A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

• Published in: Pharmacological reviews Vol. 65; no. 2; pp. 809 - 848
• Main Authors: Michel, Martin C., Foster, Carolyn, Brunner, Hans R., Liu, Lisheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2013
• Subjects: Angiotensin II Type 1 Receptor Blockers - chemistry; Angiotensin II Type 1 Receptor Blockers - pharmacokinetics; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Binding Sites; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - prevention & control; Drug Interactions; Heart Failure - drug therapy; Heart Failure - metabolism; Humans; Hypertension - drug therapy; Hypertension - metabolism; Molecular Structure; Receptor, Angiotensin, Type 1 - metabolism; Tissue Distribution; Cmax; ACE; P-gp; RAS; tmax; AT1R; OATP; AT2R; Vd; AUC; ARB; PPAR; t1/2; TM; ANG; P450; PET; AGE
• ISSN: 0031-6997; 1521-0081; 1521-0081
• DOI: 10.1124/pr.112.007278

Angiotensin II type 1 receptor antagonists (ARBs) have become an important drug class in the treatment of hypertension and heart failure and the protection from diabetic nephropathy. Eight ARBs are clinically available [azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan]. Azilsartan (in some countries), candesartan, and olmesartan are orally administered as prodrugs, whereas the blocking action of some is mediated through active metabolites. On the basis of their chemical structures, ARBs use different binding pockets in the receptor, which are associated with differences in dissociation times and, in most cases, apparently insurmountable antagonism. The physicochemical differences between ARBs also manifest in different tissue penetration, including passage through the blood-brain barrier. Differences in binding mode and tissue penetration are also associated with differences in pharmacokinetic profile, particularly duration of action. Although generally highly specific for angiotensin II type 1 receptors, some ARBs, particularly telmisartan, are partial agonists at peroxisome proliferator-activated receptor-γ. All of these properties are comprehensively reviewed in this article. Although there is general consensus that a continuous receptor blockade over a 24-hour period is desirable, the clinical relevance of other pharmacological differences between individual ARBs remains to be assessed.