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Abstract
Sildenafil is a competitive and selective inhibitor of phosphodiesterase 5. Sildenafil is cleared by hepatic CYP3A (major route) and CYP2C9 (minor route) and concomitant administration of potent CYP3A inducers (e.g., bosentan) causes decreases in plasma levels of sildenafil. CYP3A4 inhibitors (erythromycin and cimetidine) inhibit sildenafil metabolism prolonging the half-life and elevating blood levels of sildenafil. Sildenafil is a pulmonary arterial vasodilator and it has been used in the treatment of persistent pulmonary hypertension. The initial oral dose is 250 to 500 µg/kg 4 times-daily in infants and the oral dose is 10 to 20 mg thrice-daily in children with a body-weight up to 20 kg or > 20 kg, respectively. Sildenafil has been found efficacy and safe in infants and children but it may induce adverse-effects. Following an oral dosing, the absorption rate constant is 0.343 h-1, and the elimination half-life is 2.41 hours in children suggesting that sildenafil is rapidly absorbed and eliminated. The interaction of sildenafil with drugs and the metabolism of sildenafil have been extensively studied. The principal routes of sildenafil metabolism are: N-demethylation, oxidation, and aliphatic dihydroxylation, and the major metabolite is N-desmethyl sildenafil. The treatment of infants and children with sildenafil has been extensively studied. Sildenafil citrate and sildenafil cross the human placenta and sildenafil migrates into the breast-milk in significant amounts. The aim of this study is to review the sildenafil dosing, efficacy and safety, effects, adverse-effects, pharmacokinetics, interaction with drugs, metabolism, treatments, and sildenafil placental transfer and migration into the breast-milk.
Highlights
Mechanism of action of sildenafilSildenafil, which structurally mimics the purine ring of cGMP, is a competitive and selective inhibitor of phosphodiesterase 5
The aim of this study is to review the sildenafil dosing, efficacy and safety, effects, adverse-effects, pharmacokinetics, interaction with drugs, metabolism, treatments, and sildenafil placental transfer and migration into the breast-milk
Children with Down syndrome may be less responsive to sildenafil for pulmonary arterial hypertension [8]
Summary
Mechanism of action of sildenafilSildenafil, which structurally mimics the purine ring of cGMP, is a competitive and selective inhibitor of phosphodiesterase 5. Sildenafil has a relatively high selectivity (>1,000-fold) for human phosphodiesterase 5 over other phosphodiesterases. By inhibiting cGMP hydrolysis, sildenafil elevates cellular levels of cGMP and augments signalling through the cGMP-protein kinase G pathway, provided guanylyl cyclase is active [1]. Administration distribution metabolism and excretion of sildenafil. Sildenafil is rapidly absorbed and reaches a peak plasma concentration 1 hour after oral administration. Sildenafil and its major active metabolite, N-desmethyl sildenafil, have terminal half-lives of about 4 hours in adults. Both the parent compound and the major metabolite are highly bound to plasma protein (96%). Metabolites are predominantly excreted into the faeces (73 to 88%) and to a lesser extent into the urine; non-metabolised sildenafil is not detected in urines or faeces. The clearance is reduced in elderly (> 65 years), leading to an increase in the AUC values for the parent drug and the N-desmethyl metabolite [1]
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