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Alkylamine Antihistamine Toxicity and Review of Pediatric Toxicology Registry of the National Association of Medical Examiners: Report 4: Alkylamines

Jumbelic, Mary I. M.D.; Hanzlick, Randy M.D.; Cohle, Steve M.D.

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From the Onondaga County Medical Examiner's Office (MIJ), Syracuse, New York; Center for Disease Control (RH), Atlanta, Georgia; and Department of Laboratory Medicine (SC), Blodgett Memorial Medical Center, Grand Rapids, Michigan, U.S.A.

Received May 4, 1995; accepted June 24, 1995.

Address correspondence and reprint requests to Dr Mary I. Jumbelic, Deputy Chief Medical Examiner, Onondaga County Medical Examiner's Office, 330 W. Onondaga Street, Syracuse, NY, 13202, U.S.A.

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Abstract

Antihistamines are popular nonprescription medications for the treatment of allergy and cold symptoms. Accidental exposures to these preparations are common with >14,000 occurring annually in children under the age of 6 years (1). Despite this, there is limited information about toxic and lethal concentrations of these drugs in children. We present a case of a pediatric fatality due to a common brompheniramine and phenylpropanolamine preparation and review available Pediatric Toxicology Registry data on alkylamine antihistamines. The data collected by the Pediatric Toxicology Registry on the drug phenylpropanolamine has been previously reported (2).

A review of the Registry data suggests that postmortem blood brompheniramine concentrations of 0.4 mg/L and greater in children is indicative of brompheniramine poisoning. However, pheniramine was also present in the blood in the same case and may have caused an additive effect. The data are insufficient to establish the threshold of fatal blood pheniramine concentration in children. Data for chlorpheniramine are lacking.

Antihistamines are H1 receptor blocking agents that reversibly and competitively bind effector cells in smooth muscle and vessels, limiting vasodilatation, capillary permeability, and tissue edema. Their success in limiting rhinorrhea and sinus congestion have made them ubiquitous remedies for allergies and the common cold. Antihistamine blockage of the H1 receptors of the central nervous system is beneficial for the treatment of nausea, motion sickness, and dystonia.

There are several classes of antihistamine compounds: alkylamines, ethanolamines, ethylenediamines, piperazines, phenothiazines, and piperidines (Table 1). They all share the basic parent chemical structure. Alkylamines, one of the most commonly used classes, have three forms: chlorpheniramine, brompheniramine, and pheniramine. Chlorpheniramine and brompheniramine are widely used with the former present in 69 and the latter in 16 preparations listed in the 1995 Physicians' Desk Reference (3) (Table 2). Chlorpheniramine is used mostly in adult preparations whereas brompheniramine is more common in pediatric preparations. Pheniramine is a more popular antihistamine in Canada where it is available in preparations of Triaminic (Sandoz, East Hanover, NJ, U.S.A.) (4).

Table 1
Table 1
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Table 2
Table 2
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Typical formulations of chlorpheniramine and brompheniramine contain 2-4 mg of the active drug with a recommended dose of 2 mg, every 4 h for children 6 to 12 years, and 4 mg every 4 h for adults. Twelve-hour preparations have concentrations of up to 12 mg/caplet. The recommended maximal daily dosage is 8 mg for children and 16 to 24 mg for adults.

Antihistamines are well absorbed from the gastrointestinal tract and the absorption is only minimally affected by food (5). The distribution and metabolism of H1 blockers have only been extensively studied in a few of the nonalkylamine chemical compounds (6).

The alkylamines are biotransformed and excreted primarily in the urine, with unchanged drug constituting 3-24% of the urinary products (7). The half-lives are long, measuring >20 h (8,9).

