Renin Inhibitor - Mechanism of Action

Mechanism of Action

Renin inhibitors bind to the active site of renin and inhibit the binding of renin to angiotensinogen, which is the rate-determining step of the RAAS cascade. Consequently, renin inhibitors prevent the formation of Ang I and Ang II. Renin inhibitors may also prevent Ang-(1-7), Ang-(1-9) and Ang-(1-5) formation, although it is not known if this is clinically important. Renin is highly selective for its only naturally occurring substrate which is angiotensinogen, and the incidence of unwanted side effects with a renin inhibitor is infrequent. and similar to angiotensin II receptor antagonists. Ang II also functions within the RAAS as a negative feedback to suppress further release of renin. A reduction in Ang II levels or blockade of angiotensin receptors will suppress the feedback loop and lead to increased plasma renin concentrations (PRC) and plasma renin activity (PRA). This can be problematic for ACE inhibitor and angiotensin II receptor antagonist therapy since increased PRA could partially overcome the pharmacologic inhibition of the RAAS cascade. Because renin inhibitors directly affect renin activity, decrease of PRA despite the increased PRC (from loss of the negative feedback) may be clinically advantageous.