AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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%).

CLINICAL

Section 3 of 11  

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History

The importance of antihistamine identification has increased with the recognition of potentially life-threatening cardiac toxicity from relatively small exposures to terfenadine. This identification often can be accomplished by recording a good history and performing a thorough physical examination. Patients who ingest the newer nonsedating antihistamines may have fewer central anticholinergic symptoms than those who ingest any of the first-generation agents. Classification of antihistamines may proceed on the basis of specific physiologic effect (eg, sedating vs nonsedating) or on the basis of chemical structure (eg, alkylamine vs piperidine derivatives).

• Sedating H1 blockers
• • Consider classic or first-generation H1-antihistamine poisoning in any patient who presents with delirium, sedation, and anticholinergic symptoms.

  • Agents include chlorpheniramine, hydroxyzine, and diphenhydramine.

• Nonsedating H1 blockers
• • Nonsedating antihistamines differ from the other antihistamines in that they do not partition into the CNS, and they have long half-lives. The half-life of loratadine, for example, is typically 10 hours but may be more than doubled in overdose. Cardiac toxicity observed with terfenadine and astemizole may be heralded by palpitations from torsade de pointes. This usually results from combining the nonsedating antihistamine with cytochrome inhibitors but also is observed following acute overdose. The parent drug (not the metabolites) induces cardiotoxicity.

  • The most commonly described interactions have involved a combination of terfenadine with erythromycin. Similar reactions have been described with both terfenadine and astemizole in combination with other macrolide antibiotics (with the exception of azithromycin), azole antifungal agents, cisapride, cimetidine, fluoxetine, nefazodone, omeprazole, protease inhibitors (eg, nelfinavir, indinavir, ritonavir), and even grapefruit juice. Prolonged QT syndrome and cardiac arrhythmias rarely have been described with loratadine.

• H2-receptor blockers
• • The H2 blockers used to treat peptic acid diseases include cimetidine, ranitidine, famotidine, and nizatidine. They are selective and do not block H1 receptors or have antimuscarinic activity.

  • Blockade of central H2 receptors alters CNS neurotransmission and may cause delirium, confusion, agitation, and seizures (rare).

• Alkylamine derivatives (eg, chlorpheniramine, brompheniramine, triprolidine) are among the most potent antihistamines. They produce more CNS stimulation and less drowsiness than other antihistamines.
• Ethanolamine derivatives (eg, doxylamine, diphenhydramine, bromodiphenhydramine) have strong atropinelike activity; drowsiness is common. Adverse gastrointestinal effects are uncommon. Seizures and cardiac conduction delays are common especially in massive diphenhydramine ingestions.
• Ethylenediamine derivatives (eg, pyrilamine, tripelennamine, antazoline) have weak CNS effects. Myoclonic jerks, hallucinations, and agitation were reported in a child with cutaneous tripelennamine exposure. Adverse GI effects are common.
• Phenothiazine derivatives (eg, promethazine, trimeprazine, methdilazine) possess considerable anticholinergic activity and minimal GI adverse effects.
• Piperidine derivatives generally have a prolonged duration of action and low incidence of drowsiness. Specific examples include hydroxyzine, cetirizine, and meclizine.
• Piperidine derivatives (eg, terfenadine, astemizole, loratadine) are peripherally selective H1 antagonists with few GI adverse effects and a low incidence of drowsiness (see Nonsedating antihistamines).
• Pharmacokinetics
• • All antihistamines are well absorbed following oral administration.

  • Most achieve peak plasma concentrations within 3 hours with the onset of symptoms occurring between 30 minutes and 2 hours of ingestion.

  • Duration of action ranges from 3 hours to more than 24 hours.

  • Hepatic metabolism is the primary route of elimination for antihistamines. As mentioned above, Asian race and autoinduction can increase catabolism of antihistamines.

