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Drug levels found in cases of fatal self-poisoning
Forensic Science International, 27 (1985) Elsevier Scientific Publishers Ireland Ltd.
129-133
129
DRUG LEVELS FOUND IN CASES OF FATAL SELF-POISONING
SUSAN C. PATERSON Department of Forensic Medicine and Toxicology, Fulham Palace Road, London W. 6 (U.K.)
Charing Cross Hospital
Medical School,
(Received August 14, 1984) (Accepted December 7,1984)
Summary A list of drug levels found in cases of fatal self-poisoning is presented here. These are all cases where only one drug was found and the cause of death in each case was attributed to an overdose of that particular drug. For each case a full drug screen was carried out. In general thin-layer chromatography (TLC) was used as the initial screening technique and any positive findings were then confirmed by gas liquid chromatography (GLC) and high performance liquid chromatography (HPLC). When the drug had been positively identified, the blood level was measured. Key words: Fatal drug levels
Introduction
This laboratory provides a toxicological service for pathologists performing post-mortem examinations in North and West London. Toxicological investigations are carried out on any case of suspected self-administered drug overdose or where the cause of death is not established at post-mortem. Blood levels of drugs found in single drug overdoses are presented, all multidrug overdoses including those where one drug was found but in combination with ethyl alcohol were excluded from this survey. This data was collected over the period 1975-1984. These levels were considered to have caused the death of the individual concerned only after a full postmortem and histological investigation had shown no causative or contributing factors. In each case a full toxicological screen was carried out and only the drug responsible for death was found to be present. A summary of the analytical methods used is given to show the origin of the data. Materials and methods Qualitative analysis
Normally urine and stomach contents were used for screening. After extraction, TLC was used as the initial screening technique. Any drugs indicated to be present by this method were confirmed either by GLC 0379-0738/85/$03.30
o 1985 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
130 TABLE COLUMN
1 AND INTERNAL
STANDARDS
(IS)
USED
FOR
QUANTIFICATION
__-
Drug
Column
Internal
Amitriptyline Amphetamine Amylobarbitone Barbitone Butobarbitone Chlormethiazole Chloroquine Chlorpromazine Cocaine Codeine Dextromoramide Dihydrocodeine Dothiepin Ethyl Alcohol
4% XE 60 5% KOH on 2% carbowax 20 M 3% ov 17 3% ov 17 3% ov 17 4% XE 60 3%OVl 3%OVl 4% XE 60 3%OVl 3% ov I. 3%OVl 3%OVl 0.2% carbowax 1500 on carbopac C 2%OV7 3% ov 17 2% SP 1000 3%OVl 3%OVl 3% ov 17 3%OVl 3% ov 17 3%OVl 3% ov 17 3% ov 17 3%OVl 3% ov 17 5 pm SILICA/lOO% MeOH 5% KOH on 2% carbowax 20 M 2% SP 1000
Protriptyline Phenylethylamine Hexobarbitone Quinalbarbitone Hexobarbitone Diethylpropion Dipipanone SKF 525A Tripelennamine cu-Methadol Dipipanone SKF 525A a-Methadol Propan-1-01 Prazepam n-Butryl-p-Aminophenol a-Methadol a-Methadol SKF 525A Nalorphine a-Methadol n-Butryl-p-Aminophenol a-Methadol Hexobarbitone Heptabarbitone Tripelennamine Hexobarbitone Tripelennamine Fenfluramine Chlorbutanol
3%OVl
Tripelennamine
Flurazepam Glutethimide Imipramine Maprotiline Methadone Morphine Orphenadrine Paracetamol Pentazocine Pentobarbitone Phenobarbitone Propranolol Quinalbarbitone Quinidine Tranyl cypramine Trichloroethanol (from chloral hydrate) Trimipramine
standards
using at least two columns or by GLC on one column plus HPLC on one column. The methods used were the standard methods described in any practical toxicology text book [ 1,2] . Quantitative analysis Once a drug had been positively identified by the methods described, the amount present in the blood was measured. This was usually by GLC using an internal standard. An example of this method is given by Minty et al. [3] . Table 1 shows the internal standard and column used for the drugs measured by GLC. It also shows the column and solvent used for the measurement of quinidine, the only drug quantified by HPLC.
