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It has many similarities to sildenafil; in fact, its molecular structure is very similar (Figure), and they share a half-life of ?4 hours. In healthy volunteers, vardenafil caused a transient reduction in supine blood pressure with a mean maximum decrease of 7 mm Hg systolic and 8 mm Hg diastolic.

Maximum reduction occurred between 1 and 4 hours after dosing.

19 A 20-mg dose of vardenafil resulted in a mean maximum increase in heart rate of 4 beats/min. Molecular structures of sildenafil, vardenafil, and tadalafil.

Note similarity in structure between sildenafil and vardenafil. Reprinted with permission from Rosen RC, Kostis JB.

Overview of phosphodiesterase 5 inhibition in erectile dysfunction.

Tadalafil was the third PDE5 inhibitor to come to market in the United States and was approved by the FDA at the end of 2003.

Its chemical structure differs substantially from that of sildenafil and vardenafil, and it has a unique, long half-life of 17.5 hours. In healthy subjects, a single oral dose of 10 or 20 mg of tadalafil did not drop systolic blood pressure significantly compared with placebo. The decrease in systolic blood pressure with 20 mg tadalafil versus placebo was ?0.2 mm Hg (95% confidence interval [CI], ?7.1 to 6.6) in the standing position. 20,21 The mean decrease in diastolic blood pressure compared with placebo was ?4.6 mm Hg (95% CI, ?7.9 to ?1.2) in the standing position. Diastolic blood pressure was generally lower for 12 hours after administration of the drug, but the decrease in pressure get viagra no prescription remained small. Changes were even less marked in the supine position. Standing and supine heart rates were not significantly different from those with placebo.

In patients with coronary artery disease, who had higher systolic blood pressures at baseline than did healthy volunteers, 10 mg tadalafil reduced standing systolic blood pressure from 134 to 127 mm Hg (?7 mm Hg) and diastolic blood pressure from 78 to 74 mm Hg (?4 mm Hg) at time to maximum plasma concentration (T max ; 2 hours) after dosing.

Hence, all 3 of the PDE5 inhibitors are mild vasodilators and may cause small drops in arterial pressure. However, the degree of drop in blood pressure is usually small. Although this is rarely a concern in healthy individuals, in cardiovascular patients with low blood pressure or hypotension at baseline, this could be a concern, as described in recent guidelines.

22 This vasodilating property would also be a concern for patients with left ventricular outflow obstruction or aortic stenosis. 22,23 This property also becomes an issue regarding the concomitant use of nitrates and ?-blockers, as described next. PDE5 inhibitors work to improve ED by preventing the breakdown of cyclic GMP, the substance that promotes relaxation of smooth muscle cells in the arteries, arterioles, and sinusoids of the corpus cavernosum of the penis. 24 Nitric oxide (NO) donors, such as nitroglycerin (short or long acting), isosorbide dinitrate, isosorbide mononitrate, and others stimulate guanylate cyclase, which increases the production of cyclic GMP. When NO donors are given at the same time as PDE5 inhibitors, there is both an increase in the production of cyclic GMP (due to the NO donor) and an inhibition of its breakdown (due to the PDE5 inhibitor) that can lead to a build-up of cyclic GMP with pronounced vasodilation and, in some patients, frank hypotension.

Organic nitrates are contraindicated with all 3 PDE5 inhibitors on the market.

19–21,25,26 Details of interaction studies are presented in the online supplement to this article. If a patient with coronary artery disease takes a PDE5 inhibitor and then develops angina pectoris, when is it safe to administer nitroglycerin?

A consensus statement from the American College of Cardiology/American Heart Association suggested that for sildenafil, 6 half-lives, or 24 hours (4 hours ? 6), pass between sildenafil intake and the administration of a nitrate.

22 This time frame was chosen to allow full washout of drug from the tissues.

In a get viagra no prescription previous analysis, 20 at 24 hours after sildenafil, there was no interaction with sublingual nitroglycerin. In a recent preliminary study of healthy individuals, the sildenafil-nitroglycerin interaction appeared to be gone as early as 4 hours. Although a detailed time-course study of the interaction between vardenafil and nitrates is not available, 1 unpublished study 19 did suggest a lack of interaction at 24 get viagra no prescription hours, consistent with a 4-hour half-life. A nitrate-tadalafil interaction study was recently reported. 28 In a population of patients who were healthy or had controlled hypertension or diabetes, 20 mg tadalafil or placebo was given daily for 7 days. On the seventh day, sublingual nitroglycerin was administered at 2, 4, 8, 24, 48, 72, or 96 hours.

There was evidence that tadalafil augmented the nitrate-induced decrease in blood pressure within the first 24 hours of its administration.

At and beyond 48 hours, the interaction was not detectable, as assessed by mean maximal falls in blood pressure or outlier criteria. Thus, the manufacturer suggests that if a patient has taken tadalafil and develops chest pain and it is deemed medically necessary that nitrates be given, at least 48 hours should elapse after the last dose of tadalafil before nitrates are given.

Even then, nitrates should be given only under close medical supervision and appropriate hemodynamic monitoring.

What should a patient do if he/she develops chest pain after having taken a PDE5 inhibitor? The patient should call for emergency assistance for hospital transport 29 and apprise the emergency medical technicians and emergency physicians regarding use of the PDE5 inhibitor.

The American College of Cardiology/American Heart Association Consensus document 22 reminds physicians that other antianginal agents can be considered in such situations. ?-Blockers, calcium channel blockers, morphine, and other anti-ischemic agents, such as oxygen, aspirin, and statins, may be safely given in the setting of a PDE5 inhibitor. Furthermore, should a patient develop a myocardial infarction while taking a PDE5 inhibitor, usual care—thrombolytics, antiplatelet agents, and percutaneous coronary intervention—is indicated. If a patient has taken a PDE5 inhibitor, inadvertently receives a nitrate, and becomes hypotensive, the American College of Cardiology/American Heart Association recommends common-sense measures: placing the patient in the Trendelenburg position, administering intravenous fluids and ?-agonists, and finally using intra-aortic balloon counterpulsation.