Diazoxide concentration-response relation in hypertension

The pharmacokinetic disposition and antihypertensive response of bolus infusions of diazoxide, 1, 2, or 4 mg/kg over 5, 10, or 20 seconds, were examined in seven patients with chronic stable essential hypertension and mean arterial pressures (MAP) between 122 and 155 mm Hg off therapy. Maximal reductions in MAP were noted 2 minutes after each dose, and a linear correlation was obtained in all patients between dose or plasma diazoxide concentration and maximal change in MAP. Individual concentration-time curves were analyzed to determine the apparent volume of distribution at steady state (Vdss range, 0.178 to 0.250 liter/kg), beta t 1/2 (range, 32 to 62.5 hours), and plasma clearance rate (Clp range, 2.2 to 5.3 ml/kg . hour-1) for the calculation of loading and maintenance doses designed to produce steady-state concentrations within 0.5 hours. These infusions resulted in steady-state reductions in MAP (16% to 30%) which could be predicted from the concentration-response curves of each patient after bolus infusions. With the use of kinetic principles, a diazoxide dose regimen (average load, 7.5 mg/kg at 7.5 mg/min; average maintenance, 10% of loading dose every 6 hours) produced gradual and predictable reductions in MAP in patients with accelerated hypertension, since the response was proportional to plasma diazoxide concentrations.