Am J Cardiol. 1999 Mar 4;83(5A):35C-44C.
Overall cardiovascular profile of sildenafil citrate. Overall cardiovascular profile of sildenafil ci... [Am J Cardiol. 1999] - PubMed - NCBI
Zusman RM1, Morales A, Glasser DB, Osterloh IH.
Abstract
Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking the breakdown of cGMP.
Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO-cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were <2% and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medications (beta blockers, alpha blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adverse events that result in discontinuation of treatment in <3% of patients.
Am J Cardiol. 1999 Mar 4;83(5A):13C-20C.
Effects of sildenafil citrate on human hemodynamics. Effects of sildenafil citrate on human hemodyna... [Am J Cardiol. 1999] - PubMed - NCBI
Jackson G1, Benjamin N, Jackson N, Allen MJ.
Abstract
Nitric oxide (NO) induces the formation of intracellular cyclic guanosine monophosphate (cGMP) by guanylate cyclase. Sildenafil, which selectively inhibits phosphodiesterase type 5 (PDE5) found predominantly in the corpora cavernosa of the penis, effectively blocks the degradation of cGMP and enhances erectile function in men with erectile dysfunction. The NO-cGMP pathway also plays an important role in mediating blood pressure. It is, therefore, possible that the therapeutic doses of sildenafil used to treat erectile dysfunction may have clinically significant effects on human hemodynamics. Three studies were undertaken to assess the effects of intravenously, intra-arterially, and orally administered doses of sildenafil on blood pressure, heart rate, cardiac output, and forearm blood flow and venous compliance in healthy men. A fourth study evaluated the hemodynamic effects of intravenous sildenafil in men with stable ischemic heart disease.
In healthy men, significant (p <0.01) decreases in supine systolic and diastolic blood pressures were observed with intravenous sildenafil (20, 40, and 80 mg) at the end of the infusion period when plasma levels of sildenafil were highest (mean decreases from baseline of 7.0/6.9 and 9.2/6.7 mm Hg, for the 40- and 80-mg doses, respectively). These changes were transient and not dose related. Modest reductions in systemic vascular resistance also were observed (maximum decrease 16%), although heart rate was not affected by sildenafil administration when compared with placebo. Single oral doses of sildenafil (100, 150, and 200 mg) produced no significant changes in cardiac index from 1-12 hours postdose between placebo- and sildenafil-treated subjects. The approved dosage strengths of sildenafil citrate are 25 mg, 50 mg, and 100 mg. The 80-mg intravenous dose and the 200-mg oral dose of sildenafil produced comparable plasma levels at twice the maximum therapeutic dose (recommended range, 25-100 mg). After brachial artery infusion of sildenafil (up to 300 microg/min), there was a modest vasodilation of resistance arteries and a reversal of norepinephrine-induced preconstriction of forearm veins. These hemodynamic effects were similar to but smaller in magnitude than those of nitrates. In a small pilot study of men with ischemic heart disease, decreases from baseline in pulmonary arterial pressure (-27% at rest and -19% during exercise) and cardiac output (-7% at rest and -11% during exercise) were observed after 40-mg intravenous doses of sildenafil. Sildenafil was well tolerated by subjects and patients in all studies, with headache and other symptoms of vasodilation the most commonly reported adverse effects of treatment. Modest, transient hemodynamic changes were observed in healthy men after single intravenous or oral doses of sildenafil even at supratherapeutic doses. In men with stable ischemic heart disease, sildenafil produced modest effects on hemodynamic parameters at rest and during exercise.
Am J Cardiol. 2003 Nov 6;92(9A):37M-46M.
Cardiovascular effects of tadalafil. Cardiovascular effects of tadalafil. [Am J Cardiol. 2003] - PubMed - NCBI
Kloner RA1, Mitchell M, Emmick JT.
Abstract
To determine the effects of tadalafil on the cardiovascular system, safety assessments were performed on a database of >4000 subjects who received tadalafil in >60 clinical pharmacology, phase 2, phase 3, and open-label studies.
In healthy subjects, tadalafil resulted in small changes in blood pressure, which are not believed to be clinically relevant. Daily administration of tadalafil 20 mg for 26 weeks in healthy male subjects or patients with mild erectile dysfunction resulted in blood pressure changes similar to those observed after placebo administration. In patients with coronary artery disease (CAD), tadalafil administration before nitrate administration resulted in small decreases in blood pressure. The resulting mean maximal change in standing systolic blood pressure (SBP) after coadministration of sublingual nitroglycerin in patients with chronic stable angina was -36 mm Hg for tadalafil 5 mg, -31 mm Hg for tadalafil 10 mg, and -28 mm Hg for placebo. In addition, a larger number of men had a standing SBP <85 mm Hg after coadministration of sublingual nitroglycerin and tadalafil 5 mg (p <0.001 vs placebo) or tadalafil 10 mg (p <0.01 vs placebo) compared with coadministration with placebo. In patients with chronic stable angina taking doses of isosorbide mononitrate on a long-term basis, the mean maximal change in standing SBP was -23 mm Hg for placebo, -23 mm Hg for tadalafil 5 mg, and -26 mm Hg for tadalafil 10 mg. In a study of older subjects (>or=55 years of age) with no overt evidence of CAD, the resulting mean maximal change in standing SBP after coadministration of sublingual nitroglycerin was -25 mm Hg for tadalafil 10 mg, -29 mm Hg for sildenafil 50 mg, and -25 mm Hg for placebo. Cardiac mortality rates in tadalafil studies are consistent with the expected rate in this male population. Across all studies, the incidence rate of myocardial infarction was low in tadalafil-treated patients (0.43 per 100 patient-years) compared with patients who received placebo (0.6 per 100 patient-years), and the incidence rate was comparable to that observed in the age-standardized male population (0.60 per 100 patient-years). The incidence rate of presumed thrombotic strokes in tadalafil studies (0.27 per 100 patient-years) is comparable to the expected rate in this patient population. The data presented herein suggest that tadalafil can be safely used by healthy subjects and by patients with cardiovascular diseases. As with sildenafil, the use of tadalafil is contraindicated in patients receiving nitrate therapy because of the potential for significant hypotensive
