Antihistamines comprise a broad class of pharmacologic agents that include the first-generation, H1-receptor antagonists (eg, diphenhydramine) capable of producing significant CNS effects and the newer, second-generation, "nonsedating" H1 blockers (eg, loratadine). H2-receptor antagonists, such as cimetidine, work primarily on gastric mucosa, inhibiting gastric secretion. Newer, experimental antihistamines act on presynaptic H3 receptors and the recently discovered H4 receptors.
While first-generation H1-receptor antagonists are responsible for the vast majority of poisonings, the nonsedating H1-receptor and H2-receptor antagonists also have been associated with serious toxicity.[1]
H1, H2, H3, and H4 receptors are the 4 human histamine receptors that have been identified.
All H1 antagonists are reversible, competitive inhibitors of histamine receptors. Some of the first-generation H1-receptor blockers (eg, diphenhydramine, clemastine, promethazine) are also potent competitive inhibitors of muscarinic receptors and may cause anticholinergic syndrome (eg, sinus tachycardia, dry skin, dry mucous membranes, dilated pupils, ileus, urinary retention, agitated delirium). H1-receptor blockers may disrupt cortical neurotransmission and block fast sodium channels. These effects can exacerbate sedation, but they also can result in seizure activity. Sodium channel blockade in the cardiac cells can cause conduction delays manifested by widening of the QRS interval and dysrhythmias.
Doxylamine exposure has been associated with rhabdomyolysis. The mechanism of its toxicity is unknown, but doxylamine may have a direct toxic effect on muscle, possibly thorough injury to the sarcolemma.[2]
Cyproheptadine is known to block serotonin receptors as do the recently discovered compounds that have dual H3 antagonist and serotonin reuptake inhibition properties.[3] The phenothiazine class of antihistamines (eg, promethazine) has alpha-adrenergic blocking activity and may cause hypotension. H1 receptors have been found on sebocytes, and the use of H1 blockers in the management of acne may have a future role.[4] There is no current clinical use for H3- and H4-receptor antagonists.
The 6 structural classes of antihistamines are as follows:
Fexofenadine, loratadine, desloratadine, astemizole, cetirizine, and levocetirizine are peripherally selective H1-receptor antagonists. Desloratadine is the most potent of these.[5] They have a distinct advantage because they bind much more selectively to peripheral H1 receptors and have a lower binding affinity for the cholinergic and alpha-adrenergic receptor sites than other antihistamines. This group of antihistamines is popular because specificity for the peripheral histamine receptor site eliminates many adverse effects, including central nervous system (CNS) depression, blurred vision, dry mouth, and tachycardia. These medications are commonly used in the treatment of allergic rhinitis and chronic idiopathic urticaria.[6, 7]
Two nonsedating antihistamines, terfenadine and astemizole, are known to inhibit the potassium rectifier currents (HERG1K), which slows repolarization. This is manifested clinically as prolongation of the QT interval and torsades de pointes. Astemizole and terfenadine have been removed from the US market. Terfenadine has been replaced by fexofenadine, which is the pharmacologically active metabolite of terfenadine. Fexofenadine has only been reported to potentially lead to one case of QT prolongation progressing to ventricular tachycardia and degenerating into ventricular fibrillation.[8] However, this particular case may have had additional risk factors that may have contributed or been responsible for such an effect.[9, 10]
Levocetirizine, which is the L-enantiomer of cetirizine (cetirizine and levocetirizine are both metabolic derivatives of hydroxyzine) has not been associated with torsades de pointes in volunteer and animal studies. See the image below.
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Terfenadine is the antihistamine most commonly associated with torsade de pointes in both acute overdose and therapeutic administration.
Diphenhydramine is known to prolong the QT interval on ECG by previously presumed inhibition of the delayed potassium rectifier channel, though recent studies show that diphenhydramine has a relatively weak affinity for the HERG1K receptor.[11] Torsades de pointes has not been documented with diphenhydramine, most likely because of the concurrent sinus tachycardia created by the anticholinergic-induced tachycardia, which shortens repolarization.
