Antihistamine poisoning

SPECIFIC SUBSTANCES

Antihistamine poisoning

anticholinergic actions both contribute to the sedative and antiemetic effects. Many sedating antihistamines also block a1adrenergic or serotonergic receptors or sodium channels; all these actions contribute to toxicity in overdose.

Simon HL Thomas

Features As would be expected, sedation is a prominent feature of overdose and is especially pronounced with promethazine, alimemazine and diphenhydramine, while chlorphenamine and cyclizine are less sedating. Sedation is exacerbated by coingestion of other CNS depressants, including alcohol. Anticholinergic effects are commonly encountered after overdose with non-specific sedating antihistamines, including gastrointestinal disturbances, dry mouth, hot dry skin, dilated pupils, tachycardia, hypertension or hypotension, ataxia, nystagmus, drowsiness and agitation.1 Occasionally, there may be convulsions, especially with diphenhydramine and hydroxyzine, although these are uncommon.1,2 Sinus tachycardia is common, while cardiac conduction abnormalities including QRS prolongation and ventricular arrhythmias have occasionally been reported, probably resulting from myocardial sodium channel blockade, with diphenhydramine and promethazine most often implicated. There are also infrequent reports of QT prolongation and torsade de pointes, most likely due to potassium channel blockade, with diphenhydramine and chlorphenamine implicated.2e5 Brugada’s syndrome has also been reported after diphenhydramine overdose.6 Psychosis, prolonged coma or delirium,7 paralytic ileus and urinary retention are other, less common features.8,9 Rhabdomyolysis10 and neuroleptic malignant syndrome11 have been reported but appear rare. Pulmonary oedema is sometimes observed in severe episodes.

Abstract Antihistamines are commonly used to treat allergy, dizziness and nausea. The sedating antihistamines are non-specific in their actions and often have marked anticholinergic effects. Features of toxicity are likely to develop within 6 hours of overdose and include tachycardia, blood pressure disturbances, dry mouth, ataxia, agitation, psychosis and, uncommonly, convulsions or arrhythmias. Sedation is exacerbated by co-ingestion of other central nervous system depressants including alcohol. Non-sedating antihistamines are less toxic in overdose but may cause tachycardia, drowsiness, gastrointestinal disturbances and headache. Arrhythmias have been reported with nonsedating antihistamine overdose but this appears to be rare. Treatment of antihistamine overdose includes activated charcoal (when indicated) and general supportive care. Cardiovascular monitoring, including of the electrocardiogram, is appropriate. Convulsions should be treated with a benzodiazepine.

Keywords Antihistamines; chlorphenamine; diphenhydramine; loratadine; overdose; poisoning

Introduction Use of the term ‘antihistamine’ generally refers to a competitive antagonist at the H1-histamine receptor and does not encompass H2-receptor antagonists such as cimetidine, ranitidine or famotidine, which are not considered further in this article. H1 antihistamines are commonly used in the treatment of allergic disorders, such as seasonal allergic rhinitis and urticaria, as well as itching associated with bites or stings, vestibular disorders and vomiting, including in palliative care. Many preparations are available without prescription, and the widespread availability of these products, including as over-the-counter sedatives, means that they are not uncommonly encountered in overdose. H1 antihistamine drugs can be divided into two general categories: sedating and non-sedating.

Non-sedating antihistamines Non-sedating antihistamines (Table 1) have largely replaced sedating agents for the treatment of allergic disorders. They are less sedating because of reduced anticholinergic actions and in some cases because lipid soluble pro-drugs are converted during first-pass metabolism to non-lipid-soluble metabolites that are active on peripheral H1 receptors but do not penetrate the CNS. Some may also be excluded actively from the CNS by cerebral endothelial P-glycoprotein.

Sedating antihistamines Sedating antihistamines are lipid-soluble drugs that rapidly penetrate the central nervous system (CNS). Examples are shown in Table 1. They are non-specific in their effects, with anticholinergic actions being prominent, especially with promethazine and alimemazine but also to a lesser extent with betahistine, cyclizine and diphenhydramine. Antihistaminergic and

Features There is less published evidence on the effects of non-sedating antihistamines in overdose, although clinical effects are generally not as marked as for sedating antihistamines, with a low propensity for sedation, anticholinergic and cardiovascular effects. Severe clinical effects are uncommon, even with very large doses. Clinical features following overdose are non-specific and include tachycardia, drowsiness or agitation, gastrointestinal disturbances, dizziness and headache. The older non-selective agents terfenadine and astemizole produced QT interval prolongation and torsade de pointes when taken in overdose and sometimes after therapeutic dosing,12,13 resulting in these drugs being withdrawn from the market. There have been occasional reports of QT prolongation or arrhythmia with therapeutic doses

Simon HL Thomas MD FRCP FRCPE is Consultant Physician in the Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK, Professor of Clinical Pharmacology and Therapeutics at Newcastle University and Director of the National Poisons Information Service (Newcastle Unit). He trained in clinical pharmacology and toxicology at St Thomas’ Hospital, London and in Newcastle upon Tyne. His research interests are adverse drug reactions and poisoning. Competing interests: none declared.