131 TABLE 2 DRUG LEVELS FOUND IN CASES OF FATAL SELF-POISONING Drug
Route of Administration
Amitriptyline Nortriptyline
Oral from Amitriptyline Oral Oral Oral Oral Oral Oral Oral
Amphetamine Amylobarbitone Barbitone Butobarbitone Chlormethiazole Chloroquine Chlorpramazine Cocaine Codeine Cyanide Dextromoramide Dihydrocodeine Dothiepin Ethyl Alcohol (mg%) Flurazepam Glutethimide Imipramine Desipramine Maprotiline Methadone Morphine Orphenadrine Paracetamol Pentazocine Pentobarbitone Phenobarbitone Propranalol Quinalbarbitone Quinidine Salicylate Tranyl cypramine Trichloroethanol (from chloral hydrate) Trimipramine
Mean (rg/mU 8.1 1.3 0.6 27.3 430 35.1 33.5 56.0 7.9 3.1 10.9 51 0.26 9.0 21.2 489 12.4 42.0 3.9
Zal Oral i.v. Oral Oral Oral Oral Oral Oral from Imipramine Oral Oral i.v. i.v. Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral
2.8 3.5 1.1 1.9 1.0 61.6 272 121 20.2 125 103.5 20.2 25.0 841 0.21
Oral Oral
128 6.4
Range (pg/mU
No. of cases
0.5 -39.4
17
0.6 -
5 1 5 1 5 8 2 4 1 1 2 1 4 7 23 2 3 5
3.0
5.0 -53.0 19.0 8.3 45.0 0.8
-49.4 -78.0 -66.0 -27.0
12.0 -89.0 7.2 5.1 414 0.8 30.0 1.1
-12.0 -62.0 -126 - 24.0 - 56.0 - 12.5
0.322.4 1.203.0 0.192.1 8.0 -368 190 -406 7.5 48 5.1 5.0 350
- 50.0 -348 -386 - 40.8 -1700
95 -160 4.2 8.5
1 1 3 3 7 10 6 1 10 5 4 5 1 29 1 2 2
All acid drugs were derivatised by ‘on-column’ methylation with tetramethylammonium hydroxide [4] . A derivatisation method was also used for morphine quantification. The acetylated derivative was formed using acetic anhydride and pyridine. Cyanide and salicylate were measured colourmetrically [ 5,6].
132
Results Results
are shown in Table 2.
Discussion The levels presented here are intended as an aid to the interpretation of toxicological data obtained from post-mortem samples. A wealth of data on toxic and therapeutic levels measured using serum or plasma is available [7-lo]. There is less data readily available from measurements on postof toxic levels measured using serum mortem blood [9,10] . A comparison or plasma with fatal levels measured on post-mortem blood is not always strictly valid for two reasons. Firstly most drugs are not equally distributed between red cells and serum [ 111. Secondly, toxic levels are often measured on hospitalised patients who, due to supportive therapy, may tolerate higher levels than those who die without reaching hospital. For this reason, the levels given in this study are all from fatal cases which were not admitted to hospital. Except for cyanide and salicylate, data on drugs measured spectrophotometrically have been omitted as these methods tend to measure metabolite in addition to parent drug. In general, these methods have been superceded by more specific chromatographic methods, For drugs where the metabolism is known and the active metabolite available a column was selected which separated drug and metabolite. For example, amitriptyline and nortriptyline have been separated on XE60 and imipramine and desipramine on SPlOOO. The figures for the metabolites are incomplete, as often in fatal overdose cases the subject died before any significant metabolism of the drug has taken place. The main references for fatal drug levels are listed by Baselt [lo] and Stead and Moffat [9]. Both of these authors have collected together data from a wide range of sources such as the survey presented here. These references show that very little data is available for some synthetic narcotic analgesics. For example there are only blood levels for two cases of fatal dihydrocodeine overdosage reported [ 12,131, a further four are presented here. The levels listed here show a much lower minimum lethal level than those listed by Baselt for the following drugs, amitriptyline, amylobarbitone, butobarbitone, flurazepam, imipramine and phenobarbitone. In conclusion these figures should be considered as a guide to interpreting whether a drug has caused death. In every case the history, circumstances and other possible contributing facts should also be taken into account.
