Antihistamines are a class of agents that modulate histamine receptors (H₁-H₄). H₁ receptor antagonists are commonly found in over-the-counter and prescription medications and are used for motion sickness, control of allergy-related itching, cough and cold palliation and to facilitate sleep. (Table II-9) Acute intoxication with H₁ receptor antagonists results in symptoms very similar to those of anticholinergic poisoning. H₂ receptor antagonists (cimetidine, ranitidine, and famotidine) inhibit gastric acid secretion but otherwise share no effects with H₁ agents, do not produce significant intoxication, and are not discussed here. While H₃ and H₄ receptors have been identified, no pharmaceutical agents targeting these receptors are currently on the market. Antihistamines are found in many over-the-counter combination products. Their use is not recommended in children.

1. H₁ receptor antagonists are structurally related to histamine and antagonize the effects of histamine at H₁ receptor sites. First generation antihistamines (diphenhydramine, doxylamine, dimenhydrinate, chlorpheniramine, brompheniramine, promethazine, hydroxyzine) have greater CNS penetration causing sedation and anticholinergic effects. Paradoxically, they may also cause CNS excitation. Some agents (eg, diphenhydramine) have local anesthetic and sodium channel blocking properties in large doses. Second generation or “nonsedating agents” (cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine) have less CNS penetration and therefore less sedation and anticholinergic effects.
2. Pharmacokinetics. Most antihistamines are rapidly absorbed following oral administration with peak plasma concentrations of 2-3 hours in therapeutic dosing. In overdose, absorption may be delayed and peak effects prolonged due to the pharmacologic effects on the GI tract. Volumes of distribution are generally large (0.5-30 L/kg). Most undergo hepatic metabolism, with exception of cetirizine, levocetirizine, and fexofenadine. Elimination half-lives are highly variable, ranging from 1-4 hours for diphenhydramine to 7-24 hours for many of the others (see also Table II-63).

The estimated fatal oral dose of diphenhydramine is 20-40 mg/kg. Children are more sensitive to the toxic effects of antihistamines than are adults. Pediatric ingestions of less than 7.5 mg/kg of diphenhydramine are not expected to cause significant toxicity. The nonsedating agents are associated with less toxicity.

1. An overdose results in many symptoms similar to those of anticholinergic poisoning: drowsiness, dilated pupils, flushed dry skin, fever, tachycardia, delirium, hallucinations, and myoclonic or choreoathetoid movements. Hyperthermia may occur due to impaired ability to sweat. Convulsions, rhabdomyolysis, and hyperthermia may occur with a serious overdose, and complications such as renal failure and pancreatitis have been reported. Elderly patients may be more susceptible to the clinical effects due to age-related altered renal and hepatic metabolism.
2. Massive diphenhydramine overdoses have been reported to cause QRS widening and myocardial depression, similar to tricyclic antidepressant overdoses.
3. QT-interval prolongation and torsade-type atypical ventricular tachycardia have been associated with elevated serum levels of terfenadine or astemizole. (Both of these drugs have been removed from the US market.) It has also been reported with a large diphenhydramine overdose.

Is generally based on the history of ingestion and is supported by the presence of an anticholinergic toxidrome. Comprehensive urine toxicology screening will detect most common antihistamines.

1. Specific levels are not generally available or useful.
2. Other useful laboratory studies include electrolytes, serum creatinine, BUN, liver aminotransferases, glucose, creatine kinase (CK), blood gases or pulse oximetry, lipase, and ECG monitoring (diphenhydramine, terfenadine, or astemizole). Obtain serum acetaminophen concentration in all patients as it is commonly included with antihistamines in many cough and cold preparations.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat coma, seizures, hyperthermia, rhabdomyolysis, and atypical ventricular tachycardia if they occur.
   3. Monitor the patient on a continuous cardiac monitor for at least 6-8 hours after ingestion.
2. Specific drugs and antidotes. There is no specific antidote for antihistamine overdose. Treat agitation and psychosis with benzodiazepines. Physostigmine has been used for the treatment of severe anticholinergic delirium. However, because antihistamine overdoses carry a greater risk for seizures and wide-complex tachycardia, physostigmine is not recommended routinely. Sodium bicarbonate, 1-2 mEq/kg IV, should be used in cases of QRS-interval prolongation after a massive diphenhydramine overdose.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly. Because of slowed GI motility, gut decontamination procedures may be helpful, even in late-presenting patients.
4. Enhanced elimination. Hemodialysis, hemoperfusion, peritoneal dialysis, and repeat-dose activated charcoal are not effective.