In addition to differences in peripheral versus central binding, the propensity to cause sedation among the various antihistamines may be related to disease process (ie, atopic dermatitis vs allergic rhinitis), receptor internalization after binding and the interaction of P-glycoprotein (a protein responsible for facilitating transport across various cell membranes and found in many tissues including the blood-brain barrier).[12, 13, 14]
A new class of selective nonsedating H1 antagonists, the norpiperidine imidazoazepines, is currently in clinical trials. Current in vitro and in vivo safety studies show no increase in incidence of cardiac dysrhythmia.
Lucero et al reported that bilastine, a new H1 agonist, has demonstrated a favorable profile in animal models in preclinical trials.[15] In 2010, its use was authorized in the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria in adults and children older than 12 years.
H2 receptors are primary regulators of gastric acid secretion. In the CNS, histamine (H1, H2) modulates activities such as arousal, thermoregulation, neuroendocrine, and vegetative functions. At therapeutic dosing, H2-receptor antagonists have been implicated in drug-induced delirium when used for ulcer prophylaxis.[16] These agents are considered relatively benign in overdose; as observed with cimetidine, the primary adverse reaction is confusion. Cimetidine also inhibits hepatic oxidative metabolism by most cytochrome P450 enzymes and, thus, the metabolism of a variety of drugs including propranolol, carbamazepine, quinidine, theophylline, and certain tricyclic antidepressants.
Other H2-receptor blockers (eg, ranitidine, famotidine) do not seem to interfere with hepatic oxidation. Cimetidine competitively blocks creatinine tubular transport in the nephron, and measuring creatinine clearance after a bolus of cimetidine may be a more accurate measurement of glomerular filtration rate (GFR) in renal transplant patients.[17]
The H3 receptor is a presynaptic auto- and hetero-receptor that controls the release of histamine and a variety of other neurotransmitters in the brain. Modulation of this receptor may have various clinical effects on wakefulness, cognition, and hunger.[18] Phase IIb clinical trials are already underway. H3 receptor modulation may add to the armamentarium for the treatment of obesity, epilepsy, cognitive impairment, Alzheimer disease, schizophrenia, neuropathic pain, ADHD, sleep-wake disorders, antipsychotic-induced weight gain, cholangiocarcinoma, cerebral malaria, and addiction disorders.[19, 20, 21, 22, 23, 24, 25, 26, 27, 28]
Currently, no products are commercially available, but several compounds, including conessine; diazepam amides; and diamine, dihydrobenzoxathiin, biphenyl sulfonamide, and benzoquinoline derivatives, have been shown to interact with the H3 receptor.[3, 29, 30, 31, 32, 33]
H4 receptors have been identified on cells of hematopoietic lineage (dendritic cells, mast cells, eosinophils, basophils, T cells, NK cells). Several ligands have been identified with affinity for this receptor. Modulation may have effects on nociception, inflammation, pruritus, and autoimmune disorders.[34, 35, 36] Phase II clinical trials involving antagonism of the H4 receptor for treatment of asthma, dermatitis, and rhinitis are underway.
The American Association of Poison Control Centers' National Poison Data System (NPDS) annual report for 2010[37] ascribes 95,880 exposures to either H1 or H2 blockers representing or 3.4% all reported exposures for the year. Antihistamines ranked 9th in frequency among reported human exposure. Diphenhydramine was the most common antihistamine exposure, with 39,028 reports being made to poison centers.
Mortality/Morbidity
Of all antihistamine exposures reported to US poison control centers in 2010 (NPDS data), 3,541 (3.7%) resulted in moderate-to-major toxicity and 12 (0.013%) resulted in fatality.[37] The vast majority of fatalities were associated with diphenhydramine.
First-generation H1-receptor antagonists, such as diphenhydramine, may be particularly dangerous because they may cause pronounced agitation and seizures, resulting occasionally in rhabdomyolysis and acidosis. Also, a quinidinelike sodium channel blocking effect, and at high doses, a potassium channel blocking effect (HERG1K), may cause delayed conduction (prolonged QRS) and repolarization (prolonged QT) and contribute to ventricular dysrhythmias.
Second-generation H1-receptor antagonists, such as terfenadine and astemizole (now removed from the US market), may result in QT interval prolongation and life-threatening polymorphic ventricular tachycardia (torsade de pointes), particularly when combined with erythromycin.