Physical

The mnemonic, "dry as a bone, red as a beet, hot as a hare, mad as a hatter, and blind as a bat," summarizes the classic combination of central and peripheral anticholinergic effects of antihistamine poisoning. In mixed ingestions, elderly patients, or very young patients, the physical findings may be variable and the clinical picture may not be clear.

Other manifestations of toxicity, such as seizures, cardiac arrhythmias, and hypotension, are not uncommon and may be explained by mechanisms other than anticholinergic effects.

• Anticholinergic syndrome
• • Peripheral manifestations include dry mucous membranes and hot, dry, flushed skin that result from inhibition of secretions from salivary glands, bronchioles, and sweat glands.

  • Vasodilation occurs in peripheral blood vessels, especially of the face and skin surfaces. Patients appear flushed and warm without sweat, despite agitation. The body temperature rises due to an inability to sweat and because of altered CNS thermoregulation.

  • Pupils are markedly dilated and vision is blurred with loss of accommodation. Lack of cholinergic stimuli alters peristalsis and may cause an intestinal ileus. Prolonged symptoms secondary to delayed drug absorption then may occur. Sinus tachycardia is one of the earliest signs of muscarinic receptor blockade. Urinary retention may contribute to the patient's agitation and placement of a Foley catheter may have a promptly calming effect.

  • The central anticholinergic syndrome normally occurs concomitantly with the peripheral signs of poisoning, although occasionally it has been reported to occur without evidence of peripheral signs. Symptoms include disorientation, agitation, impairment of short-term memory, nonsensical or incoherent speech, and meaningless motor activity that includes repetitive picking or grabbing. Visual hallucinations may be prominent. Central anticholinergic syndrome may be contrasted with pure psychosis that is often accompanied by paranoia, auditory hallucinations, and, more commonly, an intact sensorium.

  • Agitation (physical or psychic perturbation) may complicate either anticholinergic delirium or psychosis and may be a reflection of underlying pain, drug withdrawal, or sympathomimetic overdose. Anticholinergic delirium has been misdiagnosed as meningoencephalitis, dementia, and sepsis.

• Seizures are not a common manifestation of antihistamine poisoning and are generally short-lived if they occur.
• • Large doses of diphenhydramine, pyrilamine, and hydroxyzine have, however, resulted in prolonged or repeated seizure activity.

  • Researchers have suggested a natural anticonvulsant role of histamine because H1 receptors coalesce around epileptogenic foci in brain and inhibit generalization of seizure activity.

  • Antihistamines also are known to increase electroencephalographic (EEG) abnormalities and are suspected to produce seizures in patients with epilepsy.

• Other CNS effects
• • In a review of 136 patients with diphenhydramine overdose, somnolence, lethargy, and coma were the most common findings, occurring in approximately 55% of reported overdoses.

  • Catatonic stupor was considered to be highly specific, occurring in 15% of patients.

  • Acute extrapyramidal movement disorders, severe anxiety reactions, and toxic psychosis also have been reported.

  • In a report of chronic abuse, diphenhydramine resulted in withdrawal symptoms. A 34-year-old patient with schizophrenia had been ingesting approximately 800 mg of diphenhydramine twice daily for one month to achieve sedation and euphoria. Diphenhydramine was tapered to 600 mg daily in divided doses over the first 3 days of hospitalization and then was reduced more slowly with the last dose being administered on the ninth day of hospitalization. The patient developed recurrence of insomnia during the withdrawal period and increased daytime restlessness, irritability, and excessive blinking; extrapyramidal symptoms and psychosis were absent.

• Cardiac toxicity
• • Sinus tachycardia, ventricular tachycardia, torsades de points, cardiogenic shock, and hypertension have all been reported following overdose with antihistamines. Sinus tachycardia is the most common toxic cardiovascular effect from antihistamines with prominent anticholinergic properties.

  • Antihistamines with anticholinergic effects and the potential to cause quinidinelike conduction abnormalities include diphenhydramine, chlorpheniramine, pyrilamine, and certain phenothiazines.

