Sildenafil Vasodilator

Synonym. UK-9248010 1-[[3-(4,7-Dihydro1methyl7oxo3propyl1H-pyrazolo[4,3-d]-pyrimidin5yl)-4 ethoxyphenyl]sulfonyl]-4methylpiperazine C22H30N6O4S=474.6 CAS139755832

Crystals. M. p. 187 to 189.

Sildenafil Citrate
Proprietary name. Viagra C22H30N6O4S,C6H8O7=666.7 CAS171599830 A white to offwhite crystalline powder.

Dissociation Constant.
pKa8.7.

Infrared Spectrum.
Principal peaks at wavenumber 760, 1695, 1169, 946 cm1

Mass Spectrum.
Principal ions at m/z 99, 404, 56, 100, 405, 70, 312, 381.

High Performance Liquid Chromatography.

Column: RP C4 (Kromasil, 150 4.6 mm i.d., 5 m). Column temperature: 40. Mobile phase: acetonitrile:potassium dihydrogen phosphate (0.5 M, with diethylamine hydrochloride (10 mM)) (32:68), flow rate 0.7 mL/min. UV detection ( = 230 nm). Retention time: 10.3 min [M. Lee and D. I. Min,Ther. Drug Monit.,2001, 23, 2126]. Column: C18 (Bondapak, 300 3.9 mm i.d., 10 m). Mobile phase: ammonium acetate (0.2 M, pH 7.0):acetonitrile (1:1), flow rate 1 mL/min. UV detection ( = 240 nm). Retention time: 9.0 min [N. Daraghmeh et al.,J. Pharm. Biomed. Anal.,2001, 25, 483492].

Quantification
Gas chromatography. In hair: limit of quantification 0.1 ng/g. MS detectionK. Saisho et al.,Biol. Pharm. Bull.,2001, 24, 13841388. High performance liquid chromatography. In plasma: sildenafil and Ndesmethylsildenafil, limit of quantification 1 g/L. UV detection ( = 230 nm)J. D. H. Cooper et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 701, 8795.

Disposition in the Body.

Sildenafil is rapidly absorbed after oral administration. Peak plasma concentrations occur within about 30 to 120 min. Rate of absorption is reduced when taken with food. It is widely distributed into tissues and metabolised in the liver primarily by CYP3A4; some is also metabolised by CYP2C9. The major metabolite formed, Ndesmethylsildenafil (UK103,320) has some activity and makes up 30 to 40% of the total plasma drug concentration after a single dosing regimen. Sidenafil is excreted predominantly as metabolites in faeces (about 80% of administered dose) and to a lesser extent in urine (about 13% of administered dose with <2% as the parent drug). Clearance may be reduced in the elderly and in patients with severe renal or hepatic impairment. Therapeutic concentration 4 groups of healthy males, approximately 14 per group, aged between 18 and 45 years, were administered with a single oral dose of 100 mg sildenafil. The mean peak drug concentrations were 0.296, 0.302, 0.321 and 0.325 mg/L observed at 2.1, 3.1, 2.0 and 2.3 h, respectively. Peak concentrations for the metabolite, UK-103,320, were 0.116, 0.118, 0.132 and 0.160 mg/L at 2.5, 3.5, 2.0 and 2.5 h [G. J. Muirhead et al.,Br. J. Clin. Pharmacol.,2000, 502, 99107]. Toxicity Since 6 million prescriptions have been dispensed, the US Food and Drug Administration have reported 130 deaths in males taking sildenafil. The cause of death was unknown for 48 of these cases, 41 were caused by known or suspected myocardial function, 27 suffered from cardiac arrest, 6 with other cardiac symptoms and 3 with coronary artery disease. All were a known risk factor or contraindication to use of drug, for example, coadministration with another drug or substance. [US Food & Drug Administration report, Rockville, MD, USA, 1998]. A 43yearold man, treated for cardiovascular disease and erectile dysfunction with sildenafil citrate (Viagra), was found dead in a hotel room. Several tablets of verapamil, trimetazidine, yohimbine and bromazepam were found at the scene as well as a box of Viagra with two 25 mg tablets missing. Postmortem examination revealed sildenafil concentrations of 105, 246, 1206 and 754 g/L in blood, urine, bile and gastric content, respectively. Hair concentration was 177 ng/g. The desmethyl metabolite was measured as 143 g/L in urine. Blood levels of verapamil and trimetazidine were found to be 659 and 2133 g/L respectively. Trinitrine and yohimbine were not detected [V. Dumestre-Toulet et al.,Forensic. Sci. Int.,2002, 126, 7176]. A 42yearold female ingested 20 tablets of Viagra (100 mg per tablet) in a suicide attempt. Upon admission, she was oriented but nervous and complained of general weakness, palpitations, headache, dizziness and abdominal fullness. She underwent a gastrointestinal decontamination procedure, recovered and was discharged 12 h later [D. Z. Hung and D. Y. Yang,J. Toxicol. Clin. Toxicol.,2001, 39, 423424].

Bioavailability. 40%. Halflife. Plasma halflife, sildenafil, 3 to 5 h; Ndesmethylsildenafil, 4 h. Clearance. Plasma clearance, 41 L/h. Volume of distribution. Approx. 105 L. Protein binding. In plasma, 96% (both sildenafil and Ndesmethylsildenafil). Note. For a review of sildenafil see H. D. Langtry and A. Markham,Drugs,1999, 57, 967989.

Dose.
Usually the equivalent of 50 mg of sildenafil.