Why Isosorbide Dinitrate 5mg is Given in 2 Doses
Isosorbide dinitrate 5mg is given in 2 doses (rather than 3 or more frequent dosing) to prevent nitrate tolerance while maintaining anti-anginal efficacy throughout the day by providing a mandatory nitrate-free interval of at least 14 hours. 1, 2
The Tolerance Problem
Nitrate tolerance is the critical issue that dictates the dosing schedule:
- Tolerance develops rapidly with continuous nitrate exposure, typically becoming clinically significant after 24 hours of sustained therapy 3, 1
- Most controlled trials of isosorbide dinitrate given every 12 hours or more frequently showed statistically significant anti-anginal efficacy for only 2 hours after dosing when used for several weeks, despite initial effectiveness 2
- Research demonstrates that during sustained therapy with isosorbide dinitrate given four times daily, partial tolerance to both antianginal and circulatory effects develops rapidly, with exercise tolerance improvements lasting only 2 hours during sustained therapy compared to 8 hours during acute therapy 4
The Solution: Asymmetric Twice-Daily Dosing
The ACC/AHA guidelines specifically recommend dosing regimens that provide at least a 14-hour nitrate-free interval to prevent tolerance 5:
- Optimal regimen: Doses given at 0800 and 1400 hours (or similar asymmetric schedule like 0800,1400, and 1800 for three-times-daily dosing of higher doses) 2
- This creates a nitrate-free period overnight (roughly 1800-0800 hours = 14 hours)
- Once-daily regimens and regimens with one daily dose-free interval of at least 14 hours have shown efficacy after the first dose that was similar to single-dose studies 2
Why Not More Frequent Dosing?
The evidence clearly shows that more frequent dosing is counterproductive:
- A study of 8 patients given isosorbide dinitrate at 0800,1300, and 1800 hours for 2 weeks revealed that significant anti-anginal effectiveness was discontinuous and totaled only about 6 hours in a 24-hour period 2
- The FDA label explicitly states that controlled trials of multiple-dose oral isosorbide dinitrate taken every 12 hours or more frequently for several weeks showed statistically significant anti-anginal efficacy for only 2 hours after dosing 2
- Higher frequency dosing (4 times daily) led to rapid tolerance development, with effectiveness reduced from 8 hours during acute therapy to only 2 hours during sustained therapy 4
Clinical Implications
The 5mg twice-daily dose represents the lower end of the therapeutic range (guidelines recommend 5-80mg given 2-3 times daily) 5:
- This low dose is appropriate for patients requiring minimal nitrate therapy or those at risk for hypotension 2
- The twice-daily schedule (rather than three times daily) maximizes the nitrate-free interval while providing daytime coverage
- From available evidence, the maximal achievable daily duration of anti-anginal effect from isosorbide dinitrate is about 12 hours, making the asymmetric twice-daily dosing physiologically rational 2
Critical Pitfall to Avoid
Never prescribe isosorbide dinitrate on a symmetric 12-hour schedule (e.g., 0800 and 2000 hours) as this eliminates the essential nitrate-free interval and will lead to rapid tolerance development 1, 2. The doses must be given closer together during waking hours to preserve the overnight nitrate-free period.