First generation (Typical) antipsychotic medication poisoning
- Eric J Lavonas, MD
Eric J Lavonas, MD
- Interim Director, Department of Emergency Medicine
- Attending Physician, Rocky Mountain Poison and Drug Center, Denver Health
- Professor of Emergency Medicine
- University of Colorado School of Medicine
Antipsychotic medications are primarily used to treat agitation, hallucinations, and other manifestations of psychosis arising from numerous causes, including psychiatric illnesses (schizophrenia, mania), medical illnesses (alcohol withdrawal), and neurologic disease (Alzheimer disease). When used to treat psychiatric diseases, they also aid in restructuring disordered thinking.
Antipsychotic medications are also used to treat a number of nonpsychiatric conditions, including nausea and vomiting (prochlorperazine, promethazine, droperidol), vertigo (prochlorperazine, droperidol), itching (promethazine, hydroxyzine), migraine headache (prochlorperazine, haloperidol, droperidol), Tourette's syndrome (haloperidol, pimozide), postherpetic neuralgia (fluphenazine), and hiccups (chlorpromazine).
Typical antipsychotic medications were first used clinically in 1951. Although their use in psychiatric disorders has been outpaced by that of atypical antipsychotic agents, they remain widely used to treat nausea. Poisoning and overdose from these drugs remains common. The Centers for Disease Control estimates that approximately 5800 patients are treated in US emergency departments annually for adverse effects from typical antipsychotic medication, including unintentional overdose, a rate of 26 ED visits per 10,000 outpatient prescription visits . Haloperidol was responsible for a higher rate of ED visits (43.3 per 10,000 outpatient prescription visits) than any other psychiatric medication. In 2014, American poison control centers reported more than 4600 exposures to phenothiazines, resulting in one death [2,3].
Antipsychotic medications are generally categorized as "low potency," "high potency," or "atypical" agents. This topic review will discuss the management of typical, high, and low potency antipsychotic medication poisoning (table 1). A summary table to facilitate emergent management is provided (table 2). Poisoning from atypical antipsychotic agents is discussed separately. (See "Second generation (atypical) antipsychotic medication poisoning".)
PHARMACOLOGY AND CELLULAR TOXICOLOGY
The typical antipsychotic agents antagonize dopamine (D) receptors in several areas of the brain, including the cortex, basal ganglia, limbic system, hypothalamus, and chemoreceptor trigger zone. The efficacy and potency of these agents is directly related to D2 receptor binding affinity [4,5]. However, not all forms of D2 receptor blockade are desirable. D2 antagonism in the mesocortical regions impairs cognition and exacerbates the negative symptoms of schizophrenia, such as avolition, anhedonia, poverty of speech, flattened affect, and social withdrawal.
- Hampton LM, Daubresse M, Chang HY, et al. Emergency department visits by adults for psychiatric medication adverse events. JAMA Psychiatry 2014; 71:1006.
- Bronstein AC, Spyker DA, Cantilena LR Jr, et al. 2011 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila) 2012; 50:911.
- Mowry JB, Spyker DA, Brooks DE, et al. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila) 2015; 53:962.
- Sekine Y, Rikihisa T, Ogata H, et al. Correlations between in vitro affinity of antipsychotics to various central neurotransmitter receptors and clinical incidence of their adverse drug reactions. Eur J Clin Pharmacol 1999; 55:583.
- White, SR. Acute dystonic reaction and the neuroleptic malignant syndrome. J Pharm Practice 2005; 18:175.
- Crumb WJ Jr, Ekins S, Sarazan RD, et al. Effects of antipsychotic drugs on I(to), I (Na), I (sus), I (K1), and hERG: QT prolongation, structure activity relationship, and network analysis. Pharm Res 2006; 23:1133.
- Drolet B, Zhang S, Deschênes D, et al. Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current. J Cardiovasc Electrophysiol 1999; 10:1597.
- Reilly JG, Ayis SA, Ferrier IN, et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355:1048.
- Buckley NA, Whyte IM, Dawson AH. Cardiotoxicity more common in thioridazine overdose than with other neuroleptics. J Toxicol Clin Toxicol 1995; 33:199.
- Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002; 62:1649.
- Salih IS, Thanacoody RH, McKay GA, Thomas SH. Comparison of the effects of thioridazine and mesoridazine on the QT interval in healthy adults after single oral doses. Clin Pharmacol Ther 2007; 82:548.
- Di Salvo TG, O'Gara PT. Torsade de pointes caused by high-dose intravenous haloperidol in cardiac patients. Clin Cardiol 1995; 18:285.
- Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001; 158:1774.
- Berling I, Isbister GK. Prolonged QT Risk Assessment in Antipsychotic Overdose Using the QT Nomogram. Ann Emerg Med 2015; 66:154.
- Arita M, Nagamoto Y, Saikawa T. Intraventricular conduction disturbance due to delayed recovery from ventricular inactivation in chlorpromazine-treated dogs. Recent Adv Stud Cardiac Struct Metab 1976; 11:85.
- Ogata N, Narahashi T. Block of sodium channels by psychotropic drugs in single guinea-pig cardiac myocytes. Br J Pharmacol 1989; 97:905.