  • These drugs slow sodium conduction through cardiac sodium channels and result in decreased conduction and myocardial contractility. Rarely, myocardial pump failure occurs with large overdoses.

  • Ventricular tachycardias are less common but can occur at up to 4 times greater frequency in patients taking nonsedating antihistamines. Phenothiazines, diphenhydramine, and piperidine antihistamines are associated with prolongation of the QT interval. Torsade de pointes is likely to occur only following ingestion of the piperidine antihistamines, in particular astemizole and terfenadine. Other cardiac conduction disturbances, including atrioventricular dissociation and bundle branch blocks, were reported in a 3-year-old girl who ingested 100 mg of astemizole.

• Pulmonary findings: Pulmonary congestion was the most common finding on autopsy in a review of 76 reported deaths from diphenhydramine between 1946 and 2003. This is presumably of a cardiogenic origin due to cardiovascular collapse and ventricular failure, although the coincidence of myocardial toxicity is not reported.

DIFFERENTIALS

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Other Problems to be Considered

Toxicity, neuroleptic agents
Toxicity, antiarrhythmic agents

WORKUP

Section 5 of 11  

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Lab Studies

• Toxicologic screens
• • Obtaining either qualitative or quantitative testing of blood or urine for antihistamines has little justification.

  • Most laboratories are not capable of testing for antihistamines, and pharmacokinetic studies have not been performed to establish therapeutic or toxic blood levels. However, a review of deaths from diphenhydramine monointoxication showed average lethal levels of diphenhydramine 19.5 mg/L in adults, 7.4 mg/L in children, and 1.53 mg/L in infants.

  • Screening may be important when clinical history is lacking and the diagnosis is in question.

  • Toxicologic screening for drugs of abuse is not generally necessary because patients usually can be treated based on clinical presentation.

• Testing blood for presence of salicylate and acetaminophen is recommended for all patients because many cough and cold preparations combine antihistamines, antipyretics, and analgesics.
• Check serum electrolyte levels to rule out metabolic abnormalities for patients who are confused or exhibit evidence of cardiotoxicity.
• Draw blood cultures to rule out sepsis if the patient is hyperthermic, seriously ill, or the diagnosis of anticholinergic poisoning is questionable.
• Complete blood count and liver function tests
• • Chronic toxicity from antihistamines is uncommon, but agranulocytosis has been reported with chlorpheniramine and brompheniramine.

  • Cholestatic jaundice was reported after prolonged treatment with cyproheptadine.

  • Hepatitis has been reported following prolonged therapy with terfenadine.

Imaging Studies

• Electrocardiogram - To rule out conduction delays and dysrhythmias
• Computerized tomography (CT) scan of the head
• • Consider a CT scan in any patients presenting with seizures or altered mental status.

  • CT scan may not be necessary in patients with progressive improvement, supportive history, a nonfocal neurological examination, and/or a positive response to physostigmine

  • Chest radiography

Procedures

• Perform a lumbar puncture in cases involving fever and altered mental status unless patient progressively improves with observation or physostigmine.

TREATMENT

Section 6 of 11  

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Prehospital Care

Paramedics should follow set protocols for gastric decontamination, hypotension, and seizures; symptomatic patients should be transported rapidly with intravenous access and cardiac monitoring.

Emergency Department Care

Basic tenets of emergency care should dictate therapy. Perform bedside determinations of glucose for patients with altered levels of conscious and treat with IV dextrose, if appropriate. For hypotensive patients, administer 0.9% sodium chloride solution or lactated Ringer solution as boluses. Dopamine, or other cardiac pressor, may be titrated to achieve an acceptable blood pressure.

