharmacokinetics of amlodipine. In the 4 hours after dosing, differences in the mean maximum change from baseline in supine sys tolic and diastolic blood pressures between the sildenafil plus amlodipine and the placebo plus amlodipine treatment periods were -8 mm Hg and -7 mm H g, respectively (p less than or equal to 0.002). The mean maximum supine he art rate increased 2.1 beats/min during sildenafil plus amlodipine treatmen t and decreased 1.5 beats/min during placebo plus amlodipine treatment (p < 0.02). The adverse events in this study were predominantly mild or moderat e and did not cause discontinuation of treatment. Adverse events considered to be related to sildenafil treatment included headache, nausea, and dyspe psia. In patients with hypertension who were taking amlodipine therapy, sildenafi l produced additive, but not synergistic, reductions in blood pressure. The difference in the mean maximum change from baseline in blood pressure betw een sildenafil plus amlodipine and placebo plus amlodipine was comparable t o the decrease in blood pressure reported for healthy men taking sildenafil alone. Thus, no synergistic interaction was observed between sildenafil an d the calcium antagonist amlodipine in patients with hypertension. (C) 1999 by Excerpta Medico, Inc.