Cough, Cold, and Allergy Preparation Toxicity Clinical Presentation
- Author: Laleh Gharahbaghian, MD; Chief Editor: Timothy E Corden, MD more...
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.
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.
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 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:
Dry, hot, flushed skin
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.
Abnormal findings may include the following:
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:
Nasal dryness and stuffiness
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.
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.
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. This was presumably of cardiogenic origin due to cardiovascular collapse and ventricular failure, although the coincidence of myocardial toxicity is not reported.
Abnormal neurologic findings include the following:
Toxic psychosis (anxiety, agitation, hallucination)
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. It can result in acute kidney injury.
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
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)
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:
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 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. 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.
Jo YI, Song JO, Park JH, Koh SY, Lee SM, Seo TH, et al. Risk factors for rhabdomyolysis following doxylamine overdose. Hum Exp Toxicol. 2007 Aug. 26(8):617-21. [Medline].
Vernacchio L, Kelly JP, Kaufman DW, Mitchell AA. Cough and cold medication use by US children, 1999-2006: results from the slone survey. Pediatrics. 2008 Aug. 122(2):e323-9. [Medline].
US allergy market affecting the daily life of millions of Americans. Companies and Markets.com. Available at http://www.companiesandmarkets.com/News/Healthcare-and-Medical/US-allergy-market-affecting-the-daily-life-of-millions-of-Americans/NI6717. Accessed: August 21, 2013.
Kernan WN, Viscoli CM, Brass LM, Broderick JP, Brott T, Feldmann E, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000 Dec 21. 343(25):1826-32. [Medline].
Spiller HA, Beuhler MC, Ryan ML, Borys DJ, Aleguas A, Bosse GM. Evaluation of changes in poisoning in young children: 2000 to 2010. Pediatr Emerg Care. 2013 May. 29(5):635-40. [Medline].
Mazer-Amirshahi M, Reid N, van den Anker J, Litovitz T. Effect of Cough and Cold Medication Restriction and Label Changes on Pediatric Ingestions Reported to United States Poison Centers. J Pediatr. 2013 Jun 12. [Medline].
Yin HS, Parker RM, Wolf MS, et al. Health literacy assessment of labeling of pediatric nonprescription medications: examination of characteristics that may impair parent understanding. Acad Pediatr. 2012 Jul-Aug. 12(4):288-96. [Medline].
Smith SM, Schroeder K, Fahey T. Over-the-counter (OTC) medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev. 2012 Aug 15. 8:CD001831. [Medline].
Sharfstein JM, North M, Serwint JR. Over the counter but no longer under the radar--pediatric cough and cold medications. N Engl J Med. 2007 Dec 6. 357(23):2321-4. [Medline].
Revised product labels for pediatric over-the-counter cough and cold medicines. MMWR Morb Mortal Wkly Rep. 2008 Oct 31. 57(43):1180. [Medline].
[Guideline] Ostroff C, Lee CE, McMeekin J. Unapproved prescription cough, cold, and allergy drug products: recent US Food and Drug Administration regulatory action on unapproved cough, cold, and allergy medications. Chest. 2011 Aug. 140(2):295-300. [Medline].
Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006 Jan. 129(1 Suppl):1S-23S. [Medline]. [Full Text].
Yanai K, Rogala B, Chugh K, Paraskakis E, Pampura AN, Boev R. Safety considerations in the management of allergic diseases: focus on antihistamines. Curr Med Res Opin. 2012 Apr. 28(4):623-42. [Medline].
Ly KS, Letavic MA, Keith JM, Miller JM, Stocking EM, Barbier AJ, et al. Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors. Bioorg Med Chem Lett. 2008 Jan 1. 18(1):39-43. [Medline].
Sasho S, Seishi T, Kawamura M, Hirose R, Toki S, Shimada JI. Diamine derivatives containing imidazolidinylidene propanedinitrile as a new class of histamine H3 receptor antagonists. Part I. Bioorg Med Chem Lett. 2008 Apr 1. 18(7):2288-91. [Medline].
Zhao C, Sun M, Bennani YL, Gopalakrishnan SM, Witte DG, Miller TR, et al. The alkaloid conessine and analogues as potent histamine H3 receptor antagonists. J Med Chem. 2008 Sep 11. 51(17):5423-30. [Medline].
Sasaki T, Takahashi T, Nagase T, Mizutani T, Ito S, Mitobe Y, et al. Synthesis, structure-activity relationships, and biological profiles of a dihydrobenzoxathiin class of histamine H(3) receptor inverse agonists. Bioorg Med Chem Lett. 2009 Aug 1. 19(15):4232-6. [Medline].