• Administer activated charcoal to patients who are cooperative, can retain a good gag reflex, and can take liquids by mouth safely. Perform endotracheal intubation before instillation of activated charcoal for patients with significant CNS depression and unprotected airway.
• Gastric emptying has not proven beneficial if the patient presents more than one hour postingestion, although case reports involving anticholinergic agents have demonstrated erratic absorption and repeated worsening of anticholinergic symptoms over 9 days. Ipecac syrup is not recommended in the ED because it may delay the administration of activated charcoal and seizures may occur at any time, with the possibility of aspiration. Repeated doses of activated charcoal may prevent continued absorption, although the development of ileus generally limits its use.
• Agitation
• • Anticholinergic-induced delirium ranges from mild confusion to severe agitation with associated hyperthermia and rhabdomyolysis. The administration of chemical and physical restraints often is necessary to prevent patients from harming themselves or others. Controlling muscular activity is crucial in severely agitated patients, because agitation may exacerbate muscle injury, acidosis, rhabdomyolysis, and hyperthermia. Although benzodiazepines often are considered first-line, physostigmine is safe and effective for the treatment of agitated delirium, provided that the ECG does not demonstrate conduction disturbances (ie, PR and QRS prolongation); a recent study suggests that physostigmine is more effective and just as safe as benzodiazepines to control anticholinergic-associated agitated delirium. Neuroleptic agents, such as haloperidol, have been used but have anticholinergic effects and may exacerbate hyperthermia or provoke a dystonic reaction.

  • Physostigmine, a naturally occurring alkaloid obtained from the West African vine Physostigma venenosum, is the only reversible acetylcholinesterase inhibitor lacking a charged quaternary amine moiety. As a tertiary amine, physostigmine traverses the blood-brain barrier and binds to central acetylcholinesterase, increasing acetylcholine levels and, thus, reversing central anticholinergic delirium. Peripheral signs and symptom also are reversed.

    Considering that patients with anticholinergic symptoms usually fare well with supportive therapy alone, physostigmine is indicated only in the following limited circumstances:

    • Pronounced hallucinations and agitation unresponsive to high doses of benzodiazepines, generally when the patient is a danger to themselves or others

    • Intractable seizures resistant to all other treatments

    • Narrow complex supraventricular arrhythmias clearly resulting in hemodynamic instability when other attempts to control heart rate have failed or are believed to be too risky

    Case series of patients taking maprotiline indicated that seizures developed in 6 out of 7 patients treated with physostigmine. Other reports describe development of asystole for the administration of physostigmine after cyclic antidepressant poisoning. In a series of 21 patients receiving physostigmine, 2 patients experienced seizures and 2 experienced cholinergic reactions (hypersalivation in one patient, bradycardia and hypotension in the other). Thus, use physostigmine cautiously.

• Manage hyperthermia, especially when severe agitation is present, with neuromuscular paralysis and evaporative cooling if temperature is higher than 105°F. Use of dantrolene or bromocriptine is controversial.
• Cardiovascular toxicity
• • Sinus tachycardia usually does not require treatment. Sedation with a benzodiazepine may be helpful when agitation is also present. Intravenous sodium bicarbonate improves impaired sodium conduction that may result from antihistamines with quinidinelike membrane stabilizing effects (eg, diphenhydramine, pyrilamine).

  • Provide support for patients with profound cardiovascular toxicity, in refractory shock, or who have been supported by placement of an intra-aortic balloon pump for several hours.

• Case reports suggest that physostigmine ends seizures, but clinical experience is limited and no proof of its efficacy for seizure control exists. Treat antihistamine-induced seizures with benzodiazepines and barbiturates. Reserve physostigmine for refractory seizures. One case of using flumazenil for successful reversal of antihistamine-induced depressed mental status in a 7-month-old infant was reported in 2003. Evidence to recommend this therapy is insufficient.

Consultations

• Regional poison control center or a medical toxicologist as soon as possible
• Intensivist for invasive monitoring and hemodynamic support in complicated cases
• Psychiatry for intentional overdoses

MEDICATION

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Most poisonings result from first-generation antihistamines. The majority of patients present with anticholinergic symptoms and generally have good outcomes with simple observation and meticulous attention to supportive care. Limit treatment with physostigmine to severe cases. For treatment of cardiac toxicity, include careful monitoring and aggressive treatment of conduction delays or torsade de pointes.

