Brands, Medical Use, Clinical Data
- Vasodilator Agents
- Phosphodiesterase Inhibitors
Brands / Synonyms
Revatio; Sildenafil Viagra; Viagra; Viagra
For the treatment of erectile dysfunction
Sildenafil is used to treat male erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH). Part of the physiological process of erection involves the release of nitric oxide (NO) in the corpus cavernosum. This then activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in the corpus cavernosum, resulting in increased inflow of blood and an erection. Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum. This means that, with Sildenafil on board, normal sexual stimulation leads to increased levels of cGMP in the corpus cavernosum which leads to better erections. Without sexual stimulation and no activation of the NO/cGMP system, Sildenafil should not cause an erection.
Mechanism of Action
Sildenafil inhibits the cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by Sildenafil enhances erectile function by increasing the amount of cGMP.
Biotrnasformation / Drug Metabolism
Consistent with its known effects on the nitric oxide/cGMP pathway , sildenafil citrate was shown to potentiate
the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates either
regularly and/or intermittently in any form is therefore contraindicated.
After patients have taken sildenafil citrate, it is unknown when nitrates, if necessary, can be safely
administered. Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers,
the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of
approximately 440 ng/mL). In the following patients: age >65, hepatic impairment (e.g., cirrhosis), severe
renal impairment (e.g., creatine clearance <30 mL/min), and concomitant use of potent cytochrome P450 3A4
inhibitors (erythromycin), plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times
higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours post dose are much
lower than at peak concentration, it is unknown whether nitrates can be safely coadministered at this time point.
Sildenafil citrate is contraindicated in patients with a known hypersensitivity to any component of the
Effects of Other Drugs on Sildenafil Citrate
In Vitro Studies: Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP)
isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil
In Vivo Studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma
sildenafil concentrations when coadministered with sildenafil citrate (50 mg) to healthy volunteers.
When a single 100 mg dose of sildenafil citrate was administered with erythromycin, a specific CYP3A4 inhibitor,
at steady state (500 mg bid for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In
addition, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200
mg tid) with sildenafil citrate (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a
210% increase in sildenafil AUC. Sildenafil citrate had no effect on saquinavir pharmacokinetics. Stronger CYP3A4
inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data
from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with
CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine).
Coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady
state (400 mg bid) with sildenafil citrate (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil
Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil
were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is
consistent with ritonavir's marked effects on a broad range of P450 substrates. Sildenafil citrate had no effect on
It can be expected that concomitant administration of CYP3A4 inducers, such as rifampin, will decrease plasma
levels of sildenafil.
Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil
Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9
inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors,
tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of
the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by
nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.
Effects of Sildenafil Citrate on Other Drugs
In Vitro Studies: Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19,
2D6, 2E1 and 3A4 (IC50 >150 mM). Given sildenafil peak plasma concentrations of approximately 1 mcM after
recommended doses, it is unlikely that sildenafil citrate will alter the clearance of substrates of these
In Vivo Studies: When sildenafil citrate 100 mg oral was coadministered with amlodipine, 5 mg or 10
mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are
metabolized by CYP2C9.
Sildenafil citrate (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Sildenafil citrate (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean
maximum blood alcohol levels of 0.08%.
Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir
and ritonavir, both of which are CYP3A4 substrates.