What are the uses for sildenafil (phosphodiesterase type 5 (PDE5) inhibitor)?

Uses for Sildenafil

Sildenafil is FDA-approved for two primary indications: erectile dysfunction (ED) and pulmonary arterial hypertension (PAH). 1

Erectile Dysfunction

Oral PDE5 inhibitors like sildenafil should be offered as first-line therapy for erectile dysfunction unless contraindicated. 2

Mechanism and Efficacy

• Sildenafil selectively inhibits phosphodiesterase type 5 (PDE5), which increases cyclic GMP levels in the corpus cavernosum, causing smooth muscle relaxation and enhanced blood flow to the penis during sexual stimulation 3, 4
• The drug requires sexual stimulation to be effective—it has no effect in the absence of sexual arousal 4
• In clinical trials, 69% of men using sildenafil reported successful sexual intercourse attempts compared to 33% with placebo 5
• Efficacy is maintained with long-term use up to 1 year 3

Dosing for Erectile Dysfunction

• Starting dose is typically 50 mg taken approximately 1 hour before sexual activity, not more than once daily 3
• Maximum dose is 100 mg once daily 3
• Lower doses (25 mg) should be used in elderly patients, those with hepatic or renal impairment, or those receiving CYP3A4 inhibitors such as ritonavir, ketoconazole, or erythromycin 3
• Peak plasma concentrations occur within 30-120 minutes after oral dosing in the fasting state 4

Special Populations for ED

• Spinal cord injury patients (T6-L5): Sildenafil significantly improves erectile quality, with 75% reporting improved erections versus 7% on placebo 6
• Diabetic patients: Have more severe ED at baseline and may respond less robustly to PDE5 inhibitors 5, 7
• Post-prostatectomy patients: Show reduced response compared to the general population due to more severe baseline ED 5, 7

Pulmonary Arterial Hypertension

Sildenafil is approved for treatment of pulmonary arterial hypertension by causing vasodilation of the pulmonary vascular bed. 1

Mechanism in PAH

• Sildenafil inhibits PDE5 in pulmonary vascular smooth muscle, increasing cGMP and causing relaxation of pulmonary vessels 1
• This leads to vasodilation of the pulmonary vascular bed and, to a lesser degree, systemic circulation 1

Dosing for PAH

• The typical dose for PAH is 20 mg three times daily (80 mg TID in clinical trials) 1
• After chronic dosing of 80 mg TID to PAH patients, mean reductions in systolic and diastolic blood pressure were only 2 mmHg 1

Important PAH Considerations

• Pediatric mortality warning: In long-term trials in pediatric patients with PAH, an increase in mortality with increasing sildenafil dose was observed; chronic use is not recommended in children 1
• Pulmonary veno-occlusive disease (PVOD): Sildenafil is not recommended in PVOD patients as pulmonary vasodilators may significantly worsen cardiovascular status 1
• If pulmonary edema occurs during sildenafil administration, consider the possibility of PVOD 1

Critical Safety Considerations Across All Uses

Absolute Contraindications

• Nitrate use: Sildenafil combined with organic nitrates can cause dangerous, potentially fatal hypotension and is absolutely contraindicated 5, 1, 4
• Patients must be explicitly questioned about all forms of nitrate use before prescribing 5
• Suggested safe time interval for nitrate administration after sildenafil is 24 hours under close medical supervision 2

High-Risk Cardiac Patients

Patients at high cardiovascular risk should not receive sildenafil for ED until their cardiac condition has stabilized. 2, 7 This includes those with:

• Unstable or refractory angina 2, 7
• Uncontrolled hypertension 2, 7
• Left ventricular dysfunction/CHF (NYHA class II or greater) 2, 7
• MI or CVA within previous 2 weeks 2, 7
• High-risk arrhythmias 2, 7
• Hypertrophic obstructive cardiomyopathies 2, 7
• Moderate-to-severe valvular disease 2, 7

Cardiovascular Effects

• Single oral doses produce mean maximum decreases in blood pressure of 8/5 mmHg, most notable 1-2 hours after dosing 1
• Blood pressure should be monitored when co-administering with antihypertensive drugs 1
• Carefully consider use in patients with resting hypotension (BP <90/50), fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction 1

Other Serious Warnings

• Visual loss (NAION): Non-arteritic anterior ischemic optic neuropathy has been reported; patients should seek immediate medical attention for sudden vision loss 1
• Hearing loss: Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported; patients should seek prompt medical attention 1
• Priapism: Use with caution in patients with anatomical penile deformation or conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia); erections lasting >4 hours require immediate medical attention 1
• Epistaxis: Incidence was 13% in PAH patients with connective tissue disease, and higher (9% vs 2%) in those taking concomitant vitamin K antagonists 1

Common Adverse Effects

• Headache, flushing, dyspepsia, nasal congestion, and abnormal vision are the most common side effects 3, 4
• These are typically transient and mild to moderate in severity 3
• Tolerability is maintained with long-term use up to 1 year 3

Important Clinical Pearls

• Do not combine with other PDE5 inhibitors: Sildenafil for PAH (20 mg) should not be combined with sildenafil for ED (25-100 mg) or other PDE5 inhibitors 1
• Tissue selectivity: Sildenafil is approximately 4,000-fold selective for PDE5 versus PDE3 (which controls cardiac contractility), explaining its lack of direct cardiac effects 1, 8
• No PDE5 in cardiac myocytes: Human cardiac ventricle contains primarily PDE1 but no detectable PDE5, consistent with sildenafil's lack of direct cardiac contractility effects 8