Antihistaminic side effects include sedation and anticholinergic symptoms. The most serious effects of high doses of antihistamines are seizures and central nervous system depression with coma, although hematological reactions such as agranulocytosis and hemolytic anemia have been reported (10). A few anecdotal cases of brompheniramine overdose have been described with symptoms of seizures, hyperactivity, coma, and facial dyskinesia (11,12). None of these reported cases included serum or tissue concentrations of the drug. Children may be more sensitive to the toxic side effects of antihistamines, which reportedly evoke seizures at lower levels than in adults (10). One study reported eight deaths in children due to antihistamine drugs but none of these were due to alkylamines (10).

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CASE REPORT

The deceased was a 1-year-old previously healthy female child found dead in her bed by her mother. An initial investigation and autopsy determined the cause of death to be sudden infant death syndrome (SIDS). Subsequent allegations of maternal neglect and overuse of Dimetapp (A.H. Robins, Richmond, VA, U.S.A.) for sedation prompted further investigation. An exhumation and second autopsy were performed. Neither autopsy revealed any anatomic abnormalities. Blood, vitreous, liver, heart muscle, skeletal muscle, and a bladder wall swab were taken at the time of the first autopsy. The source of the blood was not specified. Additional specimens were taken from formalin-fixed embalmed tissue at the second autopsy.

Assays of these specimens revealed the concentrations shown in Table 3, most importantly a blood brompheniramine concentration of 0.99 mg/L and blood phenylpropanolamine concentration of 6.3 mg/L.

Table 3
Table 3
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Criminal investigation disclosed the mother to be chronically administering Dimetapp to her four children, of which the deceased was the youngest, while she entertained men at her home. She was convicted of involuntary manslaughter by jury trial.

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PEDIATRIC TOXICOLOGY REGISTRY DATA

The Pediatric Toxicology Registry Committee was established in 1985 by the National Association of Medical Examiners (NAME). Since that time more than 500 cases have been reported to the Registry (13). The analysis of this data may be helpful in establishing toxic and lethal levels of drugs in children.

A review of the Registry database to March 1993 reveals 18 cases with alkylamines present in postmortem blood (Table 4). The mean age of decedents was 4 months (range: 1.5 to 12 months). The male to female ratio was 3.5 to 1. The cause of death was listed as SIDS in 13 cases, Reye's syndrome in 1, undetermined but suspicious of drug intoxication in 2, and drug overdose in 2. Both of the suspicious and both of the deaths attributed to drug overdose involved the drug brompheniramine (Table 4).

Table 4
Table 4
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For the five cases in which brompheniramine was detected, the blood concentration ranged from 0.05 to 0.99 mg/L. The blood concentrations of pheniramine ranged from 0.06 to 1.62 mg/L in the 15 cases in which this drug was detected, and 2 of these cases also had brompheniramine. Liver concentrations determined in 10 cases, were 0.05 to 4.2 mg/kg for brompheniramine and 0.08 to 4.10 mg/kg for pheniramine.

The liver to blood ratio was not helpful in separating deaths regarded as suspicious or due to overdose from those deaths attributed to natural causes.

Additional drugs were present in 50% of the reported cases and the majority were at nontoxic blood concentrations. Dextromethorphan and theophylline were detected in five and one cases, respectively. Acetaminophen was detected in one natural death and in one that was undetermined. Phenylpropanolamine was present in one drug overdose death at a high blood concentration (reported case) and one case that was undetermined at a moderately elevated blood concentration (0.23 mg/L). Diphenhydramine was found in one death of undetermined manner at a blood concentration of 0.11 mg/L.

In three cases, both a peripheral and central blood source were measured for drug levels. In one case sagittal sinus blood contained 0.2 mg/L and the heart contained 0.1 mg/L of brompheniramine. Pheniramine was detected in two cases that had two sources of blood; one case had a sagittal sinus blood concentration of 0.32 mg/L and heart blood concentration of 0.22 mg/L; the second yielded a concentration of 0.44 mg/L in the subclavian blood and 0.43 mg/L in the heart blood.

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DISCUSSION

There is limited information on the pharmacology of alkylamine antihistamines in children. The reported therapeutic dose of chlorpheniramine is 0.13 mg/kg with a peak blood concentration of this drug 0.012 ± 0.003 mg/L achieved at approximately 3 h after taking the oral medication (14). No pediatric therapeutic ranges have been published for brompheniramine.

