result of a few case reports of fetal malformation associated with 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. However, because of the continuing controversy, adverse publicity, and lawsuits, the manufacturer of Bendectin withdrew the product from the market, Doxylamine is still available over-the-counter asa sleep aid. Toxicity ‘The wide spectrum of adverse effects of the H; antihistamines is described above. Several of these effects (sedation, antimuscarinic action) have been used for therapeutic purposes, especially in OTC remedies (see Chapter 64: Therapeutic & Toxic Potential of Over-the-Counter Agents). 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 Hi antagonists. The effects of severe systemic overdosage of the older agents resemble those of atropine overdosage and are treated in the same way (see Chapter 8: Cholinoceptor-Blocking Drugs and Chapter 59: Management of the Poisoned Patient). Overdosage of astemizole or terfenadine ‘may induce cardiac atthythmias, but these drugs are no longer marketed in the USA; the same effect may be caused by interaction with enzyme inhibitors (see Drug Interactions, below). Drug Interactions Lethal ventricular arrhythmias occurred in several patients taking either of the early second generation agents, terfenadine or astemizole, in combination with ketoconazole, itraconazole, or macrolide antibiotics such as erythromycin. These antimicrobial drugs inbibit the metabolism of many drugs by CYP3A4 and cause significant increases in blood concentrations of the antihistamines. The mechanism of this toxicity involves blockade of the potassium channels in the heart that are responsible for repolarization of the action potential, the Ix channels (see Chapter 14: Agents Used in Cardiac Arrhythmias). The result is prolongation of the action potential, and excessive prolongation leads to arrhythmias. Both terfenadine and astemizole were withdrawn from the United States market in recognition of these problems. Where stil] available, terfenadine and astemizole should be considered to be contraindicated in patients taking ketoconazole, itraconazole, ‘or macrolides and in patients with liver disease. Grapefruit juice also inhibits CYP3A4 and has been, shown to increase terfenadine’s blood levels significantly. For those Hy antagonists that cause significant sedation, concurrent 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 muscarinic and a-blocking drugs. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth, Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > H; Receptor Antagonists ‘The development of Hy receptor antagonists was based on the observation that Hy antagonists had no effect on histamine-induced acid secretion in the stomach. Molecular manipulation of the histamine molecule resulted in a compound that blocked rather than stimulated acid production and