From 1990-2005 the Civil Aerospace Medical Institute (CAMI) reported that antihistamines were found in 338 of 5383 pilot fatalities. It was felt that antihistamines were a factor in or the cause of 50 and 13 cases, respectively. The prevalence of antihistamine use among fatal crashes increased from 4% to 11% over this time span, indicating a worrisome trend that has led to protocols on allowed agents and abstinence time requirements.[38, 39]
Reports of delayed pulmonary edema from antihistamine overdose have been reported.[40]
Famotidine has been shown to cause a significant increase in serum phosphate levels among hemodialysis patients taking calcium carbonate (even at the recommended dose of 10 mg/d).[41]
Neuropsychiatric symptoms in patients with underlying hepatic or renal dysfunction have been reported with administration of cimetidine. In severely ill patients, intravenous administration can result in bradycardia and hypotension that can progress to cardiac arrest.[42]
Race
Acetylation of diphenhydramine to a nontoxic metabolite occurs twice as rapidly in individuals of Asian descent as it does in white individuals; thus, Asians are much less sensitive to the effects on psychomotor performance and the sedative effects. Antihistamines are capable of inducing the hepatic microsomal enzymes and may enhance their own rate of elimination in patients using them chronically. This phenomenon often is referred to as autoinduction of metabolism.
H2-receptor antagonist use has been implicated as a potential risk factor for the development of cognitive impairment in African Americans.[43]
Paradoxical excitation in CYP2D6 ultrarapid metabolizers has been reported with diphenhydramine use.[44]
Age
According to the 2010 NPDS data, the number of toxic antihistamine exposures in patients younger than 6 years was 47,674.[37] The relationship between ingested dose and severity of symptoms has been shown in one retrospective review to be insignificant.[45]
The 2010 NPDS data also indicate that antihistamines were the 7th most frequently reported exposure among children younger than 5 years.[37]
A positive association between depression symptoms among elderly persons (>65 y) and H2 blocker use has been reported.[46]
Inappropriate use of antihistamines for URI symptoms and otitis media may unnecessarily expose children to the potential side effects of this class of medication. Furthermore, no study has shown a benefit in the management of these conditions with either antihistamines or decongestants.[47]
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).
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]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 with nonsedating antihistamines 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.
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.[48]
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.
Piperazine 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).
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. 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.[49]
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
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.[50]
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.[51]
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.[52]
Pulmonary findings
Pulmonary congestion was the most common finding on autopsy in a review of 76 reported deaths from diphenhydramine between 1946 and 2003.[53] 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.[54]
Musculoskeletal
Exposure to doxylamine is associated with rhabdomyolysis, especially if ingested dose is larger than 20 mg/kg.[55]
Renal
Rhabdomyolysis secondary to doxylamine exposure can result in acute renal failure.[56]
Obtaining either qualitative or quantitative testing of blood or urine for antihistamines has little clinical justification. Most laboratories are not capable of testing for antihistamines, and pharmacokinetic studies have not been performed to establish therapeutic or toxic blood levels. However, a review of deaths from diphenhydramine monointoxication showed average lethal levels of diphenhydramine to be 19.5 mg/L in adults, 7.4 mg/L in children, and 1.53 mg/L in infants.[53] Screening may be important when clinical history is lacking and the diagnosis is in question.
Toxicologic screening for drugs of abuse is not generally necessary because patients usually can be treated based on clinical presentation.
Testing blood for presence of salicylate and acetaminophen is recommended for all patients because many cough and cold preparations combine antihistamines, antipyretics, and analgesics.
Check serum electrolyte levels to rule out metabolic abnormalities for patients who are confused or exhibit evidence of cardiotoxicity.
Check serum creatinine kinase level, especially if patient was exposed to doxylamine or if he or she experienced seizures in order to rule out rhabdomyolysis.
Obtain blood cultures to rule out sepsis if the patient is hyperthermic, seriously ill, or the diagnosis of anticholinergic poisoning is questionable.
Chronic toxicity from antihistamines is uncommon, but agranulocytosis has been reported with chlorpheniramine and brompheniramine. Cholestatic jaundice was reported after prolonged treatment with cyproheptadine. Hepatitis has been reported following prolonged therapy with terfenadine. Patients with moderate hepatic impairment experienced a greater increase in desloratadine exposure than those with normal LFTs even at the same dose.[57]
Electrocardiography can be performed to rule out conduction delays and dysrhythmias.
