DESCRIPTION

Antihistamines include pharmaceuticals used in a wide range of products for over-the-counter (OTC) use.

FORMS AND USES

• OTC pharmaceutical preparations include antazoline, azatadine, bromodiphenhydramine, brompheniramine, buclizine, chlorcyclizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorphen-iramine, dimenhydrinate, diphenhydramine, diphenylpyraline, doxylamine, hydroxyzine, meclizine, methapyrilene, methdilazine, phen-indamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, trimeprazine, tripelennamine, and triprolidine.
• These drugs are used in the treatment of allergic reactions and pruritus; in many combination products for the treatment of cold, cough, and allergy symptoms; as sleep aids; to treat motion sickness; and to treat dystonic reactions.

TOXIC DOSE

Toxic dose is variable; the estimation of dose is not clinically useful.

PATHOPHYSIOLOGY

• Therapeutic effects are due to competitive antagonism of the H₁-receptor.
• Toxicity is primarily due to anticholinergic (antimuscarinic) effects.

EPIDEMIOLOGY

• Poisoning is common.
• Toxic effects following exposure are typically mild to moderate.
• Death occurs in patients with large overdose.

CAUSES

• Toxic ingestion is usually suicidal or associated with recreational abuse.
• Child neglect or abuse should be considered if the patient is less than 1 year of age, suicide attempt if the patient is over 6 years of age.

RISK FACTORS

• Children may be more prone to CNS excitation and seizures.
• OTC antihistamines have abuse potential for psychedelic effects, particularly in adolescents.
• Elderly patients may be prone to CNS depression or hallucinosis at therapeutic doses and may be less tolerant of tachycardia.

DRUG AND DISEASE INTERACTIONS

• OTC antihistamines increase CNS depression when taken with other CNS depressants.
• Increased anticholinergic effect occurs when OTC antihistamines are taken with other anticholinergic agents.

PREGNANCY AND LACTATION

• Azatadine, chlorpheniramine, cyproheptadine dexchlorpheniramine, doxylamine, meclizine, and tripelennamine. US FDA Pregnancy Category B. Animal studies indicate no fetal risk and there are no controlled human studies, or animal studies show an adverse fetal effect but well-controlled studies in pregnant women do not.
• Antazoline, bromodiphenhydramine, brompheniramine, buclizine, chlorcyclizine, clemastine, cyclizine, dexbrompheniramine, dimenhydrinate, diphenhydramine, hydroxyzine, methdilazine, pheniramine, phenyltoloxamine, prometh-azine, pyrilamine, trimeprazine, and triprolidine. US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• RISK FACTORS
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Toxicologic causes of anticholinergic effects include belladonna alkaloids, ophthalmic cycloplegics, antiparkinsonian drugs, antispasmodics, plants of the Datura genus (jimson weed), morning glory seeds, nutmeg, and several others.
• Other drugs that cause CNS depression or hallucinations and tachycardia include antidepressants, LSD, some mushrooms, cocaine, amphetamines, and phencyclidine.
• Nontoxicologic causes of altered mental status include conditions such as CNS infection, mass, or bleed; hyperthermia; and sepsis.

SIGNS AND SYMPTOMS

• Muscarinic anticholinergic effects predominate, including fever, tachycardia, mydriasis, flushed dry skin, CNS stimulation or depression, hallucinations, decreased bowel sounds, and urinary retention.
• Dysrhythmia, coma, seizures, and hypotension may develop in severe cases.

Vital Signs

• Tachycardia and mild hyperthermia are common.
• Mild hypertension may develop.
• Hypotension may develop with severe overdose.

HEENT

Mydriasis, blurred vision, and dry mucous membranes are common antimuscarinic effects.

Dermatologic

Skin is usually dry and flushed.

Cardiovascular

• Tachycardia and mild hypertension are common.
• QRS interval widening, ventricular dysrhythmias, QT prolongation, and hypotension may develop with severe overdose.

Gastrointestinal

Decrease in bowel sounds is common.

Hepatic

Cholestatic jaundice and hepatitis occur rarely.

Renal

• Urinary retention is common.
• Renal failure may occur rarely due to rhabdomyolysis or hypotension.

Fluids and Electrolytes

Metabolic acidosis may occur rarely due to hypotension or seizure.

Musculoskeletal

Rhabdomyolysis may occur rarely due to seizures or coma.

Neurologic

• CNS depression is common and may progress to coma.
• Paradoxically, CNS stimulation is also common and is characterized by agitation and hallucinations; in severe cases seizures may develop.
• Dystonia, chorea, parkinsonism, and dyskinesia have been reported with chronic use.

PROCEDURES AND LABORATORY TESTS

Essential Tests

No tests may be needed in minimally symptomatic patients with a clear history of nonsuicidal antihistamine ingestion.

Recommended Tests

• Complete blood count, blood cultures, and CSF should be assayed as needed to rule out other causes of altered mental status or hyperthermia.
• ECG, serum acetaminophen, and aspirin levels should be checked in an overdose setting to detect occult ingestion.
• Urine toxicology screen should be performed in patients with persistent tachycardia, QRS widening, prolonged QTc, or altered mental status of unclear etiology.
• Head CT is used as needed to determine cause of seizure or altered mental status.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Gastrointestinal
  • Hepatic
  • Renal
  • Fluids and Electrolytes
  • Musculoskeletal
  • Neurologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests

• Dose and time of exposure should be determined for all substances involved.
• Treatment should focus on controlling agitation, maintaining the airway, reversing hyperthermia, and hemodynamic support.

