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Chapter: Basic & Clinical Pharmacology : Histamine, Serotonin, & the Ergot Alkaloids

Clinical Pharmacology of H1-Receptor Antagonists

First-generation H1-receptor blockers are among the most extensively promoted and used over-the-counter drugs.


Clinical Uses

First-generation H1-receptor blockers are among the most extensively promoted and used over-the-counter drugs. The prevalence of allergic conditions and the relative safety of the drugs contribute to this heavy use. The fact that they do cause sedation contributes to heavy prescrib-ing and over-the-counter use of second-generation antihistamines.

A. Allergic Reactions

The H1 antihistaminic agents are often the first drugs used to prevent or treat the symptoms of allergic reactions. In allergic rhinitis (hay fever), the H1 antagonists are second-line drugs after glucocorticoids administered by nasal spray. In urticaria, in which histamine is the primary mediator, the H1 antagonists are the drugs of choice and are often quite effective if given before expo-sure. However, in bronchial asthma, which involves several media-tors, the H1 antagonists are largely ineffective.

Angioedema may be precipitated by histamine release but appears to be maintained by peptide kinins that are not affected by antihistaminic agents. For atopic dermatitis, antihistaminic drugs such as diphenhydramine are used mostly for their sedative side effect, which reduces awareness of itching.

The H1 antihistamines used for treating allergic conditions such as hay fever are usually selected with the goal of minimizing sedative effects; in the USA, the drugs in widest use are the alkylamines and the second-generation nonsedating agents. However, the sedative effect and the therapeutic efficacy of differ-ent agents vary widely among individuals. In addition, the clinical effectiveness of one group may diminish with continued use, and switching to another group may restore drug effectiveness for as yet unexplained reasons.

The second-generation H1 antagonists are used mainly for the treatment of allergic rhinitis and chronic urticaria. Several double-blind comparisons with older agents (eg, chlorpheniramine) indi-cated about equal therapeutic efficacy. However, sedation and interference with safe operation of machinery, which occur in about 50% of subjects taking first-generation antihistamines, occurred in only about 7% of subjects taking second-generation agents. The newer drugs are much more expensive, even in over-the-counter generic formulations.

B. Motion Sickness and Vestibular Disturbances

Scopolamine  and certain first-generation H1 antagonists are the most effective agents available for the preven-tion of motion sickness. The antihistaminic drugs with the great-est effectiveness in this application are diphenhydramine and promethazine. Dimenhydrinate, which is promoted almost exclu-sively for the treatment of motion sickness, is a salt of diphenhy-dramine and has similar efficacy. The piperazines (cyclizine and meclizine) also have significant activity in preventing motion sick-ness and are less sedating than diphenhydramine in most patients. Dosage is the same as that recommended for allergic disorders (Table 16–2). Both scopolamine and the H1 antagonists are more effective in preventing motion sickness when combined with ephedrine or amphetamine.

It has been claimed that the antihistaminic agents effective in prophylaxis of motion sickness are also useful in Ménière’s syn-drome, but efficacy in the latter application is not established.

C. Nausea and Vomiting of Pregnancy

Several H1-antagonist drugs have been studied for possible use in treating “morning sickness.” The piperazine derivatives were with-drawn from such use when it was demonstrated that they have teratogenic effects in rodents. Doxylamine, an ethanolamine H1 antagonist, was promoted for this application as a component of Bendectin, a prescription medication that also contained pyridoxine. Possible teratogenic effects of doxylamine were widely publicizedin the lay press after 1978 as a result of a few case reports of fetal malformation that occurred after maternal ingestion of Bendectin. However, several large prospective studies involving over 60,000 pregnancies, of which more than 3000 involved maternal Bendectin ingestion, disclosed no increase in the incidence of birth defects. Nonetheless, because of the continuing controversy, adverse publicity, and lawsuits, the manufacturer of Bendectin withdrew the product from the market.


The wide spectrum of nonantihistaminic effects of the H1 antihista-mines is described above. Several of these effects (sedation, antimus-carinic action) have been used for therapeutic purposes, especially in over-the-counter remedies . Nevertheless, these two effects constitute the most common undesirable actions when these drugs are used to block histamine receptors.

Less common toxic effects of systemic use include excitation and convulsions in children, postural hypotension, and allergic responses. Drug allergy is relatively common after topical use of H1 antago-nists. The effects of severe systemic overdosage of the older agents resemble those of atropine overdosage and are treated in the same way. Overdosage of astemizole or terfena-dine may induce cardiac arrhythmias; the same effect may be caused at normal dosage by interaction with enzyme inhibitors (see Drug Interactions). These drugs are no longer marketed in the USA.

Drug Interactions

Lethal ventricular arrhythmias occurred in several patients taking either of the early second-generation agents, terfenadine or astem-izole, in combination with ketoconazole, itraconazole, or mac-rolide antibiotics such as erythromycin. These antimicrobial drugs inhibit the metabolism of many drugs by CYP3A4 and cause sig-nificant increases in blood concentrations of the antihistamines. The mechanism of this toxicity involves blockade of the HERG (IKr) potassium channels in the heart that contribute to repolariza-tion of the action potential . The result is prolon-gation and a change in shape of the action potential, and these changes lead to arrhythmias. Both terfenadine and astemizole were withdrawn from the US market in recognition of these problems. Where still available, terfenadine and astemizole should be consid-ered to be contraindicated in patients taking ketoconazole, itra-conazole, or macrolides and in patients with liver disease. Grapefruit juice also inhibits CYP3A4 and has been shown to increase blood levels of terfenadine significantly.

For those H1 antagonists that cause significant sedation, con-current use of other drugs that cause central nervous system 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-carinic and α-blocking drugs.

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