Practical relevance of the 24-hour trough: peak ratio of antihypertensive drugs

Abstract

INTRODUCTION OF THE TROUGH:PEAK RATIO: The mean antihypertensive effect of a drug, measured just before the next dose in a multiple-dose regimen, is generally used as a criterion for approval by regulatory agencies. However, for many short-acting drugs very high doses may be required to maintain some antihypertensive activity at the end of the dosing interval. This may lead to an excessive reduction in blood pressure at the time of peak drug effect. In order to avoid unnecessarily large doses, regulatory agencies have introduced a new standard, the trough:peak ratio, which may be 50-60% but should should ideally be higher. BENEFITS OF HIGH TROUGH:PEAK RATIO: A high trough:peak ratio indicates a long duration of action. This may provide a better risk:benefit ratio compared to shorter acting antihypertensive agents by giving optimal therapeutic coverage for 24 h or even longer. Greater benefit may be gained from better control of overnight blood pressure, especially in the early morning hours when both a steep rise in blood pressure and a higher rate of cardiovascular events have been observed. Large swings in blood pressure may occur when the peak is too high in relation to the trough, increasing blood pressure variability, which may in turn increase target organ damage. A high trough:peak ratio may protect the patient against drug-induced blood pressure fluctuations. It may also produce fewer adverse effects as the blood pressure may fall further and the onset of action may be more gradual. This, together with an effective single daily dose, may increase patient compliance. Furthermore, an antihypertensive effect that lasts more than 24 h protects the patient against a rapid loss of blood pressure control when a dose is omitted or delayed. TROUGH:PEAK RATIO OF AVAILABLE ANTIHYPERTENSIVE DRUGS: We performed a literature survey to evaluate the practical relevance of the trough:peak ratio and to determine how it might help in the choice of antihypertensive agents. The results suggested that not all single daily doses of angiotensin converting enzyme inhibitors or calcium antagonists had a trough:peak ratio of > 50%. We conclude that specially designed, prospective clinical trials should be conducted to address this issue.