Page 298 - Basic _ Clinical Pharmacology ( PDFDrive )

284 SECTION IV Drugs with Important Actions on Smooth Muscle

Angioedema may be precipitated by histamine release but Toxicity
appears to be maintained by peptide kinins that are not affected by
antihistaminic agents. For atopic dermatitis, antihistaminic drugs The wide spectrum of nonantihistaminic effects of the
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such as diphenhydramine are used mostly for their sedative side H antihistamines is described above. Several of these effects
effect, which reduces awareness of itching. (sedation, antimuscarinic action) have been used for thera-
The H antihistamines used for treating allergic conditions peutic purposes, especially in over-the-counter remedies (see
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such as hay fever are usually selected with the goal of minimiz- Chapter 63). Nevertheless, these two effects constitute the
ing sedative effects; in the USA, the drugs in widest use are most common undesirable actions when these drugs are used
the alkylamines and the second-generation nonsedating agents. to block peripheral histamine receptors.
However, the sedative effect and the therapeutic efficacy of differ- Less common toxic effects of systemic use include excitation
ent agents vary widely among individuals. In addition, the clinical and convulsions in children, postural hypotension, and allergic
effectiveness of one group may diminish with continued use, and responses. Drug allergy is relatively common after topical use
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switching to another group may restore drug effectiveness for as of H antagonists. The effects of severe systemic overdosage of
yet unexplained reasons. the older agents resemble those of atropine overdosage and are
The second-generation H antagonists are used mainly for treated in the same way (see Chapters 8 and 58). Overdosage of
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the treatment of allergic rhinitis and chronic urticaria. Several astemizole or terfenadine may induce cardiac arrhythmias; the
double-blind comparisons with older agents (eg, chlorpheniramine) same effect may be caused at normal dosage by interaction with
indicated about equal therapeutic efficacy. However, sedation enzyme inhibitors (see Drug Interactions). These drugs are no
and interference with safe operation of machinery, which occur longer marketed in the USA.
in about 50% of subjects taking first-generation antihistamines,
occurred in only about 7% of subjects taking second-generation Drug Interactions
agents. The newer drugs are much more expensive, even in over- Lethal ventricular arrhythmias occurred in several patients taking
the-counter generic formulations. either of the early second-generation agents, terfenadine or
astemizole, in combination with ketoconazole, itraconazole, or
B. Motion Sickness and Vestibular Disturbances macrolide antibiotics such as erythromycin. These antimicrobial
Scopolamine (see Chapter 8) and certain first-generation drugs inhibit the metabolism of many drugs by CYP3A4 and
H antagonists are the most effective agents available for the cause significant increases in blood concentrations of the anti-
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prevention of motion sickness. The antihistaminic drugs with the histamines. The mechanism of this toxicity involves blockade of
greatest effectiveness in this application are diphenhydramine and the HERG (I ) potassium channels in the heart that contribute
Kr
promethazine. Dimenhydrinate, which is promoted almost exclu- to repolarization of the action potential (see Chapter 14). The
sively for the treatment of motion sickness, is a salt of diphen- result is prolongation and a change in shape of the action poten-
hydramine and has similar efficacy. The piperazines (cyclizine tial, and these changes lead to arrhythmias. Both terfenadine and
and meclizine) also have significant activity in preventing motion astemizole were withdrawn from the US market in recognition of
sickness and are less sedating than diphenhydramine in most these problems. Where still available, terfenadine and astemizole
patients. Dosage is the same as that recommended for allergic should be considered to be contraindicated in patients taking
disorders (Table 16–2). Both scopolamine and the H antagonists ketoconazole, itraconazole, or macrolides and in patients with
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are more effective in preventing motion sickness when combined liver disease. Grapefruit juice also inhibits CYP3A4 and has been
with ephedrine or amphetamine. shown to increase blood levels of terfenadine significantly.
It has been claimed that the antihistaminic agents effective For those H antagonists that cause significant sedation,
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in prophylaxis of motion sickness are also useful in Méniére’s concurrent use of other drugs that cause central nervous system
syndrome, but efficacy in the latter condition is not established. depression produces additive effects and is contraindicated while
driving or operating machinery. Similarly, the autonomic blocking
effects of older antihistamines are additive with those of antimus-
C. Nausea and Vomiting of Pregnancy carinic and α-blocking drugs.
Several H -antagonist drugs have been studied for possible use
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in treating “morning sickness.” The piperazine derivatives were H -RECEPTOR ANTAGONISTS
withdrawn from such use when it was demonstrated that they 2
have teratogenic effects in rodents. Doxylamine, an ethanolamine The development of H -receptor antagonists was based on the
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H antagonist, was promoted for this application as a component of observation that H antagonists had no effect on histamine-
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Bendectin, a prescription medication that also contained pyridox- induced acid secretion in the stomach. Molecular manipulation of
ine. Possible teratogenic effects of doxylamine were widely publi- the histamine molecule resulted in drugs that blocked acid secre-
cized in the lay press after 1978 as a result of a few case reports tion and had no H agonist or antagonist effects. Like the other
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of fetal malformation that occurred after maternal ingestion of histamine receptors, the H receptor displays constitutive activity,
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Bendectin. However, several large prospective studies disclosed no and some H blockers are inverse agonists.
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increase in the incidence of birth defects, thereby justifying the The high prevalence of peptic ulcer disease created great interest
reintroduction of a similar product. in the therapeutic potential of the H -receptor antagonists when
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