What are examples of phosphodiesterase (PDE) inhibitors?

Phosphodiesterase Inhibitors: Medication Examples

Phosphodiesterase inhibitors are a class of medications that includes multiple FDA-approved agents, with the most clinically relevant being the PDE-5 inhibitors (sildenafil, tadalafil, vardenafil, and avanafil) used for erectile dysfunction and pulmonary hypertension, as well as PDE-3 inhibitors (milrinone, amrinone) for cardiac conditions. 1, 2

PDE-5 Inhibitors (Most Commonly Used)

FDA-Approved Agents

• Sildenafil - The first FDA-approved PDE-5 inhibitor, marketed as Viagra for erectile dysfunction and Revatio for pulmonary arterial hypertension 3
• Tadalafil - Distinguished by its significantly longer half-life of 17.5 hours compared to other PDE-5 inhibitors, providing approximately 36 hours of action 4, 1
• Vardenafil - A twice-daily PDE-5 inhibitor with similar efficacy to other agents in this class 2, 5
• Avanafil - The newest FDA-approved PDE-5 inhibitor with the lowest rates of dyspepsia among this drug class 6, 1

Mechanism of Action

• These medications inhibit the cGMP-degrading enzyme phosphodiesterase type-5, resulting in vasodilation through the NO/cGMP pathway 2
• PDE-5 is strongly expressed in the pulmonary vasculature, making these agents effective for pulmonary arterial hypertension 2
• They exert both vasodilatory and antiproliferative effects on vascular smooth muscle 2

Clinical Applications

• Erectile dysfunction: All four FDA-approved PDE-5 inhibitors demonstrate similar efficacy, improving erections in 73-88% of cases compared to 26-32% with placebo 1
• Pulmonary arterial hypertension: Sildenafil (20 mg three times daily) and tadalafil (40 mg once daily) are approved for WHO functional class II-III patients 2

PDE-3 Inhibitors

Cardiac Applications

• Milrinone and amrinone - Used for myocardial dysfunction, though they have relatively weak effects on the pulmonary circulation compared to PDE-5 inhibitors 2
• Theophylline - A non-selective PDE inhibitor historically used for asthma treatment 2, 7

Other PDE-5 Inhibitors (Less Common)

Investigational or Regional Agents

• Dipyridamole - An early PDE-5 inhibitor that can lower pulmonary vascular resistance but has limited potency and selectivity 2
• Mirodenafil and udenafil - Evaluated in clinical trials with demonstrated efficacy but not FDA-approved in the United States 1
• Zaprinast, E4021, and DMPPO - Experimental compounds that cause pulmonary vasodilation in animal models 2, 7

Critical Safety Considerations

Absolute Contraindications

• Never combine PDE-5 inhibitors with nitrate medications due to risk of severe, potentially fatal hypotension 4, 6, 8
• Wait at least 24 hours after sildenafil or vardenafil before administering nitrates 4
• Wait at least 48 hours after tadalafil before administering nitrates due to its longer half-life 4

Drug Interactions

• Co-administration with CYP3A inhibitors increases PDE-5 inhibitor plasma concentrations and requires dose adjustment 9
• Caution is advised when combining with alpha-blockers due to additive blood pressure lowering effects 5, 8
• Patients should be stable on alpha-blocker therapy before initiating PDE-5 inhibitors 5

Common Side Effects

• Headache, flushing, nasal congestion, dyspepsia, back pain, myalgia, and visual disturbances are the most frequently reported adverse events 2, 6
• Tadalafil has lower rates of flushing compared to other PDE-5 inhibitors 4, 6
• The incidence of serious adverse events is less than 2%, with no significant difference between medications and placebo 4