Computerized tomography (CT) scan of the head can be considered in any patient presenting with seizures or altered mental status. CT scan may not be necessary in patients with progressive improvement, supportive history, and a nonfocal neurologic examination.
Paramedics should follow set protocols for gastric decontamination, hypotension, and seizures; symptomatic patients should be transported rapidly with intravenous access and cardiac monitoring. Benzodiazepines may be used for agitation or seizures.
Basic tenets of emergency care should dictate therapy. Perform bedside determinations of glucose for patients with altered levels of conscious and treat with intravenous dextrose, if appropriate. For hypotensive patients, administer 0.9% sodium chloride solution or lactated Ringer solution as boluses. Dopamine, or other cardiac pressor, may be titrated to achieve an acceptable blood pressure.
Administer activated charcoal to patients who are cooperative, can retain a good gag reflex, and can take liquids by mouth safely. Perform endotracheal intubation before instillation of activated charcoal for patients with significant CNS depression and unprotected airway. The clinician should be aware that a severely toxic patient can experience seizures and aspirate charcoal.
Gastric emptying has not proven beneficial if the patient presents more than one hour postingestion, although case reports involving anticholinergic agents have demonstrated erratic absorption and repeated worsening of anticholinergic symptoms over 9 days. Ipecac syrup is not recommended in the ED because it may delay the administration of activated charcoal and seizures may occur at any time, with the possibility of aspiration. Repeated doses of activated charcoal may prevent continued absorption, although the development of ileus generally limits its use.
Anticholinergic-induced delirium ranges from mild confusion to severe agitation with associated hyperthermia and rhabdomyolysis. The administration of chemical and physical restraints often is necessary to prevent patients from harming themselves or others. Controlling muscular activity is crucial in severely agitated patients, because agitation may exacerbate muscle injury, acidosis, rhabdomyolysis, and hyperthermia. Although benzodiazepines often are considered first-line, physostigmine is safe and effective for the treatment of antihistamine-induced agitated delirium, provided that the ECG does not demonstrate conduction disturbances (ie, PR and QRS prolongation); one study suggests that physostigmine is more effective and just as safe as benzodiazepines to control antihistamine-induced agitated delirium.[58]
Neuroleptic agents, such as haloperidol, have been used but have anticholinergic effects and may exacerbate hyperthermia or provoke a dystonic reaction and their use should be discouraged.
Physostigmine, a naturally occurring alkaloid obtained from the Ordeal bean Physostigma venenosum, is the only reversible acetylcholinesterase inhibitor lacking a charged quaternary amine moiety. As a tertiary amine, physostigmine traverses the blood-brain barrier and binds to central acetylcholinesterase, increasing acetylcholine levels and, thus, reversing central anticholinergic delirium. Peripheral signs and symptom also are reversed. Considering that patients with anticholinergic symptoms usually fare well with supportive therapy alone, physostigmine is indicated only in the following limited circumstances:
Single-drug (anticholinergic) exposure[58]
Pronounced hallucinations, delirium, or agitation (suggesting a CNS effect) unresponsive to benzodiazepines
Intractable seizures resistant to all other treatments
Absence of QRS prolongation on ECG
Physostigmine should not be used in known antidepressant overdoses. Case series of patients taking maprotiline indicated that seizures developed in 6 out of 7 patients treated with physostigmine. Other reports describe development of asystole for the administration of physostigmine after cyclic antidepressant poisoning. In a series of 21 patients receiving physostigmine, 2 patients experienced seizures and 2 experienced cholinergic reactions (hypersalivation in one patient, bradycardia and hypotension in the other). Thus, use physostigmine cautiously.
Always have atropine at bedside when using physostigmine in order to reverse excessive cholinergic activity (eg, bradycardia, salivation)
Manage hyperthermia, especially when severe agitation is present, with neuromuscular paralysis, evaporative cooling, and ice-bath immersion if temperature is higher than 105°F. Use of dantrolene or bromocriptine is controversial.
Sinus tachycardia usually does not require treatment. Sedation with a benzodiazepine may be helpful when agitation is also present. Intravenous sodium bicarbonate improves widening of QRS that may result from antihistamines with sodium channel blocking properties (eg, diphenhydramine, pyrilamine). Provide support for patients with profound cardiovascular toxicity. In rare cases of refractory shock, placement of an intra-aortic balloon pump for several hours may bridge the patient through a period of cardiovascular collapse.
