Clinical relevance of optimal pharmacokinetics in the treatment of hypertension

BACKGROUND: Although it is well recognized that many antihypertensive drugs exhibit large interpatient variability in their disposition characteristics, the concept that this translates into a high variability in antihypertensive response, by some form of concentration-effect relationship, has largely been ignored. PHARMACOKINETICS AS A DETERMINANT OF RESPONSE: Inferentially, there is a volume of evidence that the pharmacokinetic characteristics of an antihypertensive drug translate, in part, to the haemodynamic characteristics. Thus, agents with an intrinsically long elimination half-life and low variability in drug clearance tend to produce a sustained and consistent reduction in blood pressure. PHARMACOKINETIC-PHARMACODYNAMIC MODELLING: With a rigorous approach to study design, the pharmacokinetic and pharmacodynamic responses to many antihypertensive drugs can be integrated, and thus the concentration-effect relationship can be modelled. This approach has been used on a population basis to model the blood pressure, heart rate and P-Q interval responses to mibefradil. The results of this analysis have demonstrated clearly that for blood pressure and the heart rate, the baseline or pretreatment characteristics of the patients are important determinants of the response. CONCLUSION: For many antihypertensive drugs, the circulating concentrations are an important, if not the most important, determinant of response. Characterizing concentration-effect relationships is an important route to optimizing antihypertensive drug therapy.