Clinical pharmacology of doxazosin in patients with essential hypertension

Abstract

Doxazosin is a new quinazoline derivative that, like prazosin, has selectivity for .alpha.1-receptors. A three-way crossover, randomized, open study in 18 patients with essential hypertension was conducted to investigate the clinical pharmacokinetics of 2, 4, and 8 mg doxazosin at steady state. The pharmacokinetics of the initial 2 mg dose was also studied. Doxazosin showed linear pharmacokinetics. Increases in doses from 2 to 8 mg (steady state) produced proportional increases in doxazosin serum levels (maximum plasma drug concentration [Cmax] minimum plasma drug concentration [Cmin], and O-24-hour area under the curve [AUC(p-24)], whereas half-life (t1/2) (19.4, 18.7, and 19.7 hours, respectively), volume of distribution (3.4, 3.4, and 3.6 L/kg, respectively), clearance from serum (2.2, 2.2, and 2.1 ml/min/kg, respectively), and degree of protein binding (1.2%, 1.0%, and 1.0% unbound, respectively) were dose independent. Similar t1/2 and time to reach peak concentration (tmax) were obtained with 2 mg initial dose and 2 mg steady state. .alpha.1-Acid glycoprotein levels were unchanged during doxazosin treatment. Doxazosin lowered supine and standing systolic and diastolic blood pressure. The blood pressure reduction was associated with an increase in heart rate. Peak hypotensive and tachycardic effects occurred 5.7 .+-. 0.1 hours after administration, whereas Cmax was achieved at 2.4 .+-. 0.7 hours (tmax). Greater decreases in systolic blood pressure and increases in heart rate were seen in standing than in supine position. The reduction in standing systolic and diastolic blood pressure with 8 mg was greater than with 2 mg (P < 0.05); however, the increases in heart rate were not different. Dizziness, headaches, and dry mouth were the most frequent side effects. This study indicates that doxazosin shows linear pharmacokinetics between 2 and 8 mg and that because of its long t1/2, once-a-day administration should be adequate for the treatment of hypertension.