michigan hypertension core curriculum - State of Michigan

the effect found by the ACE inhibitors. The peak effect of ARBs was also similar, with an average
BP reduction of approximately 12/7 mm Hg. All the ARBs studied were essentially equivalent in
effectiveness. Much like ACE the inhibitors, ARBs were as effective at lower doses as they were at the
manufacturer’s highest recommended doses. Again, similar to the ACE inhibitors, this observation
reflects the relatively flat dose-response curve of the ARBs.
Pharmacology/Mechanism of Action:
Once it was determined in the 1930s that renin was not the direct cause of increased BP in
experimental animals but rather an enzyme that led to the production of the culprit agent, angiotensin
II, efforts were made to identify agents that could block the actions of angiotensin II at its receptor.
Angiotensin II exerts its pharmacologic effect at the AT1 receptor which is a G protein-linked
transmembrane protein found mainly in the heart, adrenal glands, brain, liver and kidneys where it
effects vasoconstriction, aldosterone release, renal sodium reabsorption and vasopressin secretion.
Angiotensin I Type 2 (AT2) receptors are highly expressed in the developing fetus but they decline
rapidly after birth. In the adult, AT2 receptors are present only at low levels and are mostly found in
the heart, adrenal glands, uterus, ovaries, kidneys and brain. 13 The AT3 and AT4 receptors have been
described but there function not yet elucidated.
Initial pharmacologic success at the AT1 receptor was accomplished with saralasin, a modified
form of the angiotensin II peptide that was developed in the early 1970s. Saralasin was not clinically
useful however, because it was poorly bioavailable, had a short duration of action, and acted as a
partial agonist at the receptor. 14 Nevertheless, studies with saralasin confirmed the importance of
angiotensin II in the control of BP and, after many years of laboriously screening candidate compounds
and performing function testing, researchers at Merck Pharmaceuticals developed the first angiotensin
receptor blocker, losartan. Losartan was introduced into clinical use in 1995 and there are today 9
separately marketed ARBs available. 11
The ARBs have no effect on bradykinin metabolism and are therefore more selective blockers
of angiotensin effects than ACE inhibitors. ARBs block activation of the AT 1 receptor by its agonist
angiotensin II. They also have the potential for more complete inhibition of angiotensin action
compared with ACE inhibitors because enzymes other than ACE are capable of generating angiotensin
II via non-ACE pathways. Angiotensin receptor blockers provide benefits similar to those of ACE
inhibitors in patients with heart failure and chronic kidney disease.
196 Hypertension Core Curriculum