It is difficult to interpret the levels reported to the Pediatric Toxicology Registry. Prior cases of alkylamine toxicity in children have not reported drug blood concentrations (11,12). Only a few fatal cases have been reported in adults and none have been reported in the literature for children. Even in the fatal adult overdoses other drugs have been present and may have been causative factors.

The Registry data on brompheniramine may be helpful in interpreting pediatric blood concentrations of this drug (see Fig. 1. The two reported Registry overdose cases had levels of 0.4 and 0.99 mg/L, which are 20 to 50 times higher than the adult steady state blood concentrations (0.02 mg/L) after 1 week of oral administration of this drug (15). Therefore, 0.4 mg/L may represent a fatal blood concentration in children. Lower blood concentrations are more difficult to interpret. One suspicious case had a blood concentration of 0.15 mg/L, whereas the other suspicious case had 0.05 mg/L in the blood. A death attributed to natural causes had a blood concentration 6.5 times greater than the adult therapeutic concentration reported in the literature (case level of 0.1 mg/L vs. therapeutic level of 0.015 mg/L) and fell between the concentrations in the two suspicious cases (16).

The Registry contains no data on blood concentrations of chlorpheniramine.

A majority of the cases reported contained the drug pheniramine, which is popular in the Canadian formulary. Only one blood concentration was below the reported 2-h postdosage concentration in adults (0.01-0.19 mg/L) (17). All the other blood concentrations of this drug exceeded adult therapeutic concentrations by factors of 2 to 15. None were as great as the fatal levels reported in adults (1.9-30 mg/L), although one case had a blood pheniramine concentration of 1.62 mg/L, which is approximately 20 times the therapeutic blood concentration (7,17). Postmortem increases in blood pheniramine concentration are a possibility and the Registry data do not allow definitive statements about toxic or fatal levels in children.

More information on antihistamine toxicity and pharmacology is available in the adult medical literature. For example, therapeutic blood concentrations for brompheniramine in adults range from 0.005 to 0.015 mg/L (16). Steady-state concentrations in adults receiving 12 mg/day range from 0.005 mg/L on day 1 to 0.02 mg/L by day 5 (15).

Adult therapeutic blood concentrations for chlorpheniramine are similar, ranging from 0.004 to 0.017 mg/L (18). Blood concentrations of pheniramine following an oral dose of 75 mg average 0.11 mg/L at 2 h (17).

A few fatal cases due to alkylamine exposure have been reported in adults: one with brompheniramine, one with chlorpheniramine, and three with pheniramine. The single case of brompheniramine involved a 55-year-old female suicide victim who ingested 30 Parnate (Smith, Kline & French, Philadelphia, PA, U.S.A.) tablets and 30 Drixoral (Schering, Kenilworth, NJ, U.S.A.) capsules (3 mg brompheniramine/capsule). Three hours later, following her death, the brompheniramine concentration in the blood was 0.2 mg/L and in the liver 4.5 mg/kg (19). The single case of chlorpheniramine overdose was in an adult man with a postmortem blood concentration of 1.1 mg/L in combination with an alcohol level of 0.12 g/dL (20). The three cases of pheniramine overdose showed blood concentrations ranging from 1.9 to 30 mg/L with an average of 14 mg/L (7,17). One of these cases involved a multiple drug overdose with methadone and barbiturates, also present at lethal levels.

The Pediatric Toxicology Registry is deficient in its current state owing to problems associated with voluntary reporting, and to regional differences in investigative, toxicologic, and death certification methods. As noted in Table 4, much of the data on pheniramine is reported from one province in Canada. No corresponding data are available from the United States.

The lack of mandatory reporting means the Registry must rely on a few conscientious offices. In addition, there is no standardization for drug testing. Investigative and circumstantial details are often not submitted with the case reports, raising questions about the thoroughness of the investigation. The accuracy of the assigned cause of death in reported cases cannot be evaluated using Registry information alone.