DIRECTING PATIENT COURSE

The health-care professional should call the poison control center when:

• Coma, seizure, dysrhythmia, or other severe effects are present.
• The use of physostigmine is considered.
• Toxic effects are not consistent with antihistamine poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• A child has ingested more then three times the maximum daily dose of the medication. (Children who have ingested three times the maximum daily dose may be observed without gastric decontamination.)
• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Toxic effects are present.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management is warranted if the patient exhibits altered mental status, seizure, persistently abnormal vital signs, or dysrhythmia.

DECONTAMINATION

Out of Hospital

Decontamination is not recommended.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for large ingestion presenting within 1 hour of ingestion or if serious effects are present.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.

ANTIDOTES

Physostigmine is used for the diagnosis of antihistamine poisoning.

Indications

To distinguish altered mental status secondary to anticholinergic toxicity from other causes of agitation and hallucination.

Contraindications

• Known allergy to cholinergic agonist or sulfites
• Known or suspected tricyclic antidepressant overdose, or ECG findings suggestive of tricyclic antidepressant overdose (QRS interval widening, R wave in ECG lead aVR)
• Underlying health problems: asthma, heart disease, diabetes, inflammation of iris or ciliary body

Method of Administration

• Patient should be placed on cardiac monitor and have atropine available at the bedside.
• Adult dose is 1.0 to 2.0 mg, administered by slow intravenous push over 5 minutes; pediatric dose is 0.02 mg/kg up to 2.0 mg.
• Dose may be repeated once after 5 to 10 minutes if needed.
• Physostigmine will reverse behavioral effects, but symptoms will usually recur within 30 to 60 minutes.
• Repeated doses of physostigmine are not generally recommended for behavior control.

Adverse Effects

• Muscarinic effects may include nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, bradycardia, and hypotension; cardiac dysrhythmia may occur.
• Nicotinic symptoms (weakness, fasciculation) may also occur; seizures may occur.

ADJUNCTIVE TREATMENT

Agitation or Hallucinosis

A benzodiazepine may be used to control symptoms until resolution occurs.

• Diazepam. Adult dose is 5 to 10 mg (pediatric dose 0.2-0.5 mg/kg up to 5 mg) intravenously; doses may be repeated at 5-minute intervals, titrated to effect.
• Lorazepam. Adult dose is 2 to 4 mg (pediatric dose 0.05-0.1 mg/kg up to 2 mg) intravenously; doses may be repeated at 5-minute intervals, titrated to effect, while airway is monitored closely.

Hypotension

Hypotension should be treated in the standard manner, beginning with 10 to 20 ml/kg 0.9% saline intravenously.

Seizures

Seizures are treated in the standard manner, starting with a benzodiazepine.

Dysrhythmias or Conduction Abnormalities

• The initial effort should be to secure the airway, control seizures, and correct acidemia.
• If QRS widening or dysrhythmia persists, sodium bicarbonate should be administered as 1 to 2 mEq/kg intravenous bolus; this can be repeated as needed for widened QRS, but the pH should not be allowed to exceed 7.55.
• Lidocaine can be used for ventricular tachycardia or multifocal premature ventricular complexes.
  • Adult dose is 50 to 100 mg intravenous bolus followed by infusion of 2 to 4 mg per minute, titrated to effect.
  • Pediatric dose is 1 mg/kg bolus followed by infusion of 20 to 50 µg/kg/min, titrated to effect.
  • Bolus dose may be repeated in 10 to 15 minutes.

Section Outline:

• DIRECTING PATIENT COURSE
  • The health-care professional should call the poison control center when:
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
  • Indications
  • Contraindications
  • Method of Administration
  • Adverse Effects
• ADJUNCTIVE TREATMENT
  • Agitation or Hallucinosis
  • Hypotension
  • Seizures
  • Dysrhythmias or Conduction Abnormalities

PATIENT MONITORING

Electrolytes as well as respiration and cardiac function should be monitored throughout hospitalization.

EXPECTED COURSE AND PROGNOSIS

• Most patients recover uneventfully with supportive care.
• Sequelae of anoxia may develop if medical care is delayed.
• CNS effects may require several days to resolve.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Patients who have not developed altered mental status, seizure, or dysrhythmia during 6 to 12 hours of observation may be discharged following gastrointestinal decontamination and psychiatric evaluation, if needed.
• From the hospital. A patient may be discharged after signs of toxicity have resolved for at least 12 hours.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

A history of ingestion may be difficult to obtain due to recreational abuse.

TREATMENT

Anticholinergic effects generally recur 30 to 45 minutes after physostigmine administration.

Poisoning by primarily systemic agents: antiallergic and antiemetic drugs.

See Also: SECTION II, Hypotension, Seizure, and Ventricular Dysrhythmia chapters; and SECTION III, Physostigmine chapter.

RECOMMENDED READING

Koppel C, Tenczer J, Ibe K. Poisoning with over-the-counter doxylamine preparations: an evaluation of 109 cases. Hum Toxicol 1987;6:355-359.

Author: Katherine M. Hurlbut

Reviewer: Luke Yip