Drug Category: Cholinergic agents

Acetylcholinesterase inhibitors are indicated to reverse central and peripheral toxicity of anticholinergic substances.

Drug Category: Benzodiazepines

Indicated for the control of anxiety, agitation, and seizures.

Drug Name	Midazolam (Versed)
Description	Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Second-line agent because of shorter anticonvulsant effect and shorter duration of sedation.
Adult Dose	0.05 mg/kg IV; not to exceed 2.5 mg
Pediatric Dose	<32 weeks: 0.5 mcg/kg/min IV infusion >32 weeks: 1 mcg/kg/min IV infusion Children: 0.05-0.2 mg/kg IV over 2-3 min, followed by 1-2 mcg/kg/min continuous infusion
Contraindications	Documented hypersensitivity; preexisting hypotension; narrow-angle glaucoma; sensitivity to propylene glycol (diluent)
Interactions	Sedative effects may be antagonized by theophyllines; narcotics and erythromycin may accentuate sedative effects because of decreased clearance; may potentiate sedative effects of other sedatives including H1 blockers; reduce dose of thiopental by 15% when using together
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in congestive heart failure, pulmonary disease, renal impairment, hepatic failure, neuromuscular disease, hypotension, and patients >60 y; monitor for respiratory depression with high or repeated doses; consider lower dosages in patients with organic brain syndrome and patients who may have inhibition of benzodiazepine metabolism and clearance (eg, using nicotine, taking cimetidine)

Drug Name	Diazepam (Valium)
Description	Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Third-line agent for agitation or seizures because of shorter duration of anticonvulsive effects and accumulation of active metabolites that may prolong sedation.
Adult Dose	5-10 mg IV q10-15min until symptoms resolve; not to exceed 30 mg
Pediatric Dose	<30 days: Not established 30 days to 5 years: 0.2-0.5 mg IV (slowly) q2-5min until symptoms resolve; not to exceed 5 mg >5 years: 1 mg IV (slowly) q2-5min until symptoms resolve; not to exceed 10 mg
Contraindications	Documented hypersensitivity; hypotension; acute narrow-angle glaucoma
Interactions	Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, H1 blockers, barbiturates, alcohols, and MAOIs
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution with other CNS depressants, low albumin levels, or renal and hepatic disease (may increase toxicity); monitor for respiratory depression with high or repeated doses

Drug Category: Cardiovascular agents

These agents alter the electrophysiologic mechanisms responsible for arrhythmia.

Drug Name	Magnesium sulfate
Description	First-line agent in the treatment of antihistamine-associated torsade de pointes.
Adult Dose	2-4 g slow IV push over 3-5 min; follow with infusion of 3-20 mg/min for 5-24 h
Pediatric Dose	25-50 mg/kg/dose IV over 3-5 min; infuse at 60 mg/kg/d IV
Contraindications	Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis
Interactions	Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade observed with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants and betamethasone; may increase cardiotoxicity of ritodrine
Pregnancy	A - Safe in pregnancy
Precautions	May alter cardiac conduction leading to heart block in digitalized patients; monitor respiratory rate, deep tendon reflex, and renal function when electrolyte is administered parenterally; caution when administering magnesium dose because may produce significant hypertension or asystole; in overdose, calcium gluconate (10-20 mL IV of 10% solution) can be administered as antidote for clinically significant hypermagnesemia

Drug Category: GI decontaminant

Used to limit absorption of ingested antihistamine. Protect airway if patient has diminished mental status.

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• Rhabdomyolysis
• • Treat with aggressive fluid support to maintain urine output at 2 mg/kg/h.

  • Consider using sodium bicarbonate to alkalinize the urine.

  • Consult nephrology for oliguria or renal failure and arrange hemodialysis for the anuric or severely acidotic patient.