The Pediatric Toxicology Registry can be a useful source of information and deserves increased support by NAME members through the contribution of thoroughly investigated and reported cases.

Routine toxicology testing in cases of unexplained sudden death in infants and children is essential in establishing an accurate cause of death. Accidental (unintentional) or intentional overdose of medication should be considered in the investigation of the unexplained and sudden death of a child.

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REFERENCES

1. Litovitz T, Holm K, Bailey K, Schmitz B. Demographic profile of exposure cases by generic category of substances and products: nonpharmaceuticals. Annual Report of the American Association of Poison Control Centers National Data Collection System, 1991;477-489.

2. Hanzlick R, Davis G. National Association of Medical Examiners Pediatric Toxicology Registry, Report 1: Phenylpropanolamine. Am J Forensic Med Pathol 1992;13(I):37-41.

3. Schaefer J. Physicians' desk reference. 49th ed., Montvale, NJ: Medical Economics, 1995.

4. Krogh CM. Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993;1,256-7.

5. Chao ST, Prather D, Pinson D, Coen P, Pruitt B, Knowles M, Place V. Effect of food on bioavailability of pseudoephedrine and brompheniramine administered from a gastrointestinal therapeutic system. J Pharm Sci 1991;80:432-5.

6. Gilman AG, Goodman LS, Gilman A. The pharmacological basis of therapeutics. 6th ed. New York: Macmillan, 1980.

7. Baselt RC, Cravey RH. Disposition of toxic drugs and chemicals in man. 4th ed. Foster City, California: Chemical Toxicology Institute, 1995.

8. Paton DM, Webster DR. Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines). Clin Pharmacokinet 1985;10(VI):477-97.

9. Chiou WL, Athanikar NK, Huang S. Long half-life of chlorpheniramine. N Engl J Med 1979;300:501.

10. Wyngaarden JB, Seevers MH. The toxic effects of antihistaminic drugs. J Am Med Assoc 1951;145(V):277-82.

11. Gilmore E, Athreya BH. Recovery after accidental ingestion of a fatal dose of brompheniramine tablets. Mass Med Soc 1960;263(III):149-50.

12. Barone DA, Raniolo J. Facial dyskinesia from overdose of an antihistamine. N Engl J Med 1980;303(II):107.

13. Hanzlick R. Pediatric Toxicology Registry Contributors. NAME News 1993;1(III):1.

14. Simons FER, Luciuk GH, Simons KJ. Pharmacokinetics and efficacy of chlorpheniramine in children. J Allergy Clin Immunol 1982;69(IV):376-81.

15. Lim CC, Kim HK, Lim J, Digiore C, Symchowicz S, Gural R. Steady-state bioavailability of dexbrompheniramine and pseudoephedrine from a repeat-action combination tablet. J Pharm Sci 1985;74(I):25-8.

16. Bruce RB, Pitts JE, Pinchbeck FM. Determination of brompheniramine in blood and urine by gas-liquid chromatography. Anal Chem 1968;40(VIII):1246-50.

17. Queree EA, Dickson SJ, Missen AW, Pannell LK. Therapeutic and toxic levels of pheniramine in biological specimens. J Anal Toxicol 1979;3:253-5.

18. Peets EA, Jackson M, Symchowicz S. Metabolism of chlorpheniramine maleate in man. J Pharmacol Exp Ther 1972;180(II):464-74.

19. Baselt RC, Shaskan E, Gross EM. Tranylcypromine concentrations and monoamine oxidase activity in tissues from a fatal poisoning. J Anal Toxicol 1977;1:168-9.

20. Reed D. A fatal case involving chlorpheniramine. Clin Toxicol 1981;18(VIII):941-3.

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Keywords:

Alkylamines; Brompheniramine; Antihistamines; Toxicity; Fatality; Pediatric Toxicology Registry

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