Download The features and management of poisoning with drugs used to treat

Q J Med 1997; 90:613-616
Review
QJM
The features and management of poisoning with drugs used
to treat Parkinson's disease
A.L. JONES and A.T. PROUDFOOT
Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh NHS Trust, Edinburgh, UK
Introduction
Drugs used in the treatment of patients with
Parkinson's disease are occasionally taken in overdose. This review summarizes world-wide experience
of poisoning with such drugs, and their features in
overdosage, as no clinician will have seen a large
number of cases, that the recognition and management of such rare cases may be optimized.
Benzhexol and benztropine
Benzhexol and benztropine are anticholinergic
agents used as adjuncts in the treatment of
Parkinson's disease. Toxicity is due to both peripheral
and central anticholinergic effects. The peripheral
symptoms of overdose include nausea, dizziness,
blurred vision, a dry mouth and urinary retention,
and signs include hyperpyrexia, dilated pupils, dry
mouth and skin, flushed faces, tachycardia and a
distended bladder. Central nervous system manifestations include excitement, confusion, restlessness,
paranoid ideation and euphoria. Vivid visual hallucinations and a feeling that time is 'standing still'
are said to be especially prominent symptoms.1'2
Tactile hallucinations and actions such as gathering,
grasping or plucking imaginary objects from the air
have also been described3'4 as well as auditory
hallucinations.5'6 These features are sometimes
referred to as the central anticholinergic syndrome,
and not surprisingly bring the patient to public
attention within a few hours of a large overdose.1
Acute dystonia has been reported following benztrop-
ine ingestion by a 20-month-old boy7 and after an
overdose of benztropine and alcohol in an adult.6 A
30-year-old man took an overdose of benztropine
mesylate and developed an anticholinergic syndrome
which lasted nine days. Fluctuating serum benztropine concentrations over that time suggested that his
lengthy intoxication may have been secondary to
prolonged, intermittent absorption rather than from
slow plasma clearance.8 One death has been
reported due to benzhexol toxicity in a 48-year-old
schizophrenic male, however death may have
resulted from the underlying bronchopneumonia and
empyema.9
The management of benzhexol and benztropine
overdoses is supportive. Gastric lavage is indicated
only if a substantial overdose has been ingested
within 1-2 h of presentation. In view of the potent
anticholinergic action of the drugs which delay
gastric emptying, some toxicologists recommend
extension of gastric lavage time up to 4 h. The
anticholinergic effects can be reversed by slow
intravenous injection of 2 mg physostigmine.
However, increased bronchial secretions, bronchospasm and convulsions10 may be provoked by its
use and as the duration of action of physostigmine
averages 30 min to 2 h and benztropine and
benzhexol have a considerably longer half-life, toxic
manifestations may recur. For these reasons the use
of physostigmine has been abandoned. Experience
has shown that it is better to handle patients with
reassurance, rather than drugs; if sedation is needed,
diazepam is the drug of choice.
Address correspondence to Dr A.L. Jones, Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh NHS Trust,
1 Lauriston Place, Edinburgh EH3 9YW
© Oxford University Press 1997
614
A.L. Jones and A.T. Proudfoot
Orphenadrine
Orphenadrine has been used as a skeletal muscle
relaxant, in the treatment of Parkinson's disease and
to overcome the Parkinsonian side-effects of phenothiazines.11 Up to 1981, 271 cases of orphenadrine
overdose (including 37 deaths) were described by
Sangster.12 Both adults and children have died following poisoning. 13 ' 14
The features of overdose are predominantly anticholinergic. Within 2 h of ingestion of an overdose,
coma, mydriasis, loss of pupil reactivity and tachycardia can develop.15 Urinary retention and hot dry
skin are also anticholinergic features, but occur
slightly later. Athetosis and hypothermia have been
described.16 More serious effects include convulsions, respiratory depression and cardiac arrhythmias,
and death may ensue within 12-18 h of ingestion. 17 ' 18 Orphenadrine has a negative inotropic effect
on the myocardium and can slow cardiac conduction. 16 ' 19 Arrhythmias may be worsened by the presence of hypoxia and have been fatal 12-18 h after
ingestion. Hypoglycaemia, prolongation of the
prothrombin time, abnormal liver function tests
resulting from hepatic necrosis, and disseminated
intravascular coagulation have been reported occasionally after overdose. Post-mortem findings have
included cerebral and pulmonary oedema.14
Management is supportive, but as there can be
marked cardiorespiratory depression, assisted ventilation may be required. Gastric lavage is indicated
only if a substantial overdose has been ingested
within 1-2 h of presentation. The value of activated
charcoal, forced diuresis, haemodialysis, peritoneal
dialysis or haemoperfusion has not been fully
assessed and therefore none of these is recommended.20
Apart from its adverse effects, arrhythmias are
almost certainly the result of the direct cardiotoxicity
of orphenadrine rather than its anticholinergic
actions.19 They should be treated only when causing
significant haemodynamic impairment. The role of
physostigmine in the management of orphenadrine
cardiotoxicity is very controversial. It was used in a
3-year-old boy with ventricular tachycardia which
was unresponsive to cardioversion and was successful, 21 but is not routinely recommended because of
the adverse effects noted above. External cardiac
pacing may be ineffective for treatment of arrhythmias
because of the depressant action of orphenadrine on
myocardial excitation. Orphenadrine concentrations
can be measured using GLC or HPLC,22'23 but are of
no help in management.
