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

Thioperamide was the first “specific” H 3
antagonist/inverse
agonist available experimentally, but it turned out to be equally effective
on the H 4
receptor. A number of other imidazole derivatives have
been developed as H 3
antagonists, including clobenpropit, ciproxifan,
and proxyfan. However, the imidazole group can bind to and
inhibit CYPs, reduce bioavailability in and penetration into the CNS,
and enhance binding to H 4
receptors, prompting efforts to develop
more selective H 3
-receptor antagonists using non-imidazolebased
structures. This has resulted in the generation of numerous
antagonists/inverse agonists representing a remarkably broad variety
of structural classes (Sander et al., 2008; Esbenshade et al., 2008).
Although none is approved for clinical use, several non-imidazole H 3
antagonists/inverse agonists are in phase II clinical trials for treating
epilepsy, narcolepsy and other sleep disorders, cognitive impairment,
Alzheimer’s disease, schizophrenia, and ADHD; these include tiprolisant
(BF2.649), GSK189254, GSK239512, JNJ-17216498, and
MK0249.
THE HISTAMINE H 4
RECEPTOR
AND ITS ANTAGONISTS
The discovery of a fourth histamine receptor with a
unique pharmacology and distribution has further
expanded the search for new drugs based on histamine
function in inflammation (Leurs et al., 2009; Thurmond
et al., 2008). The H 4
receptor has the highest homology
with the H 3
receptor and binds many H 3
ligands, especially
those with imidazole rings, although sometimes
with different effects. For example, thioperamide is an
effective inverse agonist at both H 3
and H 4
receptors,
whereas H 3
inverse agonist clobenpropit is a partial
agonist of the H 4
receptor; impentamine (an H 3
agonist)
and iodophenpropit (an H 3
inverse agonist) are both
neutral H 4
antagonists (Lim et al., 2005).
Because the H 4
receptor is expressed on cells with inflammatory
or immune functions (see the discussion earlier), there is great
interest in developing H 4
antagonists to treat various inflammatory
conditions (Thurmond et al., 2008). Indeed, H 4
receptors can mediate
histamine-induced chemotaxis, induction of cell shape change,
secretion of cytokines, and upregulation of adhesion molecules. For
example, the H 4
receptor likely accounts for early reports of
histamine-dependent eosinophil chemotaxis, which was independent
of H 1
receptors and inhibited by H 2
receptors (Clark et al., 1977). The
presence of H 4
receptors in the CNS and animal studies with H 4
agonists
and antagonists also have indicated a role for this receptor in
pruritus and neuropathic pain (Leurs et al., 2009). The first selective
H 4
antagonist, JNJ7777120, exhibits ~1000-fold selectivity over
other H receptors, has acceptable oral bioavailability, and has in vivo
activity; however, its short t 1/2
(~0.8 hour) limits its potential clinical
usefulness. In addition to derivatives of the benzimidazole
JNJ7777120, promising H 4
antagonists have been developed using
several different scaffolds, including methylpiperazine-substituted
2-quinoxalinones, quinazolines, and aminopyrimidines (Leurs et al.,
2009). Although these are high-affinity ligands, relatively high doses
are required for significant anti-inflammatory effects in vivo, possibly
due to either their pharmacokinetic properties or competition with
endogenous histamine, which also has a high affinity for the receptor
(Leurs et al., 2009). No H 4
antagonists have yet been tested in clinical
trials.
CLINICAL SUMMARY: ANTI-HISTAMINES
H 1
Antihistamines. These medications are used widely
in the treatment of allergic disorders. H 1
antihistamines
are most effective in relieving the symptoms of seasonal
rhinitis and conjunctivitis (e.g., sneezing; rhinorrhea;
itching of the eyes, nose, and throat). In bronchial
asthma, they have limited beneficial effects and are not
useful as sole therapy. H 1
antagonists are useful
adjuncts to epinephrine in the treatment of systemic
anaphylaxis or severe angioedema. Certain allergic dermatoses,
such as acute urticaria, respond favorably to
H 1
antagonists, which help to relieve the itch in atopic
or contact dermatitis but have no effect on the rash.
Physical and chronic urticaria may require increased
dosage to counter the levels of skin histamine generated
(Siebenhaar et al., 2009).
Side effects are most prominent with first-generation
H 1
antihistamines (e.g., diphenhydramine,
chlorpheniramine, doxepin, hydroxyzine), which cross
the blood-brain barrier and cause sedation. Some of the
first-generation H 1
receptor antagonists also have anticholinergic
properties that can be responsible for symptoms
such as dryness of the mouth and respiratory
passages, urinary retention or frequency, and dysuria.
The second-generation drugs (e.g., levocetirizine, cetirizine,
loratadine, desloratadine, fexofenadine) are
largely devoid of these side effects because they do not
penetrate the CNS and do not have antimuscarinic properties.
Thus, they usually are the drugs of choice for the
treatment of allergic disorders.
The significant sedative effects of some firstgeneration
antihistamines have led to their use in treating
insomnia, although better drugs are available. Some
first-generation H 1
antagonists (e.g., dimenhydrinate,
cyclizine, meclizine, and promethazine) can prevent
motion sickness, although scopolamine is more effective.
Antiemetic effects of these H 1
antihistamines can be
beneficial in treating vertigo or postoperative emesis.
Many H 1
antihistamines are metabolized by CYPs.
Thus, inhibitors of CYP activity, such as macrolide
antibiotics (e.g., erythromycin) or imidazole antifungals
(e.g., ketoconazole) can increase H 1
antihistamine levels,
leading to toxicity. Some newer antihistamines, such
as cetirizine, fexofenadine, levocabastine, and acrivastine,
are not subject to these drug interactions.
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CHAPTER 32
HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS