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Cough, Cold, and Allergy Preparation Toxicity Clinical Presentation

  • Author: Laleh Gharahbaghian, MD; Chief Editor: Timothy E Corden, MD  more...
 
Updated: Dec 29, 2015
 

History

Eliciting the specific over the counter (OTC) medication ingested is important, because different preparations may contain different agents or combinations. For example, dextromethorphan is often present in combination with pseudoephedrine, antihistamines/anticholinergics, and acetaminophen.

Classification of antihistamines may proceed based on specific physiologic effect (eg, sedating vs nonsedating) or chemical structure (eg, alkylamine vs piperidine derivatives). Patients who ingest the newer nonsedating antihistamines may have fewer central anticholinergic symptoms than those who ingest any of the first-generation agents.

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 antihistamines differ from the other antihistamines in that they do not partition into the central nervous system (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. Prolonged QT syndrome and cardiac arrhythmias rarely have been described with loratadine.

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.[63]

Ethanolamine derivatives (eg, doxylamine, diphenhydramine, bromodiphenhydramine) have strong atropinelike activity; drowsiness is common. Adverse gastrointestinal effects are uncommon. Doxylamine can cause rhabdomyolysis and renal failure.

Seizures and cardiac conduction delays are common, especially in massive diphenhydramine ingestions. However, in an observational case series of acute, single ingestions of diphenhydramine in children under 6 years old, 99.6% of patients who reportedly ingested doses of less than 7.5 mg/kg did not develop serious clinical effects or require admission.[64]

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.

Piperazine derivatives generally have a prolonged duration of action and low incidence of drowsiness. Specific examples include hydroxyzine, cetirizine, and meclizine.

Piperidine derivatives (eg, loratadine) are peripherally selective H1 antagonists with few GI adverse effects and a low incidence of drowsiness.

With regard to 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.

Next

Physical Examination

Physical findings widely vary, depending on the agent or combination of agents ingested. 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.

If a single antihistamine agent has been ingested, a predominance of anticholinergic effects are demonstrated. The anticholinergic toxidrome consists of the following:

  • Agitation
  • Fever
  • Urinary retention
  • Dry, hot, flushed skin
  • Dilated pupils

The mnemonic, "dry as a bone, red as a beet, hot as a hare, mad as a hatter, and blind as a bat," summarizes this classic combination of central and peripheral anticholinergic effects. Other manifestations of toxicity, such as seizures, cardiac arrhythmias, and hypotension, are not uncommon and may be explained by mechanisms other than anticholinergic effects.

Although most cough and cold preparations are a combination of medications, a single toxidrome may not be present. The history is helpful to guide the expected physical examination findings; however, the history is often inaccurate.

The following physical examination findings are examples of what is possible, in addition to the common findings; however, the presentation of a patient with a toxic ingestion is not always straightforward. In general, the combined effects of the various classes of drugs in OTC preparations have been broken down into the following systems based on the approach in POISINDEX.

Vital signs

Abnormal findings may include the following:

  • Hyperthermia
  • Tachypnea
  • Tachycardia
  • Hypertension

Hyperthermia has been reported with ingestion of both diphenhydramine and OTC antihistamine/decongestant combinations. In case reports of combination product exposure, findings are ascribed to the sympathomimetic component.

Head, ears, eyes, nose, and throat (HEENT)

Anticholinergic effects include the following:

  • Mydriasis
  • Nasal dryness and stuffiness
  • Eye dryness
  • Mouth and throat dryness

Dilated and minimally reactive pupils have been seen with antihistamine toxicity related to anticholinergic effects. Mydriasis and nystagmus may be observed with dextromethorphan ingestion.

Cardiovascular

The antihistamine and the sympathomimetic components of cold and allergy preparations can cause cardiac abnormalities that include arrhythmia (eg, atrioventricular [AV] block) and cardiac arrest.

Sinus tachycardia, ventricular tachycardia, torsade 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, increasing the risk for ventricular tachyarrhythmias.

