Drug Interactions With Phosphodiesterase-5 Inhibitors Used for the Treatment of Erectile Dysfunction or Pulmonary Hypertension

Abstract

Sildenafil and tadalafil were the 32nd and 74th, respectively, most popular prescription drugs dispensed in the United States in 2006. Erectile dysfunction (ED) currently affects >30 million men in the United States and >150 million men worldwide and will become more prevalent as the population ages.1 Phosphodiesterase-5 (PDE5) inhibitors (PDE5Is) (sildenafil [Viagra],2 vardenafil [Levitra],3 and tadalafil [Cialis]4) are first-line therapy for ED. Use of PDE5Is will increase because sildenafil (Revatio)5 and tadalafil (Adcirca)6 are now prescribed as first-line therapy for many patients with pulmonary hypertension (PHT).5–8 Several pooled analyses comprising dozens of trials and thousands of patients, including patients with coronary artery disease and on antihypertensive medications, reported that PDE5Is did not significantly affect the incidence of adverse cardiovascular events.9–12 However, PDE5 is distributed in many tissues, including platelets, veins, and arterial smooth muscle (pulmonary, coronary, and systemic arteries).13 Thus, PDE5Is affect the cardiovascular system, mostly via vasodilation, and often cause small decreases in blood pressure (BP). When PDE5Is are coadministered with nitrates or α-blockers, pronounced systemic vasodilation and severe hypotension are possible. Many patients with ED are elderly and have the same risk factors as patients with coronary artery disease, so these drug combinations are commonly considered or encountered in clinical practice.1 This article covers the important PDE5I drug interactions, including antihypertensive agents, nitrates, α-blockers, PHT agents, cytochrome P450 inhibitors, and other miscellaneous drugs. Sildenafil is metabolized mainly by the cytochrome P450 3A4 pathway (79%) and to a lesser extent by 2C9 (20%).14,15 Vardenafil is metabolized in a similar manner, mainly by 3A4 with a smaller contribution by 2C9.15 Tadalafil is metabolized almost solely by 3A4.15 Therefore, drugs that inhibit the 3A4 pathway decrease the metabolism and increase the plasma concentrations of PDE5Is (Table 1). Area …