Contraindication to Phosphodiesterase Inhibitors

Mechanism of Dangerous Interaction

The American College of Cardiology states that PDE5 inhibitors block the enzyme that degrades cyclic guanosine monophosphate (cGMP), which is the same pathway through which nitrates cause vasodilation, leading to profound hypotension, myocardial infarction, and potentially death in patients with stable angina 1, 2
The combination of nitrates and PDE5 inhibitors produces markedly exaggerated and prolonged vasodilation, representing a Class III recommendation (harm) in ACC/AHA guidelines, meaning the combination should never be performed, as it can cause severe hypotension and myocardial infarction 1, 2, 3

The American College of Cardiology recommends that no nitrates can be administered within 24 hours after taking sildenafil or vardenafil, and at least 48 hours after the last dose of tadalafil, due to its longer elimination half-life, to avoid severe hypotension and myocardial infarction 1, 2, 3
The American Heart Association guidelines state that patients currently using nitrates cannot safely take any PDE5 inhibitor, and if angina control allows discontinuation of nitrates, the patient must remain nitrate-free for the appropriate washout period (24-48 hours depending on which PDE5 inhibitor is chosen) before starting therapy, to minimize the risk of severe hypotension and myocardial infarction 1, 2, 4

The American College of Cardiology suggests that optimizing angina management to potentially eliminate or reduce the need for sublingual nitroglycerin could eventually allow PDE5 inhibitor use, and alternative erectile dysfunction treatments include intracavernosal prostaglandin E1 injections, intraurethral alprostadil, vacuum erection devices, or penile prosthesis if other options fail, with a strength of evidence level of moderate 3