Forensic Science, 9 (1977) 53 - 62 0 Elsevier Sequoia S.A., Lausanne - Printed
FORENSIC
TOXICOLOGY
ANN E. ROBINSON, II. SATTAR
ANN.
OF
T.
Department of Forensic Medicine, London El 2AD (Ct. Britain) (Received
October
11,1976;
accepted
in the Netherlands
ORPHENADRINE-RELAT
SOME
HOLDER,
London November
R.
D.
Hospital
McDOWALL,
Medical
R.
College,
POWELL
Turner
and
Street,
16,1976)
SUMMARY Toxicological data for orphenadrine in ten cases of fatal poisoning are presented together with results for a further eight cases in which orphenadrine was present in combination with alcohol or another drug. Collapse and convulsions occur within an hour of ingestion of an overdose and death supervenes soon after. Autopsy blood concentrations of orphenadrine in such acute fatal poisonings range from 5.5537 ~.~g/ml. The unchanged drug was found in the bile and urine and the concentrations in the liver, lung and kidney, though differing between cases, were of the same order in any one case.
INTRODUCTION
Orphenadrine, N,Ndimethyl-2-(cr-o-tolylbenzyloxy)-ethylamine, is a weak parasympatholytic drug with some antihistaminic activity used in the treatment of paralysis agitans in various forms of Parkinsonism. It is usually given in tablet form, as the hydrochloride or citrate, in daily total doses of 200400 mg. It is often prescribed to control the extrapyramidal effects of some of the phenothiazine derivative tranquillisers. This paper presents toxicological data for a number iof deaths attributed with other drugs or alcohol. to orphenadrine per se and in combination
EXPERIMENTAL
Preliminary qualitative analysis of portions of urine and stomach content was carried out as described previously [l] to ascertain the nature of the drugs present. Using Merck Silica Gel G plates the Rf value for orphenadrine on chromatograms developed in (a) methanol-ammonia (100 : l.5 by volume) was 0.68 + 0.09 (b) ethylacetate-methanol-ammonia (85 : 10 : 5 by volume) was 0.70 + 0.12 and (c) benzene-dioxar-ethanol-ammonia (50 : 4 by volume) was 0.60 + 0.06.
54
The quantitative determination of orphenadrine was as follows: 5 ml of blood, urine or tissue homogenate (or 1 ml bile or stomach content) was made alkaline to pH 12 with 1 ml of N sodium hydroxide solution and extracted with 50 ml chloroform. The organic phase was filtered through Whatman No, 41 paper and, after addition of 100 @ benzhexol hydrochloride as external standard, -evaporated to dryness over a boiling water bath. The residue was reconstituted in about 50 d of ethanol and approximately 3 ,ul was injected into the gas chromatograph. Aqueous standard solutions of orphenadrine were extracted in parallel with the biological specimens. The ratio of the areas of the peaks, orphenadrine: benzhexol showed a linear relationship to the concentration of orphenadrine over the range 5-200 pg. Codeine (100 pg) was a satisfactory alternative external standard. Gas chromatography was performed using a Hewlett-Packard 5750 gas chromatograph fitted with a flame ionisation detector and 1.8 m glass column, 3.5 mm internal diameter, packed with 3.8% W-98 on 80-100 mesh AW-DMCS Chromosorb W. The oven temperature was maintained at 220 “C with the injection port at 250 “C and detector at 400 “C. Nitrogen was the carrier gas at a flow rate of 40 ml/min. Under these conditions the retention times were as follows: orphenadrine 2.1 mins, benzhexol 4.7 mins, amitriptyline 5.4 mins, codeine 9.4 mins and dothiepin 9.5 mins.
RESULTS
AND
DISCUSSION
Quantitative data for autopsy specimens from ten cases in which orphenadrine was the only drug found by preliminary qualitative analysis are presented in Table 3.. Results for a further eight cases, in which alcohol or another drug(s) was present in addition to orphenadrine are given in Table 2. Both Tables include brief case histories based upon all available information Case his tories Apart from Case 1, a child poisoned accidentally by tablets he found in a handbag and swallowed, and Case 18, in which the other drugs appear to be of greater significance in relation to the cause of death, all of the deaths appear to have followed deliberate overdosage of orphenadrine. In most, collapse, unconsciousness and convulsions followed within a short time of administration, the onset sometimes occurring in about 0.5 h. Death usually supervened within a few hours, often despite prompt resuscitative treatment in hospital. In Case 17, the orphenadrine-induced fits were not controlled by the administration of phenobarbitone or, later, of diazepam. A common feature of the past histories of many of the cases was mental illness and, frequently, the prescription of a variety of anti-depressant and tranquillising drugs. Often, orphenadrine seemed to have been given to counteract the anticipated extra-pyramidal side-effects of phenothiazine derivatives rather than in treatment of such symptoms. The comparatively
55
greater toxicity of orphenadrine compared with (say) chlorpromazine, especially in overdose, does not seem to be appreciated by prescribing physicians. Au topsy findings At autopsy, the findings in the acute fatalities included congestion of the lungs and often also of the brain. Only in Case 18, in which significant concentrations of phenobarbitone and paracetamol were present, was the survival period long enough for bronchopneumonia to have developed. In none of the cases was there evidence of sufficient natural disease to provide a cause of death. There are comparatively few published reports of orphenadrine poisoning. Heinonen and co-workers [Z] described the successful treatment in hospital of a 19 year old woman found 20 mins after ingestion of a large number of tablets containing orphenadrine and admitted deeply unconscious and having convulsions. Similar findings were noted in the ‘known’ fatal and recovered overdose cases summarised by these authors but, unfortunately, no blood. or tissue concentrations were reported. Toxicological
data
Considering the results in Table 1, it appears that a peripheral blood concentration at autopsy of about 5 Mgorphenadrinelml is consistent with an acute fatal response to administration of the drug (Cases 3, 5 and 6). The overall range of blood orphenadrine concentrations of the acute deaths was 5.5-37 &/ml; a lower level of 1.1 &ml was found in Case 10 in which death was delayed. Similarly the autopsy blood concentration of the child (Case 1) was low in comparison with that found in a sample of blood taken after admission to hospital but about 45 h before death. Alha and Korte [3] noted an autopsy blood level of 3.0 pg orphenadrine/ ml in one fatal case of poisoning. Winek [4] offers the guidance that a ‘toxic’ blood level of orphenadrine is about 2 PgIml and a ‘lethal’ concentration of the order of 4-8 ,ug/ml. There is little published information on the blood levels of orphenadrine that result from therapeutic dosage and no data for the plasma: whole blood ratio. Plasma samples, taken 2 and 4 h after a dose, from patients given 100 mg orphenadrine hydrochloride every eight hours showed concentrations ranging from ‘undetectable’ to 0.85 pg/ml, about half of the samples being found to contain approximately 0.2 yg/ml [5] ; these patients were also having 100 mg chlorpromazine every eight hours. The authors were unable to correlate the plasma level of the drug with the dose or time of administration. Unchanged orphenadrine was found in all the bile and urine samples available for analysis; the concentration in the bile alwa:ys exceeded that in the blood, often by a large factor. Some care is needed, therefore, in the
4%
2
17
24
25
26
Sex
M
M
M
M
M
1
2
3
4
5
Case No.
results
analytical
I
Quantitative
TABLE
content
Blood Liver blood Urine *Stomach content Liver Lung Spleen Kidney
Blood Urine *Stomach
Blood Liver blood Urine *Stomach content
Blood Liver blood Bile Urine *Stomach content
AM blood Urine Stomach aspirate PM blood Urine
Specimen
for the distribution
6.0 10.0 67 1.86g 110** 45 110 105
18.0 85.3 llmg
7.0 21.0 3.0 520mg
16.5 20.4 127 4.9 44mg
0.1 4.0
6mg
3.0 48
&g/ml)
Orphenadrine
of orphenadrine
specimens
from
ten cases of fatal
orphenadrine
poisoning
had been
prescribed
a variety
of drugs.
Schizophrenic from 15 y. Various drugs prescribed. Collapsed in street, admitted to hospital 0.5 h later deeply unconscious and fitting. Died 1.5 h after admission (Diagnosed as brain stem haemorrhage). Post-mortem findings were those associated with hypoxia.
History of depressive illness. Took unknown number of tablets, possibly 50, vomited 0.5 h later, had convulsions, collapsed and was admitted to hospital. Resuscitation was not successful. At autopsy the lungs were congested though the brain was not.
Deceased
Took mother’s tablets, began to twitch within 0.5 h. Admitted to hospital unconscious and fitting and had a cardiac arrest 1% h. after ingestion. EEG was flat at 24 h. Life support systems maintained for 48 h. Lungs and brain congested and tablet debris present in oesophagus and stomach at autopsy.
in autopsy
:
43
46
49
M
F
F
8
9
10
expressed
34
F
7
*Stomach content **/Jg/g for organs.
26
F
6
as total
amount
of orphenadrine
base present
1.1 0.5 0
Blood Liver blood *Stomach content
in specimen.
Long history of mental illness and one previous Had a fall and collapsed unconscious. Admitted remained in coma and died the following day. -
to
of
drug overdose. to hospital but
evidence
and admittorphenadri1.5 h after
prescribed.
Long history of mental illness. Found unconscious ed to hospital, possibly 1.5 h from an overdose of Suffered a cardiac arrest about ne, convulsing. admission to hospital. Resuscitat.ion not successful. At autopsy the lungs were congested and there was liver disease.
drugs had been
5.5 9.6 234 33 23mg
various
Blood Liver blood Bile Urine *Stomach content
history;
Psychiatric
37 53 102 122 7.5g
Blood Liver blood Bile Urine *Stomach content
Found unconscious and convulsing and died within 3 h. History of depressive illness and of previous attempts commit suicide.
Psychiatric history and had taken drug overdoses in past. Found unconscious within an hour, resuscitation attempted but brought dead to hospital about 1.5 h after taking overdose. (Orphenadrine and nitrazepam had been prescribed.) Post-mortem findings included congestion of liver, lungs, spleen and brain, occasional epicardial petechiae and agonal inhalation of vomit,
content
33 82 202 105mg 23*” 19.5 26.5 20 9.8 3.3 14 85 53 50mg
Blood Bile Urine *Stomach
Blood Liver blood Bile *Stomach content Liver R and L lung Spleen Right kidney Left kidney Brain
2
Age
27
69
30
31
Sex
F
F
M
M
11
12
13
.4
0.6
19 7 23 264 324 51mg
Heart blood Leg blood Liver blood Bile Urine *Stomach content
2.6 71 9.8 31mg
2.6 1.9 11.6
FORENSIC
TOXICOLOGY
ANN E. ROBINSON, II. SATTAR
ANN.
OF
T.
Department of Forensic Medicine, London El 2AD (Ct. Britain) (Received
October
11,1976;
accepted
in the Netherlands
ORPHENADRINE-RELAT
SOME
HOLDER,
London November
R.
D.
Hospital
McDOWALL,
Medical
R.
College,
POWELL
Turner
and
Street,
16,1976)
SUMMARY Toxicological data for orphenadrine in ten cases of fatal poisoning are presented together with results for a further eight cases in which orphenadrine was present in combination with alcohol or another drug. Collapse and convulsions occur within an hour of ingestion of an overdose and death supervenes soon after. Autopsy blood concentrations of orphenadrine in such acute fatal poisonings range from 5.5537 ~.~g/ml. The unchanged drug was found in the bile and urine and the concentrations in the liver, lung and kidney, though differing between cases, were of the same order in any one case.
INTRODUCTION
Orphenadrine, N,Ndimethyl-2-(cr-o-tolylbenzyloxy)-ethylamine, is a weak parasympatholytic drug with some antihistaminic activity used in the treatment of paralysis agitans in various forms of Parkinsonism. It is usually given in tablet form, as the hydrochloride or citrate, in daily total doses of 200400 mg. It is often prescribed to control the extrapyramidal effects of some of the phenothiazine derivative tranquillisers. This paper presents toxicological data for a number iof deaths attributed with other drugs or alcohol. to orphenadrine per se and in combination
EXPERIMENTAL
Preliminary qualitative analysis of portions of urine and stomach content was carried out as described previously [l] to ascertain the nature of the drugs present. Using Merck Silica Gel G plates the Rf value for orphenadrine on chromatograms developed in (a) methanol-ammonia (100 : l.5 by volume) was 0.68 + 0.09 (b) ethylacetate-methanol-ammonia (85 : 10 : 5 by volume) was 0.70 + 0.12 and (c) benzene-dioxar-ethanol-ammonia (50 : 4 by volume) was 0.60 + 0.06.
54
The quantitative determination of orphenadrine was as follows: 5 ml of blood, urine or tissue homogenate (or 1 ml bile or stomach content) was made alkaline to pH 12 with 1 ml of N sodium hydroxide solution and extracted with 50 ml chloroform. The organic phase was filtered through Whatman No, 41 paper and, after addition of 100 @ benzhexol hydrochloride as external standard, -evaporated to dryness over a boiling water bath. The residue was reconstituted in about 50 d of ethanol and approximately 3 ,ul was injected into the gas chromatograph. Aqueous standard solutions of orphenadrine were extracted in parallel with the biological specimens. The ratio of the areas of the peaks, orphenadrine: benzhexol showed a linear relationship to the concentration of orphenadrine over the range 5-200 pg. Codeine (100 pg) was a satisfactory alternative external standard. Gas chromatography was performed using a Hewlett-Packard 5750 gas chromatograph fitted with a flame ionisation detector and 1.8 m glass column, 3.5 mm internal diameter, packed with 3.8% W-98 on 80-100 mesh AW-DMCS Chromosorb W. The oven temperature was maintained at 220 “C with the injection port at 250 “C and detector at 400 “C. Nitrogen was the carrier gas at a flow rate of 40 ml/min. Under these conditions the retention times were as follows: orphenadrine 2.1 mins, benzhexol 4.7 mins, amitriptyline 5.4 mins, codeine 9.4 mins and dothiepin 9.5 mins.
RESULTS
AND
DISCUSSION
Quantitative data for autopsy specimens from ten cases in which orphenadrine was the only drug found by preliminary qualitative analysis are presented in Table 3.. Results for a further eight cases, in which alcohol or another drug(s) was present in addition to orphenadrine are given in Table 2. Both Tables include brief case histories based upon all available information Case his tories Apart from Case 1, a child poisoned accidentally by tablets he found in a handbag and swallowed, and Case 18, in which the other drugs appear to be of greater significance in relation to the cause of death, all of the deaths appear to have followed deliberate overdosage of orphenadrine. In most, collapse, unconsciousness and convulsions followed within a short time of administration, the onset sometimes occurring in about 0.5 h. Death usually supervened within a few hours, often despite prompt resuscitative treatment in hospital. In Case 17, the orphenadrine-induced fits were not controlled by the administration of phenobarbitone or, later, of diazepam. A common feature of the past histories of many of the cases was mental illness and, frequently, the prescription of a variety of anti-depressant and tranquillising drugs. Often, orphenadrine seemed to have been given to counteract the anticipated extra-pyramidal side-effects of phenothiazine derivatives rather than in treatment of such symptoms. The comparatively
55
greater toxicity of orphenadrine compared with (say) chlorpromazine, especially in overdose, does not seem to be appreciated by prescribing physicians. Au topsy findings At autopsy, the findings in the acute fatalities included congestion of the lungs and often also of the brain. Only in Case 18, in which significant concentrations of phenobarbitone and paracetamol were present, was the survival period long enough for bronchopneumonia to have developed. In none of the cases was there evidence of sufficient natural disease to provide a cause of death. There are comparatively few published reports of orphenadrine poisoning. Heinonen and co-workers [Z] described the successful treatment in hospital of a 19 year old woman found 20 mins after ingestion of a large number of tablets containing orphenadrine and admitted deeply unconscious and having convulsions. Similar findings were noted in the ‘known’ fatal and recovered overdose cases summarised by these authors but, unfortunately, no blood. or tissue concentrations were reported. Toxicological
data
Considering the results in Table 1, it appears that a peripheral blood concentration at autopsy of about 5 Mgorphenadrinelml is consistent with an acute fatal response to administration of the drug (Cases 3, 5 and 6). The overall range of blood orphenadrine concentrations of the acute deaths was 5.5-37 &/ml; a lower level of 1.1 &ml was found in Case 10 in which death was delayed. Similarly the autopsy blood concentration of the child (Case 1) was low in comparison with that found in a sample of blood taken after admission to hospital but about 45 h before death. Alha and Korte [3] noted an autopsy blood level of 3.0 pg orphenadrine/ ml in one fatal case of poisoning. Winek [4] offers the guidance that a ‘toxic’ blood level of orphenadrine is about 2 PgIml and a ‘lethal’ concentration of the order of 4-8 ,ug/ml. There is little published information on the blood levels of orphenadrine that result from therapeutic dosage and no data for the plasma: whole blood ratio. Plasma samples, taken 2 and 4 h after a dose, from patients given 100 mg orphenadrine hydrochloride every eight hours showed concentrations ranging from ‘undetectable’ to 0.85 pg/ml, about half of the samples being found to contain approximately 0.2 yg/ml [5] ; these patients were also having 100 mg chlorpromazine every eight hours. The authors were unable to correlate the plasma level of the drug with the dose or time of administration. Unchanged orphenadrine was found in all the bile and urine samples available for analysis; the concentration in the bile alwa:ys exceeded that in the blood, often by a large factor. Some care is needed, therefore, in the
4%
2
17
24
25
26
Sex
M
M
M
M
M
1
2
3
4
5
Case No.
results
analytical
I
Quantitative
TABLE
content
Blood Liver blood Urine *Stomach content Liver Lung Spleen Kidney
Blood Urine *Stomach
Blood Liver blood Urine *Stomach content
Blood Liver blood Bile Urine *Stomach content
AM blood Urine Stomach aspirate PM blood Urine
Specimen
for the distribution
6.0 10.0 67 1.86g 110** 45 110 105
18.0 85.3 llmg
7.0 21.0 3.0 520mg
16.5 20.4 127 4.9 44mg
0.1 4.0
6mg
3.0 48
&g/ml)
Orphenadrine
of orphenadrine
specimens
from
ten cases of fatal
orphenadrine
poisoning
had been
prescribed
a variety
of drugs.
Schizophrenic from 15 y. Various drugs prescribed. Collapsed in street, admitted to hospital 0.5 h later deeply unconscious and fitting. Died 1.5 h after admission (Diagnosed as brain stem haemorrhage). Post-mortem findings were those associated with hypoxia.
History of depressive illness. Took unknown number of tablets, possibly 50, vomited 0.5 h later, had convulsions, collapsed and was admitted to hospital. Resuscitation was not successful. At autopsy the lungs were congested though the brain was not.
Deceased
Took mother’s tablets, began to twitch within 0.5 h. Admitted to hospital unconscious and fitting and had a cardiac arrest 1% h. after ingestion. EEG was flat at 24 h. Life support systems maintained for 48 h. Lungs and brain congested and tablet debris present in oesophagus and stomach at autopsy.
in autopsy
:
43
46
49
M
F
F
8
9
10
expressed
34
F
7
*Stomach content **/Jg/g for organs.
26
F
6
as total
amount
of orphenadrine
base present
1.1 0.5 0
Blood Liver blood *Stomach content
in specimen.
Long history of mental illness and one previous Had a fall and collapsed unconscious. Admitted remained in coma and died the following day. -
to
of
drug overdose. to hospital but
evidence
and admittorphenadri1.5 h after
prescribed.
Long history of mental illness. Found unconscious ed to hospital, possibly 1.5 h from an overdose of Suffered a cardiac arrest about ne, convulsing. admission to hospital. Resuscitat.ion not successful. At autopsy the lungs were congested and there was liver disease.
drugs had been
5.5 9.6 234 33 23mg
various
Blood Liver blood Bile Urine *Stomach content
history;
Psychiatric
37 53 102 122 7.5g
Blood Liver blood Bile Urine *Stomach content
Found unconscious and convulsing and died within 3 h. History of depressive illness and of previous attempts commit suicide.
Psychiatric history and had taken drug overdoses in past. Found unconscious within an hour, resuscitation attempted but brought dead to hospital about 1.5 h after taking overdose. (Orphenadrine and nitrazepam had been prescribed.) Post-mortem findings included congestion of liver, lungs, spleen and brain, occasional epicardial petechiae and agonal inhalation of vomit,
content
33 82 202 105mg 23*” 19.5 26.5 20 9.8 3.3 14 85 53 50mg
Blood Bile Urine *Stomach
Blood Liver blood Bile *Stomach content Liver R and L lung Spleen Right kidney Left kidney Brain
2
Age
27
69
30
31
Sex
F
F
M
M
11
12
13
.4
0.6
19 7 23 264 324 51mg
Heart blood Leg blood Liver blood Bile Urine *Stomach content
2.6 71 9.8 31mg
2.6 1.9 11.6
