Download Acute coronary syndrome secondary to methylphenidate overdose

Hong Kong Journal of Emergency Medicine
Acute coronary syndrome secondary to methylphenidate overdose
OF Wong
, KL Tsui
, HT Fung
A 28-year-old lady presented to the emergency department after an overdose of methylphenidate. She
complained of chest pain and developed an acute coronary syndrome with marked ST segment depression in
the electrocardiogram and elevated troponin I level. She was closely monitored in the cardiac care unit and
was treated with the standard therapy for acute coronary syndrome. Echocardiogram showed global left
ventricle impairment. The follow-up echocardiogram showed that the left ventricular function normalised
and the subsequent coronary angiogram was normal. The clinical use, abuse potential, toxicity and overdose
treatment of methylphenidate are discussed. (Hong Kong j.emerg.med. 2010;16:66-70)
28
ST
-I
Keywords: Amphetamine, cocaine, myocardial ischemia, substance-related disorders
Introduction
Methylphenidate, an amphetamine-related drug, is
widely used in paediatric patients with attention-deficit
hyperactivity disorder (ADHD). The therapeutic dose
for children ranges from 5 mg twice daily to a maximal
daily dose of 60 mg. 1 Serious adverse effects from
therapeutic use of methylphenidate are rare and the
commonest adverse effects include sleep problems,
anorexia and tics. 2 Methylphenidate, at therapeutic
dose, increases the heart rate and blood pressure3 but
its cardiovascular effects are considered to be clinically
insignificant.4 In a systematic review for the safety of
methylphenidate uses in adults, chest pain was reported
as one of the adverse events in 3 out of 26 placebocontrolled trials but the frequency was statistically
i n s i g n i f i c a n t . 5 T h e o r e t i c a l l y, o v e r d o s e o f
methylphenidate may result in sympathomimetic
syndrome. Myocardial ischaemia and infarction are
important cardiovascular manifestations in this
situation. A case of acute coronary syndrome (ACS)
secondary to methylphenidate overdose in a young lady
is reported.
Case report
Correspondence to:
Wong Oi Fung, MRCSEd, FHKCEM, FHKAM(Emergency Medicine)
Tuen Mun Hospital, Accident and Emergency Department, Tsing
Chung Koon Road, Tuen Mun, N. T., Hong Kong
Email: [email protected]
Tsui Kwok Leung, FRCSEd, FHKCEM , FHKAM(Emergency Medicine)
Fung Hin Tat, MRCP(UK), FRCSEd, FHKAM(Emergency Medicine)
A 28-year-old lady presented to our emergency
department (ED) with drug overdose for suicidal
attempt in October 2008. She had taken 18 tablets of
methylphenidate (5 mg/tablet) and a few tablets of
other medications (paracetamol and "anti-cold"
remedy) two hours before arrival. She had no history
67
Wong et al./Methylphenidate overdose
of drug abuse and the medication was obtained from
her son who had ADHD treated by methylphenidate.
At presentation, she had Glasgow Coma Scale score of
15/15, blood pressure 147/111 mmHg, pulse rate 123
beats per minute and temperature 37.1 o C. She
complained of chest discomfort during the ED
assessment. The electrocardiogram (ECG) revealed
sinus tachycardia with T wave inversion and ST
depression in the inferior leads (II, III, aVF) and lateral
chest leads (V3 to V6) (Figure 1). The chest X-ray
showed clear lung fields and normal mediastinum. She
was treated with oxygen and intravenous isosorbide
dinitrate (Isoket) infusion and subsequently transferred
t o t h e c a rd i a c c a re u n i t ( C C U ) f o r f u r t h e r
management. Her chest discomfort subsided soon after
the initiation of Isoket infusion and her vital signs
remained stable. The subsequent investigations revealed
an elevation of serum troponin I up to 7.7 ng/ml
(reference range <0.06 ng/ml) at 14 hours postingestion. The ST change in ECG was normalised in
the CCU (Figure 2). The Isoket infusion was continued
for a total of eleven hours. Echocardiogram was done
Figure 1. ECG of the patient on arrival showing marked ST segment depression over leads II, III, aVF, V3
to V6.
Figure 2. ECG of the patient around seven hours after admission showing disappearance of the ST changes.
68
on the next day of admission and showed global left
ventricle impairment with ejection fraction of 30%.
