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

932 thrombin generation following cardiopulmonary bypass surgery,
including kallikrein and plasmin. Administration of aprotinin
reduces requirements for blood products in patients undergoing coronary
artery bypass grafting (Waxler and Rabito, 2003). Recent retrospective
meta-analyses and a prospective multicenter trial linked
aprotinin use with higher mortality and renal morbidity (Dietrich,
2009). Although there is controversy regarding the validity of these
conclusions, the manufacturer has withdrawn the drug from the market
(Dietrich, 2009); it remains available through a special investigational
treatment protocol. Ecallantide (DX-88), a synthetic plasma
kallikrein inhibitor, inhibits acute episodes of angioedema in patients
with hereditary angioedema (Schneider et al., 2007).
Bradykinin and the Effects of ACE Inhibitors. ACE
inhibitors are widely used in the treatment of hypertension,
and they reduce mortality in patients with diabetic
nephropathy, left ventricular dysfunction, previous
myocardial infarction, or coronary artery disease (Pfeffer
and Frohlich, 2006). ACE inhibitors block the conversion
of Ang I to Ang II, a potent vasoconstrictor and
growth promoter (Figure 32–4) (Chapter 25). Studies
with the kinin B 2
antagonist HOE-140 demonstrate that
bradykinin also contributes to many of the protective
effects of ACE inhibitors. For example, administration
of HOE-140 in animal models attenuates the favorable
effects of ACE inhibitors on blood pressure, myocardial
infarct size, and ischemic preconditioning. Bradykinin
receptor antagonism also attenuates blood pressure lowering
by acute ACE inhibition in humans (Gainer et al.,
1998). These effects may result not only from decreased
degradation of bradykinin by ACE but also from induction
of enhanced receptor sensitivity by ACE inhibitors
(Marcic et al., 1999; Biyashev et al., 2006).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
A rare side effect of ACE inhibitors is angioedema, which
may occur shortly after initiating therapy. This is a class effect of
ACE inhibitors and may be connected to the inhibition of kinin
metabolism by ACE (Slater et al., 1988). ACE inhibitor–associated
angioedema is more common in blacks than in Caucasians. A common
side effect of ACE inhibitors is a chronic, nonproductive cough
that dissipates when the drug is stopped. The finding that angiotensin
AT 1
receptor antagonists do not cause cough supports the role of
bradykinin in this effect, but the mechanism has not been clearly
defined.
Bradykinin also may contribute to the effects of the AT 1
-
receptor antagonists. During AT 1
receptor blockade, Ang II concentrations
increase, which enhances signaling through the unopposed
AT 2
subtype receptor, causing an increase in renal bradykinin concentrations
(Widdop et al., 2003).
A new class of antihypertensive agent was developed to
inhibit two major kinin-degrading enzymes, ACE and neprilysin, and
the added inhibition of bradykinin metabolism was expected to
enhance therapeutic effectiveness. In phase III clinical trials, the prototype
drug omapatrilat was an effective antihypertensive agent but
was associated with a 3-fold higher incidence of angioedema than
with an ACE inhibitor alone, causing withdrawal of the drug.
Kinin Receptor Antagonists. The substitution of a D-Phe for Pro at
position 7 in bradykinin conferred weak antagonist activity at the
B 2
receptor and blocked the action of ACE. The addition of an
N-terminal, D-Arg substitution of hydroxyproline in position 3 and
thienylalanine at positions 5 and 8 resulted in the first useful and
potent B 2
antagonist with in vivo activity (NPC-349; Table 32–3)
(Stewart, 2004). However, this antagonist had a short t 1/2
owing to
enzymatic degradation by carboxypeptidase N in vivo, which converted
it into a B 1
antagonist. Based on NPC-349, the longer-acting
selective B 2
receptor antagonist HOE-140 (icatibant) was developed
by substituting synthetic amino acids at positions 7 [D-tetrahydroisoquinoline-3-carboxylic
acid (Tic)] and 8 [octahydroindole-2-
carboxylic acid (Oic)] (Table 32–3). Icatibant (FIRAZYR) has been
approved in the E.U. for treatment of acute episodes of swelling in
patients with hereditary angioedema (Bork et al., 2008). It is administered
by subcutaneous injection.
Orally active non-peptide receptor antagonists would be
preferable for therapeutic use. The first of these for the B 2
receptor,
WIN64338, had significant muscarinic cholinergic activity. In animals,
a newer, more specific non-peptide B 2
antagonist, FR173657
(Table 32–3), decreased bradykinin-induced edema, hypotension,
pain, bronchoconstriction, and inflammatory responses (Leeb-
Lundberg et al., 2005; Abraham et al., 2006). This has led to increased
interest by the drug industry and the generation of several new nonpeptide
B 2
antagonists with good oral bioavailability and in vivo stability
and activity (Leeb-Lundberg et al., 2005; Abraham et al., 2006).
On the other hand, synthetic B 2
receptor agonists (such as FR190997;
Table 32–3) may be cardioprotective. Synthetic small-molecule
bradykinin agonists or antagonists would not necessarily bind to the
same regions of the B 2
receptor as the peptide (Heitsch, 2003).
Peptide antagonists of the B 1
receptor include des-Arg 10 -
[Leu 8 ]-kallidin and [des-Arg 10 ]-HOE-140 (Table 32–3), among
others (Campos et al., 2006). More recently, several non-peptide B 1
antagonists with in vivo activity have been developed (Campos et al.,
2006; Feng et al., 2008); the most promising of these is SSR240612
(Table 32–3), which is orally active and inhibits inflammation
and neuropathic pain in animal studies. None has yet been tested
clinically.
CLINICAL SUMMARY: KININS
Aprotinin (TRASYLOL), the potent inhibitor of kallikrein
and other serine proteases, has been employed clinically
to reduce blood loss in patients undergoing coronary
artery bypass surgery, but unfavorable survival
statistics in retrospective and prospective studies have
resulted in its discontinuation (Dietrich, 2009).
Because kinins and [des-Arg]-kinins enhance
pain and inflammation via activation of the two kinin
receptors, B 2
and B 1
, antagonists may be useful in
treating inflammatory diseases. A peptide-based B 2
receptor antagonist, icatibant (FIRAZYR), has been
approved in the E.U. for treatment of acute episodes
of swelling in patients with hereditary angioedema
(Bork et al., 2008).