Concentration-effect relationships and individual responses to doxazosin in essential hypertension.
1. This study investigates aspects of the pharmacokinetics, pharmacodynamics and concentration-effect relationships in 10 patients with essential hypertension during acute and chronic treatment with doxazosin, an alpha 1-adrenoceptor antagonist. 2. Following the first dose of doxazosin (2 mg) there were significant reductions in blood pressure, increases in heart rate and in plasma noradrenaline, and parallel rightward shifts of the phenylephrine pressor response curves, consistent with alpha-adrenoceptor antagonism. There was no significant change in the pressor response to angiotensin II. 3. Using an integrated kinetic-dynamic model, individual blood pressure responsiveness was characterised as the fall in blood pressure (mm Hg) per unit drug concentration. Responsiveness to the first dose of doxazosin was directly correlated with the responsiveness after 1 and 6 weeks treatment although there was a systemic reduction (of approximately 30%) which occurred during the first week of treatment. 4. Neither the acute nor long-term responsiveness to doxazosin was related to age, plasma renin activity, plasma noradrenaline or the pretreatment sensitivity to phenylephrine. There was a significant relationship between responsiveness and the height of the initial (pretreatment) blood pressure. 5. Integration of pharmacokinetic and pharmacodynamic data provides a reproducible index of responsiveness which can be used to investigate the consistency of the long-term anti-hypertensive response, to identify factors which influence the magnitude of the response, and to optimise the choice of dose and dose interval.
Donnelly
R
R
University Department of Materia Medica, Stobhill General Hospital, Glasgow.
Elliott
H L
HL
Meredith
P A
PA
Reid
J L
JL
D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017292:Doxazosin; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D010656:Phenylephrine / Q000008:administration & dosage; D011224:Prazosin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000959:Antihypertensive Agents; D010656:Phenylephrine; D017292:Doxazosin; D009638:Norepinephrine; D011224:Prazosin