The creatine kinase level was normal. There was no
serological evidence of viral myocarditis or vasculitis
of autoimmune causes. The blood paracetamol level
was below treatment threshold (375 umol/L 5 hours
post-ingestion). The urine toxicology screening showed
positive results of methylphenidate and metabolite of
brompheniramine reflecting the "anti-cold" medication
exposure. She was assessed by the psychiatrist with a
diagnosis of adjustment disorder secondary to stress
from child care issue. The patient was discharged after
six days of hospitalisation and was put on aspirin and
perindopril. A repeat echocardiogram was done six
months after the event and showed normal left
ventricular function with ejection fraction of 76%. The
coronary angiogram was normal.
Discussion
Methylphenidate, a piperidine-derived central nervous
system stimulant, is widely used for the management
of ADHD.1 It was first synthesised in the year 1944
and was initially used as an analeptic for the reversal
of barbiturate-induced coma. 6 Methylphenidate is
approved by the Food and Drug Administration for
the treatment of ADHD and narcolepsy. 7 The exact
mechanism on behavioural response and hyperactivity
is unknown but it is believed that the pharmacological
effect of methylphenidate is due to its activity on the
dopaminergic areas of the brain.8
Methylphenidate is almost completely absorbed after
ingestion and is primarily metabolised by de-esterification
to ritalinic acid, an inactive metabolite, with peak plasma
concentration between 1 to 3 hours and a plasma halflife of 1.5 to 2.5 hours.1 High level of ritalinic acid but
undetectable methylphenidate was found in the
postmortem blood sample in a patient who died from
methylphenidate abuse9 due to the rapid conversion of
methylphenidate into ritalinic acid after systemic
absorption. However, ritalinic acid is not routinely
analysed in our comprehensive drug screening set. Other
known methylphenidate metabolites include the
corresponding lactams and p-hydromethylphenidate.10
Formation of ethylphenidate in humans has been
Hong Kong j. emerg. med. „ Vol. 17(1) „ Jan 2010
reported in patients with co-ingestion of methylphenidate
and ethanol. In contrast to cocaethylene which is a
potent cardiotoxic compound formed by cocaineethanol metabolic transesterification in humans,11 the
clinical significance and toxicity of ethylphenidate are
unknown. The presence of ethylphenidate merely
indicates co-ingestion with ethanol.10
Because of the similar effects to cocaine and
amphetamines, there are recent concerns on the abuse of
methylphenidate in the United States12,13 especially in
adolescents. The primary source of methylphenidate for
abuse in adolescents is mainly the diversion from ADHD
patients taking methylphenidate therapeutically.14 The
"street names" of methylphenidate in the United States
include vitamin R, R-ball and Skippy. Methylphenidate,
similar to cocaine, can be abused orally, intra-nasally or
even parenterally by injecting a solution from dissolving
tablets in water. Notably, severe complications of
methylphenidate abuse are associated with the intravenous
route of administration because of the insoluble excipients
in the tablet;15 however, there were reported cases of
fatality resulting from both intranasal and intravenous
routes of abuse.9,16 Despite the almost identical regional
distribution and receptor binding sites for both cocaine
and methylphenidate in the brain, the lower incidence
of methylphenidate abuse compared with cocaine, from
the pathophysiological point of view, may be explained
by the slower clearance rate of methylphenidate from the
brain.17
Abuse of methylphenidate has not yet been reported
in Hong Kong. Methylphenidate is classified as Part 1
dangerous drug 18 and its inventory or dispensing is
under strict control locally. Detailed records of the
amount dispensed and the patient's personal
information are required by the Law. However,
therapeutic medication could still be a potential source
for abuse after diversion.