Covel JA, Santora VJ, Smith JM, Hayashi R, Gallardo C, Weinhouse MI, et al. Design and evaluation of novel biphenyl sulfonamide derivatives with potent histamine H(3) receptor inverse agonist activity. J Med Chem. 2009 Sep 24. 52(18):5603-11. [Medline].
Josef KA, Aimone LD, Lyons J, Raddatz R, Hudkins RL. Synthesis of constrained benzocinnolinone analogues of CEP-26401 (irdabisant) as potent, selective histamine H3 receptor inverse agonists. Bioorg Med Chem Lett. 2012 Jun 15. 22(12):4198-202. [Medline].
Stocking EM, Letavic MA. Histamine H3 antagonists as wake-promoting and pro-cognitive agents. Curr Top Med Chem. 2008. 8(11):988-1002. [Medline].
Sander K, Kottke T, Stark H. Histamine H3 receptor antagonists go to clinics. Biol Pharm Bull. 2008 Dec. 31(12):2163-81. [Medline].
Medhurst SJ, Collins SD, Billinton A, Bingham S, Dalziel RG, Brass A, et al. Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain. Pain. 2008 Aug 15. 138(1):61-9. [Medline].
Bembenek SD, Keith JM, Letavic MA, Apodaca R, Barbier AJ, Dvorak L, et al. Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling. Bioorg Med Chem. 2008 Mar 15. 16(6):2968-73. [Medline].
Masaki T, Yoshimatsu H. Therapeutic approach of histamine H3 receptors in obesity. Recent Pat CNS Drug Discov. 2007 Nov. 2(3):238-40. [Medline].
Deng C, Weston-Green K, Huang XF. The role of histaminergic H1 and H3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain?. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Feb 1. 34(1):1-4. [Medline].
Beghdadi W, Porcherie A, Schneider BS, Morisset S, Dubayle D, Peronet R, et al. Histamine H(3) receptor-mediated signaling protects mice from cerebral malaria. PLoS One. 2009 Jun 23. 4(6):e6004. [Medline]. [Full Text].
Alleva L, Tirelli E, Brabant C. Therapeutic potential of histaminergic compounds in the treatment of addiction and drug-related cognitive disorders. Behav Brain Res. 2013 Jan 15. 237:357-68. [Medline].
Bhowmik M, Khanam R, Vohora D. Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives. Br J Pharmacol. 2012 Dec. 167(7):1398-414. [Medline]. [Full Text].
Vohora D, Bhowmik M. Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse. Front Syst Neurosci. 2012. 6:72. [Medline]. [Full Text].
Altenbach RJ, Adair RM, Bettencourt BM, Black LA, Fix-Stenzel SR, Gopalakrishnan SM, et al. Structure-activity studies on a series of a 2-aminopyrimidine-containing histamine H4 receptor ligands. J Med Chem. 2008 Oct 23. 51(20):6571-80. [Medline].
Kiss R, Kiss B, Könczöl A, Szalai F, Jelinek I, László V, et al. Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening. J Med Chem. 2008 Jun 12. 51(11):3145-53. [Medline].
Tiligada E, Zampeli E, Sander K, Stark H. Histamine H3 and H4 receptors as novel drug targets. Expert Opin Investig Drugs. 2009 Oct. 18(10):1519-31. [Medline].
Larbi EB. Drug-induced rhabdomyolysis. Ann Saudi Med. 1998 Nov-Dec. 18(6):525-30. [Medline].
Pelle E, McCarthy J, Seltmann H, Huang X, Mammone T, Zouboulis CC, et al. Identification of histamine receptors and reduction of squalene levels by an antihistamine in sebocytes. J Invest Dermatol. 2008 May. 128(5):1280-5. [Medline].
Devillier P, Roche N, Faisy C. Clinical pharmacokinetics and pharmacodynamics of desloratadine, fexofenadine and levocetirizine : a comparative review. Clin Pharmacokinet. 2008. 47(4):217-30. [Medline].
De Vos C, Mitchev K, Pinelli ME, Derde MP, Boev R. Non-interventional study comparing treatment satisfaction in patients treated with antihistamines. Clin Drug Investig. 2008. 28(4):221-30. [Medline].
Walsh GM. A review of the role of levocetirizine as an effective therapy for allergic disease. Expert Opin Pharmacother. 2008 Apr. 9(5):859-67. [Medline].
Scherer CR, Lerche C, Decher N, Dennis AT, Maier P, Ficker E, et al. The antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia. Br J Pharmacol. 2002 Nov. 137(6):892-900. [Medline]. [Full Text].
Soldovieri MV, Miceli F, Taglialatela M. Cardiotoxic effects of antihistamines: from basics to clinics (...and back). Chem Res Toxicol. 2008 May. 21(5):997-1004. [Medline].
