Indian J Physiol Pharmacol 1999; 43 (2): 160-164

MINI REVIEW

PHARMACOLOGY OF SILDENAFIL CITRATE

DHANANJAY N. UMRANI AND RAMESH K. GOYAL*

Department of Pharmacology,L. M. College of Pharmacy,Ahmedabad - 380 009

(Received on December 18, 1998)

Abstract: Erectile dysfunction is a common and multi-factorial diseasethat strongly impairs the quality of life in men. During the past decade,many new therapeutic strategies have become available. But the need fororal treatment was strongly felt. This need appears to have been fulfilledwith the introduction of sildenafil. The drug acts by enhancing smoothmuscle relaxant effect of nitric oxide. A number of clinical studies havenow proved its safety and efficacy. The drug has shaken social life all overthe world and to accept this "magic pill" or not remains the question ofindividual choice.

Key words : erectile dysfunction

Erectile dysfunction (ED) is a commonand multi-factorial disease that stronglyimpairs the quality of life in men. It isexpected to affect about 10-20 million menin the USA. In India, possibly because ofthe cultural, religious and malepredominance nature of the society, data isnot clearly available. During the pastdecade, many advances in theunderstanding of the pathophysiology of theerectile dysfunction have been made andnew therapeutic strategies have becomeavailable. It has been established that aninsufficient production of nitric oxide (NO)by penile nerve terminals and/or vascularendothelium may result in. an impairederection or impotence (1). ED is morecommon in older men, especially those withother chronic illnesses such as hypertension,atherosclerosis, and diabetes (2). The search

sildenafil ni tric oxide

for a treatment that is easier to administerand fulfils at least the part of the 'idealmedical treatment' like effectiveness,nontoxic, easy to administer and affordablecontinues (3).

Intracavernous injection of papaverinewas first used as monotherapy, but becauseof side effects such as priapism and fibrosisof the corpus cavernosum its use becamelimited. Later, combinations of papaverinewith phentolamine and/or PGE-1 wereused. Other combination therapies such asvasoactive intestinal peptide +phentolamine, or calcitonin gene relatedpeptide+PGE-1, have been suggested (4).

Sildenafil (VIAGRATM),was introducedby Pfizer Inc. on 27th March 1998.Sildenafil citrate is chemically 5-[2-ethoxy-

*Corresponding .Author

Indian J Physiol Pharmacol 1999; 43(2)

5-( 4-methy lp ip er azi n e-1-y Is u lfony I)phenyl] -1-methyl-3-propyl-6, 7-dihydro-1-H-pyrazolol [4-3-d] pyrimidin-7-one.With molecular formula-C22H30N60 45 (Fig. 1).

o

~CH3

Fig. 1: Chemical structure of sildenafil citrate.

Mechanism of action:

Unlike previously approved treatmentsfor impotence, sildenafil does not directlycause penile erection; but affects theresponse to sexual stimulation. The drugacts by enhancing the smooth musclerelaxant effects of nitric oxide (Fig. 2).

The physiologic mechanism of theerection of penis involves release of nitricoxide (NO) in the corpus cavernosum duringsexual stimulation. NO then activates theenzyme guanylate cyclase, which results inincreased levels of cyclic guanosinemonophosphotase (cGMP), producing inflowof blood. Sildenafil has no direct relaxanteffect on isolated human corpus cavernosum;but enhances the effect of nitric oxide (NO)by inhibiting phosphodiesterase type V (PDEV), which is responsible for the degradationof cGMP in the corpus cavernosum. When

Si llenafil Citrate 161

sexual stimulation causes local r el ea selevels of cGMP in the corpus cavernosum,resulting in smooth muscle relaxation andinflow of blood to the corpus cavernosum.Sildenafil at recommended doses has noeffects in the absence of sexual stimulation(5).

NITRIC OXIDE

J+IGUANYLATE CYCLASE

1

SILDENAFIL

1-'PDE - V

1GTP ----- ..••~ cGMP ------II~~ GMP

(ACTIVE) (INACTIVE)

Fig. 2 : Arrow diagram showing mechanism of actionof sildenafil.