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SPECIFIC SUBSTANCES

corrected. Torsade de pointes should be treated with intravenous magnesium sulfate in the first instance. QRS widening may indicate sodium channel blockage and, if severe or accompanied by ventricular arrhythmias, should be treated with intravenous sodium bicarbonate. Patients who have not developed clinical features within 6 hours of antihistamine overdose are unlikely to do so and can be considered for discharge. A

Examples of antihistamines Sedating C

C C

C C C C C C C C C

Alimemazine (previously termed trimeprazine) Buclizine Chlorphenamine (previously termed chlorpheniramine) Cinnarizine Clemastine Cyclizine Cyproheptadine Diphenhydramine Hydroxyzine Ketotifen Promethazine Triprolidine

Non-sedating C C C C C C C C C

Acrivastine Bilastine Cetirizine Desloratadine Fexofenadine Levocetirizine Loratadine Mizolastine Rupatadine

REFERENCES 1 Mullins ME, Pinnick RV, Terhes JM. Life-threatening diphenhydramine overdose treated with charcoal hemoperfusion and hemodialysis. Ann Emerg Med 1999; 33: 104e7. 2 Nine JS, Rund CR. Pediatric cinnarizine overdose and toxicokinetics. Am J Forensic Med Pathol 2006; 27: 36e41. 3 Thakur AC, Aslam AK, Aslam AF, Vasavada BC, Sacchi TJ, Khan IA. QT interval prolongation in diphenhydramine toxicity. Int J Cardiol 2005; 98: 341e3. 4 Joshi AK, Sljapic T, Borghei H, Kowey PR. Case of polymorphic ventricular tachycardia in diphenhydramine poisoning. J Cardiovasc Electrophysiol 2004; 15: 591e3. 5 Sharma AN, Hexdall AH, Chang EK, Nelson LS, Hoffman RS. Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate. Am J Emerg Med 2003; 21: 212e5. 6 Lopez-Barbeito B, Lluis M, Delgado V, et al. Diphenhydramine overdose and Brugada sign. Pacing Clin Electrophysiol 2005; 28: 730e2. 7 Scott J, Pache D, Keane G, Buckle H, O’Brien N. Prolonged anticholinergic delirium following antihistamine overdose. Australas Psychiatry 2007; 15: 242e4. 8 Radovanovic D, Meier PJ, Guirguis M, Lorent JP, Kupferschmidt H. Dose-dependent toxicity of diphenhydramine overdose. Hum Exp Toxicol 2000; 19: 489e95. 9 Timnak C, Gleason O. Promethazine-induced psychosis in a 16year-old girl. Psychosomatics 2000; 45: 89e90. 10 Khosla U, Ruel KS, Hunt DP. Antihistamine-induced rhabdomyolysis. South Med J 2003; 96: 1023e6. 11 Mendhekar DN, Andrade C. Neuroleptic malignant syndrome with promethazine. Aust N Z J Psychiatry 2005; 39: 113e4. 12 Davies AJ, Harindra V, Mcewan A, Ghose RR. Cardiotoxic effect with convulsions in terfenadine overdose. BMJ 1989; 298: 325. 13 Leor J, Harman M, Rabinowitz B, Mozes B. Giant U waves and associated ventricular tachycardia complicating astemizole overdose: successful therapy with intravenous magnesium. Am J Med 1991; 91: 94e7. 14 Kuchar DL, Walker BD, Thorburn CW. Ventricular tachycardia following ingestion of a commonly used antihistamine. Med J Aust 2002; 176: 429e30. 15 Cowen PJ. Toxic psychosis with antihistamines reversed by physostigmine. Postgrad Med J 1979; 55: 556e7.

Table 1

of newer agents (e.g. loratadine),14 but if there is a risk, it appears very small. Metabolic acidosis, seizures and cardiac arrest have been reported rarely after massive overdose.

Management It is reasonable to give activated charcoal to patients presenting within an hour of ingesting substantial amounts of antihistamines, especially the more toxic sedating agents, although there is no specific evidence of clinical benefit. For sedating antihistamines, patients should be monitored for conscious level and respiration, and given appropriate supportive measures should coma or respiratory depression develop. Intravenous fluids should be given to patients developing hypotension, and convulsions should be treated using diazepam or lorazepam. When treating delirium or agitation, cautious treatment with benzodiazepines may be useful if drug treatment cannot be avoided. There are reports of benefit from use of anticholinesterases such as physostigmine,15 although this drug is not available in the UK. Hypotension may be due to a-adrenoceptor blockade and usually responds to intravenous fluids. An electrocardiogram (ECG) should be performed after overdose with any antihistamine because of their capacity to cause tachycardia and the residual uncertainty about their potential to cause arrhythmia in overdose. This is particularly important in diphenhydramine overdose, where the risks appear larger. The QRS and QT intervals should be assessed, and patients with abnormal ECGs or other signs of evolving toxicity should undergo continuous ECG monitoring. Should torsade de pointes or other ventricular arrhythmias develop, hypoxia, acidosis and electrolyte abnormalities should be

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