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

924 Ethylenediamines (Prototype: Pyrilamine). These include some of
the most specific H 1
antagonists. Although their central effects are
relatively feeble, somnolence occurs in a fair proportion of patients.
GI side effects are quite common.
Alkylamines (Prototype: Chlorpheniramine). These are among the
most potent H 1
antagonists. The drugs are less prone to produce
drowsiness and are more suitable for daytime use, but a significant
proportion of patients do experience sedation. Side effects involving
CNS stimulation are more common than with other groups.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
First-Generation Piperazines. The oldest member of this group, chlorcyclizine,
has a more prolonged action and produces a comparatively
low incidence of drowsiness. Hydroxyzine is a long-acting compound
that is used widely for skin allergies; its considerable CNSdepressant
activity may contribute to its prominent anti-pruritic
action. Cyclizine and meclizine have been used primarily to counter
motion sickness, although promethazine and diphenhydramine are
more effective (as is the antimuscarinic scopolamine; see “H 1
Antihistamines”).
Second-Generation Piperazines (Cetirizine). Cetirizine is the only
drug in this class. It has minimal anticholinergic effects. It also has
negligible penetration into the brain but is associated with a
somewhat higher incidence of drowsiness than the other second-generation
H 1
antagonists. The active enantiomer levocetirizine has
slightly greater potency and may be used at half the dose with less
resultant sedation.
Phenothiazines (Prototype: Promethazine). Most drugs of this class
are H 1
antagonists and also possess considerable anticholinergic
activity. Promethazine, which has prominent sedative effects, and its
many congeners are used primarily for their antiemetic effects
(Chapter 37).
First-Generation Piperidines (Cyproheptadine, Phenindamine).
Cyproheptadine uniquely has both antihistamine and anti-serotonin
activity. Cyproheptadine and phenindamine cause drowsiness and
also have significant anticholinergic effects and can increase appetite.
Second-Generation Piperidines (Prototype: Terfenadine). Terfenadine
and astemizole were withdrawn from the market. Current drugs in
this class include loratadine, desloratadine, and fexofenadine. These
agents are highly selective for H 1
receptors, lack significant anticholinergic
actions, and penetrate poorly into the CNS. Taken
together, these properties appear to account for the low incidence of
side effects of piperidine antihistamines.
H 2 RECEPTOR ANTAGONISTS
The pharmacology and clinical utility of H 2
antagonists to
inhibit gastric acid secretion are described in Chapter 45.
THE HISTAMINE H 3
RECEPTOR
AND ITS ANTAGONISTS
The H 3
receptor was characterized as a novel G i
-coupled
receptor using (R)-α-methylhistamine, a selective H 3
agonist, and thioperamide, an antagonist (Arrang et al.,
1987). The cloning of its cDNA revealed it to be a
GPCR with low sequence identity (~20%) to H 1
and H 2
receptors (Lovenberg et al., 1999). Further studies on
the H 3
receptor uncovered a variety of functional isoforms
resulting from alternative splicing, many within
a pseudo-intron in the third intracellular loop that may
control constitutive activity (Arrang et al., 2007); this,
combined with the influence of cell type, signaling
pathway, and interspecies differences, yields H 3
receptors
with a variety of binding and signaling properties
(Esbenshade et al., 2008).
H 3
receptors are presynaptic autoreceptors on histaminergic
neurons that originate in the tuberomammillary nucleus in the hypothalamus
and project throughout the CNS, most prominently to the
hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum,
hypothalamus, and cortex (Haas et al., 2008; Sander et al.,
2008). The activated H 3
receptor depresses neuronal firing at the
level of cell bodies/dendrites and decreases histamine release from
depolarized terminals. Thus, H 3
agonists decrease histaminergic
transmission, and antagonists increase it. H 3
receptors also are presynaptic
heteroreceptors on a variety of neurons in brain and peripheral
tissues, and their activation inhibits release from noradrenergic,
serotoninergic, GABA-ergic, cholinergic, and glutamatergic neurons,
as well as pain-sensitive C fibers. H 3
receptors in the brain have
significant constitutive activity in the absence of agonist, which
varies according to splicing isoform, cell type, and signaling pathway
stimulated; consequently, inverse agonists will activate these
neurons.
In the enterochromaffin-like cells of the stomach, H 3
receptors
inhibit gastrin-induced release of histamine and, therefore,
decrease HCl secretion mediated by H 2
receptors, but the effect is not
large enough to warrant development of therapeutic agents. H 3
agonists
decrease tachykinin release from capsaicin-sensitive C-fiber
terminals and thereby reduce capsaicin-induced plasma extravasation
and are antinociceptive. H 3
agonists also depress exaggerated
catecholamine release in the heart (e.g., during ischemia).
By blocking H 3
autoreceptors on histaminergic neurons and
H 3
heteroreceptors on other neurons, H 3
antagonists/inverse agonists
have a wide range of central effects; for example, they promote
wakefulness, improve cognitive function (e.g., enhance memory,
learning, and attention), and reduce food intake (Esbenshade et al.,
2008; Sander et al., 2008). As a result, there is considerable interest
in developing H 3
antagonists for possible treatment of sleeping disorders,
attention-deficit hyperactivity disorder (ADHD), epilepsy,
cognitive impairment, schizophrenia, obesity, neuropathic pain, and
Alzheimer’s disease (Esbenshade et al., 2008; Sander et al., 2008).
However, this task is complicated by the heterogeneity in receptor
isoforms and signaling pathways, varying levels of constitutive H 3
activity, species differences in ligand affinities, and the effects of H 3
antagonists/inverse agonists on the release of neurotransmitters in
addition to histamine (e.g., DA, ACh, NE, GABA, glutamate, and
substance P) (Sander et al., 2008; Esbenshade et al., 2008). Although
drug development is focused on inverse agonists to block basal and
agonist-stimulated H 3
activity, it is not yet clear that such drugs will
necessarily be clinically superior to neutral antagonists.