• Treat acute dystonic reactions with benzodiazepines.
• Multiple doses of activated charcoal are not recommended because charcoal concretions may form leading to intestinal obstruction or ileus. Antihistamines may induce intestinal ileus causing delayed absorption of drug and delayed toxicity.
• Perform cardiac monitoring on all symptomatic patients or as long as tachycardia, conduction delays, or prolonged QT intervals persist.

Transfer

• If intensive care units or telemetry is unavailable, benefits of transfer may outweigh benefits of keeping the patient.

Deterrence/Prevention

• Childproof safety caps and clear labeling have been shown to decrease toxic exposures in young children and elderly individuals.

Complications

• Multisystem organ failure and death have resulted from severe overdose.

Prognosis

• Among first-generation antihistamines, mortality from diphenhydramine occurs more than any other agent.
• In the US, diphenhydramine is used more commonly than other antihistamines. It also is associated with more cardiotoxicity and a higher incidence of seizures than other first-generation antihistamines.
• Pheniramine, an antihistamine commonly used in Australia, also is associated with a relatively high incidence of seizures.
• Among nonsedating piperidine antihistamines, terfenadine has been implicated more often than astemizole, loratadine, or fexofenadine in the formation of prolonged QT syndrome and torsade de pointes.
• The prognosis is affected by the presence of underlying medical conditions, co-ingestions, and the amount of drug ingested.
• The vast majority of patients recover with supportive care and observation.

Patient Education

• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to recognize the anticholinergic syndrome
• Failure to control severe agitation and seizures in a patient with severe delirium and uncontrolled muscular activity
• Reliance on a toxicology screen instead of clinical presentation to make the diagnosis of antihistamine poisoning
• Failure to diagnosis and treat associated acetaminophen poisoning
• Failure to provide adequate cardiac monitoring for patients with persistent QRS or QT interval prolongation
• Casual administration of physostigmine to patients with contraindications to its use (eg, co-ingestion of cyclic antidepressants, cardiac conduction delays)
• Failure to rapidly control severe hyperthermia in patients with paralysis and aggressively perform cooling measures
• Failure to monitor paralyzed patients with continuous EEG for evidence of ongoing seizure activity

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Terfenadine is the antihistamine most commonly associated with torsade de pointes in both acute overdose and therapeutic administration.
	View Full Size Image
Media type:  Rhythm Strip

