What is tachyphylaxis to oral nitrates?

From the Guidelines

To prevent tachyphylaxis to oral nitrates, implement a nitrate-free interval of 10-12 hours daily, typically overnight.

Specific Recommendations

• Prescribe long-acting nitrates (e.g., isosorbide mononitrate) to be taken once daily in the morning 1.
• For twice-daily dosing, schedule doses at 8 AM and 2 PM.
• Avoid continuous 24-hour nitrate therapy, as it can lead to tolerance development 1.

Additional Considerations

• Educate patients about the importance of adhering to the dosing schedule to maintain therapeutic efficacy.
• Monitor for symptoms during the nitrate-free interval, especially initially, and consider alternative or additional antianginal medications for nighttime coverage if needed.
• The use of a nitrate-free interval is supported by the European Society of Cardiology guidelines, which recommend avoiding continuous nitrate therapy to prevent tolerance development 1.

Justification

Tachyphylaxis occurs due to continuous nitrate exposure, leading to depletion of sulfhydryl groups necessary for nitrate bioactivation and reduced nitric oxide production 1. The nitrate-free interval allows for replenishment of these sulfhydryl groups, restoring nitrate sensitivity and maintaining therapeutic efficacy. This approach balances the need for angina prevention with the prevention of tolerance development, ensuring long-term effectiveness of nitrate therapy. According to the ACC/AHA 2007 guidelines, tolerance to the hemodynamic effects of nitrates is dose and duration dependent and typically becomes important after 24 h of continuous therapy with any formulation 1.

From the FDA Drug Label

In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs

• Tachyphylaxis to oral nitrates refers to the development of tolerance, where the body becomes less responsive to the medication over time.
• This can occur with long-term use of oral nitrates, such as isosorbide mononitrate, as seen in industrial workers with high doses of organic nitrates 2.
• It is essential to follow the prescribed schedule of dosing to maintain the antianginal efficacy of isosorbide mononitrate.

From the Research

Definition of Tachyphylaxis to Oral Nitrates

Tachyphylaxis to oral nitrates refers to the rapid development of tolerance to the therapeutic effects of nitrates, leading to a decrease in their clinical efficacy during long-term use 3, 4, 5, 6.

Mechanisms of Tachyphylaxis

The exact mechanisms of tachyphylaxis to oral nitrates are not fully understood, but several factors have been proposed, including:

• Loss of SH groups 7
• Activation of humoral feedback mechanisms, with an increase of circulating catecholamine levels, activation of the R-A-A system, and increased plasma volume 7
• Development of reactive oxygen species (ROS) inside the muscular cell of a vessel wall, which bind with nitric oxide (NO) and decrease NO activity 6

Prevention of Tachyphylaxis

To prevent or reduce the development of tachyphylaxis, a nitrate-free interval is required, which can be achieved by:

• Providing a daily low-nitrate interval 3, 4, 7
• Using intermittent therapy with once-daily ingestion of high-dose sustained-release nitrates 3
• Using sustained-release formulations with a single daily dose 4
• Leaving a patch-free interval of 10-12 hours per day when using transdermal nitrates 7

Clinical Relevance

Tachyphylaxis to oral nitrates is a significant clinical concern, as it can lead to a loss of anti-anginal and anti-ischemic protection, and may result in rebound angina and myocardial ischemia during periods of absent nitrate levels 5. However, some nitrates, such as pentaerythritol tetranitrate (PETN), may have a lower potential to induce tolerance and cross-tolerance 6.