.Acknowledgement I would like to thank Professor D.A. Ll. Bowen, Mr. P.S.B. Minty and all other members of the department for their help and encouragement.
133
References
4 5 6 I 8 9 10 11 12 13
of Drugs, Vol. 1, The Pharmaceutical Press, E.G.C. Clarke, Isolation and Identification London, 1969. I. Sunshine, Handbook of Analytical Toxicology, CRC Press, Cleveland, Ohio, 1969. P.S.B. Minty, S.C. Paterson and T.M.T. Sheenan, Toxicological findings in nine fatal cases of propranalol overdose. Proceedings of The First Scandanauian Conference in Forensic Science, Linkoping University Press, 1980, pp. 183-188. J.W. Garrod and A.H. Beckett, Drug Metabolism in Man, Taylor and Francis Ltd., London, 1978, p. 185. Methodology for Analytical Toxicology, CRC Press, Cleveland, Ohio, I. Sunshine, 1975, pp. 114-115. I. Sunshine, Methodology for Analytical Toxicology, CRC Press, Cleveland, Ohio, 1975, pp. 342-393. Update Books Ltd., J.A. Vale and T.J. Meredith, Poisoning Diagnosis and Treatment, 1981. A. Richens and V. Marks, Therapeutic Drug Monitoring, Churchill Livingstone, 1981. R.C. Baselt, Disposition of Toxic Drugs and Chemicals in Man, Vol. 1 and Vol. 2, Biomedical Publications, Canton, Connecticut, 1978. A.H. Stead and A.C. Moffat. A collection of therapeutic toxic and fatal blood concentrations in man. Hum. Toxicol., 3 (1983) 437-464. M.D. Osselton, M.D. Hammond and A.C. Moffat, Distribution of drugs and toxic chemicals in blood. J. Forensic Sci. Sot., 20 (1980) 187-193. S. Dawling and B. Widdop, A fatal case involving dihydrocodeine. Bull. Int. Assoc. Forensic Toxicol., 16 (1981) 25-26. M.A. Peat and A. Sengupta, Toxicological investigations of csses of death involving codeine and dihydrocodeine. Forensic Sci., 9 (1977) 21-32.
129-133
129
DRUG LEVELS FOUND IN CASES OF FATAL SELF-POISONING
SUSAN C. PATERSON Department of Forensic Medicine and Toxicology, Fulham Palace Road, London W. 6 (U.K.)
Charing Cross Hospital
Medical School,
(Received August 14, 1984) (Accepted December 7,1984)
Summary A list of drug levels found in cases of fatal self-poisoning is presented here. These are all cases where only one drug was found and the cause of death in each case was attributed to an overdose of that particular drug. For each case a full drug screen was carried out. In general thin-layer chromatography (TLC) was used as the initial screening technique and any positive findings were then confirmed by gas liquid chromatography (GLC) and high performance liquid chromatography (HPLC). When the drug had been positively identified, the blood level was measured. Key words: Fatal drug levels
Introduction
This laboratory provides a toxicological service for pathologists performing post-mortem examinations in North and West London. Toxicological investigations are carried out on any case of suspected self-administered drug overdose or where the cause of death is not established at post-mortem. Blood levels of drugs found in single drug overdoses are presented, all multidrug overdoses including those where one drug was found but in combination with ethyl alcohol were excluded from this survey. This data was collected over the period 1975-1984. These levels were considered to have caused the death of the individual concerned only after a full postmortem and histological investigation had shown no causative or contributing factors. In each case a full toxicological screen was carried out and only the drug responsible for death was found to be present. A summary of the analytical methods used is given to show the origin of the data. Materials and methods Qualitative analysis