Torsades de pointes was principally associated with the piperidine antihistamines astemizole and terfenadine, which led to the removal of these drugs from the market in the United States. 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.[65]

Respiratory

Findings include respiratory depression and adult respiratory distress syndrome. Pulmonary congestion was the most common finding on autopsy in a review of 76 reported deaths from diphenhydramine between 1946 and 2003.[66] This was presumably of cardiogenic origin due to cardiovascular collapse and ventricular failure, although the coincidence of myocardial toxicity is not reported.

Neurologic

Abnormal neurologic findings include the following:

  • Dizziness
  • Ataxia
  • Hyperexcitability
  • Somnolence
  • Seizures
  • Dystonia
  • Dyskinesia
  • Toxic psychosis (anxiety, agitation, hallucination)
  • Intracranial hemorrhage
  • Coma

Gastrointestinal and genitourinary

Gastroenteritis (diarrhea, nausea, vomiting) can occur with the ethanolamine class of antihistamines. Urinary retention is a common anticholinergic adverse effect of the antihistamines.

Rhabdomyolysis ( ie, decreased urinary output and increased creatinine phosphokinase) has been associated with doxylamine overdose, especially if the ingested dose is larger than 20 mg/kg.[1] It can result in acute kidney injury.[67]

Other

Findings may also include the following:

  • Hematologic effects, which are usually secondary to long-term use, include hemolytic anemia, thrombocytopenia, and agranulocytosis
  • Psychiatric effects include visual hallucinations in children receiving therapeutic doses of triprolidine (antihistamine/pseudoephedrine) combinations
  • Dermatologic effects include urticaria and hot, dry skin; rarely, fixed drug eruptions have been demonstrated with the use of cetirizine [68]
  • Potential changes in behavior of an infant exposed through breastfeeding include irritability, disturbed sleep patterns, and excessive crying.

Drug interactions between dextromethorphan and monoamine oxidase inhibitors (MAOIs) or serotonin reuptake inhibitors may result in a serotonin syndrome, which consists of the following:

  • Mental status changes (eg, agitation)
  • Myoclonus
  • Hyperreflexia
  • Diaphoresis
  • Shivering
  • Tremor
  • Diarrhea
  • Headache
  • Fever
  • Incoordination

Anticholinergic syndrome

Peripheral manifestations include dry mucous membranes and hot, dry, flushed skin. These 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 the following:

  • Disorientation
  • Agitation
  • Impairment of short-term memory
  • Nonsensical or incoherent speech
  • Meaningless motor activity that includes repetitive picking or grabbing
  • Visual hallucinations may be prominent

Central anticholinergic syndrome may be contrasted with pure psychosis, which 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

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.[69] 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.[70]

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Contributor Information and Disclosures
Author

Laleh Gharahbaghian, MD Director, Emergency Ultrasound Program and Fellowship, Clinical Associate Professor, Department of Surgery, Division of Emergency Medicine, Stanford University Medical Center

Laleh Gharahbaghian, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Nicholas Lopez, MD Attending Physician, Department of Emergency Medicine, Queen of the Valley Medical Center, Sutter Solano Medical Center

Nicholas Lopez, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, Emergency Medicine Residents' Association

Disclosure: Nothing to disclose.

Chief Editor

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, Wisconsin Medical Society

Disclosure: Nothing to disclose.

Acknowledgements

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.

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

Disclosure: Nothing to disclose.

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.

Annette M Lopez, MD Toxicology Fellow, Oregon Health and Science University School of Medicine

Disclosure: Nothing to disclose.

David J McCann, MD Resident Physician, Department of Emergency Medicine, Harvard University Affiliated Emergency Medicine Residency Program, Harvard Medical School

Disclosure: Nothing to disclose.

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

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.

Jennifer A Oman, MD Associate Clinical Professor, Department of Emergency Medicine, University of California, Irvine, School of Medicine

Jennifer A Oman, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, Council of Emergency Medicine Residency Directors, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Brett Roth, MD  Assistant Professor, Department of Emergency Medicine, Division of Clinical Toxicology, University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School

Disclosure: Nothing to disclose.

Anne Rutkowski, MD Resident Physician, Department of Emergency Medicine, Harbor-University of California at Los Angeles Medical Center

Disclosure: Nothing to disclose.

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.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Merck Salary Employment

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.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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