When does nitrate tolerance develop? What dosages and which intervals are necessary to ensure maintained effectiveness?

Abstract

To address the issues of tolerance development and its circumvention during long-term treatment with nitrates, several controlled studies have been performed. In patients with coronary artery disease, during long-term treatment with isosorbide dinitrate (ISDN) in sustained-release form at dosages of 20 mg t.i.d., 40 mg t.i.d. and 60 mg t.i.d., both the rate of anginal attacks and the ischaemic reaction to exercise were unaffected. After a marked acute anti-ischaemic effect to 40 mg ISDN in nonsustained-release form, during chronic administration of the same dose four times daily, in association with continuously-high nitrate plasma concentrations, similarly, there were no significant effects. On use of nitroglycerin (NTG) transdermal patches delivering 10 mg, 15 mg and 30 mg per 24 hours, respectively, renewed patch application after 24 hours was not met with the same marked response observed after initial application. Clearly attenuated effects could be seen within 8 to 12 hours. These results show that tolerance development is incurred when the incrementation in plasma concentration after a repeated nitrate dose is of relatively limited magnitude with respect to baseline values. The observation of rapid reversibility of nitrate tolerance lead to the concept of interval treatment which on daily use incorporates a sufficiently long period without nitrate administration. On use of a nitrate-free treatment interval employing a regimen of 20 mg ISDN nonsustained-release form twice daily in the morning and at midday, 120 mg ISDN sustained-release form once daily or 50 or 100 mg isosorbide 5-mononitrate once daily, maintained effectiveness has been documented, as it has also been shown for treatment with NTG patches delivering 10 mg per 24 hours on incorporation of a 12-hour patch-free interval. The currently available patch system with discontinuous NTG delivery does not incur a complete loss of action but a considerable attenuation of its effects indicates the need for further refinements. Thus interval treatment guarantees maintenance of nitrate effects, albeit with the limitation that 24-hour therapeutic coverage is not enabled.

Effect of Intermittent Administration of Sustained Release Isosorbide Dinitrate (sr-ISDN) in Rats with Pressure-Overload Heart

“…Nitrates have been shown to induce immediate tolerance in previous studies conducted in vivo and in vitro [8,9,19,28], although the mechanism of tolerance induction through nitrate administration has been unclear until the present time. However, it has been demonstrated that the intermittent administration of nitrates with a drug-free time of 10 to 12 hours can prevent development of tolerance [10,24].…”

The Effect of Intermittent Administration of Sustained Release Isosorbide Dinitrate (sr-ISDN) in Rats with Volume Overload Heart

“…Since nitrates are generally used to improve angina pectoris with resultant-induced tolerance, studies on nitrate have focused on its acute effects [13,28]. Nitrates have been shown to induce immediate tolerance in previous in vivo and in vitro studies [12,34]. Whereas the mechanism that induces tolerance through nitrate administration was unclear until recently [14,16], setting a drug-free time of 10 to 12 hr has been shown to prevent tolerance development [7,11,29].…”

“…Nitrates have been used for more than 100 years in the treatment of angina pectoris [2,19], ischemic heart disease, and chronic heart failure [8,9,24,30]. Unfortunately, the use of nitrates has the disadvantage of inducing tolerance when administered for long periods [12,13,22,34]. The effect of prolonged use of nitrates on the prognosis for survival and prophylaxis of future cardiac events remains unclear [26].…”

Slow Release Isosorbide-5-Mononitrate Therapy in Angina Pectoris

“…In the recent decades the expanding knowledge on the pharmacodynamic and pharmacokinetic properties of nitrates al lowed new therapeutic approaches to long term treatment of coronary artery disease and heart failure [1,6,[8][9][10][11].…”

“…Continuous administration of nitrates, regardless of the formulation, results in at tenuation of their hemodynamic and antiischemic effects [9], This tolerance can be avoided by interval (intermittent) adminis tration [12][13][14], High doses of slow-releasc IS-5-MN, once daily in the morning, result in therapeutic plasma levels for 12-15 h with lowering during the night, which is sufficient to prevent tolerance [9,[15][16][17][18][19][20].…”