Excerpt from Toxicity, Antihistamine

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Background

Antihistamines comprise a broad class of pharmacologic agents that include the first-generation, centrally acting, H1-receptor antagonists (eg, diphenhydramine) and the newer, second-generation, nonsedating H1 blockers (eg, loratadine). Other antihistaminic agents, such as cimetidine, work primarily at H2 receptors causing inhibition of gastric secretion; still other experimental antihistamines act on presynaptic H3 receptors.

While first-generation H1-receptor antagonists are responsible for the vast majority of poisonings, all antihistamine classes have been associated with serious toxicity.

Pathophysiology

H1, H2, and H3 receptors are the 3 histamine receptors that have been identified.

All H1 histamine antagonists are reversible competitive inhibitors of histamine receptors. First-generation H1-receptor blockers also are potent competitive inhibitors of muscarinic receptors and may cause anticholinergic syndrome (eg, sinus tachycardia, dry skin, dry mucous membranes, dilated pupils, ileus, urinary retention, agitated delirium). In addition, antihistamines disrupt cortical neurotransmission and block fast sodium channels. These effects exacerbate sedation and seizure activity and may cause cardiac conduction delays manifested by widening of the QRS interval. The phenothiazine class of antihistamines (eg, promethazine) has alpha-adrenergic blocking activity and may cause hypotension.

The 6 structural classes of antihistamines are as follows:

1. Alkylamines (eg, brompheniramine, triprolidine, pheniramine)
2. Ethanolamines (eg, clemastine, diphenhydramine, doxylamine)
3. Ethylenediamines (eg, tripelennamine)
4. Phenothiazines (eg, promethazine)
5. Piperidines (eg, fexofenadine and loratadine; terfenadine and astemizole (recalled from US market)
6. Piperazines (eg, cetirizine, levocetirizine, meclizine)

Fexofenadine, loratadine, astemizole, and cetirizine are peripherally selective H1-receptor antagonists. They have a distinct advantage because they bind much more selectively to peripheral H1 receptors and have a lower binding affinity for the cholinergic and alpha-adrenergic receptor sites than other antihistamines. This group of antihistamines is popular because specificity for the peripheral histamine receptor site eliminates many adverse effects, including central nervous system (CNS) depression, blurred vision, dry mouth, and tachycardia.

Two nonsedating antihistamines, terfenadine and astemizole, are known to inhibit the potassium rectifier currents, which slows repolarization. This is manifested clinically as prolongation of the QT interval and torsade de pointes. Astemizole and terfenadine have been removed from the US market. Terfenadine has been replaced by fexofenadine, which is the pharmacologically active metabolite of terfenadine. Fexofenadine has not been associated with torsade de pointes in volunteer and animal studies. Diphenhydramine is known to prolong the QT interval on ECG by presumed inhibition of the delayed potassium rectifier channel. Torsade de pointes has not been documented with diphenhydramine, most likely because of the concurrent sinus tachycardia created by the anticholinergic-induced tachycardia, which shortens repolarization.

A new class of selective nonsedating H1 antagonists, the norpiperidine imidazoazepines, is currently in clinical trials. Current in vitro and in vivo safety studies show no increase in incidence of cardiac dysrhythmia.

H2 receptors are primary regulators of gastric acid secretion. In the CNS, histamine (H1, H2) modulates activities such as arousal, thermoregulation, neuroendocrine, and vegetative functions. H2-receptor antagonists are considered relatively benign in overdose; as observed with cimetidine, the primary adverse reaction is confusion. Cimetidine also inhibits hepatic oxidative metabolism by most cytochrome P450 enzymes and, thus, the metabolism of a variety of drugs including propranolol, carbamazepine, quinidine, theophylline, and certain tricyclic antidepressants. Other H2-receptor blockers (eg, ranitidine, famotidine) do not seem to interfere with hepatic oxidation.

H3 receptors are presynaptic regulators of synthesis and release of histamine into the synapse. Use of H3 receptors has been limited to experimental settings only.

Frequency

United States

The American Association of Poison Control Centers Toxic Exposure Surveillance System (AAPCC-TESS) annual report for 2004 ascribes 72,762 exposures to either H1 or H2 blockers. H2 blockers were associated with 8,659 exposures, while H1 blockers were associated with 64,103. A total of 24,498 patients exposed to either H1 or H2 blockers were treated in a healthcare facility. Diphenhydramine was the most common antihistamine exposure, with 29,501 reports being made to poison centers.

Mortality/Morbidity

• Of all antihistamine exposures reported to US poison control centers in 2004 (AAPCC-TESS data), 7049 (7.4%) resulted in moderate-to-major toxicity and 55 (0.076%) resulted in fatality. The vast majority of fatalities (54%) were associated with diphenhydramine.
• First-generation H1-receptor antagonists, such as diphenhydramine, may be particularly dangerous because they may cause pronounced agitation leading to rhabdomyolysis and acidosis. Also, a quinidinelike sodium channel blocking effect, and at high doses a potassium channel blocking effect, may cause delayed conduction and repolarization and contribute to ventricular dysrhythmias.
• Second-generation H1-receptor antagonists, such as terfenadine and astemizole (now removed from the US market), may result in QT interval prolongation and life-threatening polymorphic ventricular tachycardia (torsade de pointes).

Race

• Individuals of Asian descent can acetylate diphenhydramine to a nontoxic metabolite twice as rapidly as white individuals; thus, Asians are much less sensitive to the effects on psychomotor performance and the sedative effects.
• Antihistamines are capable of inducing the hepatic microsomal enzymes and may enhance their own rate of elimination in patients using them chronically. This phenomenon often is referred to as autoinduction of metabolism.

Age

According to the 2004 AAPCC-TESS data, the greatest number of toxic antihistamine exposures is associated with patients younger than 6 years (34,401 or 47%).

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