Case reports suggest that physostigmine ends seizures, but clinical experience is limited and no proof of its efficacy for seizure control exists. Treat antihistamine-induced seizures with benzodiazepines and barbiturates. Reserve physostigmine for refractory seizures. One case of using flumazenil for successful reversal of antihistamine-induced depressed mental status in a 7-month-old infant was reported in 2003. Evidence to recommend this therapy is insufficient.
The American Association of Poison Control Centers has issued evidence-based consensus guidelines on the out-of-hospital management of diphenhydramine and dimenhydrinate poisoning.
Most poisonings result from first-generation antihistamines. Most patients present with anticholinergic symptoms and generally have good outcomes with simple observation and meticulous attention to supportive care. Limit treatment with physostigmine to severe cases. For treatment of cardiac toxicity, include careful monitoring and aggressive treatment of conduction delays or torsade de pointes.
Clinical Context:
Activated charcoal may be administered as long as 4 hours post ingestion, with potential benefit. Anticholinergic features of antihistamines may delay gastric emptying. It is available as an aqueous solution or with a cathartic (sorbitol 70%).
Clinical Context:
By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS, including limbic and reticular formation. It is the drug of choice because of a more prolonged anticonvulsant effects than diazepam or midazolam (4-6 h vs 1-3 h). It has an excellent safety profile.
Clinical Context:
Midazolam is used as an alternative in the termination of refractory status epilepticus. Because it is water soluble, it takes approximately 3 times longer than diazepam to peak EEG effects. Thus, the clinician must wait 2-3 minutes to fully evaluate sedative effects before initiating a procedure or repeating a dose. It is a second-line agent because of its shorter anticonvulsant effect and shorter duration of sedation.
Clinical Context:
Diazepam depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing the activity of GABA. It is a third-line agent for agitation or seizures because of its shorter duration of anticonvulsive effects and accumulation of active metabolites that may prolong sedation.
Clinical Context:
Physostigmine is a reversible cholinesterase inhibitor that increases the concentration of ACh in the myoneural junction. It readily crosses the blood-brain barrier to produce desired CNS effects.
Clinical Context:
Sodium bicarbonate is the first-line agent for prolongation of QRS interval after an overdose with antihistamine with quinidinelike effects.
Treat rhabdomyolysis with aggressive fluid support to maintain urine output at 2 mg/kg/h. Consider using sodium bicarbonate to alkalinize the urine. Consult a nephrologist for oliguria or renal failure, and arrange hemodialysis for the anuric or severely acidotic patient.
Treat acute dystonic reactions with benzodiazepines.
Multiple doses of activated charcoal are not recommended because charcoal concretions may form leading to intestinal obstruction or ileus. Antihistamines may induce intestinal ileus causing delayed absorption of drug and delayed toxicity.
Perform cardiac monitoring on all symptomatic patients or as long as tachycardia, conduction delays, or prolonged QT intervals persist.
Among first-generation antihistamines, mortality from diphenhydramine occurs more than any other agent.
In the United States, diphenhydramine is used more commonly than other antihistamines. It also is associated with more cardiotoxicity and a higher incidence of seizures than other first-generation antihistamines.
Pheniramine, an antihistamine commonly used in Australia, also is associated with a relatively high incidence of seizures.
Among nonsedating piperidine antihistamines, terfenadine has been implicated more often than astemizole, loratadine, or fexofenadine in the formation of prolonged QT syndrome and torsade de pointes.
The prognosis is affected by the presence of underlying medical conditions, co-ingestions, and the amount of drug ingested.
The vast majority of patients recover with supportive care and observation.
Annette M Lopez, MD, Toxicology Fellow, Oregon Health & Sciences University, Portland, Oregon
Disclosure: Nothing to disclose.
Coauthor(s)
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
Disclosure: Nothing to disclose.
Specialty Editors
David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
Disclosure: Nothing to disclose.
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
Disclosure: Nothing to disclose.
Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
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
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.
Additional Contributors
Loren Keith French, MD Attending Physician of Toxicology, Department of Emergency Medicine, Oregon Health and Sciences University and Oregon Poison Center
Guide for Aviation Medical Examiners: Pharmaceuticals (Therapeutic Medications) Allergy-Antihistimines. Federal Aviation Administration; October 24, 2012. 207.
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