Relationship between the cardiovascular effects and steady-state kinetics of clonidine in hypertension. Demonstration of a therapeutic window in man.

Clonidine was given orally as monotherapy in increasing daily doses from 3.1 to 25.7 micrograms/kg to patients with essential hypertension (n = 6). When a steady state concentration in plasma was reached at each dose level, the blood pressure (BP) and heart rate were measured during a dosage interval. Effect time-plasma concentration data were submitted to nonlinear regression analysis, which showed that the observed BP effects could be dissociated into depressor and pressor components. A window for the anti-hypertensive effect was established. At a plasma clonidine concentration of 0.65 +/- 0.07 ng/ml 50% of the maximal depressor effect was found, and it was only separated by a factor of 2 from the half maximal pure pressor concentration in plasma. No relationship between the change in heart rate and the plasma clonidine was observed. The findings strengthen the importance of close monitoring of clonidine therapy.