Izumi N, Mizuguchi H, Umehara H, Ogino S, Fukui H. Analysis of disease-dependent sedative profiles of H(1)-antihistamines by large-scale surveillance using the visual analog scale. Methods Find Exp Clin Pharmacol. 2008 Apr. 30(3):225-30. [Medline].
Hishinuma S, Sato Y, Kobayashi Y, Komazaki H, Saito M. Intact cell binding for in vitro prediction of sedative and non-sedative histamine H1-receptor antagonists based on receptor internalization. J Pharmacol Sci. 2008 May. 107(1):66-79. [Medline].
Obradovic T, Dobson GG, Shingaki T, Kungu T, Hidalgo IJ. Assessment of the first and second generation antihistamines brain penetration and role of P-glycoprotein. Pharm Res. 2007 Feb. 24(2):318-27. [Medline].
de Leon J, Nikoloff DM. Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports. CNS Spectr. 2008 Feb. 13(2):133-5. [Medline].
Lucero ML, Arteche JK, Sommer EW, Casadesus A. Preclinical toxicity profile of oral bilastine. Drug Chem Toxicol. 2012 Jun. 35 Suppl 1:25-33. [Medline].
Bektas F, Eken C, Oktay C. Pseudoephedrine-induced paroxysmal supraventricular tachycardia: a case report. J Emerg Med. 2010 Jun. 38(5):e53-7. [Medline].
Bilici M, Turkay S, Yilmaz AE, Kurtaran H, Catal F, Tonbul A, et al. Effect of pseudoephedrine on cardiac rhythm of children with rhinitis. Indian J Pediatr. 2011 Nov. 78(11):1361-4. [Medline].
American Hospital Association (AHA) Annual Survey Database,. Fiscal Year 2003. Health Forum LLC,. One North Franklin Street, Chicago, IL 60606: Copyright 2003, .
Bryner JK, Wang UK, Hui JW, Bedodo M, MacDougall C, Anderson IB. Dextromethorphan abuse in adolescence: an increasing trend: 1999-2004. Arch Pediatr Adolesc Med. 2006 Dec. 160(12):1217-22. [Medline]. [Full Text].
Flynn CA, Griffin GH, Schultz JK. WITHDRAWN: Decongestants and antihistamines for acute otitis media in children. Cochrane Database Syst Rev. 2007 Jul 18. CD001727. [Medline].
Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015 Dec. 53 (10):962-1147. [Medline].
Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Dart RC. 2010 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 28th Annual Report. Clin Toxicol (Phila). 2011 Dec. 49(10):910-41. [Medline]. [Full Text].
Sen A, Akin A, Craft KJ, Canfield DV, Chaturvedi AK. First-generation H1 antihistamines found in pilot fatalities of civil aviation accidents, 1990-2005. Aviat Space Environ Med. 2007 May. 78(5):514-22. [Medline].
Guide for Aviation Medical Examiners: Pharmaceuticals (Therapeutic Medications) Allergy-Antihistimines. Federal Aviation Administration; October 24, 2012. 207. Available at http://www.faa.gov/about/office_org/headquarters_offices/avs/offices/aam/ame/guide/.
Kamijo Y, Soma K, Sato C, Kurihara K. Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to percutaneous cardiovascular support. Clin Toxicol (Phila). 2008 Nov. 46(9):864-8. [Medline].
Matsunaga C, Izumi S, Furukubo T, Satoh M, Yamakawa T, Uchida T, et al. Effect of famotidine and lansoprazole on serum phosphorus levels in hemodialysis patients on calcium carbonate therapy. Clin Nephrol. 2007 Aug. 68(2):93-8. [Medline].
Karpa KD, Felix TM, Lewis PR. Adverse Effects of Common Drugs: Children and Adolescents. FP Essent. 2015 Sep. 436:17-22. [Medline].
Yang M, So TY. Revisiting the safety of over-the-counter cough and cold medications in the pediatric population. Clin Pediatr (Phila). 2014 Apr. 53 (4):326-30. [Medline].
Birring SS, Kavanagh J, Lai K, Chang AB. Adult and paediatric cough guidelines: Ready for an overhaul?. Pulm Pharmacol Ther. 2015 Feb 11. [Medline].
Tashiro M, Sakurada Y, Mochizuki H, Horikawa E, Maruyama M, Okamura N, et al. Effects of a sedative antihistamine, D-chlorpheniramine, on regional cerebral perfusion and performance during simulated car driving. Hum Psychopharmacol. 2008 Mar. 23(2):139-50. [Medline].
