DESCRIPTION

The nonsedating antihistamines are prescription antihistamine medications that do not cause drowsiness.

FORMS AND USES

• Pharmaceutical preparations include acrivastine (Semprex-D, which also contains pseudoephedrine), astemizole (Hismanal), cetirizine (Zyrtec), fexofenadine (Allegra), and loratidine (Claritin; Claritin-D also contains pseudoephedrine).
• See also SECTION IV, Terfenadine chapter.
• These drugs are used in the treatment of seasonal allergic rhinitis, perennial allergic rhinitis, and chronic idiopathic urticaria.
  • The recommended dose for astemizole is 10 mg daily for patients 12 years of age and older.
  • The recommended dose for cetirizine is 5 to 10 mg daily for patients 12 years of age and older.
  • The recommended dose for fexofenadine is 60 mg twice a day for patients 12 years of age and older.
  • The recommended dose for loratidine is 10 mg daily for patients 12 years of age and older.

TOXIC DOSE

• Due to relatively recent availability, little information is available.
• Astemizole typically produces toxicity at therapeutic doses as a drug interaction that produces high plasma levels.
• Large doses of the other agents are usually needed to produce any toxicity.

PATHOPHYSIOLOGY

• Second-generation antihistamines are selective, peripheral H₁-receptor antagonists.
• Decreased occupancy of H₁-receptors in the brain is believed to be the mechanism of decreased drowsiness.
• These antihistamines are metabolized in the liver by the A3 family of cytochrome P450 enzymes, and drugs that interfere with metabolism may cause toxicity.

EPIDEMIOLOGY

• Poisoning is common.
• Toxic effects are typically mild with many of these products, but death has occurred with astemizole drug interaction or massive overdose of other agents.

CAUSES

• Toxic ingestion is usually suicidal.
• Toxic effects may occur when these antihistamines are taken in combination with other drugs.
• 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

Toxicity is possible with therapeutic astemizole dose in patients with QT prolongation, kidney or liver dysfunction, or drug interaction.

DRUG AND DISEASE INTERACTIONS

• Drugs that inhibit the metabolism of astemizole may lead to severe dysrhythmia (ketoconazole, itraconazole, indinavir, fluvoxamine, clarithromycin, troleandomycin, and others).
• Drugs known to cause QT prolongation should be avoided (quinidine, disopyramide, procainamide, sotalol, ibutilide, pentamidine, propoxyphene, thioridazine, and others).

PREGNANCY AND LACTATION

• Acrivastine, cetirizine, loratidine. 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.
• Astemizole, fexofenadine. 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.
• Loratidine and cetirizine appear in human breast milk and are generally not recommended for nursing mothers.

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 syncope, QT prolongation, or torsade de pointes that may mimic astemizole toxicity include most antidysrhythmic drugs, thioridazine, and tricyclic antidepressants, among others.
• Nontoxicologic causes include severe hypomagnesemia, hypokalemia, ischemic heart disease, or any cause of ventricular dysrhythmia.

SIGNS AND SYMPTOMS

• Astemizole toxicity usually produces only mild symptoms such as dizziness; syncope, QT prolongation, torsade de pointes, and other conduction abnormalities may develop in severe cases.
• Acrivastine, cetirizine, loratidine, and fexofenadine produce mild effects, usually limited to nausea, headache, and sedation.

Vital Signs

Tachycardia may develop.

HEENT

Dry mouth and dizziness are common with each of the agents.

Dermatologic

Rash and urticaria occur rarely.

Cardiovascular

Astemizole may produce QT prolongation, torsade de pointes, ventricular dysrhythmia, hypotension, and cardiovascular collapse.

Gastrointestinal

Each of these agents cause nausea in overdose.

Hepatic

Hepatitis is reported rarely, after chronic use.

Neurologic

Anxiety, headache, somnolence, ataxia, tremors, and seizures may occur with large overdose.

PROCEDURES AND LABORATORY TESTS

Essential Tests

Asymptomatic patients may not require any laboratory studies.

Recommended Tests

• Serum electrolytes, BUN, and creatinine should be tested to assess other causes of cardiac dysrhythmia.
• Serum calcium and magnesium should be measured to assess their contribution to cardiac dysrhythmia.
• Serum acetaminophen and aspirin levels should be assayed to evaluate analgesic ingestion.
• Arterial blood gas, urine drug screen, and liver enzyme tests may be needed as indicated by clinical presentation.
• ECG and continuous cardiac monitoring are recommended; QT prolongation and ventricular dysrhythmias may occur, most likely after astemizole during drug interaction or overdose.

