RISK OF REBOUND PHENOMENON DURING NITRATE WITHDRAWAL

Organic nitrates are first-line drugs in the therapy and prevention of angina. These compounds, are acutely effective yet some formulations demonstrate a rapid decline in effect with chronic use. In this review the mechanisms of development of nitrate tolerance and the different strategies to prevent it are considered. If frequent dosing, high dosages and long acting preparations giving constant 24 h plasma GTN levels are more likely to cause tolerance, nitrate-low periods seem to be effective in restoring the drug's efficacy. Intermittent therapy with GTN patches, an effective way to prevent tolerance, raises the problem of the rebound phenomenon during the removal period. Considerable variations in its occurrence have been reported and in this review the factors that may influence the incidence of the rebound are discussed. The dangers of rebound can be lessened by concomitant anti-anginal drugs or avoiding any abrupt decline in blood nitrate concentrations. The use of beta-blockers or calcium channel blockers during intermittent therapy with GTN patches and oral preparations of isosorbide dinitrate or isosorbide 5-mononitrate seem to be effective for this purpose.