Clinical Toxicology Downloaded from informahealthcare.com by University of Newcastle on 12/28/14 For personal use only.
CLINICAL TOXICOLOGY 8(3), pp. 271-275 (1975)
A Fatal Case Involving Propranolol and Codeine
J. E. TURNER and R H. CRAVEY
Office of the Sheriff-Coroner Toxicology Laboratory Santa Ana, California
Suicide cases frequently involve a multiplicity of drugs. While i t may be easier to evaluate tissue concentrations in cases where a single drug is involved, interpretation is also possible in cases of multiple drug ingestion where each is taken in a meaningful quantity. This case involves the ingestion of propranolol, a beta-adrenergic receptor blocking agent, and codeine, an analgesic. CASE HISTORY A 38-year-old female, diagnosed as schizophrenic, left a mental hospital without permission and returned home. According to hospital notes, she had attempted suicide on several occasions prior to hospitalization. When she was found, there were empty medication bottles in the vicinity of the body, which had contained Inderal (propranolol), codeine (methylmorphine), and Cogentin (benztropine). PATHOLOGY Except for mild pulmonary edema, no significant pathologic findings were noted. 271 Copyright 0 1975 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
TURNERANDCRAVEY
272
TABLE 1. Drug Concentrations Found in a Fatal Case ~~
Clinical Toxicology Downloaded from informahealthcare.com by University of Newcastle on 12/28/14 For personal use only.
Specimen
Propranolol
Blood"
16
Liver"
254
Brain"
41
Kidneya
71
Lune
62
Urine"
2
GastricC
320 mg
Codeine
Salicylate
180 mg
16 mg
a
Values given are in ,ug/ml o r gm. bn/d = not determined. CRecovery from total gastric contents. TOXICOLOGIC FINDINGS A systematic analysis of the viscera revealed the presence of salcylate, codeine, and propranolol (Table 1). Thin-layer chromatography and ultraviolet spectroscopy were utilized in screening procedures. Codeine and propranolol were quantitated by gas chromatography utilizing the Beckman Clinascreen equipped with a flame ionization detector and a Beckman ?'base" column. Conditions were as follows: Inlet temperature: 275°C Detector temperature: 275"C Column temperature: 220°C C a r r i e r gas flow rate: 40 cc/min, helium Relative retention times under these conditions were: Propranolol 2.4 min 6.0 min Codeine Promazine 4.2 min (internal standard) Propranolol was also detected and quantitated by ultraviolet spectrophotometry. After tissue extraction with chloroform from a basic medium, followed by extraction of the chloroform layer with 0.2 N sulfuric acid, the acid layer was scanned from 340 to 110 nm. Maximum absorptivity was observed at 288, 304, and 318 nm (Fig. 1). The maximum absorptivity does not significantly change in 0.5 N sodium hydroxide.
Clinical Toxicology Downloaded from informahealthcare.com by University of Newcastle on 12/28/14 For personal use only.
PROPRANOLOL AND CODEINE
FIG. 1. Ultraviolet spectrum of propranolol. 2 73
TURNER AN’Q CRAVEY
274
Clinical Toxicology Downloaded from informahealthcare.com by University of Newcastle on 12/28/14 For personal use only.
DISCUSSION When propranolol is taken in doses greater than therapeutic, the drug is said to exert a quinidine-like or anesthetic-like action that depresses cardiac function [ 11. However, Boakes and Boeree [ 21 point out that large doses have been administered without ill effect after gradual titration. Zacharias and Cowen [3] found that more than 15% of their hypertensive patients required 1 gm or more daily. Kincaid-Smith et al. [ 41 report using doses up to 2 gm daily, and Pritchard [ 51 found some patients who required up to 4 gm daily. Therapeutic plasma concentrations of propranolol have been reported as ranging from 0.036 to 0.212 pg/ml following oral administration of 80 mg [ 61. An attempted suicide reported by Wermut and Wojcincki [ 7 ] involved a 45-year-old male who ingested 2 gm of propranolol and arrived at the hospital several hours later in good condition. They claim that the massive dose produced no signs of depression on the heart and concluded that the effects of the drug on the healthy heart need to be reconsidered. Robinson [ 81 analyzed tissue from a fatal case thought to have ingested 3.6 gm of propranolol and found a blood concentration of 8.0 pg/ml. No other drugs or toxic substances were found, and death was attributed to propranolol. Schmerzler et al. [ 91 have reported plasma concentrations ranging from 0.026-0.033 pg/ml following the oral administration of 15 mg of codeine. According to Clarke [lo], rather large overdoses do not produce the degree of central nervous system depression character istic of morphine, and it is to this that he attributes the lack of fatal case data in the literature. Winek and Collom [ 111 reported a fatal codeine ingestion in which 9.3 pg/ml was found in the bile, but other drugs were found that may have been contributory. In a recent case in which 1.5 g m of codeine was thought to have been ingested, we found the following concentrations: blood, 11 pg/ml; liver, 160 pg/gm; bile 103 pg/ml; and 78 mg recovered from the total gastric. Since high concentrations of secobarbital, amobarbital, and pentobarbital were also found in the tissue, death was attributed to the drugs in combination. Since the propranolol blood level in the case reported here was at least eight times therapeutic, and the blood codeine level was as much as 400 times greater than therapeutic, the cause of death was attributed to the combined effects of both drugs.
PROPRANOLOL AND CODEINE
275
SUMMARY
Clinical Toxicology Downloaded from informahealthcare.com by University of Newcastle on 12/28/14 For personal use only.
Tissue concentrations are given in a fatal case involving both propranolol and codeine. Methods for the detection and quantitation of the compounds are briefly described. REFERENCES Product Report, Ayerst Laboratories, New York. 5893, 675 A. J. Boakes and B. H. Boeree, Brit. Med. J., (1973).
,
F. J. Zacharias and K. J. Cowen, Brit. Med. J., A, 491 (1970). P. Kincaid-Smith, P. Fang, andM. C. Laver, Clin. Sci. Mol. 4 3 758 (1973). .Med N. B. C. Pritchard, Brit. J. Hosp. Med., lo,45 (1973). D. G. Shand, E. N. Nuckolls, and J. A. Oates, Clin. Pharm. Therap., G, 112 (1970). W, Wermut and M. Wojcincki, Brit. Med. J., 5880, 591 (1973). R. Robinson, personal communication, 1973. E. Schmerzler, W. Yu, M. I. Hewitt, and I. J. Greenblatt, J. Pharm. Sci., g,155 (1966). E. G. C. Clarke, Isolation and Identification of Drugs, Pharmaceutical Press, London, 1969. C. L. Winek and W. D. Collom, Clin. Toxicol., 3, 97 (1970).
CLINICAL TOXICOLOGY 8(3), pp. 271-275 (1975)
A Fatal Case Involving Propranolol and Codeine
J. E. TURNER and R H. CRAVEY
Office of the Sheriff-Coroner Toxicology Laboratory Santa Ana, California
Suicide cases frequently involve a multiplicity of drugs. While i t may be easier to evaluate tissue concentrations in cases where a single drug is involved, interpretation is also possible in cases of multiple drug ingestion where each is taken in a meaningful quantity. This case involves the ingestion of propranolol, a beta-adrenergic receptor blocking agent, and codeine, an analgesic. CASE HISTORY A 38-year-old female, diagnosed as schizophrenic, left a mental hospital without permission and returned home. According to hospital notes, she had attempted suicide on several occasions prior to hospitalization. When she was found, there were empty medication bottles in the vicinity of the body, which had contained Inderal (propranolol), codeine (methylmorphine), and Cogentin (benztropine). PATHOLOGY Except for mild pulmonary edema, no significant pathologic findings were noted. 271 Copyright 0 1975 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
TURNERANDCRAVEY
272
TABLE 1. Drug Concentrations Found in a Fatal Case ~~
Clinical Toxicology Downloaded from informahealthcare.com by University of Newcastle on 12/28/14 For personal use only.
Specimen
Propranolol
Blood"
16
Liver"
254
Brain"
41
Kidneya
71
Lune
62
Urine"
2
GastricC
320 mg
Codeine
Salicylate
180 mg
16 mg
a
Values given are in ,ug/ml o r gm. bn/d = not determined. CRecovery from total gastric contents. TOXICOLOGIC FINDINGS A systematic analysis of the viscera revealed the presence of salcylate, codeine, and propranolol (Table 1). Thin-layer chromatography and ultraviolet spectroscopy were utilized in screening procedures. Codeine and propranolol were quantitated by gas chromatography utilizing the Beckman Clinascreen equipped with a flame ionization detector and a Beckman ?'base" column. Conditions were as follows: Inlet temperature: 275°C Detector temperature: 275"C Column temperature: 220°C C a r r i e r gas flow rate: 40 cc/min, helium Relative retention times under these conditions were: Propranolol 2.4 min 6.0 min Codeine Promazine 4.2 min (internal standard) Propranolol was also detected and quantitated by ultraviolet spectrophotometry. After tissue extraction with chloroform from a basic medium, followed by extraction of the chloroform layer with 0.2 N sulfuric acid, the acid layer was scanned from 340 to 110 nm. Maximum absorptivity was observed at 288, 304, and 318 nm (Fig. 1). The maximum absorptivity does not significantly change in 0.5 N sodium hydroxide.
Clinical Toxicology Downloaded from informahealthcare.com by University of Newcastle on 12/28/14 For personal use only.
PROPRANOLOL AND CODEINE
FIG. 1. Ultraviolet spectrum of propranolol. 2 73
TURNER AN’Q CRAVEY
274
Clinical Toxicology Downloaded from informahealthcare.com by University of Newcastle on 12/28/14 For personal use only.
DISCUSSION When propranolol is taken in doses greater than therapeutic, the drug is said to exert a quinidine-like or anesthetic-like action that depresses cardiac function [ 11. However, Boakes and Boeree [ 21 point out that large doses have been administered without ill effect after gradual titration. Zacharias and Cowen [3] found that more than 15% of their hypertensive patients required 1 gm or more daily. Kincaid-Smith et al. [ 41 report using doses up to 2 gm daily, and Pritchard [ 51 found some patients who required up to 4 gm daily. Therapeutic plasma concentrations of propranolol have been reported as ranging from 0.036 to 0.212 pg/ml following oral administration of 80 mg [ 61. An attempted suicide reported by Wermut and Wojcincki [ 7 ] involved a 45-year-old male who ingested 2 gm of propranolol and arrived at the hospital several hours later in good condition. They claim that the massive dose produced no signs of depression on the heart and concluded that the effects of the drug on the healthy heart need to be reconsidered. Robinson [ 81 analyzed tissue from a fatal case thought to have ingested 3.6 gm of propranolol and found a blood concentration of 8.0 pg/ml. No other drugs or toxic substances were found, and death was attributed to propranolol. Schmerzler et al. [ 91 have reported plasma concentrations ranging from 0.026-0.033 pg/ml following the oral administration of 15 mg of codeine. According to Clarke [lo], rather large overdoses do not produce the degree of central nervous system depression character istic of morphine, and it is to this that he attributes the lack of fatal case data in the literature. Winek and Collom [ 111 reported a fatal codeine ingestion in which 9.3 pg/ml was found in the bile, but other drugs were found that may have been contributory. In a recent case in which 1.5 g m of codeine was thought to have been ingested, we found the following concentrations: blood, 11 pg/ml; liver, 160 pg/gm; bile 103 pg/ml; and 78 mg recovered from the total gastric. Since high concentrations of secobarbital, amobarbital, and pentobarbital were also found in the tissue, death was attributed to the drugs in combination. Since the propranolol blood level in the case reported here was at least eight times therapeutic, and the blood codeine level was as much as 400 times greater than therapeutic, the cause of death was attributed to the combined effects of both drugs.
PROPRANOLOL AND CODEINE
275
SUMMARY
Clinical Toxicology Downloaded from informahealthcare.com by University of Newcastle on 12/28/14 For personal use only.
Tissue concentrations are given in a fatal case involving both propranolol and codeine. Methods for the detection and quantitation of the compounds are briefly described. REFERENCES Product Report, Ayerst Laboratories, New York. 5893, 675 A. J. Boakes and B. H. Boeree, Brit. Med. J., (1973).
,
F. J. Zacharias and K. J. Cowen, Brit. Med. J., A, 491 (1970). P. Kincaid-Smith, P. Fang, andM. C. Laver, Clin. Sci. Mol. 4 3 758 (1973). .Med N. B. C. Pritchard, Brit. J. Hosp. Med., lo,45 (1973). D. G. Shand, E. N. Nuckolls, and J. A. Oates, Clin. Pharm. Therap., G, 112 (1970). W, Wermut and M. Wojcincki, Brit. Med. J., 5880, 591 (1973). R. Robinson, personal communication, 1973. E. Schmerzler, W. Yu, M. I. Hewitt, and I. J. Greenblatt, J. Pharm. Sci., g,155 (1966). E. G. C. Clarke, Isolation and Identification of Drugs, Pharmaceutical Press, London, 1969. C. L. Winek and W. D. Collom, Clin. Toxicol., 3, 97 (1970).