Not Recommended Tests

Serum drug levels are not readily available or useful.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Gastrointestinal
  • Hepatic
  • Neurologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Treatment should focus on airway management and cardiac dysrhythmia.
• Dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

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

• Altered mental status, seizure, cardiac dysrhythmia, or other severe effects are present.
• Toxic effects are not consistent with the reported poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

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

• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Symptoms develop.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management in a cardiac-monitored setting is warranted if:

• Patient is known to have astemizole overdose.
• Patient with ingestion of another nonsedating antihistamine has CNS complaint such as syncope or who develops CNS or cardiac toxicity.

DECONTAMINATION

Out of Hospital

Emesis should not be induced.

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

There is no specific antidote for nonsedating antihistamines.

ADJUNCTIVE TREATMENT

Torsade de Pointes

• Electrolyte abnormalities, if present, should be corrected.
• Administration of quinidine, disopyramide, procainimide, amiodarone, or bretylium should be avoided because these drugs also prolong the QT interval.
• Magnesium sulfate (MgSO₄) should be administered.
  • Adult dose is 1 to 2 g by intravenous push; a continuous intravenous infusion should also be started at 2 to 4 g/h, titrated to antidysrhythmic effect. A repeat bolus of 1 to 2 g may be administered if dysrhythmia recurs.
  • Pediatric dose is 25 to 50 mg/kg intravenously over 5 minutes.
• Isoproterenol (2-4 µg/ml) should be administered to adult patients at an initial rate of 0.5 to 1.0 µg/min, titrated to effect; pediatric dose is 0.1 µg/kg/min, titrated to effect.
• Torsade de pointes may require cardiac overdrive pacing.
• Ventricular dysrhythmias may require cardioversion.

Seizure

Seizures should be controlled with benzodiazepine followed by phenytoin or phenobarbital, if needed.

Hypotension

• Patient should receive 10 to 20 ml/kg 0.9% saline and be placed in the Trendelenburg position.
• Further fluid therapy should be guided by central pressure monitoring to avoid volume overload.
• If hypotension is unresponsive, a vasopressor should be administered.
  • Dopamine: 2 to 5 µg/kg/min, titrated to effect; rates above 20 µg/kg/min are unlikely to provide further benefit.
  • Norepinephrine infusion may be added at a rate of 0.1 to 0.2 µg/kg/min, titrated to effect if hypotension continues to be unresponsive.
  • High rate of infusion may cause tissue ischemia.
• Hemodialysis and hemoperfusion are not recommended.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT
  • Torsade de Pointes
  • Seizure
  • Hypotension

PATIENT MONITORING

• Respiratory and cardiac function should be monitored continuously for at least 24 hours or as long as QTc is prolonged or dysrhythmias persist.
• Electrolytes and magnesium level should be monitored throughout the treatment course.

EXPECTED COURSE AND PROGNOSIS

• Most patients experience only sedation, which peaks and resolves during the first 24 hours.
• If ventricular dysrhythmia develops, sequelae are determined by occurrence of hypoxic injury.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Asymptomatic patients who ingested cetirizine, loratidine, fexofenadine, or acrivastine may be discharged after decontamination, 6 hours of observation, and psychiatric evaluation, if needed.
• From the hospital
  • Asymptomatic patients can be discharged after a 24-hour monitoring period and documentation of normal QTc and ECG.
  • QT prolongation may persist for days; monitoring should continue until QTc is normal.

PATIENT EDUCATION

Patients taking astemizole should be made aware of potential drug interactions.

Section Outline:

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

DIAGNOSIS

• Signs and symptoms of overdose may initially be absent or nonspecific.
• Cardiac effects have been delayed up to 22 hours.
• QTc prolongation and torsade de pointes may be unrecognized.

TREATMENT

• Drugs that prolong QT interval should be avoided.
• Astemizole toxicity may require prolonged cardiac monitoring.

Section Outline:

• DIAGNOSIS
• TREATMENT

Poisoning by antiallergic and antiemetic drugs.

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

RECOMMENDED READING

Nightingale SL. US Food and Drug Administration warnings issued on nonsedating antihistamines, terfenadine and astemizole. JAMA 1992;268:705.

Woosley RL. Cardiac actions of antihistamines. Ann Rev Pharmacol Toxicol 1996;36:233-252.

Author: Steven A. Seifert

Reviewer: Richard C. Dart