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Chapter: Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Gastrointestinal and Endocrinal Drugs

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Sildenafil - Drugs Used in the Treatment of Impotence

Till recently, there was no really satisfactory method or drug available to effectively treat male impotence or erectile dysfunc-tion.

DRUGS USED IN THE TREATMENT OF IMPOTENCE

Till recently, there was no really satisfactory method or drug available to effectively treat male impotence or erectile dysfunc-tion. The following were tried with varying degrees of success: intracavernosal injection of vasoactive agents, transurethral delivery of prostaglandin E1, implantation of penile prosthesis, and venous or arterial surgery. Oral therapy was almost non-existent (except for tentative trials with apomorphine and phen-tolamine), until the arrival of sildenafil. Today, this drug has become one of the largest selling drugs in the world, since it is claimed to be very effective.

Sildenafil

Sildenafil was developed by Pfizer initially as an anti-anginal and antihypertensive agent, but as its reputation increased with respect to enhanced sexual performance among male subjects, the manufacturers decided to switch tracks and began to adver-tise it as an anti-impotence pill. Since then there has been no looking back, and sales of sildenafil have soared all over the world, so much so that it has become the biggest ever grosser among all pharmaceutical preparations.

Uses

·      Male erectile dysfunction: Sildenafil is effective only whenthere is at least partial erection. It is not effective in the presence of severe arteriogenic or venogenic impotence, corporal smooth muscle fibrosis, and anatomical deformi-ties of the penis. The drug has to be taken an hour before anticipated sexual activity.

·              Female impotence: Trials are on to test the efficacy of sildenafil in the treatment of female impotence. Initial reports are said to be encouraging. 

Toxicokinetics

Sildenafil is rapidly absorbed after oral administration, the absolute bioavailability being about 40%. Maximum plasma concentrations are achieved in about one hour, with mean terminal half-life of 3 to 5 hours. It is metabolised by hepatic microsomal enzyme systems—the CYP3A4 route mainly, and to a lesser extent by the CYP2C9 route. Major excretion occurs in the faeces (80%) and urine (13%).

Mode of Action

Sildenafil is a selective inhibitor of cyclic GMP specific phos-phodiesterase (PDE) type 5, the predominant enzyme which metabolises cyclic GMP in the corpus cavernosum. When sexual excitement causes local release of nitric oxide, inhibi-tion of PDE5 by sildenafil results in increased levels of cyclic GMP, which leads to smooth muscle relaxation and inflow of blood into the corpus cavernosum.

Sildenafil also inhibits PDE6, which is found in retina and is believed to be involved in phototransduction. This explains the colour vision abnormalities encountered at high doses of the drug.

Adverse Effects

·      General: headache, facial flushing, dyspepsia, and diar-rhoea.

·      CVS: sudden drop in blood pressure (especially if the patientis on nitrate therapy).

·      Visual: light sensitivity, bluish tinged vision.

Clinical (Toxic) Features

·              Chest pain, stroke, cardiac arrhythmias, heart failure.

Forensic Issues

·              Deaths have been reported in elderly males who participated in sexual activity after ingesting sildenafil. In most of these cases there was underlying cardiac diasease or hypertension. 

Since there are indications of sildenafil misuse among the youth (who do not really require the drug), in the form of a recreational drug, there are concerns about acute toxicity, especially in the presence of concomitant intake of amyl nitrite. The latter is not uncommonly abused for its “high” during the course of rave parties.


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