Why is nitroglycerin contraindicated with Phosphodiesterase (PDE) inhibitors?

From the Guidelines

Nitroglycerin is contraindicated with phosphodiesterase (PDE) inhibitors due to the risk of severe, potentially fatal hypotension. The most recent and highest quality study, the 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease 1, emphasizes that PDE inhibitors should not be used concomitantly with nitrate medications, including nitroglycerin, because of the potential for severe hypotension. Specific PDE5 inhibitors to avoid include sildenafil, tadalafil, vardenafil, which are commonly used for erectile dysfunction.

Key Considerations

• The timing restriction is significant: nitroglycerin should be avoided within 24 hours of taking sildenafil or vardenafil, and within 48 hours of taking tadalafil due to its longer half-life.
• This dangerous interaction occurs because both medications work through nitric oxide pathways that cause vasodilation.
• Nitroglycerin releases nitric oxide directly, while PDE inhibitors prevent the breakdown of cGMP, which is produced in response to nitric oxide.
• When combined, these mechanisms create an additive effect that can cause profound vasodilation, leading to severe hypotension, cardiovascular collapse, and potentially death.

Clinical Implications

• Patients experiencing chest pain who have recently taken PDE inhibitors should inform emergency medical personnel immediately to ensure appropriate treatment choices.
• The decision to use a PDE inhibitor in patients on long-acting nitrate therapy should be guided by the need for continued nitrate therapy versus other alternative options available to the treating clinician, as stated in the 2023 guideline 1.
• It is crucial to consider the potential risks and benefits of concomitant use of nitrates and PDE inhibitors, taking into account the patient's individual clinical profile and medical history.

From the FDA Drug Label

Administration of nitroglycerin sublingual tablets are contraindicated in patients who are using a phosphodiesterase-5 (PDE-5) inhibitor (e.g., sildenafil citrate, tadalafil, vardenafil hydrochloride) since these compounds have been shown to potentiate the hypotensive effects of organic nitrates. Nitroglycerin is contraindicated with PDE inhibitors because they can cause a potentiation of the hypotensive effects of organic nitrates, leading to hypotension 2.

• The concomitant use of nitroglycerin and PDE inhibitors can result in a significant increase in the risk of hypotension.
• This contraindication applies to specific PDE-5 inhibitors, such as sildenafil citrate, tadalafil, and vardenafil hydrochloride.

From the Research

Nitroglycerin Contraindication with PDE Inhibitors

• Nitroglycerin is contraindicated with Phosphodiesterase (PDE) inhibitors due to the synergistic decrease in blood pressure, which can lead to hypotension 3, 4, 5, 6, 7.
• The combination of nitroglycerin and PDE inhibitors can cause a profound decline in blood pressure, making it a contraindication for patients taking organic nitrates 3, 5.
• The duration of interaction between PDE inhibitors and nitrate administration depends on the specific drug being studied, with the interaction lasting up to 24 hours for short-acting PDE inhibitors and up to 48 hours for long-acting PDE inhibitors 3, 4, 7.
• Patients receiving nitrates who wish to use PDE inhibitors should be educated regarding the interaction and should be evaluated to determine whether nitrate treatment can be discontinued 4.

Mechanism of Interaction

• PDE inhibitors, such as sildenafil, vardenafil, and tadalafil, are mild vasodilators that can enhance the hypotensive effects of nitrates 3, 5.
• The combination of PDE inhibitors and nitrates can cause a significant decrease in blood pressure, leading to hypotension and potentially other cardiovascular complications 3, 4, 5, 6, 7.

Clinical Recommendations

• PDE inhibitors are contraindicated in patients taking organic nitrates, and caution should be exercised when using these medications in combination with other vasodilators or antihypertensive agents 3, 4, 5, 6, 7.
• Patients should be educated about the potential risks of combining PDE inhibitors with nitrates and should be monitored closely for signs of hypotension or other cardiovascular complications 4.