In vitro studies have shown thatsildenafil is selective for PDE V. Its effectis more potent on PDE V than on otherknown phosphodiesterases (>80 fold for PDEI, >1000 fold for PDE II, PDE III and PDEIV). Approximately 4000 fold selectivity forPDE V versus PDE III is important as PDEis involved in control of cardiac contrctility.Sildenafil is only about 10 fold as potentfor PDE VI, an enzyme found in the retina.This lower selectivity is thought to be thebasis for abnormalities related to colourvision observed with higher doses (6).

Pharmacodynamics:

In clinical studies, sildenafil has beenassessed for its effect on the ability of men

Indian J Physiol Pharmacol 1999; 43(2)

was mixed in the remaining 18% of men.Efficacy was assessed by a self-administeredquestionnaire at week 8. In response to aglobal assessment question (Did treatmentimprove your erections ?), 27.7% of thepatients in the placebo group answered 'yes'compared to 47.7% of the sildenafil 4 mggroup, 60.9% of the 25 mg group, 72.9% ofthe 50 mg group, and 77 .8% of the 100 mggroup, indicating that sildenafil appears towork in men with organic impotence as wellas in those with psychogenic impotence (13).

A meta-analysis of 10 studies in 3361patients with erectile dysfunction showedthat sildenafil 50 or 100 mg wassignificantly more effective than placebo interms of frequency of penetration andfrequency of maintained erections (14). Ameta-analysis of 8 studies of sildenafil in2705 elderly patients showed that it wasequally effective in elderly (>=65 years) aswell as in younger patients with erectiledysfunction (15).

Pharmacokinetics and Metabolism:

Sildenafil is rapidly absorbed after oraladministration, with absolute bioavailabilityof about 40%. Its pharmacokinetics is doseproportional over the recommended doserange (25, 50· and 100 grn), I( is eliminatedpredominantly by hepatic metabolism(mainly cytochrome P450 3A4) and isconverted to an active metabolite withproperties similar to parent moleculesildenafil. Both, sildenafil and itsmetabolite, have terminal half-lives of about4 hours. Maximum observed plasmaconcentrations are reached within 30 to 120min. of oral dosing in fasted state. Whentaken with a high fat meal, the rate of

Sildenafil Citrate 163

absorption is reduced, with a mean delay inTmax of 60 min. and a mean reduction inCmax of 29%. The mean steady state volumeof distribution (Vss ) for dildenafil is 105L.Sildenafil is cleaved predominantly byhepatic microsomal isoenzymes CYP 3A4(major route) and CYP2C9 (minor route).The major circulating metabolite resultsfrom N-desmethylation of sildenafil, and isitself further metabolized. Sildenafil, and itsmajor circulating N-desmehyl metabolite areboth approx. 96% bound to the plasmaproteins. After either oral or i.v.administration, sildenafil is excreted asmetabolites predominantly in the feaces andto a lesser extent in the urine.

Drug Interactions:

As sildenafil metabolism is principallymediated by the cytochrome P450 isoforms3A4 and 2C9 the inhibitors of theseisoenzymes may reduce sildenafil clearance.e.g. cimetidine, erythromycin. It has beenfound to produce postural hypotension whencombined with nitrates in hypertensionprobably because sildenafil potentiatesaction of NO; which is also the mediator fornitrates. So sildenafil should be strictlyavoided in patients on nitrate therapy.

Adverse Reactions and precautions:

One out of 10 men in clinical trialsdeveloped blinding headaches. There can besudden drops in blood pressure leading toblackouts. Although priapism neverhappened in trials, there is theoretical riskthat men with sickle cell anemia orleukemia could develop priapism. Sometimesimpotence is an early indication of heartdisease, diabetes and some types of cancer.

164 Umrani and Goyal

Taking sildenafil could mask these life-threatening conditions (6).

Cardiovascular status of patient shouldbe taken into consideration before initiatingtreatment for ED. The safety and efficacyof the combinations of sildenafil with othertreatments for ED have not been studied.Therefore, use of such combinations is notrecommended.

Indian J Physiol Pharmacol 1999; 43(2)

Phase II safety trials for sildenafil areunderway in Europe, because it may alsohave the potential to help treat women withsexual dysfunction. To date, sildenafil hasnot been shown to have positive effects inwomen with this condition. Scientists areworking to develop a second generation drugbased on sildenafil that will work faster andbe devoid of the adverse effects associatedwith sildenafil (6).

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