DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Bradykinin
ACE
Inactive
peptides
DRI
Angiotensin-Converting
Enzyme Inhibitors
Angiotensinogen
Angiotensin I (1-10)
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
1 2 3 4 5 6 7 8 9 10
ACE-I
ARB
Renin
ACE
chymase
Angiotensin II (1-8)
AT 1
Figure 26-8. Inhibitors of the RAS. ACE-I, angiotensinconverting
enzyme inhibitor; ARB, angiotensin receptor blocker;
DRI, direct renin inhibitor.
History. In the 1960s, Ferreira and colleagues found that the venoms
of pit vipers contain factors that intensify vasodilator responses to
bradykinin. These bradykinin- potentiating factors are a family of
peptides that inhibit kininase II, an enzyme that inactivates
bradykinin. Erdös and coworkers established that ACE and kininase
II are the same enzyme, which catalyzes both the synthesis
of AngII and the destruction of bradykinin. Based on these findings,
the nonapeptide teprotide (snake venom peptide that inhibits
kininase II and ACE) was later synthesized and tested in human
subjects. It lowered blood pressure in many patients with essential
hypertension and exerted beneficial effects in patients with heart
failure.
The orally effective ACE inhibitor captopril was developed by
a rational approach that involved analysis of the inhibitory action of
teprotide, inference about the action of ACE on its substrates, and analogy
with carboxypeptidase A, which was known to be inhibited by
D- benzylsuccinic acid. Ondetti, Cushman, and colleagues argued that
inhibition of ACE might be produced by succinyl amino acids that
corresponded in length to the dipeptide cleaved by ACE. This led to the
synthesis of a series of carboxy alkanoyl and mercapto alkanoyl derivatives
that are potent competitive inhibitors of ACE. Most active was
captopril (Vane, 1999).
Pharmacological Effects in Normal Laboratory Animals
and Humans. The effect of ACE inhibitors on the RAS
is to inhibit the conversion of AngI to the active AngII.
Inhibition of AngII production will lower blood pressure
and enhance natriuresis. ACE is an enzyme with
many substrates, and inhibition of ACE may also
induce effects unrelated to reducing the levels of AngII.
ACE inhibitors increase bradykinin levels and
bradykinin stimulates prostaglandin biosynthesis; both
may contribute to the pharmacological effects of ACE
inhibitors. ACE inhibitors increase by 5-fold the circulating
levels of the natural stem cell regulator N-
acetyl-seryl-aspartyl-lysyl-proline, which may contribute
to the cardioprotective effects of ACE inhibitors
(Rhaleb et al., 2001). In addition, ACE inhibitors will
increase renin release and the rate of formation of AngI
by interfering with both short- and long- loop negative
feedbacks on renin release (Figure 26–2A).
Accumulating AngI is directed down alternative metabolic
routes, resulting in the increased production of
vasodilator peptides such as Ang(1–7). In healthy, Na + -
replete animals and humans, a single oral dose of an
ACE inhibitor has little effect on systemic blood pressure,
but repeated doses over several days cause a small
reduction in blood pressure. By contrast, even a single
dose of these inhibitors lowers blood pressure substantially
in normal subjects depleted of Na + (Figure 26-7).
Clinical Pharmacology. ACE inhibitors can be classified
into three broad groups based on chemical structure: (1)
sulfhydryl- containing ACE inhibitors structurally
related to captopril; (2) dicarboxyl- containing ACE
inhibitors structurally related to enalapril (e.g., lisinopril,
benazepril, quinapril, moexipril, ramipril, trandolapril,
perindopril); and (3) phosphorus- containing ACE
inhibitors structurally related to fosinopril. Many ACE
inhibitors are ester- containing prodrugs that are 100-
1000 times less potent but have a better oral bioavailability
than the active molecules. Currently, 11 ACE
inhibitors are available for clinical use in the U.S.
(Figure 26–9). They differ with regard to potency,
whether ACE inhibition is primarily a direct effect of
the drug itself or the effect of an active metabolite, and
pharmacokinetics.
With the exceptions of fosinopril and spirapril
(which display balanced elimination by the liver and
kidneys), ACE inhibitors are cleared predominantly by
the kidneys. Impaired renal function significantly
diminishes the plasma clearance of most ACE
inhibitors, and dosages of these drugs should be
reduced in patients with renal impairment. Elevated
plasma renin activity renders patients hyperresponsive
to ACE inhibitor–induced hypotension, and initial
dosages of all ACE inhibitors should be reduced in
patients with high plasma levels of renin (e.g., patients
with heart failure and salt- depleted patients).
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CHAPTER 26
RENIN AND ANGIOTENSIN