tailieunhanh - Color Atlas of Pharmacology (Part 12): Inhibitors of the RAA System

Inhibitors of the RAA System lasting effect than does captopril. Indications are hypertension and cardiac failure. Lowering of an elevated blood pressure is predominantly brought about by diminished production of angiotensin II. Impaired degradation of kinins that exert vasodilating actions may contribute to the effect. In heart failure, cardiac output rises again because ventricular afterload diminishes due to a fall in peripheral resistance. Venous congestion abates as a result of (1) increased cardiac output and (2) reduction in venous return (decreased aldosterone secretion, decreased tonus of venous capacitance vessels). Undesired effects. The magnitude of the antihypertensive effect of ACE inhibitors. | 124 Inhibitors of the RAA System Inhibitors of the RAA System Angiotensin-converting enzyme ACE is a component of the antihypotensive renin-angiotensin-aldosterone RAA system. Renin is produced by specialized cells in the wall of the afferent arteriole of the renal glomerulus. These cells belong to the juxtaglomerular apparatus of the nephron the site of contact between afferent arteriole and distal tubule and play an important part in controlling nephron function. Stimuli eliciting release of renin are a drop in renal perfusion pressure decreased rate of delivery of Na or Cl- to the distal tubules as well as p-adrenoceptor-medi-ated sympathoactivation. The glycoprotein renin enzymatically cleaves the decapeptide angiotensin I from its circulating precursor substrate angiotensi-nogen. ACE in turn produces biologically active angiotensin II ANG II from angiotensin I ANG I . ACE is a rather nonspecific peptidase that can cleave C-terminal dipeptides from various peptides dipeptidyl carboxypeptidase . As kininase II it contributes to the inactivation of kinins such as bradykinin. ACE is also present in blood plasma however enzyme localized in the luminal side of vascular endothelium is primarily responsible for the formation of angiotensin II. The lung is rich in ACE but kidneys heart and other organs also contain the enzyme. Angiotensin II can raise blood pressure in different ways including 1 vasoconstriction in both the arterial and venous limbs of the circulation 2 stimulation of aldosterone secretion leading to increased renal reabsorption of NaCl and water hence an increased blood volume 3 a central increase in sympathotonus and peripherally enhancement of the release and effects of norepinephrine. ACE inhibitors such as captopril and enalaprilat the active metabolite of enalapril occupy the enzyme as false substrates. Affinity significantly influences efficacy and rate of elimination. Enalaprilat has a stronger and longer- lasting effect than does captopril. .