Phosphodiesterase Type 5 Inhibitor; Impotence drug
Mechanism of Action: The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by Sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.
Pharmacokinetics and Metabolism: Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25-63%). It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, Sildenafil. Both Sildenafil and the metabolite have terminal half lives of about 4 hours.
Absorption and Distribution: Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When Sildenafil is taken with a high fat meal, the rate of absorption is reduced.
Metabolism and Excretion: Sildenafil is cleared by hepatic microsomal isoenzymes. After either oral or intravenous administration, Sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
Pharmacokinetics in Special Populations: Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of Sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of Sildenafil compared to those seen in healthy younger volunteers.
The usual starting dose of Sildenafil is 50 mg once daily. It should be taken before 30-40 minutes of intercourse. Depending on effectiveness & tolerance; the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum dosing frequency is once per day. Sildenafil may takes longer time to work if you take it with a heavy meal.
Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes 15 may reduce Sildenafil clearance and inducers of these isoenzymes may increase Sildenafil clearance. Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma Sildenafil concentrations when coadministered with Sildenafil (50 mg) to healthy volunteers. When a single 100 mg dose of Sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in Sildenafil systemic exposure (AUC). In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Sildenafil (100 mg single dose) resulted in a 140% increase in Sildenafil Cmax and a 210% increase in Sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in Sildenafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine). In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with Sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in Sildenafil Cmax and a 1000% (11-fold) increase in Sildenafil plasma AUC. At 24 hours the plasma levels of Sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when Sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics. Although the interaction between other protease inhibitors and Sildenafil has not been studied, their concomitant use is expected to increase Sildenafil levels. In a study of healthy male volunteers, co-administration of Sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of Sildenafil AUC and a 55% decrease in Sildenafil Cmax. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of Sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of Sildenafil. Pharmacokinetic data from patients in clinical trials showed no effect on Sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl Sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by 16 nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.
Sildenafil was shown to potentiate the hypotensive effects of nitrates & its administration to patients who are using organic nitrates, either regularly & or intermittently, in any form is therefore contraindicated.
Sildenafil: Sudden wheeziness, difficulty in breathing or dizziness, swelling of the eyelids, face, lips or throat. Common side effect includes headache, facial flushing, indigestion, effects on vision, light sensitivity, blurred vision or reduced, stuffy nose & dizziness. Uncommon side effect includes vomiting, skin rash, bleeding at the back of the eye, red eyes, eye pain, double vision, abnormal sensation in the eye, irregular or rapid heartbeat, muscle pain, feeling sleepy, reduced sense of touch, vertigo, ringing in the ears, nausea, dry mouth, chest pain & feeling tired.
Sildenafil is not indicated for use in newborns, children & women.
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates and severities were increased. 24 In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as Sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.
Keep in a dry place, away from light and heat. Keep out of the reach of children.
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