Amantadine
Amantadine is dopaminergic and weakly anticholinergic. It is an N-methyl-D-aspartate receptor antag-
onist with neuroprotective properties.24 Ninety per
cent of a therapeutic dose is excreted unchanged in
the urine and intoxication has been reported in
patients as a result of renal insufficiency.25'26
The features of overdosage are largely cardiovascular and neurological. 27 Doses of 800 mg have
been associated with convulsions in adults.27 An
adult who took approximately 2.8 g amantadine
developed an acute toxic psychosis with disorientation, visual hallucinations, aggression and urinary
retention and dilated pupils. 28 Another patient
ingested 1.3 g and developed altered mental status
and complex
ventricular
arrhythmias
which
responded to intravenous lignocaine.29
Management of a patient with toxicity from amantadine is supportive. Gastric lavage is indicated if a
potentially life-threatening amount has been ingested
within the previous 1-2 h. Benzodiazepine therapy
should be used for sedation or control of convulsions.
Use of physostigmine reversed amantadine-induced
confusion and myoclonus in one patient,30 but would
not normally be expected to be used for the reasons
discussed above. The large volume of distribution of
amantadine would indicate that haemodialysis is
unlikely to increase drug elimination effectively.
Levodopa
L-dopa is converted by dopa decarboxylase to dopamine, an active catecholamine with prominent alphaand beta-adrenergic effects, and toxicity appears to
be a direct effect and also receptor-mediated.31
There are few reports of acute overdose in the
literature. A 61-year-old man (on 7.5 g levodopa
daily) ingested up to 100g levodopa together with
alcohol over a period of 12 h. Initial hypertension
was followed by prolonged symptomatic hypotension, sinus tachycardia, mental confusion, agitation,
insomnia and anorexia.32 Nausea, vomiting, dyskinesia, arrhythmias and renal and hepatic damage were
not encountered. Improvement began on the second
day, but it was 7 days before features finally disappeared. Analyses of serum and urine for dopa and
its metabolites confirmed the overdose. One patient
died after the ingestion of 11 g levodopa, but there
was no definite evidence that levodopa was the
cause of death.33
Supportive measures should be used, with gastric
lavage if the patient presents within 1-2 h of ingestion of a large amount of levodopa. The cardiac
rhythm should be monitored. Pyridoxine (vitamin
B6) 50 mg tds acts as a co-factor for dopadecarboxylase, and reverses the neurotoxicity of
levodopa by increasing its peripheral decarboxylation. 34
Drugs and Parkinson's disease
Levodopa with benserazide
Dopa decarboxylase, the enzyme responsible for
peripheral metabolism of L-dopa, is inhibited by
benserazide. No data on overdosage with levodopa/
benserazide combinations are available. However, it
would be expected that the presence of benserazide
would enhance the central toxicity of levodopa,
leading to postural hypotension and psychiatric disturbances. The peripheral effects of levodopa, such
as nausea, vomiting and cardiac arrhythmias, would
be expected to be less than with levodopa alone.
Overdosage of benserazide with levodopa should
be managed with supportive measures, as for levodopa alone with the exception that pyridoxine
(Vitamin B6) has no benefit when benserazide has
been taken in addition to L-dopa.
Levodopa with carbidopa
Carbidopa is also a dopa decarboxylase inhibitor.
There are few reports of overdosage with the combination of L-dopa and carbidopa.
A 57-year-old woman ingested approximately
2.25 g carbidopa and 22.5 g levodopa in a combined
formulation along with unknown amounts of ibuprofen, carisprodol, hydrocodeine, and paracetamol.
