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