Sildenafil (Viagra / Revatio)

You likely mean sildenafil - here is a full pharmacological overview based on authoritative medical textbooks.

Drug Class

Selective phosphodiesterase type 5 (PDE5) inhibitor. Structurally mimics the purine ring of cGMP.

Mechanism of Action

Sexual stimulation triggers release of nitric oxide (NO) from nerve endings and vascular endothelium in the penis. NO activates guanylyl cyclase, raising intracellular cGMP, which lowers cytoplasmic calcium and causes smooth muscle relaxation - producing penile erection.

Sildenafil works by competitively inhibiting PDE5, the enzyme that degrades cGMP. By blocking cGMP hydrolysis, it elevates cellular cGMP levels and amplifies the NO-cGMP-PKG signaling pathway.

Selectivity: >1,000-fold for PDE5 over other PDEs
Requires sexual stimulation to work - it does not cause erections independently
In the pulmonary vasculature, the same mechanism reduces vascular resistance, making it useful in pulmonary arterial hypertension (PAH)

(Goodman & Gilman's Pharmacological Basis of Therapeutics)

Pharmacokinetics (ADME)

Parameter	Details
Absorption	Rapid oral absorption; peak plasma levels ~1 hour
Protein binding	96% plasma protein bound
Metabolism	Hepatic - CYP3A (major) and CYP2C9 (minor); active metabolite: N-desmethyl sildenafil
Half-life	~4 hours (parent + active metabolite)
Elimination	Predominantly feces (73-88%); minimal urinary excretion
Food effect	High-fat meals delay absorption
Elderly	Reduced clearance → increased AUC

Clinical Uses

1. Erectile Dysfunction (ED)

First-line therapy (alongside vardenafil, tadalafil, avanafil)
Efficacy: 56-84% of patients on 25-100 mg report improved erectile function vs. 25% placebo
Effective across wide etiologies: hypertension (70%), diabetes (57%), radical prostatectomy (43%), spinal cord injury (80%)
Dose: 50 mg orally 1 hour before intercourse (range 25-100 mg); effect lasts ~4 hours
Also reported to reverse SSRI-induced anorgasmia in men

(Smith and Tanagho's General Urology; Kaplan and Sadock's Synopsis of Psychiatry)

2. Pulmonary Arterial Hypertension (PAH)

Dose: 20 mg three times daily (titrated up to 80 mg TID in some protocols)
Improves exercise capacity, functional class, and hemodynamics
Also used adjunctively with long-term epoprostenol therapy

(Murray & Nadel's Respiratory Medicine; Goodman & Gilman's)

Contraindications

Organic nitrates in any form (nitroglycerin, amyl nitrite/"poppers") - combination causes precipitous, potentially fatal hypotension by additive cGMP amplification
Concurrent use with riociguat (guanylate cyclase stimulator)
Pulmonary hypertension secondary to sickle cell disease (associated with vaso-occlusive crises)
Not recommended in children (chronic use associated with increased mortality in PAH trials)

Adverse Effects

Common (dose-dependent):

Headache (16%)
Flushing (10%)
Stomach pain, nasal congestion, diarrhea, dizziness

Ophthalmologic:

Transient blue-green tinting of vision (inhibition of retinal PDE6, which is involved in phototransduction)
Rare: Nonarteritic anterior ischemic optic neuropathy (NAION) - restriction of blood flow to the optic nerve; can cause permanent vision loss; onset within 24 hours of use; incidence ~1 in 1 million

Other rare effects:

Sudden hearing loss (reported post-marketing)
Priapism

Drug Interactions

Interacting Drug/Class	Effect
Organic nitrates	Severe, potentially fatal hypotension - absolutely contraindicated
CYP3A inhibitors (erythromycin, protease inhibitors, cimetidine)	Increased sildenafil levels, prolonged half-life
CYP3A inducers (bosentan)	Substantially decreased sildenafil plasma levels
Alpha-adrenergic blockers	Additive hypotension

Cardiovascular Cautions

Sildenafil itself does not independently increase myocardial infarction risk. However, sexual intercourse places increased oxygen demand on the heart. Patients with prior MI, stroke, hypertension, diabetes, or age >70 should be evaluated by a cardiologist before use, with specific attention to exercise tolerance and nitrate use.

Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics; Smith and Tanagho's General Urology (19th ed.); Kaplan and Sadock's Synopsis of Psychiatry; Murray & Nadel's Textbook of Respiratory Medicine

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