Sildenafil citrate (Viagra, Pfizer Pharmaceuticals) is a selective inhibitor of phosphodiesterase-5 (PDE5), the enzyme that breaks down the intracellular second messenger of erection cGMP and thus enhances penile erection. The clinical efficacy and safety of sildenafil was evaluated in many placebo-controlled, double-blind trials and open-label studies (Goldstein et al, 1998, Morales et al, 1998). Improvement in erections was reported in 56-84% of subjects taking 25-100 mg of sildenafil and 25% in the placebo group. Treatment effect was principally assessed by items 3 and 4 of the IIEF-15 questionnaires (ability to initiate and maintain erection). Overall responses to sildenafil appear to be dosage related over the range 25-100 mg, with little ED benefit and considerably more side effects above 100 mg. Sildenafil is effective in patients with organic, psychogenic, and mixed-etiology ED. An overall beneficial treatment effect was seen in 70% of patients. As fas as specific etiologies of ED, sildenafil was effective in 70% of hypertensive patients, 57% of diabetic patients, 43% of radical prostatectomy patients, and 80% of spinal cord injury patients. Since PDE5 inhibitor proerectile effects are only seen with sexual stimulation and depend on intact cavernous nerve function (release of NO), a positive treatment effect would not be expected in patients with cavernous nerve injury due to non-nerve sparing pelvic surgery.

The peak blood level is achieved about 1 h following oral administration. A high-fat meal slows the rate of absorption and may delay peak plasma concentrations by 2 h and in some cases reduce peak plasma concentrations by 25%. Older age (>  65 years), hepatic impairment, drugs that inhibit the cytochrome P450 isoenzyme (cimetidine, ketoconazole, erythromycin), and severe renal insufficiency are associated with increased plasma levels of sildenafil; therefore, the dosage should be reduced in these patients.

Principal adverse events with a dose of 25-100 mg are headache (15.8%), flushing (10.5%), dyspepsia (6.5%), nasal congestion (4.2%), altered vision (2.7%), diarrhea (2.6%), dizziness (2.2%), and arthralgia (2.0%). Sildenafil is absolutely contraindicated for men using nitrates (oral, sublingual, or topical) because sildenafil potentiates the hypotensive effects of all nitrates. ED is common among men who have atherosclerotic coronary artery disease. Data from the Framingham Heart Study suggest that the risk of myocardial infarction in a healthy 50-year-old US male is 1% per year or 1 per million men per hour. The risk of myocardial infarction is 2 in a million during and within 2 h after sexual activity (_{Moller et al, 2001}). The American College of Cardiology and American Heart Association guidelines caution that sildenafil dosing is potentially hazardous in men with coronary ischemia (positive exercise test), men with congestive heart failure and borderline low blood pressure and low blood volume, and men taking complicated multidrug antihypertensives (_{Cheitlin et al, 1999}). In these patients a referral to cardiology is strongly recommended if the patient desires sildenafil therapy.

Yohimbine

Yohimbine is a centrally acting alpha-2-adrenergic antagonist obtained from the bark of the yohim tree. Although it has been highly effective in castrated rats, several clinical studies have shown only moderate success in men. In clinical studies, yohimbine seems to be effective in patients with psychogenic but not organic ED. As an initial treatment 5.4 mg 3 times daily has been recommended; others have reported efficacy by doubling that dosage or using on an as-needed basis (2 tablets 1-2 h prior to anticipated sexual activity). Side effects of yohimbine include palpitations, headache, agitation, anxiety, and increase in blood pressure (precautions are advised in men with cardiovascular disease).

Trazodone

Trazodone is a commonly prescribed mild antidepressant with a rare incidence of priapism. Several small clinical trials have shown a positive effect on nocturnal penile erection (_{Saenz de Tejada et al, 1991}) and a modest effect on sexually stimulated erection. A dual mechanism of (peripheral) alpha-adrenergic blocking and (central) inhibition of serotonin reuptake (increasing 5HT-1c) is the proposed mechanism of action. Dosages ranging from 25 mg to 200 mg nightly have been used. A combination of trazodone and yohimbine has also been reported to improve erectile function in some patients (_{Montorsi et al, 1994}). Side effects include drowsiness, nausea, emesis, blood pressure changes (both hypotension and hypertension are reported), urinary retention, and priapism (especially at therapeutic antidepressant levels).

Apomorphine

Apomorphine is a D1/D2 dopamine receptor agonist, activating D1 and D2 receptors. Dopaminergic stimulation is proerectile; early reports of patients treated for Parkinson disease showed increased spontaneous erections, without increased libido. A sublingual form of apomorphine (Uprima) has been approved for ED in Europe but has not been approved by the FDA in the United States.

In a double-blind, placebo-controlled study, at dosages of 2 and 4 mg, subjects reporting erections firm enough for intercourse were 45% and 55%, respectively, with placebo responses of 35% and 36%. Sexual attempts resulting in intercourse were 40% and 49%, respectively, on 2 and 4 mg; placebo dosing resulted in intercourse in 30% of attempts. Self-assessment of success was 47% at 2-mg dosing and 59.9% at 4-mg dosing (_{Heaton, 2001}).

The drug has a rapid onset of action, with a window of sexual opportunity of approximately 2 h from ingestion. Maximal plasma concentrations are reached in 50 min. Adverse events described in clinical trials were nausea, 16.9%; dizziness, 8.3%; sweating, 5%; somnolence, 5.8%; yawning, 7.9%; and emesis, 3.7%. At the highest recommended dosage syncope occurred in 0.6% of patients and was accompanied by a clear prodrome suggestive of a vasovagal event: nausea, vomiting, sweating, dizziness, and lightheadedness (_{Heaton, 2001}). There were no documented food/drug interactions in clinical trials (with the exception of ethanol) and specifically no documented pharmacologic interactions for subjects using nitrate drugs.