PDE-4 Inhibitors

he contraindication for nitroglycerin specifically applies to phosphodiesterase type 5 (PDE5) inhibitors, not to all classes of phosphodiesterase inhibitors. PDE5 inhibitors, which include sildenafil (Viagra, Revatio), tadalafil (Cialis), and vardenafil (Levitra), prevent the breakdown of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle. Nitroglycerin increases cGMP levels through nitric oxide–mediated vasodilation. When these medications are combined, excessive accumulation of cGMP can cause profound, sometimes life-threatening hypotension (Kloner & Mitchell, 2005).

By contrast, PDE4 inhibitors such as roflumilast (used for COPD) act on a different enzyme system that regulates cyclic adenosine monophosphate (cAMP), not cGMP. Because this mechanism does not potentiate the effects of nitrates, there is no clinically significant interaction between PDE4 inhibitors and nitroglycerin (StatPearls, 2023). For this reason, nitroglycerin can be safely administered to patients taking PDE4 inhibitors unless another contraindication exists, such as hypotension or right ventricular infarction.

The reference in the companion document to “phosphodiesterase inhibitors” should be interpreted as referring to PDE5 inhibitors only. These are the agents commonly prescribed for erectile dysfunction, pulmonary hypertension, and certain cases of heart failure. Withholding nitroglycerin solely on the basis of PDE4 inhibitor use, while cautious, is not required under the intended scope of the contraindication.

References
Kloner, R. A., & Mitchell, M. I. (2005). Pharmacology and drug interaction effects of the interaction between tadalafil and nitroglycerin. Journal of the American College of Cardiology, 42(11), 1855–1860.
StatPearls. (2023). Nitroglycerin. In StatPearls [Internet]. National Center for Biotechnology Information.