Inhibitors of the renin-angiotensin system. Clinical pharmacology studies on kinetics, dynamics and concentration-effect relationships.
Drug induced modification of the renin-angiotensin system is of established benefit in the treatment of hypertension and heart failure. The responses to the angiotensin converting enzyme (ACE) inhibitor enalapril (CAS 75847-73-3) have been studied in essential hypertension and normotensive controls. The kinetics and dynamics of enalapril have been characterised in an integrated concentration-effect model to identify factors underlying responsiveness to the ACE inhibitor. In addition models to predict the response to long-term treatment from changes after the first dose have been developed. Enalapril response could be described by a non linear (Emax) model defined by two parameters - the maximum response (Emax) and the drug concentration required to cause 50% of the maximum response (C50). Acute dosing accurately predicted the Emax after 6 weeks treatment. In addition to individual pharmacokinetics, pretreatment blood pressure was the most important determinant of response to enalapril. In caucasian salt-replete essential hypertension neither age nor plasma renin activity were major factors. However, in states of sodium restriction and/or diuretic treatment, the response to enalapril was greatly increased. The angiotensin II receptor antagonist, losartan has been reported to be without effect on blood pressure in salt-replete normals. Salt restriction together with furosemide for 3 days led to dose-related falls in blood pressure in normal subjects after losartan 25-100 mg. Concentration-effect analysis can be used to describe blood pressure responses, to predict the responses to long-term treatment and also to identify quantitatively important factors determining the response in individual patients.
Department of Medicine and Therapeutics, University of Glasgow, Scotland, UK.
J L
JL
Reid
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D006801:Humans; D012084:Renin-Angiotensin System / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II