AT(1)-receptor blockers: differences that matter.
The available angiotensin II type 1 (AT(1))-receptor blockers differ markedly in their pharmacological properties and clinical efficacy. Losartan shifts the dose-response curve for angiotensin II to the right without affecting the maximal response; this antagonism can be overcome by increasing concentrations of angiotensin II and thus losartan acts as a surmountable antagonist. By contrast, other agents suppress the maximal response to angiotensin II to varying extents; this can not be overcome by increasing angiotensin concentrations and hence these agents are insurmountable antagonists. Receptor binding studies have shown that candesartan has the highest affinity for the AT(1)-receptor, followed by irbesartan, valsartan and losartan, and that candesartan dissociates from the receptor more slowly than other antagonists. A meta-analysis using an E(Max) model has shown that differences in receptor binding activity are reflected in differences in maximal antihypertensive effect, and this finding is supported by the results of comparative clinical trials. Moreover, the prolonged binding of candesartan to the receptor is reflected in a longer duration of action, compared with losartan; the antihypertensive effect of candesartan persists for 48 h after dosing, compared with approximately 24 h with losartan. Candesartan thus offers extended therapeutic coverage, an important consideration since a majority of patients miss occasional doses of antihypertensive medication. There is currently no evidence that differences in receptor binding between AT(1)-receptor blockers translate into differences in tolerability. In summary, therefore, pharmacological differences between AT(1)-receptor blockers are reflected in clinically important differences in maximal antihypertensive effect, response rate, and duration of action.
Gradman
A H
AH
Division of Cardiovascular Diseases, The Western Pennsylvania Hospital, Pittsburgh 15224, USA.
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II