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

918 by H 2
blockade. In asthmatic subjects in particular, histamine-induced
bronchospasm may involve an additional
reflex component that arises from irritation of
afferent vagal nerve endings (Nadel and Barnes, 1984).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
The uterus of some species is contracted by histamine; in the
human uterus, gravid or not, the response is negligible. Responses of
intestinal muscle also vary with species and region, but the classical
effect is contraction. Bladder, ureter, gallbladder, iris, and many other
smooth muscle preparations are affected little or inconsistently by
histamine.
Peripheral Nerve Endings: Pain, Itch, and Indirect Effects. Histamine
stimulates various nerve endings and sensory effects. In the epidermis,
it causes itch; in the dermis, it evokes pain, sometimes accompanied
by itching. Stimulant actions on nerve endings, including
autonomic afferents and efferents, contribute to the “flare” component
of the triple response and to indirect effects of histamine on the
bronchi and other organs. In the periphery, neuronal receptors for
histamine are generally of the H 1
type (see Rocha e Silva, 1978;
Ganellin and Parsons, 1982).
Clinical Uses
The practical application of histamine is limited to use
as a diagnostic agent, such as to assess nonspecific
bronchial hyperreactivity in asthmatics or as a positive
control injection during allergy skin testing.
H 1
RECEPTOR ANTAGONISTS
History. Antihistamine activity was first demonstrated by Bovet
and Staub in 1937 with one of a series of amines with a phenolic
ether moiety. The substance 2-isopropyl-5-methylphenoxy-ethyldiethyl-amine
protected guinea pigs against several lethal doses of
histamine but was too toxic for clinical use. By 1944, Bovet and his
colleagues had described pyrilamine maleate, an effective histamine
antagonist of this category. The discovery of the highly effective
diphenhydramine and tripelennamine soon followed (Ganellin and
Parsons, 1982). In the 1980s, nonsedating H 1
histamine receptor
antagonists were developed for treatment of allergic diseases.
Despite success in blocking allergic responses to histamine, the H 1
antihistamines failed to inhibit a number of other responses, notably
gastric acid secretion. The discovery of H 2
receptors and H 2
antagonists
by Black and colleagues provided a new class of agents that
antagonized histamine-induced acid secretion (Black et al., 1972).
The pharmacology of these drugs (e.g., cimetidine, famotidine) is
described in Chapter 45.
Pharmacological Properties
Chemistry. All the available H 1
receptor “antagonists” are
actually inverse agonists (see Chapter 3) that reduce constitutive
activity of the receptor and compete with histamine
(Haas et al., 2008): Whereas histamine binding to
the receptor induces a fully active conformation, antihistamine
binding yields an inactive conformation. At the
tissue level, the effect seen is proportional to receptor
occupancy by the antihistamine. Like histamine, many H 1
antagonists contain a substituted ethylamine moiety.
Unlike histamine, which has a primary amino
group and a single aromatic ring, most H 1
antagonists
have a tertiary amino group linked by a two-or threeatom
chain to two aromatic substituents and conform
to the general formula
Ar 1
Ar 2
C C N
X C C N
where Ar is aryl and X is a nitrogen or carbon atom or
a —C—O— ether linkage to the β-aminoethyl side
chain. Sometimes the two aromatic rings are bridged, as
in the tricyclic derivatives, or the ethylamine may be
part of a ring structure (Figure 32–3) (Ganellin and
Parsons, 1982).
Mechanism of Action. Most H 1
antagonists have similar
pharmacological actions and therapeutic applications.
Their effects are largely predictable from
knowledge of the consequences of the activation of H 1
receptors by histamine.
Effects on Physiological Systems.
Smooth Muscle. H 1
antagonists inhibit most of the effects
of histamine on smooth muscles, especially the constriction
of respiratory smooth muscle. For example, a
small dose of histamine causes death by asphyxia in
guinea pigs, yet the animal may survive a hundred
lethal doses of histamine if given an H 1
antagonist. In
the same species, striking protection also is afforded
against anaphylactic bronchospasm. This is not so in
humans, where allergic bronchoconstriction appears to
be caused by a variety of alternative mediators, such as
leukotrienes (Chapter 33).
H 1
antagonists inhibit both the vasoconstrictor
effects of histamine and, to a degree, the more rapid
vasodilator effects mediated by activation of H 1
receptors
on endothelial cells (synthesis/release of NO and
other mediators). Residual vasodilation is due to H 2
receptors on smooth muscle; administration of an H 2
antagonist suppresses the effect. The efficacy of the histamine
antagonists on histamine-induced changes in
systemic blood pressure parallels these vascular effects.
Capillary Permeability. H 1
antagonists strongly block the
increased capillary permeability and formation of
edema and wheal caused by histamine.