Choreiform movements developed and persisted despite impairment of consciousness. Paralysis with
pancuronium was necessary for their control. 35
Tachycardia was present for 5 days, but the blood
pressure was not affected. The management of an
acute combined overdose of levodopa with carbidopa is as for levodopa with the exception that
pyridoxine (vitamin B6) has no benefit when carbidopa has been taken in addition to L-dopa.
Bromocriptine
Bromocriptine is a potent dopaminergic agonist.
Features of overdose include nausea and vomiting, 36 " 38 due to stimulation of the vomiting centre
and to a local effect on the gastrointestinal tract.38
Other symptoms include drowsiness,38'39 dizziness,37
sweating36 and hallucinations. 36 ' 37 Tachycardia,
pupillary dilatation, tachypnoea and hypotension
may occur.36'38 The systemic hypotension is probably
due to stimulation of peripheral dopamine receptors
and pupillary dilatation is presumed to be a sympathomimetic effect.38
Adults have taken 225 mg 37 and babies up to
7.5 mg 38 without dangerous effects. None of 18
accidental ingestions in children resulted in a fatality.38 Bromocriptine is rapidly and completely
absorbed, peak blood levels occurring within 2-3 h
after oral administration after a therapeutic dose.
615
Symptomatic management is all that is required.
In view of the potent emetic effect of the drug,
gastric lavage would not be expected to be useful
unless an extremely large number of tablets have
been ingested within 1-2 h. An antiemetic may be
given if vomiting is recurrent and persistent. Postural
hypotension is best treated with bed rest, elevation
of the foot of the bed and intravenous fluids if
necessary. Inotropic agents would not be expected
to be required.
Conclusions
Patients who have taken overdoses of antiparkinsonian agents require meticulous supportive care. Such
agents produce toxicity by either dopaminergic or
anticholinergic actions or both. It is important to
monitor patients for development of complications
of poisoning, i.e. arrhythmias, convulsions and a
distended bladder. Gastric lavage is indicated if a
substantial overdose has been ingested within 1-2 h
of presentation. Benzodiazepine agonists should be
used to control convulsions or for sedation.
Arrhythmias should only be treated if they cause
haemodynamic disturbance. The anticholinergic
effects can be reversed by physostigmine but bronchial secretions, bronchospasm and convulsions may
be promoted and thus its use has been abandoned.
The only antidote of any value appears to be vitamin
B6 for L-dopa overdose alone. Such an occurrence
is however very rare, as most L-dopa is likely
to be prescribed in combination with a dopadecarboxylase inhibitor.
There is diversity in the toxicity of the various
agents described in this review. Most deaths resulted
from orphenadrine overdosage, but no large overdose
with antiparkinsonian agents can be taken lightly. If
in doubt about the management of a particular
patient, please telephone your nearest centre of the
National Poisons Information Service.
References
1. Stephens DA. Psychotoxic effects of benzhexol
hydrochloride. BrJ Psychiatr] 967; 113:213-18.
2. MacVicar K. Abuse of antiparkinsonism drugs by psychiatric
patients. Am J Psychiatr 1977; 134:809-11.
3. Ananth JV, Jain RC. Benztropine psychosis. Can Psychiatr
AssocJ 1973; 18:409-14.
4. Woody CE, O'Brien CP. Anticholinergic toxic psychosis in
drug abusers treated with benztropine. Compr Psychiatry
1974; 15:439-42.
5. Kaminer Y, Munitz H, Wijsenbeek H. Trihexphenidyl
(Artane) abuse: euphoriant and anxiolytic. BrJ Psychiatr
1982; 140:473-4.
6. Humphreys A, Tanner AR. Acute dystonic drug reaction or
616
A.L. Jones and A.T. Proudfoot
tetanus? An unusual consequence of 'Whizz' overdose.
Hum Exp Toxicol 1994; 13:311-12.
determination of orphenadrine in human body fluids.
J Chromatogr 1977; 144:201 - 8 .
7. Howrie DL, Rowley AH, Krenzelok EP. Benztropineinduced acute dystonic reaction. Ann Emerg Med 1986;
15:594-6.
23. Furlanut M, Bettio D, Bertin I, Colombo C, Benetello P.
Orphenadrine serum levels in a poisoned patient. Human
Toxicol 1985; 4:331-3.
8. Fahy P, Arnold P, Curry SC, Bond R. Serial serum drug
concentrations and prolonged anticholinergic toxicity and
benztropine overdose. Am) Emerg Med 1989; 7:199-202.
24. Kornhuber J, Weller M, Schoppmeyer K, Riederer P.
Amantadine and memantine are NMDA receptor
antagonists with neuroprotective properties. J Neural Transm
Suppl 1994; 43:91-104.
