What intervals in oral therapy of isosorbide dinitrate in various doses are sufficient to prevent nitrate tolerance?

The organic nitrates are effective anti-anginal drugs during initial treatment, but their therapeutic value is compromised by the rapid development of tolerance during sustained therapy. The only widely accepted method of preventing tolerance is the use of intermittent administration, but without specifying to what extent the length of interval is dependent on type and dose of nitrate. The aim of this study was to evaluate how long periods free of nitrates are sufficient to prevent tolerance in long-term therapy with oral sustained-release isosorbide dinitrate (ISDN).

In a double-blind study, 38 patients with stable angina, received ISDN: 40 mg, 80 mg and 120 mg or placebo in the first ingestion (1st) and in long-term therapy in four 7 day phases: 4-times-daily (4x), 3-times-daily (3x) with 12 h nitrate-free interval, twice-daily (2x) with 18 h interval and once-daily (1x). After 1st and on the last day of each long-term phases, exercise tests with the analysis of walking times: total, to angina and to ischaemia (WTI) were performed: preceding ingestion, 2 h and 6 h after.

Six hours after 1st all doses WTI improved significantly in comparison to placebo (p < 0.0001): 40 mg by 52.5%, 80 mg by 66.0% and 120 mg by 58.4%. None of the ISDN doses improved significantly WTI in 4x phase; in 3x, only 40 mg by 12.1% (p < 0.05); in 2x, only 80 mg by 22.3% (p < 0.05) and in once-daily, 80 mg by 27.2% and 120 mg by 36.2% (p < 0.01).

12 h nitrate-free interval is sufficient in order to prevent tolerance in long-term treatment of sustained-release ISDN with 40 mg dose, 18 h with 80 mg and 24 h with 120 mg doses.