3. This product is an oral medication for erectile dysfunction (ED). It is the citrate of sildenafil, a selective inhibitor of type 5 phosphodiesterase (PDE5) specific to cyclic guanosine phosphate (cGMP).
Mechanism of action: The physiological mechanism of penile erection involves the release of nitric oxide (NO) in the penile sponge during sexual stimulation. NO activation of guanosine cyclase leads to increased levels of cyclic guanosine phosphate (cGMP), which relaxes smooth muscles and fills blood in sponges.
Efficacy of Sildenafil on erection response: Sildenafil (Viagra) is a highly selective phosphatidiesterase 5(PDE5) inhibitor. PDE5 is highly expressed in the cavernosa of the penis, but low in other tissues (including platelets, blood vessels, visceral smooth muscle, and skeletal muscle). Sildenafil leads to relaxation of the smooth muscle of the cavernosa by selectively inhibiting PDE5, enhancing the nitric oxide (NO) -CGMP pathway, and elevating the level of cGMP, leading to a natural erectile response to sexual stimulation in erectile dysfunction patients. Erectile response generally increases with sildenafil dose and plasma concentration. Experiments showed that the effect lasted up to 4 hours, but the reaction was weaker than 2 hours. Sildenafil response to myocardium: PDE5 does not exist in normal or pathological cardiac conduction tissues, myocardium cells, endothelial cells, and lymphatic tissues, so sildenafil (PDE5 inhibitor) has no positive inotropic effect and cannot directly affect myocardial systolic function.
Effect of sildenafil on cardiac parameters: a single dose of sildenafil 100mg in normal male volunteers showed no clinically significant ecg changes. Eight patients with stable ischemic heart disease received sildenafil 40mg intravenously in 4 doses monitored by a swan-ganz catheter. Systolic and diastolic blood pressure at rest decreased by 7% and 10%, respectively, from baseline. Resting right atrium, pulmonary artery pressure, pulmonary wedge pressure and cardiac output decreased by 28%, 28%, 20% and 7%, respectively. Although this intravenous dose was two to five times higher than the average peak plasma concentration of 100mg for a single oral dose of sildenafil in healthy male volunteers, these hemodynamic responses persisted during exercise.
Sildenafil response to blood pressure: in healthy men, a single dose of sildenafil 100mg resulted in a decrease in supine bp (with a mean maximum of 8.4/5.5mmHg), most significant at 1 to 2 hours after administration, with no difference from placebo at 8 hours after administration. Sildenafil 25mg, 50mg, and 100mg had similar effects on blood pressure and appeared to be independent of dose and blood concentration. Patients who also took nitrates had a greater reduction in blood pressure. Hypotension (90/50 MMHG) and nitrates or nitrate-providing drugs are strict contraindications for sildenafil use. The maximum use of sildenafil for bp occurred approximately 1 h after administration, which was consistent with the drug plasma peak. Thus, sexual activity may induce cardiac events at peak plasma concentrations of sildenafil. Although the hypotensive response to sildenafil is mild and transient (typically bp returns to baseline within 4 hours), the interaction between sildenafil and nitrates can produce a significant and longer duration of bp reduction. Sildenafil has a short half-life and can be eluted within 24 hours (about 6 half-lives). The American College of Cardiology and the American Heart Association have indicated that sildenafil should not be used in the last 24 hours if a nitrate has been used. Effects of sildenafil on vision: Studies have shown no effect on visual acuity, retinal electrogram, intraocular pressure, or visual nipple size when taken at twice the maximum recommended dose. Transient blue/green color discrimination anomalies may be present. Whether used alone or in combination with aspirin, it has no effect on the duration of bleeding. In vitro, the product enhanced the antiplatelet aggregation of sodium nitroprusside (NO donor) in humans. The combination of heparin and sildenafil has an additive effect on prolongation of bleeding time in rabbits under anesthesia, but no similar human studies have been conducted.
Sildenafil is absorbed rapidly after oral administration and has an absolute bioavailability of about 40%. Its pharmacokinetic parameters are proportional to dose within the recommended dosage range. Elimination of liver metabolism (cytochrome P450 isoenzyme 3A4 pathway) to produce an active metabolite with properties similar to sildenafil, The combination of potent inhibitors of cytochrome P450 isoenzyme 3A4 (CYP450 3A4) (e.g., erythromycin, ketoconazole, itraconazole) and nonspecific inhibitors of cytochrome P450 (CYP450), such as cimetidine and sildenafil, may lead to elevated plasma levels of sildenafil. The elimination half-life of sildenafil and its metabolites is about 4 hours. The maximum plasma concentration (Cmax) was 127 ~ 560ng/ml in about 1 h when 25 ~ 100mg was given in fasting state. Sildenafil or its main metabolite, n-desmethyl metabolite (N-Desmethyl), has a selectivity of approximately 50% against PDE5 and a protein binding rate of 96%. At the maximum plasma concentration of total sildenafil, the Cmax of free sildenafil was 22ng/ml. After oral or intravenous administration, sildenafil is excreted mainly as metabolites from the stool (about 80% of the oral dose) and a small amount from the urine (about 13% of the oral dose).
Pharmacokinetics in specific populations: Elderly: Sildenafil clearance rates were reduced in healthy older volunteers (≥65 years) and free plasma concentrations were approximately 40% higher than in young healthy volunteers (18-45 years).
Renal insufficiency: Volunteers with mild (creatinine clearance equal to 50-80ml/ min) and moderate (creatinine clearance equal to 30-49 mL/min) renal impairment had no change in the pharmacokinetics of a single dose of sildenafil 50mg. Volunteers with secondary renal impairment (creatinine clearance = ≤30ml/ min) had reduced clearance of sildenafil and almost double the area under the curve (AUC) and Cmax at treatment time compared with the same age group without renal impairment.
Liver dysfunction: Sildenafil clearance rates were reduced in volunteers with cirrhosis (child-Pugh grade A and B), and AUC and Cmax increased by 84% and 47%, respectively, compared with the same age group without liver impairment. Therefore, older than 65 years, liver function impairment, and severe renal impairment are associated with elevated plasma sildenafil levels. The appropriate starting dose for these patients is 25mg.