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

Histamine, Bradykinin, and
Their Antagonists
Randal A. Skidgel, Allen P. Kaplan,
and Ervin G. Erdös
The biogenic amine, histamine, is a major mediator of
inflammation, anaphylaxis, and gastric acid secretion;
in addition, histamine plays a role in neurotransmission.
Our understanding of the physiological and pathophysiological
roles of histamine has been enhanced by the
development of subtype-specific receptor antagonists
and by the cloning of four receptors for histamine.
Competitive antagonists of H 1
receptors have diverse
actions and are used therapeutically in treating allergies,
urticaria, anaphylactic reactions, nausea, motion
sickness, insomnia, and some symptoms of asthma.
Antagonists of the H 2
receptor are effective in reducing
gastric acid secretion. The peptide, bradykinin, has cardiovascular
effects similar to those of histamine and
plays prominent roles in inflammation and nociception.
This chapter presents the physiology and pathophysiology
of histamine and kinins and the pharmacology
of the antagonists that inhibit responses to these
mediators.
HISTAMINE
History. The history of histamine (β-aminoethylimidazole) parallels
that of acetylcholine (ACh). Both were chemically synthesized
before their biological significance was recognized; they were first
detected as uterine stimulants in, and isolated from, extracts of ergot,
where they proved to be contaminants derived from bacterial action
(Dale, 1953).
Dale and Laidlaw subjected histamine to intensive pharmacological
study (Dale, 1953), discovering that it stimulated a host of
smooth muscles and had an intense vasodepressor action.
Importantly, they observed that when a sensitized animal was
injected with a normally inert protein, the immediate responses
closely resembled those of poisoning by histamine. These observations
anticipated by many years the finding that endogenous histamine
contributes to immediate hypersensitivity reactions and to
responses to cellular injury. Best and colleagues (1927) isolated
histamine from fresh samples of liver and lung, thereby establishing
it as a natural constituent of mammalian tissues, hence the name
histamine after the Greek word for tissue, histos. The presence of
histamine in tissue extracts delayed the acceptance of the discovery
of some peptide and protein hormones (e.g., gastrin) until the technology
for separating the naturally occurring substances was sufficiently
advanced (Grossman, 1966).
Lewis and colleagues (Lewis, 1927) proposed that a substance
with the properties of histamine (“H substance”) was liberated
from the cells of the skin by injurious stimuli, including the reaction
of antigen with antibody. We now know that endogenous histamine
plays a role in the immediate allergic response and is an important
regulator of gastric acid secretion. More recently, a role for histamine
as a modulator of neurotransmitter release in the central and
peripheral nervous systems has emerged.
Early suspicions that histamine acts through more than one
receptor have been borne out by the elucidation of four classes of
receptors, designated H 1
(Ash and Schild, 1966), H 2
(Black et al.,
1972), H 3
(Arrang et al., 1987), and H 4
(Leurs et al., 2009). H 1
receptors
are blocked selectively by the classical “antihistamines.”
Second-generation H 1
antagonists are collectively referred to as
nonsedating antihistamines. The term third generation has been
applied to some recently developed antihistamines, such as active
metabolites of first- or second-generation antihistamines that are not
further metabolized (e.g., cetirizine derived from hydroxyzine or fexofenadine
from terfenadine) or to antihistamines that have additional
therapeutic effects. However, the Consensus Group on New-
Generation Antihistamines concluded that none of the currently
available antihistamines can be classified as true third-generation
drugs, defined as lacking in cardiotoxicity, drug-drug interactions,
and CNS effects or with possible additional beneficial effects (e.g.,
anti-inflammatory) (Holgate et al., 2003). The discovery of H 2
antagonists
and their ability to inhibit gastric secretion has contributed
greatly to the resurgence of interest in histamine in biology and clinical
medicine (Chapter 45). H 3
receptors were discovered as presynaptic
autoreceptors on histamine-containing neurons that mediate
feedback inhibition of the release and synthesis of histamine. The
development of selective H 3
receptor agonists and antagonists has
led to an increased understanding of the importance of H 3
receptors
in histaminergic neurons in vivo. None of these H 3
agonists or