Intermittent or continuous transdermal nitroglycerin: Still an issue, or Is the case closed?

Abstract

After a decade of controversy and debate, many experts have now concluded that continuous nitroglycerin patch treatment leads to complete tolerance development and therefore cannot be recommended for any angina patient. This conclusion is largely based on the disappointing results of the large Transdermal Nitroglycerin Cooperative Study, in which continuous patch treatment in doses of 15-105 mg daily failed to increase exercise duration more than placebo after 2 and 8 weeks of treatment. However, other well-designed studies recently reported maintained efficacy during continuous treatment, and the differences in results has remained unexplained. The disagreeing data may be better understood if certain facts are considered: (1) The cooperative study tested a patient population with a very low first-dose treatment response--only 34 seconds (or 10-12%) improvement compared with placebo. At the end of the study, 25% of the patients terminated exercise for reasons other than angina, and a reduced nitrate responsiveness had developed, even in the placebo group. (2) Patients who demonstrate a large first-dose nitrate responsiveness tend to be less susceptible to tolerance development. (3) Even during continuous therapy, maintained efficacy is often observed in exercise tests done 2-5 hours after patch renewal, while typically no effect is seen at the end of the application period. Attenuation of the initial effects is seen with all long-acting nitrate treatment regimens, but the degree of tolerance varies with the patient population, the efficacy parameter (exercise test vs. attack counts), the timing of the efficacy test, the patch dose, and whether or not nitrate-free (-low) intervals are used. In general, intermittent patch therapy is superior to continuous therapy in improving exercise duration, but even continuous therapy may retain some effect. Rebound phenomena do occur but are clinically relevant only in a minority of the patients. Rebound phenomena are not a problem during continuous therapy, which therefore may be of value in patients with frequent and/or nocturnal angina attacks. Patients experiencing angina during exercise only and with low first-dose effects are likely to benefit more from intermittent therapy. Doses of 0.6-0.8 mg/hr (15-20 mg/24 hr) are usually optimal, and the efficacy is comparable with that observed after oral nitrates.

Safeguarding the process of drug administration with an emphasis on electronic support tools

“…For instance, problems in correct identification of drug packages are likely to be associated with decreased adherence , as are difficulties in handling drugs during the personalization process (e.g. tablet splitting ), whereas errors in drug dosage and drug application are related to non‐response or toxicity . Hence, the prevention of drug administration errors appears important, particularly in the ambulatory care setting, where the incidence rate might be higher and subsequent strategies to counteract adverse outcomes following administration errors might be less accessible.…”

The pharmacokinetics of trinitroglycerin and its metabolites in patients with chronic stable angina

“…In addition, the problems of variable drug absorption and fluctuating plasma concentrations caused by GTN ointment were overcome by the transdermal patch or tape system. The continuous use of transdermal GTN tape can still lead to nitrate tolerance [2]. Recent data suggest that the intermittent application of transdermal GTN may be associated with decreased exercise capacity as well as the development of unstable angina when the tape is not applied [3].…”

Organic nitrate tolerance is induced by degradation of some cytochrome P450 isoforms

“…The purpose of this study, conducted in rats, was to confirm whether nitrate tolerance observed after chronic administration of organic nitrates to rats is due to the reduced P-450 catalyzed biotransformation of these organic nitrates to NO. In addition to the current strategy of intermittent therapy with an adequate nitrate-free interval, 6,7 P450 induction may become an effective strategy to prevent nitrate tolerance.…”