Normally urine and stomach contents were used for screening. After extraction, TLC was used as the initial screening technique. Any drugs indicated to be present by this method were confirmed either by GLC 0379-0738/85/$03.30
o 1985 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
130 TABLE COLUMN
1 AND INTERNAL
STANDARDS
(IS)
USED
FOR
QUANTIFICATION
__-
Drug
Column
Internal
Amitriptyline Amphetamine Amylobarbitone Barbitone Butobarbitone Chlormethiazole Chloroquine Chlorpromazine Cocaine Codeine Dextromoramide Dihydrocodeine Dothiepin Ethyl Alcohol
4% XE 60 5% KOH on 2% carbowax 20 M 3% ov 17 3% ov 17 3% ov 17 4% XE 60 3%OVl 3%OVl 4% XE 60 3%OVl 3% ov I. 3%OVl 3%OVl 0.2% carbowax 1500 on carbopac C 2%OV7 3% ov 17 2% SP 1000 3%OVl 3%OVl 3% ov 17 3%OVl 3% ov 17 3%OVl 3% ov 17 3% ov 17 3%OVl 3% ov 17 5 pm SILICA/lOO% MeOH 5% KOH on 2% carbowax 20 M 2% SP 1000
Protriptyline Phenylethylamine Hexobarbitone Quinalbarbitone Hexobarbitone Diethylpropion Dipipanone SKF 525A Tripelennamine cu-Methadol Dipipanone SKF 525A a-Methadol Propan-1-01 Prazepam n-Butryl-p-Aminophenol a-Methadol a-Methadol SKF 525A Nalorphine a-Methadol n-Butryl-p-Aminophenol a-Methadol Hexobarbitone Heptabarbitone Tripelennamine Hexobarbitone Tripelennamine Fenfluramine Chlorbutanol
3%OVl
Tripelennamine
Flurazepam Glutethimide Imipramine Maprotiline Methadone Morphine Orphenadrine Paracetamol Pentazocine Pentobarbitone Phenobarbitone Propranolol Quinalbarbitone Quinidine Tranyl cypramine Trichloroethanol (from chloral hydrate) Trimipramine
standards
using at least two columns or by GLC on one column plus HPLC on one column. The methods used were the standard methods described in any practical toxicology text book [ 1,2] . Quantitative analysis Once a drug had been positively identified by the methods described, the amount present in the blood was measured. This was usually by GLC using an internal standard. An example of this method is given by Minty et al. [3] . Table 1 shows the internal standard and column used for the drugs measured by GLC. It also shows the column and solvent used for the measurement of quinidine, the only drug quantified by HPLC.
131 TABLE 2 DRUG LEVELS FOUND IN CASES OF FATAL SELF-POISONING Drug
Route of Administration
Amitriptyline Nortriptyline
Oral from Amitriptyline Oral Oral Oral Oral Oral Oral Oral
Amphetamine Amylobarbitone Barbitone Butobarbitone Chlormethiazole Chloroquine Chlorpramazine Cocaine Codeine Cyanide Dextromoramide Dihydrocodeine Dothiepin Ethyl Alcohol (mg%) Flurazepam Glutethimide Imipramine Desipramine Maprotiline Methadone Morphine Orphenadrine Paracetamol Pentazocine Pentobarbitone Phenobarbitone Propranalol Quinalbarbitone Quinidine Salicylate Tranyl cypramine Trichloroethanol (from chloral hydrate) Trimipramine
Mean (rg/mU 8.1 1.3 0.6 27.3 430 35.1 33.5 56.0 7.9 3.1 10.9 51 0.26 9.0 21.2 489 12.4 42.0 3.9
Zal Oral i.v. Oral Oral Oral Oral Oral Oral from Imipramine Oral Oral i.v. i.v. Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral
2.8 3.5 1.1 1.9 1.0 61.6 272 121 20.2 125 103.5 20.2 25.0 841 0.21
Oral Oral
128 6.4
Range (pg/mU
No. of cases
0.5 -39.4
17
0.6 -
5 1 5 1 5 8 2 4 1 1 2 1 4 7 23 2 3 5
3.0
5.0 -53.0 19.0 8.3 45.0 0.8
-49.4 -78.0 -66.0 -27.0
12.0 -89.0 7.2 5.1 414 0.8 30.0 1.1
-12.0 -62.0 -126 - 24.0 - 56.0 - 12.5
0.322.4 1.203.0 0.192.1 8.0 -368 190 -406 7.5 48 5.1 5.0 350
- 50.0 -348 -386 - 40.8 -1700
95 -160 4.2 8.5
1 1 3 3 7 10 6 1 10 5 4 5 1 29 1 2 2
All acid drugs were derivatised by ‘on-column’ methylation with tetramethylammonium hydroxide [4] . A derivatisation method was also used for morphine quantification. The acetylated derivative was formed using acetic anhydride and pyridine. Cyanide and salicylate were measured colourmetrically [ 5,6].
132
Results Results
are shown in Table 2.
Discussion The levels presented here are intended as an aid to the interpretation of toxicological data obtained from post-mortem samples. A wealth of data on toxic and therapeutic levels measured using serum or plasma is available [7-lo]. There is less data readily available from measurements on postof toxic levels measured using serum mortem blood [9,10] . A comparison or plasma with fatal levels measured on post-mortem blood is not always strictly valid for two reasons. Firstly most drugs are not equally distributed between red cells and serum [ 111. Secondly, toxic levels are often measured on hospitalised patients who, due to supportive therapy, may tolerate higher levels than those who die without reaching hospital. For this reason, the levels given in this study are all from fatal cases which were not admitted to hospital. Except for cyanide and salicylate, data on drugs measured spectrophotometrically have been omitted as these methods tend to measure metabolite in addition to parent drug. In general, these methods have been superceded by more specific chromatographic methods, For drugs where the metabolism is known and the active metabolite available a column was selected which separated drug and metabolite. For example, amitriptyline and nortriptyline have been separated on XE60 and imipramine and desipramine on SPlOOO. The figures for the metabolites are incomplete, as often in fatal overdose cases the subject died before any significant metabolism of the drug has taken place. The main references for fatal drug levels are listed by Baselt [lo] and Stead and Moffat [9]. Both of these authors have collected together data from a wide range of sources such as the survey presented here. These references show that very little data is available for some synthetic narcotic analgesics. For example there are only blood levels for two cases of fatal dihydrocodeine overdosage reported [ 12,131, a further four are presented here. The levels listed here show a much lower minimum lethal level than those listed by Baselt for the following drugs, amitriptyline, amylobarbitone, butobarbitone, flurazepam, imipramine and phenobarbitone. In conclusion these figures should be considered as a guide to interpreting whether a drug has caused death. In every case the history, circumstances and other possible contributing facts should also be taken into account.
.Acknowledgement I would like to thank Professor D.A. Ll. Bowen, Mr. P.S.B. Minty and all other members of the department for their help and encouragement.
133
References
4 5 6 I 8 9 10 11 12 13
of Drugs, Vol. 1, The Pharmaceutical Press, E.G.C. Clarke, Isolation and Identification London, 1969. I. Sunshine, Handbook of Analytical Toxicology, CRC Press, Cleveland, Ohio, 1969. P.S.B. Minty, S.C. Paterson and T.M.T. Sheenan, Toxicological findings in nine fatal cases of propranalol overdose. Proceedings of The First Scandanauian Conference in Forensic Science, Linkoping University Press, 1980, pp. 183-188. J.W. Garrod and A.H. Beckett, Drug Metabolism in Man, Taylor and Francis Ltd., London, 1978, p. 185. Methodology for Analytical Toxicology, CRC Press, Cleveland, Ohio, I. Sunshine, 1975, pp. 114-115. I. Sunshine, Methodology for Analytical Toxicology, CRC Press, Cleveland, Ohio, 1975, pp. 342-393. Update Books Ltd., J.A. Vale and T.J. Meredith, Poisoning Diagnosis and Treatment, 1981. A. Richens and V. Marks, Therapeutic Drug Monitoring, Churchill Livingstone, 1981. R.C. Baselt, Disposition of Toxic Drugs and Chemicals in Man, Vol. 1 and Vol. 2, Biomedical Publications, Canton, Connecticut, 1978. A.H. Stead and A.C. Moffat. A collection of therapeutic toxic and fatal blood concentrations in man. Hum. Toxicol., 3 (1983) 437-464. M.D. Osselton, M.D. Hammond and A.C. Moffat, Distribution of drugs and toxic chemicals in blood. J. Forensic Sci. Sot., 20 (1980) 187-193. S. Dawling and B. Widdop, A fatal case involving dihydrocodeine. Bull. Int. Assoc. Forensic Toxicol., 16 (1981) 25-26. M.A. Peat and A. Sengupta, Toxicological investigations of csses of death involving codeine and dihydrocodeine. Forensic Sci., 9 (1977) 21-32.