9. Call JA, Drummer OH, Landgren AJ. Death due to
benzhexol toxicity. Forensic Sci Int 1995; 71:9-14.
10. Walker WE, Levy RC, Hanenson IB. Physostigmine—its use
and abuse. JACEP1976; 5:436-9.
11. Millar WM. Deaths after overdoses of orphenadrine. Lancet
1977; 2:566.
12. Sangster B. Orphenadrine intoxication. Ceneesmiddelen
Bulh 982; 12:53-6.
13. Tompsett SL. Death of a child aged 13 months from
orphenadrine poisoning. Bull Int Ass Forens Toxicol 1969;
6:2.
14. Bosche J, Mallach HJ. Uber anatomische und chemisch
toxicologische Befunde bei einer todlichen Vergiftung durch
Orphenadrin. Arch Toxikol 1969; 25:76-82.
15. Deceuninck F, Silverman RM, Veltman JCJ. A patient with
psychosis following orphenadrine poisoning. Ned Tijdschr
Geneesk 1973; 117:25-7.
16. Bozza-Marrubini M, Frigerio A, Chezzi R, Parelli L, Restelli
L, Selenati A. Two cases of severe orphenadrine poisoning
with atypical features. Acta Pharmacol Toxicol 1977:41
(suppl 2):137-52.
17. Sangster B, Van Heijst ANP, Zimmerman AN, de Vries HW.
Intoxication by orphenadrine HCI: Mechanism and therapy.
Acta Pharmacol Toxicol 1977; 41 (suppl 2):129-36.
18. Heinonen J, Heikkila J, Mattila MJ. Orphenadrine poisoning.
A case report supplemented with animal experiments. Arch
Toxicol 1968; 23:264-72.
19. Sangster B, Van Heijst ANP, Zimmerman AN. Treatment of
orphenadrine overdose. N EnglJ Med 1977; 296:1006.
20. Sangster B, Van Heijst ANP, Zimmerman ANE. Vergiftiging
door orphenadrine (Disipal). Ned Tijdschr Geneesk 1978;
122:988-92.
21. Danze LK, Langdorf Ml. Reversal of orphenadrine-induced
ventricular tachycardia with physostigmine. J Emerg Med
1991; 9:453-7.
22. Labout JJ, Thijssen CT, Hespe W. Sensitive and specific gas
chromatographic and extraction method for the
25. Macchio CJ, Ito V, Sahgal V. Amantadine induced coma.
Arch Phys Med Rehab 1993; 74:1119-20.
26. Miller KS, Miller JM. Toxic effects of amantadine in patients
with renal failure. C/»esM994; 105:1630.
27. Snoey ER, Bessen HA. Acute psychosis after amantadine
overdose. Ann Emerg Med 1990; 19:668-70.
28. Fahn S, Craddock C, Kumin G. Acute toxic psychosis from
suicidal overdosage of amantadine. Arch Neurol 1971;
25:45-8.
29. Pimentel L, Hughes B. Amantadine toxicity presenting with
complex ventricular ectopy and hallucinations. Pediatr
Emerg Care 1991; 7:89-92.
30. Casey DE. Amantadine intoxication reversed by
physostigmine. N Engl J Med 1978; 129:974-5.
31. Fahn S. Is levodopa toxic? Neurology 1996; 47:S184-95.
32. Hoehn MM, Rutledge CO. Acute overdose with levodopa.
Neurology 197'5; 25:792-4.
33. Sturner WQ, Carriott JC. L-dopa poisoning. J Forensic Sci
1972; 17:440-3.
34. Klawans HL, Ringel SP, Shenker DM. Failure of vitamin B6
to reverse the L-dopa effect on patients on a
dopadecarboxylase inhibitor. J Neurol Neurosurg Psychiatr
1971; 34:682-6.
35. Sporer KA. Carbidopa-levodopa overdose. AmJ Emerg Med
1991; 9:47-8.
36. Descotes J, Frantz P, Bourrat C. Intoxication aigue par
ingestion volontaire de bromocriptine. A propos de deux
observations personelles. Bull Med Leg Toxicol 1979;
22:487-90.
37. Warren DE, Nafkoor E. Acute overdose of bromocriptine.
Drug Intell Clin Pharm 1983; 17:374.
38. Vermund SH, Goldstein RG, Romano AA,
Atwood SJ. Accidental bromocriptine ingestion in
childhood. J Pediatr 1984; 105:838-40.
39. Tunca Z, Alkin T, Guven H. A case of bromocriptine
poisoning that resembles Pick-Wick syndrome. Pharmcol
Toxicol 1993; 73 (Suppl 2):78.