michigan hypertension core curriculum - State of Michigan

significant proteinuria.
Pharmacology/Mechanism of Action
The renin-angiotensin-aldosterone axis begins with the hepatic production of angiotensinogen,
a 452 amino acid alpha 2 globulin. In response to perceived hypotension or decreased delivery
of sodium and chloride at the level of the juxtaglomerular apparatus, the kidney secretes renin, a
peptide hormone that converts angiotensinogen to angiotensin I. Angiotensin I is biologically inactive.
Angiotensin converting enzyme (ACE) or kinninase II is found widely throughout the body and occurs
in three main isoforms. The enzyme is found in particularly high concentrations in the pulmonary
capillary endothelium where it catalyzes the final enzymatic step in the lysis of angiotensin I to produce
angiotensin II; inhibitor of ACE/kinninase II also raise bradykinin levels which, in turn, augment nitric
oxide (NO) levels. While the multiple enzymatic steps of the renin-angiotensin-aldosterone axis each
represent a potential target for an antihypertensive agent to act upon, the ACE inhibitors block this step
thus decreasing the amount of circulating angiotensin II. This effectively abrogates the myriad effects
of angiotensin II on the kidney and cardiovascular system, including vasoconstriction, stimulation of
aldosterone release, promotion of renal sodium reabsorption, vasopressin secretion and increased
cardiac contractility and all these effects cause a decrease in BP.
Toxicity
ACE inhibitors are very well tolerated and have a low incidence of side effects. The most
common, annoying side effect of ACE inhibitors is a dry cough appearing in 10-30% of patients. The
effect is related to the elevation in bradykinin, an enzymatic product of high molecular weight kininogen
and a potent vasodilator. Angiotensin converting enzyme normally enzymatically degrades bradykinin
but in the presence of the ACE inhibitors this process is impeded. Hypotension can also be a problem,
especially in heart failure patients. Angioedema (life-threatening airway swelling and obstruction;
0.1-0.2% of patients) and hyperkalemia (occurs because aldosterone formation is reduced) are also
adverse effects of ACE inhibition. The incidence of angioedema is 2 to 4-times higher in African
Americans compared to Caucasians; however, the absolute rates of angioedema are low in both
races. ACE inhibitors are contraindicated in pregnancy as they are associated with a variety of birth
defects. Additionally, patients with bilateral renal artery stenosis may experience renal failure if ACE
inhibitors are administered because a decrease in circulating angiotensin II alters efferent and afferent
194 Hypertension Core Curriculum