- Ogata N, Yoshii M, Narahashi T. Differential block of sodium and calcium channels by chlorpromazine in mouse neuroblastoma cells. J Physiol 1990; 420:165.
- Enyeart JJ, Dirksen RT, Sharma VK, et al. Antipsychotic pimozide is a potent Ca2+ channel blocker in heart. Mol Pharmacol 1990; 37:752.
- Van Putten T, Gelenberg AJ, Lavori PW, et al. Anticholinergic effects on memory: benztropine vs. amantadine. Psychopharmacol Bull 1987; 23:26.
- Kubo S, Orihara Y, Kitamura O, et al. An autopsy case of neuroleptic malignant syndrome (NMS) and its immunohistochemical findings of muscle-associated proteins and mitochondria. Forensic Sci Int 2001; 115:155.
- Martin DT, Swash M. Muscle pathology in the neuroleptic malignant syndrome. J Neurol 1987; 235:120.
- Caroff SN, Rosenberg H, Fletcher JE, et al. Malignant hyperthermia susceptibility in neuroleptic malignant syndrome. Anesthesiology 1987; 67:20.
- Peacock J, Whang W. Antipsychotic medications and sudden cardiac arrest: more than meets the eye? Heart Rhythm 2013; 10:531.
- Tromeur C, Couturaud F. Antipsychotic drugs and venous thromboembolism. Thromb Res 2012; 130 Suppl 1:S29.
- Weeke P, Jensen A, Folke F, et al. Antipsychotics and associated risk of out-of-hospital cardiac arrest. Clin Pharmacol Ther 2014; 96:490.
- Lopez OL, Becker JT, Chang YF, et al. The long-term effects of conventional and atypical antipsychotics in patients with probable Alzheimer's disease. Am J Psychiatry 2013; 170:1051.
- Gardette V, Lapeyre-Mestre M, Coley N, et al. Antipsychotic use and mortality risk in community-dwelling Alzheimer's disease patients: evidence for a role of dementia severity. Curr Alzheimer Res 2012; 9:1106.
- Bloechliger M, Rüegg S, Jick SS, et al. Antipsychotic drug use and the risk of seizures: follow-up study with a nested case-control analysis. CNS Drugs 2015; 29:591.
- Packard K, Price P, Hanson A. Antipsychotic use and the risk of rhabdomyolysis. J Pharm Pract 2014; 27:501.
- Masi G, Milone A, Viglione V, et al. Massive asymptomatic creatine kinase elevation in youth during antipsychotic drug treatment: case reports and critical review of the literature. J Child Adolesc Psychopharmacol 2014; 24:536.
- Isah AO, Rawlins MD, Bateman DN. Clinical pharmacology of prochlorperazine in healthy young males. Br J Clin Pharmacol 1991; 32:677.
- Klasco, RK (Ed): DRUGDEX® System, Vol. 136. Thomson Healthcare, Greenwood Village, Colorado (Edition expires 6/2008).
- Drotts DL, Vinson DR. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med 1999; 34:469.
- Canadian Movement Disorders Group. Acute Dystonic Reaction. www.cmdg.org/Movement_/drug/Acutedystonicreaction/acutedystonicreaction.htm (Accessed on October 15, 2008).
- Meulendijks D, Mannesse CK, Jansen PA, et al. Antipsychotic-induced hyponatraemia: a systematic review of the published evidence. Drug Saf 2010; 33:101.
- Vanden Hoek TL, Morrison LJ, Shuster M, et al. Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S829.
- König P, Chwatal K, Havelec L, et al. Amantadine versus biperiden: a double-blind study of treatment efficacy in neuroleptic extrapyramidal movement disorders. Neuropsychobiology 1996; 33:80.
- Adler L, Angrist B, Peselow E, et al. A controlled assessment of propranolol in the treatment of neuroleptic-induced akathisia. Br J Psychiatry 1986; 149:42.
- Stryjer R, Rosenzcwaig S, Bar F, et al. Trazodone for the treatment of neuroleptic-induced acute akathisia: a placebo-controlled, double-blind, crossover study. Clin Neuropharmacol 2010; 33:219.
- Choy AM, Lang CC, Chomsky DM, et al. Normalization of acquired QT prolongation in humans by intravenous potassium. Circulation 1997; 96:2149.
- Arizona Center for Education and Research on Therapeutics. Drugs with Risk of Torsades de Pointes. www.qtdrugs.org/medical-pros/drug-lists/list-01.cfm?sort=Generic_name (Accessed on October 15, 2008).
- PHARMACOLOGY AND CELLULAR TOXICOLOGY
- CLINICAL FEATURES OF OVERDOSE
- Physical examination
- DIFFERENTIAL DIAGNOSIS
- LABORATORY EVALUATION
- Airway, breathing, and circulation
- General treatment and antidotal therapy
- GI decontamination
- Acute extrapyramidal syndromes
- QT interval prolongation
- Anticholinergic delirium
- Neuroleptic malignant syndrome
- Extracorporeal removal
- Ongoing treatment and disposition
- PEDIATRIC CONSIDERATIONS
- ADDITIONAL RESOURCES
- SUMMARY AND RECOMMENDATIONS