Bebarta VS, Blair HW, Morgan DL, Maddry J, Borys DJ. Validation of the American Association of Poison Control Centers out of hospital guideline for pediatric diphenhydramine ingestions. Clin Toxicol (Phila). 2010 Jul. 48(6):559-62. [Medline].
Tobin JR, Doyle TP, Ackerman AD, Brenner JI. Astemizole-induced cardiac conduction disturbances in a child. JAMA. 1991 Nov 20. 266(19):2737-40. [Medline].
Nine JS, Rund CR. Fatality from diphenhydramine monointoxication: a case report and review of the infant, pediatric, and adult literature. Am J Forensic Med Pathol. 2006 Mar. 27(1):36-41. [Medline].
Mendoza FS, Atiba JO, Krensky AM, Scannell LM. Rhabdomyolysis complicating doxylamine overdose. Clin Pediatr (Phila). 1987 Nov. 26(11):595-7. [Medline].
Cravo M, Gonçalo M, Figueiredo A. Fixed drug eruption to cetirizine with positive lesional patch tests to the three piperazine derivatives. Int J Dermatol. 2007 Jul. 46(7):760-2. [Medline].
Köppel C, Ibe K, Tenczer J. Clinical symptomatology of diphenhydramine overdose: an evaluation of 136 cases in 1982 to 1985. J Toxicol Clin Toxicol. 1987. 25(1-2):53-70. [Medline].
Feldman MD, Behar M. A case of massive diphenhydramine abuse and withdrawal from use of the drug. JAMA. 1986 Jun 13. 255(22):3119-20. [Medline].
Gupta SK, Kantesaria B, Wang Z. Multiple-dose pharmacokinetics and safety of desloratadine in subjects with moderate hepatic impairment. J Clin Pharmacol. 2007 Oct. 47(10):1283-91. [Medline].
Frascogna N. Physostigmine: is there a role for this antidote in pediatric poisonings?. Curr Opin Pediatr. 2007 Apr. 19(2):201-5. [Medline].
[Guideline] Pediatric basic and advanced life support. 2005 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Circulation. 2005 Nov 29. 112(22 Suppl); III73-90.
Haase U, Rundshagen I. [Pharmacotherapy--physostigmine administered post-operatively]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2007 Mar. 42(3):188-9. [Medline].
Hulhoven R, Rosillon D, Letiexhe M, Meeus MA, Daoust A, Stockis A. Levocetirizine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study. Eur J Clin Pharmacol. 2007 Nov. 63(11):1011-7. [Medline].
Janssens F, Leenaerts J, Diels G, De Boeck B, Megens A, Langlois X, et al. Norpiperidine imidazoazepines as a new class of potent, selective, and nonsedative H1 antihistamines. J Med Chem. 2005 Mar 24. 48(6):2154-66. [Medline].
Kabat-Koperska J, Safranow K, Golembiewska E, Domanski L, Ciechanowski K. Creatinine clearance after cimetidine administration: is it useful in the monitoring of the function of transplanted kidney?. Ren Fail. 2007. 29(6):667-72. [Medline].
Lassaletta A, Martino R, Gónzalez-Santiago P, Torrijos C, Cebrero M, García-Frías E. Reversal of an antihistamine-induced coma with flumazenil. Pediatr Emerg Care. 2004 May. 20(5):319-20. [Medline].
[Guideline] Scharman EJ, Erdman AR, Wax PM, Chyka PA, Caravati EM, Nelson LS, et al. Diphenhydramine and dimenhydrinate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006. 44(3):205-23. [Medline].
Serio RN. Acute delirium associated with combined diphenhydramine and linezolid use. Ann Pharmacother. 2004 Jan. 38(1):62-5. [Medline].
Simons FE. Safety of levocetirizine treatment in young atopic children: An 18-month study. Pediatr Allergy Immunol. 2007 Sep. 18(6):535-42. [Medline].
Stojanovski SD, Baker SD, Casavant MJ, Hayes JR, Robinson RF, Nahata MC. Implications of diphenhydramine single-dose unintended ingestions in young children. Pediatr Emerg Care. 2007 Jul. 23(7):465-8. [Medline].
Sype JW, Khan IA. Prolonged QT interval with markedly abnormal ventricular repolarization in diphenhydramine overdose. Int J Cardiol. 2005 Mar 18. 99(2):333-5. [Medline].
Thakur AC, Aslam AK, Aslam AF, Vasavada BC, Sacchi TJ, Khan IA. QT interval prolongation in diphenhydramine toxicity. Int J Cardiol. 2005 Feb 15. 98(2):341-3. [Medline].
Yamaura K, Shigemori A, Suwa E, Ueno K. Expression of the histamine H4 receptor in dermal and articular tissues. Life Sci. 2013 Feb 7. 92(2):108-13. [Medline].