Angiotensin II-Receptor Antagonists: An Overview

Raquel Dina and Mahtab Jafari


Am J Health Syst Pharm. 2000;57(13) 

In This Article

Inhibitors of the Renin- Angiotensin System

Research that focused on blocking the renin-angiotensin system (RAS) led to the discovery of ACE inhibitors, which proved efficacious in the treatment of hypertension, various cardiovascular disorders (e.g., congestive heart failure and coronary insufficiency), and renal diseases.[5] However, the high frequency of cough with ACE inhibitors (up to 20% of patients)[6,7] meant that another class of equally efficacious agents with a potentially more favorable adverse- effect profile was needed.

In addition to inhibiting the conversion of AT-I to AT-II, ACE inhibitors block the degradation of bradykinin via kininase II, which has enzymatic properties similar to those of ACE. Inhibition of bradykinin degradation is thought to be responsible for the cough commonly associated with ACE inhibitors.[8]

Conversion of AT-I to AT-II is not the only pathway for AT-II generation. AT-II is also formed via pathways involving cathepsin G, elastase, tissue plasminogen activator, chymostatin- sensitive AT-II-generating enzyme, and chymase; thus, ACE inhibition only partially reduces the formation of AT-II.[9] Agents that can specifically and selectively inhibit the action of AT-II could completely block the RAS. In addition, relative to other classes of antihypertensives, such agents might decrease the frequency of common adverse effects, such as dizziness, headache, fatigue, diarrhea, cough, and edema.[10]

Currently, two classes of drugs have the mechanistic potential to completely block the RAS: renin inhibitors and AT-II-receptor antagonists. Competitive antagonism of renin would prevent the formation of AT-II by inhibiting AT-I formation; however, the development of such agents has progressed slowly because of continuing problems with bioavailability.[11] Saralasin, the first AT-II-receptor antagonist, was synthesized in 1971. An intravenous formulation of this AT-II peptide analogue was shown to lower blood pressure in direct proportion to the plasma level of renin. However, saralasin was not a feasible treatment for hypertension because it had poor bioavailability and a short duration of action and because it potentiated vasoconstriction and induced hypertensive effects in low-renin conditions. [12]


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