Effect of Intervals between Doses on the Development of Tolerance to Isosorbide Dinitrate

Abstract

We studied the development of tolerance to isosorbide dinitrate in 12 patients with chronic stable angina pectoris. The effect of 30 mg of isosorbide dinitrate on treadmill exercise performance was assessed before and at one, three, and five hours after a single dose. As compared with placebo, the drug increased treadmill walking time until the onset of angina and until the development of moderate angina over the five-hour observation period (P less than 0.05). The patients then received 30 mg of isosorbide dinitrate twice, three times, and four times daily for a period of one week, and exercise performance was assessed before and at one, three, and five hours after the final morning dose. During sustained treatment two and three times daily, treadmill walking time was longer throughout the five-hour testing period than during the placebo phase (P less than 0.05). In contrast, during treatment four times daily, treadmill walking time was prolonged at one hour (P less than 0.05) but not at three and five hours after the last dose. We conclude that tolerance to the clinical effects of isosorbide dinitrate develops with a sustained dosage of 30 mg four times daily, but not when the drug is given two or three times daily.

N‐acetylcysteine fails to attenuate haemodynamic tolerance to glyceryl trinitrate in healthy volunteers.

“…Its development is most frequently associated with those formulations or dosage regimes which attempt to provide a constant plasma nitrate level (Thadani et al, 1982;Parker & Fung 1984;Parker et al, 1987a, b). In this respect, transdermal nitroglycerine patches, which deliver GTN across the skin at a constant rate over a 24 h period, have been particularly implicated (James et al, 1985;Jordan et al, 1985;Thadani et al, 1985).…”

Self-assembly of calix[4]arene amine derivatives

“…In most mammals nitric oxide is involved in the regulation of many pathways including the cardiovascular, respiratory and nervous systems 64 . Nitric oxide has also been proven to show beneficial effects against some diseases and as such have found roles as antianginal drugs and some anti-inflammatories 65 .…”

Efficacy and Rebound Phenomenon Related To Intermittent Nitroglycerin Therapy for the Prevention of Nitrate Tolerance

“…2,5,6,21,22 A recent FDA advisory meeting concluded that interruption of nitrate exposure for as little as 8-12 h is the best means of preventing or reversing tolerance. 4 However, to our knowledge, there have been no previous investigations of the intracellular production of cGMP, the vasodilatory response and activation of neurohormonal factors during intermittent NTG therapy.…”