Med. Sci. Law (1979) Vol. 19, No.4
Printed in Great Britain
265
Chloroquine Poisoning: Two Fatal Cases* R. SARVESVARAN, MB, BS(Ceylonl. DMJ (Clin), DMJ(Path) Lecturer in Forensic Medicine, Charing Cross Hospital Medical School, University of London, Fulham Palace Road, London SUMMARY
The pharmacology of chloroquine and the mechanism of death are discussed. Two cases of death in members of the nursing profession are reported. Case 2 was complicated by the absence of a helpful history and only the previous experience of acute pulmonary oedema associated with a story of a visit to a malarial district in the recent past raised the possibility of acute chloroquine poisoning.
INTRODUCTION Chloroquine was developed primarily for the treatment of malaria and was first used in Germany in 1934 under the name Resochin (Bayer). It is now also used in the treatment of amoebiasis, rheumatoid arthritis, discoid lupus erythematosis, phemphigus and lichen planus. It has also a reputation as an abortifacient. Cann and Verhulst (1961) were the first to report in the English literature three cases of fatal chloroquine poisoning in children, death occurring between 1·5 and 2·5 h after ingestion. However, the first case was recorded by Bourrelier and Lebreton (1935) in France. Up to 1977 at least 134 overdoses by chloroquine and hydroxychloroquine have been reported, more than three-quarters of these ending fatally with an approximately equal number of fatalities among men and women and with abortion attempts accounting for 18 (Good and Shader, 1977). CASE REPORTS Case 1 A 25-year-old nursing assistant from Sierra Leone was found dead on the floor of her room, an empty chloroquine (Avloclor, lCI) container near her body. Autopsy three days later showed congestion of the
• This paper was presented at the winter meeting of the British Association of Forensic Medicine on 18 November 1978.
Table I. Toxicological findings in 2 cases of fatal chloroquine poisoning Region Stomach contents Peripheral blood Liver blood Kidney
Chloroquine (mg%) Case 1 Case 2 970
6·6 5·1 86·4
59 4·5 12·5
brain, and the lungs were markedly oedematous. No other abnormality was found. Microscopic examination showed marked congestion of the lungs with alveolar oedema. The toxicological findings are given in Table 1.
Case 2 A 29-year-old nursing sister who had recently returned from a visit to India was admitted to hospital having collapsed at home. Cardiac arrest occurred. The post-mortem findings were essentially the same as in Case 1 and the toxicological findings are shown in Table 1.
PHARMACOLOGY Chemically, chloroquine is a 7-chloro-4-(4 diethylamino-1-methylbutylamino) quinoline. The quinoline ring nucleus found in the chemical structure of chloroquine is also present in the quinine molecule and its optical isomer quinidine. The quinoline nucleus and many of its derivatives possess a variety of pharmacologic actions including antemalarial and cardiovascular effects (Riseman et al., 1954). Absorption from the small bowel occurs rapidly by diffusion although there is some evidence that the drug is retained in the stomach initially (Varga, 1966). Following absorption, it is distributed to the heart, liver, spleen, kidneys, muscles and ocular tissues in high concentrations but in low concentrations in nervous tissues (J ackson and Hopkinson,
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Med. Sci. Law (1979) Vol. 19. No.4
1964). Urinary excretion is slow and intermittent, but acidification increases its output (Knox and Owens, 1966). Only 10-20 per cent is excreted unchanged in the urine. The drug, however, is largely metabolized in the body and little as such is recoverable from faecal material. COMP L1CATIONS
The side effects attributed to chloroquine include reversible corneal and irreversible retinal lesions with macular degeneration (Ebringer and Colville, 1967), others being pigmentation of the skin, alopecia, greying of the hair, leukopenia, weakness of the proximal muscles with wasting of the muscles distally and acute psychosis. The acute toxic effects of chloroquine are exerted mainly on the heart, similar to those of quinine and quinidine, possibly a factor common to the quinoline nucleus. The drug reduces the excitability and conductivity of cardiac muscle but not the velocity of the impulse and is hence a potent myocardial depressant (Hess and Schmidt, 1959). That death occurs rapidly is well recognized (Cann and Verhulst, 1961; Wilkey, 1973; Good and Shader, 1977), but the mechanism of death