Viagra - Drug Monograph

Introduction

Viagra (sildenafil citrate) is a phosphodiesterase type 5 (PDE5) inhibitor developed by Pfizer and first approved by the FDA in 1998. It revolutionized the treatment of erectile dysfunction (ED) and remains one of the most prescribed medications for this condition worldwide. Originally investigated as an antihypertensive agent, its effects on penile erection led to its development for sexual dysfunction.

Mechanism of Action

Sildenafil exerts its therapeutic effects through selective inhibition of phosphodiesterase type 5 (PDE5), the predominant PDE isoenzyme in corpus cavernosum tissue. During sexual stimulation, nitric oxide (NO) release activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) levels. cGMP produces smooth muscle relaxation in the corpus cavernosum, allowing increased blood flow and erection. PDE5 normally degrades cGMP, but sildenafil's inhibition potentiates the natural erectile response by maintaining elevated cGMP levels.

Indications

• Treatment of erectile dysfunction (ED) in adult males
• Treatment of pulmonary arterial hypertension (PAH) in adults and children aged 1 year and older (marketed as Revatio® at different strength)

Dosage and Administration

• Initial dose: 50 mg taken approximately 1 hour before sexual activity
• Dose range: 25-100 mg based on efficacy and tolerability
• Maximum dosing frequency: Once daily
• Administration: Oral tablet taken with or without food

• Elderly: Consider starting dose of 25 mg
• Hepatic impairment: Maximum dose 25 mg in severe cirrhosis
• Renal impairment: No dose adjustment needed for mild-moderate impairment; caution advised in severe impairment
• Concomitant CYP3A4 inhibitors: Maximum dose 25 mg

Pharmacokinetics

• Absorption: Rapidly absorbed with absolute bioavailability of approximately 40%; Tmax 30-120 minutes (delayed by high-fat meal)
• Distribution: Volume of distribution 105 L; protein binding approximately 96%
• Metabolism: Extensive hepatic metabolism primarily via CYP3A4 (major) and CYP2C9 (minor) pathways; active metabolite (N-desmethyl sildenafil) has 50% potency of parent drug
• Elimination: Terminal half-life approximately 4 hours; primarily fecal excretion (80%) with minor renal elimination (13%)

Contraindications

• Concomitant use of organic nitrates in any form (regularly or intermittently)
• History of serious hypersensitivity reaction to sildenafil or any component of the formulation
• Concomitant use with guanylate cyclase stimulators (riociguat)
• Patients with hereditary degenerative retinal disorders

Warnings and Precautions

• Cardiovascular effects: Not for use in men for whom sexual activity is inadvisable due to cardiovascular status
• Priapism: Prolonged erections (>4 hours) require immediate medical attention to prevent tissue damage
• Sudden hearing loss: Reports of sudden decrease or loss of hearing; discontinue use if occurs
• Vision changes: Non-arteritic anterior ischemic optic neuropathy (NAION) reported; discontinue use if sudden vision loss occurs
• Hypotension: May potentiate hypotensive effects of other medications
• Hepatic impairment: Use with caution in severe impairment
• Renal impairment: Use with caution in severe impairment
• Penile deformity: Use with caution in patients with anatomical penile deformity

Drug Interactions

• Nitrates: Profound hypotension (contraindicated)
• Alpha-adrenergic blockers: Additive hypotension (dose adjustment may be needed)
• CYP3A4 inhibitors: Increased sildenafil concentrations (ketoconazole, ritonavir, erythromycin)
• CYP3A4 inducers: Decreased sildenafil concentrations (rifampin, carbamazepine)
• Antihypertensives: Potential additive hypotensive effects
• Guanylate cyclase stimulators: Contraindicated (riociguat)

Adverse Effects

• Headache (16%)
• Flushing (10%)
• Dyspepsia (7%)
• Nasal congestion (4%)
• Visual disturbances (3%)
• Back pain, myalgia

• Myocardial infarction
• Sudden cardiac death
• Cerebrovascular hemorrhage
• Transient ischemic attack
• Ventricular arrhythmia
• Priapism
• Sudden hearing loss
• NAION
• Severe hypotension

Monitoring Parameters

• Cardiovascular status before initiation and periodically during therapy
• Visual changes (ophthalmologic examination if visual disturbances occur)
• Hearing changes (audiologic evaluation if hearing symptoms occur)
• Response to therapy and adverse effects
• Blood pressure in patients taking antihypertensive medications

Patient Education

• Take approximately 30-60 minutes before sexual activity
• Sexual stimulation is required for medication to work
• Do not exceed one dose per day
• Seek immediate medical attention for erections lasting more than 4 hours
• Report sudden vision changes, hearing loss, chest pain, or dizziness
• Avoid grapefruit juice as it may increase drug levels
• Do not use with nitrates in any form
• Inform healthcare providers of all medications being taken
• Medication does not protect against sexually transmitted infections

References

1. FDA Prescribing Information: Viagra (sildenafil citrate) tablets. 2014 2. Goldstein I, et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338(20):1397-1404 3. Jackson G, et al. Cardiovascular safety of sildenafil citrate: clinical evidence. Int J Clin Pract. 2009;63(11):1582-1591 4. Hatzimouratidis K, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol. 2010;57(5):804-814 5. Porst H, et al. Efficacy and safety of flexible-dose sildenafil citrate in men with erectile dysfunction. J Sex Med. 2006;3(5):840-848 6. Morgentaler A, et al. Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction. Clin Ther. 2001;23(1):3-16