Antihistamine Toxicity Clinical Presentation

  • Author: Loren Keith French, MD; Chief Editor: Asim Tarabar, MD   more...
 
Updated: May 5, 2010
 

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 can often 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 based on specific physiologic effect (eg, sedating vs nonsedating) or 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, seizures, 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 torsades de pointes. This usually results from combining the nonsedating antihistamine with cytochrome inhibitors (CYP3A4) 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 (>1 quart/day). 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. D-chlorpheniramine has been shown to suppress visuospatial cognition and visuomotor coordinating functions.[36]
  • 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. Doxylamine can cause rhabdomyolysis and renal failure.
  • 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. Tripelennamine has been used to enhance opioid effects and reduce itching associated with prescription narcotic use. The combination use of pentazocine (Talwin) with tripelennamine (blue tablets), commonly known as "T's and Blue's", reportedly produces a heroinlike effect.
  • Phenothiazine derivatives (eg, promethazine, trimeprazine, methdilazine) possess considerable anticholinergic activity and minimal GI adverse effects. Akathisia and dystonic reactions are common with phenothiazines.
  • 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.
    • Cyclosporin A and rifampicin may decrease hepatic uptake of fexofenadine.[37]
Next

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, in elderly patients, or in 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.
    • However, large doses of diphenhydramine, pyrilamine, and hydroxyzine have resulted in prolonged or repeated seizure activity.
    • Researchers have suggested a natural anticonvulsant role of histamine because H1 receptors coalesce around epileptogenic foci in the 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.[38]
    • 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-like 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.[39]
    • Unlike H1 blockers, H2 blockers rarely cause CNS toxicity even in large doses, and it is usually manifested as slurred speech and confusion.
  • Cardiac toxicity
    • Sinus tachycardia, ventricular tachycardia, torsades de pointes, 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 block sodium channels 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. Torsades 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.[40]
  • Pulmonary findings: Pulmonary congestion was the most common finding on autopsy in a review of 76 reported deaths from diphenhydramine between 1946 and 2003.[41] This is presumably of a cardiogenic origin due to cardiovascular collapse and ventricular failure, although the coincidence of myocardial toxicity is not reported.
  • Skin: Rare fixed drug eruptions have been demonstrated with the use of cetirizine.[42]
  • Musculoskeletal: Exposure to doxylamine is associated with rhabdomyolysis, especially if ingested dose is larger than 20 mg/kg.[43]
  • Renal: Rhabdomyolysis secondary to doxylamine exposure can result in acute renal failure.[44]
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Contributor Information and Disclosures
Author

Loren Keith French, MD  Fellow of Toxicology, Attending Physician, Department of Emergency Medicine, Oregon Health and Sciences University and Oregon Poison Center

Disclosure: Nothing to disclose.

Coauthor(s)

Nathanael J McKeown, DO  Assistant Professor, Oregon Health and Science University; Medical Toxicologist, Oregon Poison Center; Attending Physician, Emergency Medicine, Portland Veteran Affairs Medical Center, Oregon Health and Science University

Nathanael J McKeown, DO is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

David C Lee, MD  Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD  Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Michael J Burns, MD  Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

John D Halamka, MD, MS  Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD  Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

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Terfenadine is the antihistamine most commonly associated with torsade de pointes in both acute overdose and therapeutic administration.
 
 
 
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