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

926 Caution should be used in treating pregnant or
lactating women with certain H 1
antihistamines, especially
first-generation drugs, because of their possible
teratogenic effects or symptomatic effects on infants
resulting from secretion of the drug into breast milk.
Cetirizine and loratadine are preferred if H 1
antihistamines
are required, but if they are not effective, diphenhydramine
can be used safely in pregnant (but not
breast-feeding) women.
H 2
Antihistamines. These drugs (e.g., cimetidine, ranitidine)
primarily are used to inhibit gastric acid secretion
in the treatment of GI disorders (Chapter 45).
H 3
and H 4
Antihistamines. Although specific H 3
and H 4
receptor antagonists have been developed, no drugs
have been approved for clinical use. Based on the functions
of H 3
receptors in the CNS, H 3
antagonists have
potential in the treatment of sleeping disorders, ADHD,
epilepsy, cognitive impairment, schizophrenia, obesity,
neuropathic pain, and Alzheimer’s disease. Because of
the unique localization and function of H 4
receptors, H 4
antagonists are promising candidates to treat inflammatory
conditions such as allergic rhinitis, asthma,
rheumatoid arthritis, and possibly pruritus and neuropathic
pain.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
BRADYKININ, KALLIDIN, AND
THEIR ANTAGONISTS
Tissue damage, allergic reactions, viral infections, and
other inflammatory events activate a series of proteolytic
reactions that generate bradykinin and kallidin in
the circulation or tissues. Kinin metabolites released by
basic carboxypeptidases, formerly considered inactive
degradation products, are agonists of a receptor (B 1
)
that differs from that of intact kinins (B 2
). B 1
receptor
expression is induced by tissue injury or inflammation.
These peptides contribute to inflammatory responses as
autacoids that act locally to produce pain, vasodilation,
and increased vascular permeability but can also have
beneficial effects, for example in the heart, kidney, and
circulation. Much of their activity is due to stimulation
of the release of potent mediators such as
prostaglandins, NO, or endothelium-derived hyperpolarizing
factor (EDHF). Although both B 1
and B 2
receptors
are referred to as “bradykinin” receptors, this term
properly applies only to the B 2
receptor; the B 1
receptor
binds des-Arg metabolites of the kinins (Figure
32–4). These B receptors for kinins must not be confused
with β receptors for catecholamines. Current
efforts to develop potent non-peptide B 1
and B 2
antagonists
may open novel avenues for therapeutic intervention in
chronic inflammatory conditions.
History. In the 1920s and 1930s, Frey, Kraut, and Werle characterized
a hypotensive substance in urine and found a similar material in
saliva, plasma, and a variety of tissues. The pancreas also was a rich
source, so they named this material kallikrein after a Greek synonym
for that organ, kallikréas. By 1937, Werle, Götze, and Keppler had
established that kallikreins generate a pharmacologically active substance
from an inactive precursor present in plasma; the active substance,
kallidin, proved to be a polypeptide cleaved from a plasma
globulin termed kallidinogen (see Werle, 1970).
Interest in the field intensified when Rocha e Silva, Beraldo,
and associates reported that trypsin and certain snake venoms acted
on plasma globulin to produce a substance that lowered blood pressure
and caused a slowly developing contraction of the gut (Rocha
e Silva et al., 1949; Beraldo and Andrade, 1997). Because of this
slow response, they named the substance bradykinin, a term derived
from the Greek words bradys, meaning “slow,” and kinein, meaning
“to move.” In 1960, the nonapeptide bradykinin was isolated by
Elliott and coworkers and synthesized by Boissonnas and associates.
Shortly thereafter, kallidin was found to be a decapeptide bradykinin
with an additional lysine residue at the amino terminus. These peptides,
except for Lys 1 , have identical chemical structures (Table 32–3)
and quite similar pharmacological properties. For the whole group,
the generic term kinins has been adopted. The kinins have short halflives
because they are destroyed by plasma and tissue enzymes originally
called kininase I and kininase II. Kininase I releases a single
C-terminal amino acid; kininase II releases a dipeptide (Skidgel and
Erdös, 1998). Kininase II is identical to angiotensin-converting
enzyme (ACE) (Yang et al., 1970).
Ferreira and colleagues (1970) reported the isolation of a
bradykinin-potentiating factor from the venom of the Brazilian snake
Bothrops jararaca. Ondetti and colleagues (1971) subsequently
determined the structure of a peptide from the venom that inhibited
ACE and lowered blood pressure when given intravenously to hypertensive
patients. Synthetic ACE inhibitors, administered orally
(Chapter 26), now are widely used in the treatment of hypertension,
diabetic nephropathy, congestive heart failure, and after myocardial
infarction (Pfeffer and Frolich, 2006).
Regoli and Barabé (1980) divided the kinin receptors into
B 1
and B 2
classes based on the rank order of potency of kinin
analogs, and this was validated at the molecular level by cloning of
the B 1
and B 2
receptors (Bhoola et al., 1992; Hess, 1997). A primary
feature that distinguishes peptide ligands of the B 1
and B 2
receptors is the presence of a C-terminal Arg residue; intact kinins
(bradykinin and kallidin) are agonists of the B 2
receptor, whereas
their des-Arg forms ([des-Arg 9 ]-bradykinin and [des-Arg 10 ]-
kallidin) are agonists for the B 1
receptor. First-generation B 2
kinin–receptor antagonists were developed in the mid-1980s
(Stewart, 2004), followed by second- and third-generation blockers.
These antagonists revealed the role of kinins in the therapeutic
effects of ACE/kininase II inhibitors and have led to increased
acceptance of the importance of kinins. Studies involving B 1
and B 2
receptor knockout mice (Hess, 1997; Pesquero and Bader, 2006;
Jiang et al., 2009) have furthered our understanding of the role of
bradykinin in the regulation of cardiovascular homeostasis and
inflammatory processes.