Pharmacological effects of Viagra

Pharmacological effects of Viagra

This product is an oral medication for the treatment of erectile dysfunction (ED). It is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Mechanism of action: The physiological mechanism of penile erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO activates guanylate cyclase, leading to increased levels of cGMP, which causes smooth muscle relaxation in the corpus cavernosum and allows for blood engorgement.

1. Pharmacodynamics – Effect of sildenafil on erectile response: Sildenafil (Viagra) is a highly selective inhibitor of phosphodiesterase type 5 (PDE5). PDE5 is highly expressed in the corpus cavernosum but shows low expression in other tissues (including platelets, vascular and visceral smooth muscle, and skeletal muscle). By selectively inhibiting PDE5, sildenafil enhances the nitric oxide (NO)-cGMP pathway and increases cGMP levels, thereby relaxing the smooth muscle of the corpus cavernosum and enabling patients with erectile dysfunction to achieve a natural erectile response to sexual stimulation. The erectile response generally intensifies with increasing sildenafil dosage and plasma concentration. Studies show that the therapeutic effect can last up to 4 hours, although the response is weaker at the 4-hour mark compared to the 2-hour mark. Effect of sildenafil on the myocardium: PDE5 is absent in cardiac conduction tissue, cardiomyocytes, endothelial cells, and lymphoid tissue, whether normal or diseased; consequently, sildenafil (a PDE5 inhibitor) has no positive inotropic effect and does not directly influence myocardial contractile function.

Effect of sildenafil on cardiac parameters: No clinically significant electrocardiographic changes were observed in healthy male volunteers following a single oral dose of 100 mg of sildenafil. Eight patients with stable ischemic heart disease received a total intravenous dose of 40 mg of sildenafil, administered in four separate injections, while being monitored via Swan-Ganz catheters. Results showed that, at rest, systolic and diastolic blood pressures decreased by 7% and 10% respectively compared to baseline. Resting right atrial pressure, pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output decreased by an average of 28%, 28%, 20%, and 7%, respectively. Although this intravenous dosage resulted in peak plasma concentrations two to five times higher than those observed after a single 100 mg oral dose in healthy male volunteers, the aforementioned hemodynamic responses persisted during exercise.

Regarding the effect of sildenafil on blood pressure: a single 100 mg oral dose in healthy men caused a reduction in supine blood pressure (with a mean maximum decrease of 8.4/5.5 mmHg). The drop was most pronounced 1 to 2 hours post-dose, and by 8 hours post-dose, there was no difference compared to the placebo group. The effects of 25 mg, 50 mg, and 100 mg doses were similar, appearing independent of dosage or plasma concentration. The hypotensive effect was more pronounced in patients concomitantly taking nitrates. Hypotension (90/50 mmHg) and the use of nitrates or nitric oxide donors are strict contraindications for sildenafil use. The maximal effect of sildenafil on blood pressure occurs approximately 1 hour after administration, coinciding with peak plasma concentration; consequently, sexual activity during this peak concentration period could potentially trigger cardiac events. While the hypotensive response to sildenafil is mild and transient (with blood pressure generally returning to baseline within 4 hours), the interaction between sildenafil and nitrates can result in a significant and prolonged drop in blood pressure. Sildenafil has a short half-life, and the drug is cleared from the system within 24 hours (approximately six half-lives). The American College of Cardiology and the American Heart Association have explicitly stated that sildenafil is contraindicated in patients who have used nitrates within the preceding 24 hours. Effects of sildenafil on vision: Studies indicate that at twice the maximum recommended dose, the drug has no effect on visual acuity, electroretinograms, intraocular pressure, or optic disc size. Transient abnormalities in blue/green color discrimination may occur. Whether administered alone or in combination with aspirin, the drug has no effect on human bleeding time. In vitro, the drug potentiates the anti-platelet aggregation effect of sodium nitroprusside (a nitric oxide donor). In anesthetized rabbits, the combination of heparin and sildenafil produces an additive effect on the prolongation of bleeding time, but no similar studies have been conducted in humans.

Following a single oral dose of 100 mg of sildenafil in healthy volunteers, sperm motility and morphology remained unaffected.

