VIAGRA                                        to order  (prescription not required)

Synonyms: UK-92480-10. 
Chemical Name: 5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulfonyl) -phenyl]-1,6-dihydro-1-methyl-3-propylpyrazolo[4,3- -d]pyrimidin-7-one citrate; 1-{[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl- -1H-pyrazolo[4,3-d]pyrimidin-5-yl)- -4- -ethoxyphenyl]sulfonyl}-4-methylpiperazone citrate. 

Molecular Formula: C(22)H(30)N(6)O(4)S, -C(6)H(8)O(7) 
Molecular Weight: 666.7 CAS Registry: 139755-83-2 (sildenafil); 171599-83-0 (sildenafil citrate). 

ADVERSE EFFECTS 
Adverse effects most commonly reported from sildenafil are headache, flushing, and dyspepsia. There may be visual disturbances, dizziness, and nasal congestion. Other adverse effects reported include diarrhea, muscle pain, skin rashes, and urinary- or respiratory-tract infection. Priapism has also occurred. 

EFFECTS ON THE CARDIOVASCULAR SYSTEM. 
Acute myocardial infarction developed about 30 minutes after taking sildenafil in a 65-year-old man with no apparent risk factors for cardiovascular disease and before any attempt at sexual intercourse. (1) In the USA, of 69 patients who had died after taking sildenafil 2 deaths were due to stroke and 46 from some other cardiovascular event, although whether there was an association remains unclear. (2) 
1. Feenstra J, et al. Acute myocardial infarction associated with sildenafil. Lancet 1998; 352: 957-8. 
2. Anonymous. Sildenafil for erectile dysfunction. Drug Ther Bull 1998; 36: 81-4. 

PRECAUTIONS 
The cardiovascular risks of sexual activity should be considered before beginning therapy with sildenafil; in some patients, sexual activity may be inadvisable. Caution is required in patients with renal or hepatic impairment, and dosage reduction may be necessary. Care is also needed in patients with anatomical or haematological disorders which may predispose them to priapism, and may be advisable in those with bleeding disorders or active peptic ulceration. The safety of sildenafil is uncertain in patients with hypotension, a recent history of stroke or myocardial infarction, or retinal disorders such as retinitis pigmentosa (a minority of whom have genetic disorders of retinal phosphodiesterases). Patients who experience dizziness or visual disturbances should not drive or operate hazardous machinery. 

INTERACTIONS 
Sildenafil is contra-indicated in anyone taking organic nitrates as it may potentiate their hypotensive effects. Concomitant administration of sildenafil with drugs that inhibit cytochrome CYP3A4, such as cimetidine, may reduce sildenafil clearance. 

PHARMACOKINETICS 
Sildenafil is rapidly absorbed following administration by mouth, with a bioavailability of approximately 40%. Peak plasma concentrations are attained within 30 to 120 minutes; the rate of absorption is reduced when sildenafil is administered with food. Sildenafil is widely distributed into tissues and is approximately 96% bound to plasma proteins. It is metabolised in the liver primarily by cytochrome CYP3A4 and CYP2C9 isoforms. The major metabolite N-desmethylsildenafil, also has some activity. The terminal half-lives of sildenafil and the N-desmethyl metabolite are about 4 hours. Sildenafil is excreted, predominantly as metabolites, in the faeces, and to a lesser extent the urine. Clearance may be reduced in the elderly and in patients with severe renal or hepatic impairment. 

USES AND ADMINISTRATION 
Sildenafil is a phosphodiesterase type-5 inhibitor used in the management of erectile dysfunction. It is given by mouth as the citrate although doses are expressed in terms of the base. The usual dose is 50 mg about one hour before sexual intercourse. The dose may be increased to 100 mg once a day or decreased to 25 mg once a day depending on response. An initial dose of 25 mg is recommended in elderly patients and in those with severe renal or hepatic impairment, increased according to response if appropriate. 

1. Boolell M, et al. Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol 1996; 78: 257-61. 

2. Muirhead GJ, et al. Pharmacokinetics of sildenafil (VIAGRA(TM)), a selective cGMP PDE5 inhibitor, after single oral doses in fasted and fed healthy volunteers. Br J Clin Pharmacol 1996; 42: 268P. 

3. Goldstein I, et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998; 338: 1397-1404. Correction. ibid.; 339: 59. 

4. Anonymous. Sildenafil: an oral drug for impotence. Med Lett Drugs Ther 1998; 40: 51-2. * 5. Anonymous. Sildenafil for erectile dysfunction. Drug Ther Bull 1998; 36: 81-4.

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