REFERENCES

Section 11 of 11

• Authors and Editors
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• Baker AM, Johnson DG, Levisky JA. Fatal diphenhydramine intoxication in infants. J Forensic Sci. Mar 2003;48(2):425-8. [Medline].
• Buckley NA, Whyte IM, Dawson AH, Cruickshank DA. Pheniramine--a much abused drug. Med J Aust. Feb 21 1994;160(4):188-92. [Medline].
• Burks JS, Walker JE, Rumack BH, Ott JE. Tricyclic antidepressant poisoning. Reversal of coma, choreoathetosis, and myoclonus by physostigmine. JAMA. Dec 4 1974;230(10):1405-7. [Medline].
• Clark RF, Vance MV. Massive diphenhydramine poisoning resulting in a wide-complex tachycardia: successful treatment with sodium bicarbonate. Ann Emerg Med. Mar 1992;21(3):318-21. [Medline].
• Emadian SM, Caravati EM, Herr RD. Rhabdomyolysis: a rare adverse effect of diphenhydramine overdose. Am J Emerg Med. Oct 1996;14(6):574-6. [Medline].
• Etzel JV. Diphenhydramine-induced acute dystonia. Pharmacotherapy. Jul-Aug 1994;14(4):492-6. [Medline].
• Fahy P, Arnold P, Curry SC, Bond R. Serial serum drug concentrations and prolonged anticholinergic toxicity after benztropine (Cogentin) overdose. Am J Emerg Med. Mar 1989;7(2):199-202. [Medline].
• Feldman MD, Behar M. A case of massive diphenhydramine abuse and withdrawal from use of the drug [letter]. JAMA. Jun 13 1986;255(22):3119-20. [Medline].
• Freedberg RS, Friedman GR, Palu RN, Feit F. Cardiogenic shock due to antihistamine overdose. Reversal with intra- aortic balloon counterpulsation. JAMA. Feb 6 1987;257(5):660-1. [Medline].
• Henry DA, Lowe JM, Donnelly T. Jaundice during cyproheptadine treatment. Br Med J. Mar 25 1978;1(6115):753. [Medline].
• Janssens F, Leenaerts J, Diels G. Norpiperidine imidazoazepines as a new class of potent, selective, and nonsedative H1 antihistamines. J Med Chem. Mar 24 2005;48(6):2154-66. [Medline].
• Jones J, Dougherty J, Cannon L. Diphenhydramine-induced toxic psychosis. Am J Emerg Med. Jul 1986;4(4):369-71. [Medline].
• Khosla U, Ruel KS, Hunt DP. Antihistamine-induced rhabdomyolysis. South Med J. 2003;96(10):1023-6. [Medline].
• Kirk MA. Anticholinergics and antihistamines. In: Haddad LM, Shannon MW, Winchester JF, eds. Clinical Management of Poisoning and Drug Overdose. 3^rd ed. WB Saunders Co; 1998:641-9.
• Koppel C, Ibe K, Tenczer J. Clinical symptomatology of diphenhydramine overdose: an evaluation of 136 cases in 1982 to 1985. J Toxicol Clin Toxicol. 1987;25(1-2):53-70. [Medline].
• Lassaletta A, Martino R, Gonzalez-Santiago P. Reversal of an antihistamine-induced coma with flumazenil. Pediatr Emerg Care. 2004;20 (5):319-320. [Medline].
• Litovitz TL, Klein-Schwartz W, White S, et al. 1999 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2000;18(5):517-574. [Medline].
• Nine JS, Rund CR. Fatality from diphenhydramine monointoxication: a case report and review of the infant, pediatric, and adult literature. Am J Forensic Med Pathol. Mar 2006;27(1):36-41. [Medline].
• Normann S. Antihistamines. In: POISINDEX(R) Toxicologic Management. Micromedex, Inc;1988.
• Richmond M, Seger D. Central anticholinergic syndrome in a child: a case report. J Emerg Med. 1985;3(6):453-6. [Medline].
• Schipior PG. An unusual case of antihistamine intoxication. J Pediatr. 1967;71(4):589-91. [Medline].
• Serio RN. Acute delirium associated with combined diphenhydramine and linezolid use. Ann Pharmacother. 2004;38 (1):62-5. [Medline].
• Sharma AN, Hexdall AH, Chang EK. Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate. Am J Emerg Med. May 2003;21(3):212-5. [Medline].
• Sype JW, Khan IA. Prolonged QT interval with markedly abnormal ventricular repolarization in diphenhydramine overdose. Int J Cardiol. 2005;99(2):333-5. [Medline].
• Thakur AC, Aslam AK, Aslam AF. QT interval prolongation in diphenhydramine toxicity. Int J Cardiol. 2005;98 (2):341-3. [Medline].
• Tobin JR, Doyle TP, Ackerman AD, Brenner JI. Astemizole-induced cardiac conduction disturbances in a child. JAMA. Nov 20 1991;266(19):2737-40. [Medline].
• Tuomisto L, Tacke U. Is histamine an anticonvulsive inhibitory transmitter?. Neuropharmacology. Aug 1986;25(8):955-8. [Medline].
• Weisman RS. Antihistamines. In: Goldfrank LR, ed. Goldfrank's Toxicologic Emergencies. 6^th ed. McGraw-Hill; 1998:603-9.
• Yap YG, Camm AJ. Potential cardiac toxicity of H1-antihistamines. Clin Allergy Immunol. 2002;17:389-419. [Medline].
• de Abajo FJ, Rodriguez LA. Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs. Br J Clin Pharmacol. 2000;49(4):379-80. [Medline].

Article Last Updated: Jun 21, 2007