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

H 3 CO
CH 3
CH 3
H C O CH 2 CH 2 N
H C CH 2 CH 2 N
CH 3
H
CH 3
N
DIPHENHYDRAMINE (an ethanolamine)
CHLORPHENIRAMINE (an alkylamine)
CH 2
CH 3
N CH 2 CH 2 N
H C N N CH 3
CH 3
Cl
N
PYRILAMINE (an ethylenediamine)
CHLORCYCLIZINE (a piperazine)
O OC 2 H 5
C
N
CH 3
S N CH 2 CH N
N
CH
CH 3 3
PROMETHAZINE (a phenothiazine)
Figure 32–3. Representative H 1
antagonists.
Cl
Cl
LORATADINE (a tricyclic piperidine)
919
CHAPTER 32
HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS
Flare and Itch. H 1
antagonists suppress the action of histamine on
nerve endings, including the flare component of the triple response
and the itching caused by intradermal injection.
Exocrine Glands. H 1
antagonists do not suppress gastric secretion;
they do inhibit histamine-evoked salivary, lacrimal, and other
exocrine secretions, but with variable success. However, the antimuscarinic
properties of many H 1
antagonists may contribute to lessened
secretion in cholinergically innervated glands and reduce ongoing
secretion in, e.g., the respiratory tree. Nasal sprays of some H 1
antagonists
can be used to treat allergic rhinitis.
Immediate Hypersensitivity Reactions: Anaphylaxis and
Allergy. During hypersensitivity reactions, histamine is
one of the many potent autacoids released (see “Release
of Other Autacoids”), and its relative contribution to the
ensuing symptoms varies widely with species and tissue.
The protection afforded by H 1
antagonists thus also
varies accordingly. In humans, edema formation and
itch are effectively suppressed. Other effects, such as
hypotension, are less well antagonized. This may be
explained by the participation of other types of H receptors
and by effects of other mast cell mediators, chiefly
eicosanoids (Thurmond et al., 2008; Campbell and
Falck, 2007) (Chapter 25). Bronchoconstriction is
reduced little, if at all.
Central Nervous System. The first-generation H 1
antagonists
can both stimulate and depress the CNS.
Stimulation occasionally is encountered in patients
given conventional doses; they become restless, nervous,
and unable to sleep. Central excitation also is a
striking feature of overdose, which commonly results
in convulsions, particularly in infants. Central depression,
on the other hand, usually accompanies therapeutic
doses of the older H 1
antagonists. Diminished
alertness, slowed reaction times, and somnolence are
common manifestations. Patients vary in their susceptibility
and responses to individual drugs. The
ethanolamines (e.g., diphenhydramine; Figure 32–3)
are particularly prone to causing sedation. Because of
the sedation that occurs with first-generation antihistamines,
these drugs cannot be tolerated or used safely
by many patients except at bedtime. Even then, patients
may experience an antihistamine “hangover” in the
morning, resulting in sedation with or without psychomotor
impairment (Simons, 2003). Whether tolerance
to such adverse effects results from protracted use
when administered in divided doses to patients with
chronic urticarial syndromes is unclear (Richardson