via cardiac effects has been documented only more recently (Magnussen and De Fine Olivarius, 1977). ECG changes have been noticed occasionally in the form of a bundle branch block in those taking chloroquine prophylactically. ECG tracings from acute chloroquine poisoning were first demonstrated by Don Michael and Aiwazzadeh (1970) as ventricular bradycardia with wide QRS complexes. Post-mortem findings are congestion and oedema of the lungs. The other features noted are cerebral oedema, cortical congestion of the kidneys and congestion of the gastric mucosa. Electron microscopic studies have indicated that chloroquine attacks mitochondria and that cardiac manifestations are due to the high concentrations of mitochondria in cardiac muscle (Magnussen and De Fine Olivarius, 1977). Pitt and Paterson (1978) detected chloroquine in tissues using thin layer and gas liquid chromatography and UV spectrophotometry and quantified it using gas liquid chromatography. No other drugs or alcohol were detected. Irvin et al. (1972), using three
Table II. Tissue levels following an estimated ingestion of 12 and 40 tablets of chloroquine (Robinson et al.,
1970)
Region Stomach contents Post-mortem blood Liver blood Kidney
Chloroquine (mg%) Case B Case A (12 tablets) (40 tablets]
1·80
1·60 9·00 7·00
55·20{125 mIl 1·24 4·40 30·00
different analytical methods on specimens obtained from a narcotic addict, found very close values for chloroquine indicating that chloroquine could be isolated and quantified accurately whether ingested singly or in combination with other drugs. Therapeutic blood levels range between 0·01 and 0·1 mg/1 00 ml of blood, with liver levels averaging between 1 and 2 mg/100 g tissue, obtained from those on a prophyla.ctic dose and dying from other causes. It is generally agreed that fatal results are to be expected with levels in excess of 1 mg/100 ml of blood. It is not possible to express accurately the number of tablets ingested from tissue levels. Robinson et al. (1970) obtained the tissue levels shown in Table II following an estimated ingestion of 12 and 40 tablets of chloroquine. CONCLUSION
Chloroquine is a lethal and effective suicidal agent. Death in most instances occurs within a few hours of ingestion and unless a history is forthcoming the task of the pathologist is difficult. It is made so by the absence of positive diagnostic findings at post-mortem examination, including scanty stomach contents and minimal microscopic findings. Hence, acute chloroquine poisoning must always be borne in mind in those having access to this drug in the differential diagnosis of cases of sudden death. ACKNOWLEDGEMENTS I thank HM Coroner Dr D. M. Paul for permission to present these cases, Professor D. A. L. Bowen for the encouragement given to me and Ms B. Sexton for her secretarial assistance. REFERENCES
Bourrelier J. and Lebreton R. (1935) Suicide par la Nivaquine. Ann. Med. Leg. 35, 221.
Sarvesvaran: Chloroquine Poisoning Cann H. M. and Verhulst H. L. (1961) Fatal acute chloroquine poisoning in children. Pediatrics 27,95. Don Michael T. A. and Aiwazzadeh S. (1970) The effects of acute chloroquine poisoning with special reference to the heart. Am. Heart}. 79,83. Ebringer A. and Colville P. (1967) Chloroquine neuromyopathy associated with keratopathy and retinopathy. Br. Med. }. 2, 219. Good M. I. and Shader R. I. (1977) Behavioural toxicity and equivocal suicide associated with chloroquine and its derivatives. Am. }. Psychiatry 7, 134. Hess M. E. and Schmidt C. F. (1959) Cardiovascular effects of chloroquine with special reference to its anti-fibrillatory action. Circ. Res. 7,87. Irvin H. M., Kyle V. L. and Diosi D. T. (1972) An overdose of chloroquine. Forens. Sci. I, 249 Jackson F. L. and Hopkinson L. (1964) Effects of chloroquine on growth and metabolism. Med. Neuro. 113,13.
267
Knox J. M. and Owens D. W. (1966) The chloroquine mystery. Arch. Dermatol. 94, 205. Magnussen I. and De Fine OIivarius B. (1977) Cardiamyopath after chloroquine treatment. Acta Med. Scand. 202, 429. Pitt A. and Paterson S. C. (1978) Personal communication. Riseman J. E. F., Steinberg L. A. and Altman G. E. (1954) Treatment of angina pectoris with cinchona alkaloids. Circulation 10,899. Robinson A. E., Coffer A. E. and Camps F. G. (1970) The distribution of chloroquine in man after fatal poisoning.}. Pharm. Pharmacal. 22, 700. Varga F. (1966) Intestinal absorption of chloroquine in rats. Arch. Int. Pbarmacodyn, Tber. 163, 38. Wilkey I. S. (1973) Chloroquine suicide. Med. }. Aust. I, 396.
