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

Motion Sickness, Vertigo, and Sedation. Scopolamine, the muscarinic
antagonist, given orally, parenterally, or transdermally, is the most
effective drug for the prophylaxis and treatment of motion sickness.
Some H 1
antagonists are useful for milder cases and have fewer
adverse effects. These drugs include dimenhydrinate and the piperazines
(e.g., cyclizine, meclizine). Promethazine, a phenothiazine,
is more potent and more effective; its additional antiemetic properties
may be of value in reducing vomiting, but its pronounced sedative
action usually is disadvantageous. Whenever possible, the
various drugs should be administered ~1 hour before the anticipated
motion. Treatment after the onset of nausea and vomiting rarely is
beneficial.
Some H 1
antagonists, notably dimenhydrinate and meclizine,
often are of benefit in vestibular disturbances such as Meniere’s disease
and in other types of true vertigo. Only promethazine is useful
in treating the nausea and vomiting subsequent to chemotherapy or
radiation therapy for malignancies; however, other, more effective
anti-emetic drugs (e.g., 5-HT 3
antagonists) are available (Chapter
46). Diphenhydramine can reverse the extrapyramidal side effects
caused by phenothiazines ( Chapter 16).
The tendency of some H 1
receptor antagonists to produce
somnolence has led to their use as hypnotics. H 1
antagonists, principally
diphenhydramine, often are present in various proprietary
over-the-counter remedies for insomnia. Although these drugs generally
are ineffective in the recommended doses, some sensitive individuals
may derive benefit. The sedative and mild anti-anxiety
activities of hydroxyzine contribute to its use as a weak anxiolytic.
Adverse Effects. The most frequent side effect in firstgeneration
H 1
antagonists is sedation. Although sedation
may be a desirable adjunct in the treatment of some
patients, it may interfere with the patient’s daytime
activities. Concurrent ingestion of alcohol or other CNS
depressants produces an additive effect that impairs
motor skills. Other untoward central actions include
dizziness, tinnitus, lassitude, incoordination, fatigue,
blurred vision, diplopia, euphoria, nervousness, insomnia,
and tremors.
The next most frequent side effects involve the digestive tract
and include loss of appetite, nausea, vomiting, epigastric distress, and
constipation or diarrhea. Taking the drug with meals may reduce their
incidence. H 1
antagonists such as cyproheptadine may increase
appetite and cause weight gain. Other side effects, owing to the
antimuscarinic actions of some first-generation H 1
antagonists, include
dryness of the mouth and respiratory passages (sometimes inducing
cough), urinary retention or frequency, and dysuria. These effects are
not observed with second-generation H 1
antagonists.
Drug allergy may develop when H 1
antagonists are given
orally but occurs more commonly after topical application. Allergic
dermatitis is not uncommon; other hypersensitivity reactions include
drug fever and photosensitization. Hematological complications,
such as leukopenia, agranulocytosis, and hemolytic anemia, are very
rare. Because H 1
antihistamines cross the placenta, caution is advised
for women who are or may become pregnant. Several antihistamines
(e.g., azelastine, hydroxyzine, fexofenadine) had teratogenic
effects in animal studies, whereas others (e.g., chlorpheniramine,
diphenhydramine, cetirizine, loratadine) did not (see Simons, 2003).
Antihistamines can be excreted in small amounts in breast milk, and
first-generation antihistamines taken by lactating mothers may cause
symptoms such as irritability, drowsiness, or respiratory depression
in the nursing infant (Simons, 2003). Because H 1
antagonists interfere
with skin tests for allergy, they must be withdrawn well before
such tests are performed.
In acute poisoning with H 1
antagonists, their central excitatory
effects constitute the greatest danger. The syndrome includes
hallucinations, excitement, ataxia, incoordination, athetosis, and convulsions.
Fixed, dilated pupils with a flushed face, together with
sinus tachycardia, urinary retention, dry mouth, and fever, lend the
syndrome a remarkable similarity to that of atropine poisoning.
Terminally, there is deepening coma with cardiorespiratory collapse
and death usually within 2-18 hours. Treatment is along general
symptomatic and supportive lines.
Pediatric and Geriatric Indications and Problems. Although little clinical
testing has been done, second-generation antihistamines are recommended
for elderly patients (>65 years of age), especially those
with impaired cognitive function, because of the sedative and anticholinergic
effects of first-generation drugs. Therapy should be
approached cautiously, possibly at reduced dosages, because of the
greater likelihood of compromised renal and hepatic function in
these patients, which can reduce drug elimination.
First-generation antihistamines are not recommended for use
in children because their sedative effects can impair learning and
school performance. The second-generation drugs loratadine, desloratadine,
fexofenadine, cetirizine, levocetirizine, and azelastine
(intranasal) have been approved by the FDA for use in children and
are available in appropriate lower-dose formulations (e.g., chewable
or rapidly dissolving tablets, syrup).
Use of over-the-counter cough and cold medicines (containing
mixtures of antihistamines, decongestants, antitussives, expectorants)
in young children has been associated with serious side effects and
deaths (Kuehn, 2008). In 2008, the FDA recommended that they not be
used in children <2 years of age, and drug manufacturers affiliated with
the Consumer Healthcare Products Association voluntarily re-labeled
products “do not use” for children <4 years of age. The FDA is reviewing
the safety of these medicines in children aged 2-11 years.
Available H 1
Antagonists. Summarized below are the
therapeutic side effects of a number of H 1
antagonists,
grouped by their chemical structures. Representative
preparations are listed in Table 32–2.
Dibenzoxepin Tricyclics (Doxepin). Doxepin, the only drug in this
class, is marketed as a tricyclic antidepressant (Chapter 16). It also is
one of the most potent H 1
antagonists and has significant H 2
antagonist
activity, but this does not translate into greater clinical effectiveness.
It can cause drowsiness and is associated with anticholinergic effects.
Doxepin is better tolerated by patients with depression than those
who are not depressed, where even small doses (e.g., 20 mg) may
cause disorientation and confusion.
Ethanolamines (Prototype: Diphenhydramine). These drugs possess
significant antimuscarinic activity and have a pronounced tendency
to induce sedation. About half of those treated acutely with conventional
doses experience somnolence. The incidence of GI side
effects, however, is low with this group.
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CHAPTER 32
HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS