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.
Peak serum levels of diphenhydramine (DPH) are reached approximately 2–3 hours after ingestion, and elimination half‐life is approximately 4 hours. Symptoms are dose‐dependent. Severe symptoms (delirium/psychosis, seizures, and coma) can occur with ingestion of > 1.0 g DPH. The frequency of coma and seizures may increase with ingestion of > 1.5 g DPH, and electrocardiographic disturbances may occur with ingestion of > 3.0 g DPH. Serum DPH concentrations of > 5 μg/mL have been reported in fatalities. [63]
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. [64]
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. [65]
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.
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:
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Agitation
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Fever
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Urinary retention
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Dry, hot, flushed skin
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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, the computer product database used by poison control centers.
Vital signs
Abnormal findings may include the following:
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Hyperthermia
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Tachypnea
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Tachycardia
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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:
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Mydriasis
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Nasal dryness and stuffiness
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Eye dryness
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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. [66]
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. [67] 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:
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Dizziness
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Ataxia
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Hyperexcitability
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Somnolence
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Seizures
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Dystonia
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Dyskinesia
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Toxic psychosis (anxiety, agitation, hallucination)
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Intracranial hemorrhage
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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. [3] It can result in acute kidney injury. [68]
Other
Findings may also include the following:
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Hematologic effects, which are usually secondary to long-term use, include hemolytic anemia, thrombocytopenia, and agranulocytosis
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Psychiatric effects include visual hallucinations in children receiving therapeutic doses of triprolidine (antihistamine/pseudoephedrine) combinations
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Dermatologic effects include urticaria and hot, dry skin; rarely, fixed drug eruptions have been demonstrated with the use of cetirizine [69]
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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:
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Mental status changes (eg, agitation)
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Myoclonus
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Hyperreflexia
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Diaphoresis
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Shivering
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Tremor
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Diarrhea
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Headache
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Fever
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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:
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Disorientation
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Agitation
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Impairment of short-term memory
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Nonsensical or incoherent speech
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Meaningless motor activity that includes repetitive picking or grabbing
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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. [70] 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. [71]
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Dextromethorphan.
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Terfenadine is the antihistamine most commonly associated with torsade de pointes in both acute overdose and therapeutic administration.