France. Drunken Driving A new act provides for the use of more sophisticated breathalysers, authorizes preventive tests to check drivers' alcohol consumption and specifies the offences for which drivers may be disqualified. Any motorist causing death or physical injury while driving under the influence of alcohol or caught driving while drunk, even without causing an accident, will automatically be disqualified from driving. He will have to wait at least three years before re-sitting the driving test. The new provisions should affect only the 3 per cent of motorists who cause 40 per cent of fatal road accidents while under the influence of alcohol. It will also be possible, at the prosecuting authority's request, to check in any circumstances whether the driver of the vehicle is under the influence of alcohol by administering a breathalyser,
Printed in Great Britain
265
Chloroquine Poisoning: Two Fatal Cases* R. SARVESVARAN, MB, BS(Ceylonl. DMJ (Clin), DMJ(Path) Lecturer in Forensic Medicine, Charing Cross Hospital Medical School, University of London, Fulham Palace Road, London SUMMARY
The pharmacology of chloroquine and the mechanism of death are discussed. Two cases of death in members of the nursing profession are reported. Case 2 was complicated by the absence of a helpful history and only the previous experience of acute pulmonary oedema associated with a story of a visit to a malarial district in the recent past raised the possibility of acute chloroquine poisoning.
INTRODUCTION Chloroquine was developed primarily for the treatment of malaria and was first used in Germany in 1934 under the name Resochin (Bayer). It is now also used in the treatment of amoebiasis, rheumatoid arthritis, discoid lupus erythematosis, phemphigus and lichen planus. It has also a reputation as an abortifacient. Cann and Verhulst (1961) were the first to report in the English literature three cases of fatal chloroquine poisoning in children, death occurring between 1·5 and 2·5 h after ingestion. However, the first case was recorded by Bourrelier and Lebreton (1935) in France. Up to 1977 at least 134 overdoses by chloroquine and hydroxychloroquine have been reported, more than three-quarters of these ending fatally with an approximately equal number of fatalities among men and women and with abortion attempts accounting for 18 (Good and Shader, 1977). CASE REPORTS Case 1 A 25-year-old nursing assistant from Sierra Leone was found dead on the floor of her room, an empty chloroquine (Avloclor, lCI) container near her body. Autopsy three days later showed congestion of the
• This paper was presented at the winter meeting of the British Association of Forensic Medicine on 18 November 1978.
Table I. Toxicological findings in 2 cases of fatal chloroquine poisoning Region Stomach contents Peripheral blood Liver blood Kidney
Chloroquine (mg%) Case 1 Case 2 970
6·6 5·1 86·4
59 4·5 12·5
brain, and the lungs were markedly oedematous. No other abnormality was found. Microscopic examination showed marked congestion of the lungs with alveolar oedema. The toxicological findings are given in Table 1.
Case 2 A 29-year-old nursing sister who had recently returned from a visit to India was admitted to hospital having collapsed at home. Cardiac arrest occurred. The post-mortem findings were essentially the same as in Case 1 and the toxicological findings are shown in Table 1.
PHARMACOLOGY Chemically, chloroquine is a 7-chloro-4-(4 diethylamino-1-methylbutylamino) quinoline. The quinoline ring nucleus found in the chemical structure of chloroquine is also present in the quinine molecule and its optical isomer quinidine. The quinoline nucleus and many of its derivatives possess a variety of pharmacologic actions including antemalarial and cardiovascular effects (Riseman et al., 1954). Absorption from the small bowel occurs rapidly by diffusion although there is some evidence that the drug is retained in the stomach initially (Varga, 1966). Following absorption, it is distributed to the heart, liver, spleen, kidneys, muscles and ocular tissues in high concentrations but in low concentrations in nervous tissues (J ackson and Hopkinson,
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Med. Sci. Law (1979) Vol. 19. No.4
1964). Urinary excretion is slow and intermittent, but acidification increases its output (Knox and Owens, 1966). Only 10-20 per cent is excreted unchanged in the urine. The drug, however, is largely metabolized in the body and little as such is recoverable from faecal material. COMP L1CATIONS
The side effects attributed to chloroquine include reversible corneal and irreversible retinal lesions with macular degeneration (Ebringer and Colville, 1967), others being pigmentation of the skin, alopecia, greying of the hair, leukopenia, weakness of the proximal muscles with wasting of the muscles distally and acute psychosis. The acute toxic effects of chloroquine are exerted mainly on the heart, similar to those of quinine and quinidine, possibly a factor common to the quinoline nucleus. The drug reduces the excitability and conductivity of cardiac muscle but not the velocity of the impulse and is hence a potent myocardial depressant (Hess and Schmidt, 1959). That death occurs rapidly is well recognized (Cann and Verhulst, 1961; Wilkey, 1973; Good and Shader, 1977), but the mechanism of death via cardiac effects has been documented only more recently (Magnussen and De Fine Olivarius, 1977). ECG changes have been noticed occasionally in the form of a bundle branch block in those taking chloroquine prophylactically. ECG tracings from acute chloroquine poisoning were first demonstrated by Don Michael and Aiwazzadeh (1970) as ventricular bradycardia with wide QRS complexes. Post-mortem findings are congestion and oedema of the lungs. The other features noted are cerebral oedema, cortical congestion of the kidneys and congestion of the gastric mucosa. Electron microscopic studies have indicated that chloroquine attacks mitochondria and that cardiac manifestations are due to the high concentrations of mitochondria in cardiac muscle (Magnussen and De Fine Olivarius, 1977). Pitt and Paterson (1978) detected chloroquine in tissues using thin layer and gas liquid chromatography and UV spectrophotometry and quantified it using gas liquid chromatography. No other drugs or alcohol were detected. Irvin et al. (1972), using three
Table II. Tissue levels following an estimated ingestion of 12 and 40 tablets of chloroquine (Robinson et al.,
1970)
Region Stomach contents Post-mortem blood Liver blood Kidney
Chloroquine (mg%) Case B Case A (12 tablets) (40 tablets]
1·80
1·60 9·00 7·00
55·20{125 mIl 1·24 4·40 30·00
different analytical methods on specimens obtained from a narcotic addict, found very close values for chloroquine indicating that chloroquine could be isolated and quantified accurately whether ingested singly or in combination with other drugs. Therapeutic blood levels range between 0·01 and 0·1 mg/1 00 ml of blood, with liver levels averaging between 1 and 2 mg/100 g tissue, obtained from those on a prophyla.ctic dose and dying from other causes. It is generally agreed that fatal results are to be expected with levels in excess of 1 mg/100 ml of blood. It is not possible to express accurately the number of tablets ingested from tissue levels. Robinson et al. (1970) obtained the tissue levels shown in Table II following an estimated ingestion of 12 and 40 tablets of chloroquine. CONCLUSION
Chloroquine is a lethal and effective suicidal agent. Death in most instances occurs within a few hours of ingestion and unless a history is forthcoming the task of the pathologist is difficult. It is made so by the absence of positive diagnostic findings at post-mortem examination, including scanty stomach contents and minimal microscopic findings. Hence, acute chloroquine poisoning must always be borne in mind in those having access to this drug in the differential diagnosis of cases of sudden death. ACKNOWLEDGEMENTS I thank HM Coroner Dr D. M. Paul for permission to present these cases, Professor D. A. L. Bowen for the encouragement given to me and Ms B. Sexton for her secretarial assistance. REFERENCES
Bourrelier J. and Lebreton R. (1935) Suicide par la Nivaquine. Ann. Med. Leg. 35, 221.
Sarvesvaran: Chloroquine Poisoning Cann H. M. and Verhulst H. L. (1961) Fatal acute chloroquine poisoning in children. Pediatrics 27,95. Don Michael T. A. and Aiwazzadeh S. (1970) The effects of acute chloroquine poisoning with special reference to the heart. Am. Heart}. 79,83. Ebringer A. and Colville P. (1967) Chloroquine neuromyopathy associated with keratopathy and retinopathy. Br. Med. }. 2, 219. Good M. I. and Shader R. I. (1977) Behavioural toxicity and equivocal suicide associated with chloroquine and its derivatives. Am. }. Psychiatry 7, 134. Hess M. E. and Schmidt C. F. (1959) Cardiovascular effects of chloroquine with special reference to its anti-fibrillatory action. Circ. Res. 7,87. Irvin H. M., Kyle V. L. and Diosi D. T. (1972) An overdose of chloroquine. Forens. Sci. I, 249 Jackson F. L. and Hopkinson L. (1964) Effects of chloroquine on growth and metabolism. Med. Neuro. 113,13.
267
Knox J. M. and Owens D. W. (1966) The chloroquine mystery. Arch. Dermatol. 94, 205. Magnussen I. and De Fine OIivarius B. (1977) Cardiamyopath after chloroquine treatment. Acta Med. Scand. 202, 429. Pitt A. and Paterson S. C. (1978) Personal communication. Riseman J. E. F., Steinberg L. A. and Altman G. E. (1954) Treatment of angina pectoris with cinchona alkaloids. Circulation 10,899. Robinson A. E., Coffer A. E. and Camps F. G. (1970) The distribution of chloroquine in man after fatal poisoning.}. Pharm. Pharmacal. 22, 700. Varga F. (1966) Intestinal absorption of chloroquine in rats. Arch. Int. Pbarmacodyn, Tber. 163, 38. Wilkey I. S. (1973) Chloroquine suicide. Med. }. Aust. I, 396.
France. Drunken Driving A new act provides for the use of more sophisticated breathalysers, authorizes preventive tests to check drivers' alcohol consumption and specifies the offences for which drivers may be disqualified. Any motorist causing death or physical injury while driving under the influence of alcohol or caught driving while drunk, even without causing an accident, will automatically be disqualified from driving. He will have to wait at least three years before re-sitting the driving test. The new provisions should affect only the 3 per cent of motorists who cause 40 per cent of fatal road accidents while under the influence of alcohol. It will also be possible, at the prosecuting authority's request, to check in any circumstances whether the driver of the vehicle is under the influence of alcohol by administering a breathalyser,
