The Hospice Clinician Blog

In patients with heart diseases such as coronary artery disease or heart failure, nitrates—such as isosorbide mononitrate, isosorbide dinitrate and nitroglycerin transdermal patches—are commonly prescribed. It is well understood that tolerance to these agents develops, reducing their efficacy. How important is this phenomenon in the hospice population?

The answer is that nitrate tolerance is very important, and should guide the way we schedule doses of these medications. Tolerance is not something that takes weeks or months to develop—it happens within 1-2 days of around-the-clock nitrate exposure. Furthermore, research has demonstrated that cross-tolerance happens too, meaning that not only will the patient’s longer-acting nitrate become less effective, but their rapid-acting nitroglycerin sublingual tablets or oral spray will become less effective, too.

So, how do we prevent nitrate tolerance? In studies, a daily “nitrate-free interval” (a period of time during which the patient is not exposed to a nitrate product) of 10-12 hours seems to do the trick. However, because the pharmacokinetics of the various nitrate products differ (specifically the rate at which the nitrate is eliminated from the body), the dosing schedule needed to achieve a 10-12 hour nitrate-free interval differs as well, and can be quite confusing. Use the following chart to determine how your patient’s nitrate should be dosed.

*Combining with hydralazine reduces tolerance, so the combination product can be dosed TID, every 8 hours.

**Apply the first dose in the AM, then wipe off before applying the second dose 6 hours later. Wipe off the second dose after 6-8 hours to provide a 10-12 hour dose-free interval.

 Usually, doses are scheduled so that the nitrate-free interval occurs at night, while the patient is sleeping. However, this is not a hard and fast rule. You can adjust the dosing schedule to cover the times of day during which the patient is most likely to experience angina or other symptoms, as long as the recommended dose-free interval is conserved.

One concern that has arisen is whether “rebound angina” can occur during the dose-free interval. There does not seem to be a consensus within the literature about whether or not rebound angina can occur, but if it does, it appears to occur in only a small portion of patients and to be primarily associated with the nitroglycerin patch. One way to attenuate any rebound angina is to have at least one other anti-anginal medication, such as a beta-blocker, hydralazine or an ACE inhibitor, on board in all patients taking a nitrate.

Do you notice rebound angina in your patients?

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