What is the drug class of Sildenafil (Phosphodiesterase type 5 inhibitor)?

Sildenafil Drug Class

Sildenafil is a phosphodiesterase type-5 (PDE-5) inhibitor, a class of drugs that selectively inhibit the cGMP-degrading enzyme phosphodiesterase type-5, resulting in vasodilation through the nitric oxide/cGMP pathway. 1

Mechanism of Action

Sildenafil works by inhibiting PDE-5, the enzyme responsible for degrading cyclic guanosine monophosphate (cGMP) in vascular smooth muscle. 2 This mechanism leads to:

• Increased cGMP concentrations in target tissues, which activates cGMP kinase, opens potassium channels, and causes smooth muscle relaxation and vasodilation 1
• Enhanced nitric oxide (NO) effects by preventing the rapid degradation of cGMP that normally limits NO signaling 1
• Pulmonary and systemic vasodilation at sites where PDE-5 is expressed, particularly in pulmonary vasculature and corpus cavernosum 1, 2

Selectivity Profile

Sildenafil demonstrates high selectivity for PDE-5 compared to other phosphodiesterase isoenzymes, which explains its therapeutic effects and side effect profile 2:

• Approximately 4,000-fold selectivity for PDE-5 versus PDE-3 (the isoenzyme controlling cardiac contractility), ensuring minimal direct cardiac effects 2
• Only 10-fold selectivity for PDE-5 versus PDE-6 (found in retinal tissue), which accounts for visual disturbances at higher doses or plasma levels 2
• Greater than 80-fold selectivity over PDE-1, and greater than 700-fold over PDE-2, PDE-3, PDE-4, PDE-7, PDE-8, PDE-9, PDE-10, and PDE-11 2

Other PDE-5 Inhibitors in the Same Class

All three PDE-5 inhibitors approved for erectile dysfunction—sildenafil, tadalafil, and vardenafil—cause significant pulmonary vasodilation with maximum effects at different time points (60,75-90, and 40-45 minutes respectively) 1. Additional agents in this class include:

• Avanafil, which is FDA-approved for erectile dysfunction 3
• Mirodenafil and udenafil, which have been evaluated in clinical trials 3

Clinical Applications

The PDE-5 inhibitor class has two primary FDA-approved indications:

• Erectile dysfunction: All PDE-5 inhibitors demonstrate similar efficacy (73-88% improvement vs 26-32% with placebo) 3
• Pulmonary arterial hypertension (PAH): Sildenafil at 20 mg three times daily is approved for WHO functional class II-III PAH patients, with demonstrated improvements in exercise capacity, symptoms, and hemodynamics 1

Key Pharmacologic Characteristics

Sildenafil exhibits dose-proportional pharmacokinetics over the recommended dosage range with the following properties 4:

• Rapid absorption with maximum plasma concentrations reached within 30-120 minutes after oral dosing in the fasting state 4
• 40% absolute bioavailability after oral administration 4
• Approximately 4-hour half-life, similar to vardenafil but shorter than tadalafil's 17.5-hour half-life 5
• Hepatic metabolism predominantly via CYP3A4 (major) and CYP2C9 (minor) 4