Pharmacokinetics

Sildenafil is rapidly absorbed following oral administration, with an absolute bioavailability of approximately 40%. Its pharmacokinetic parameters are dose-proportional within the recommended dosage range. Elimination occurs primarily via hepatic metabolism (mediated by the cytochrome P450 isoenzyme 3A4 pathway), yielding an active metabolite with properties similar to sildenafil. Co-administration of sildenafil with potent inhibitors of cytochrome P450 isoenzyme 3A4 (CYP450 3A4)—such as erythromycin, ketoconazole, or itraconazole—or with non-specific cytochrome P450 (CYP450) inhibitors like cimetidine may result in elevated plasma levels of sildenafil. The elimination half-life of sildenafil and its metabolites is approximately 4 hours. Following oral administration of 25–100 mg in the fasting state, maximum plasma concentration (Cmax) of 127–560 ng/mL is reached within approximately 1 hour. Sildenafil and its primary metabolite (N-desmethyl metabolite) exhibit approximately 50% of the potency of sildenafil for PDE5 selectivity; the plasma protein binding rate is 96%. At the Cmax of total sildenafil, the free sildenafil Cmax is 22 ng/mL. Following oral or intravenous administration, sildenafil is excreted primarily as metabolites in the feces (approximately 80% of the oral dose), with a smaller fraction excreted in the urine (approximately 13% of the oral dose).

Pharmacokinetics in special populations: Elderly: Sildenafil clearance is reduced in healthy elderly volunteers (≥65 years of age), resulting in free plasma concentrations approximately 40% higher than those observed in young, healthy volunteers (18–45 years of age).

Renal impairment: The pharmacokinetics of a single 50 mg oral dose of sildenafil remained unaltered in volunteers with mild (creatinine clearance 50–80 mL/min) or moderate (creatinine clearance 30–49 mL/min) renal impairment. In volunteers with severe renal impairment (creatinine clearance ≤30 mL/min), the clearance of sildenafil is reduced; compared to age-matched volunteers without renal impairment, the area under the concentration-time curve (AUC) and Cmax are approximately doubled.

Hepatic impairment: In volunteers with cirrhosis (Child-Pugh class A and B), sildenafil clearance is reduced; compared to age-matched volunteers without hepatic impairment, AUC and Cmax increase by 84% and 47%, respectively. Therefore, age over 65, hepatic impairment, and severe renal impairment can lead to elevated plasma sildenafil levels. A starting dose of 25 mg is appropriate for such patients.

Indicated for the treatment of erectile dysfunction (ED).

The Discovery of Viagra

Science Daily—Researchers at the University of Wisconsin-Madison reported this month that sildenafil—a drug originally developed by Pfizer for coronary heart disease (though later trials showed limited efficacy for that condition)—can increase the release of oxytocin. It achieves this by stimulating the posterior pituitary gland, a structure located just beneath the brain that regulates hormone levels in response to nerve signals.

"This discovery regarding the 'magic blue pill'—Viagra—reveals for the first time why drugs for erectile dysfunction, such as Viagra, have physiological effects beyond simply increasing blood flow to the sexual organs; this represents a novel function of the drug," said lead researcher Meyer Jackson, a professor of physiology at the University of Wisconsin-Madison School of Pharmacy and Public Health.

Oxytocin, sometimes referred to as the "love hormone" or the "cuddle chemical," plays several important roles in social interaction and reproduction, including the promotion of uterine contractions and childbirth. It is also released during orgasm and is associated with sexual arousal.

The release of oxytocin is controlled by an enzyme that acts like a brake; inhibiting the excitation of nerve cells can reduce hormone release. This same enzyme—phosphodiesterase type 5 (PDE5)—also reduces blood flow by causing the smooth muscle of blood vessel walls to contract. Jackson explained that sildenafil inhibits this enzyme from acting as a "brake" in two different contexts. In blood vessels, relaxing smooth muscle cells increases blood flow—an effect that corrects erectile dysfunction—while in the pituitary gland, it enhances cellular responsiveness. "The same stimulus results in greater release [of oxytocin]," he said. "I think this is an overlooked aspect when considering whether phosphodiesterase-5 (PDE5) inhibitors—such as Viagra, Levitra, and Cialis—might have other effects."

This new report was published online on August 9 and is slated for an upcoming issue of the *Journal of Physiology*. In the experiment, scientists measured the amount of oxytocin released by rat pituitary glands in response to nerve impulses. When sildenafil was applied to the pituitary gland, the amount of oxytocin released was three times higher than without the drug.

While he does not believe his findings raise safety concerns regarding Viagra use, he does think they point to other potential effects and new avenues for treatment. "A major question raised by our study is whether sildenafil can promote oxytocin release from nerve endings, just as it does in the brain," he said. In the brain, the cells that supply oxytocin to the hypothalamus—a region that also distributes hormones throughout the brain—are located within the hypothalamus itself.

Although the specific effects of sildenafil on these pathways remain unknown, research by others has shown that oxytocin-sensitive cells in the brain are linked to the neurons controlling erectile responses, suggesting that Viagra and similar drugs may act through multiple pathways.

The famous little blue pill has other effects as well. Oxytocin is associated with strong social bonding, and sildenafil has recently been shown to enhance the ability of hamsters to adjust their biological clocks to artificial jet lag. "This is one of many unexplained phenomena," Jackson said, "but it raises the possibility that drugs used to treat erectile dysfunction could have applications beyond that specific condition."