Overdose of methylphenidate may develop symptoms
similar to overdose with other amphetaminel i k e s u b s t a n c e s . A n i m a l s t u d y s h ow e d b o t h
methylphenidate and amphetamine increased synaptic
and intracellular dopamine. 19 Methylphenidate
significantly increases plasma epinephrine, heart rate,
both systolic and diastolic pressure without change in
69
Wong et al./Methylphenidate overdose
plasma norepinephrine.20 In a human voluntary study,
methylphenidate increased dopamine and epinephrine
in the striatum of the brain and plasma respectively
which are responsible for its pressor effects. 21 The
increase in adrenergic action in overdose situation can
result in sympathomimetic syndrome. Patients may
present with central nervous and cardiovascular
symptoms including irritability, agitation, euphoria,
psychosis, seizure, tachycardia, symptoms of myocardial
ischaemia or even infarction. 15 In case of severe
intoxication, there may be hyperthermia and
rhabdomyolysis. Myocardial ischaemia was reported
in a 16-year-old male after an increased dose of
methylphenidate to 100 mg/day for 3 doses. The
patient complained of crushing chest pain one hour
after his afternoon dose of methylphenidate. There was
ischemic change over the anterior chest leads of the
ECG and elevated cardiac enzyme. His pain and ECG
change subsided 12 hours later.22 There were also case
reports of acute myocardial infarction in young patients
who took therapeutic doses of methylphenidate with
concomitant use of other medications (bupropion,
e r y t h ro m yc i n a n d p e u d o e p h e d r i n e ) . 2 3 , 2 4 T h e
pathogenesis of methylphenidate-induced myocardial
ischaemia may be a result of an increased myocardial
oxygen demand caused by sympathomimetic
stimulation together with a limited or fixed oxygen
supply to the heart by the constricted coronary arteries
due to α-adrenergic stimulation. Postmortem
examination of the heart in a patient who died from
catecholamine excess and congestive cardiomyopathy
after intranasal abuse of methylphenidate, showed
microscopic foci of myocardial fibre necrosis
surrounded by inflammatory cells. The histological
findings were similar to those of catecholamine
cardiomyopathy. 9 Unlike cocaine-related myocardial
ischaemia or infarction, the effect of methylphenidate
on acceleration of atherosclerosis and thrombosis has
not been established.25
blocker, is theoretically the drug of choice for the
control of hypertension and reversal of coronary
vasoconstriction. Positive response to phentolamine has
been reported in a patient who did not benefit from
standard therapy for cocaine-associated ACS.26 Early
use of benzodiazepine with nitroglycerin has been
shown to be more efficacious in relieving cocaineassociated chest pain.27 Benzodiazepine is also effective
in reducing the sympathomimetic response and the
anxiety effects caused by amphetamine or amphetaminerelated substances. A careful assessment should be
performed to watch out for potential cardiovascular and
pulmonary complications including aortic dissection,
pneumothorax and pneumomediastinum. In contrast to
cocaine, methylphenidate has little known effect on the
sodium channel in myocardium and therefore less likely
to cause ventricular dysrhythmia but its occurrence can
be secondary to myocardial ischaemia.
Standard treatment for acute myocardial infarction,
such as MONA therapy (morphine, oxygen,
nitroglycerin and aspirin), should be provided to
patients with ACS secondar y to exposure to
amphetamine or amphetamine-related substances.
β-blockers are contraindicated because of the
unopposed α effect. Phentolamine, an α-adrenergic
3.
Conclusion
Toxicities from methylphenidate can be due to
therapeutic errors in children and intentional abuse.
We report the first case of methylphenidate-induced
myocardial ischaemia secondary to oral intentional
overdose in Hong Kong. Our patient presented with
chest pain and evidence of myocardial ischaemia with
significant ECG changes and elevated cardiac troponin.
Although methylphenidate abuse is still uncommon
in Hong Kong, emergency physicians should always
be aware of its emergence in the future.
References
1.
2.
4.
Challman TD, Lipsky JJ. Methylphenidate: its
pharmacology and uses. Mayo Clin Proc 2000;75(7):
711-21.
Rappley MD. Safety issues in the use of methylphenidate.
An American perspective. Drug Saf 1997;17(3):143-8.
Stowe CD, Gardner SF, Gist CC, Schulz EG, Wells
TG. 24-hour ambulatory blood pressure monitoring in
male children receiving stimulant therapy. Ann
Pharmacother 2002;36(7-8):1142-9.
Findling RL, Short EJ, Manos MJ. Short-term
cardiovascular effects of methylphenidate and Adderall.
J Am Acad Child Adolesc Psychiatry 2001;40(5):
525-9.
70
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Hong Kong j. emerg. med. „ Vol. 17(1) „ Jan 2010
Godfrey J. Safety of therapeutic methylphenidate
in adults: a systematic review of the evidence.
J Psychopharmacol 2009;23(2):194-205.
Wax PM. Analeptic use in clinical toxicology: a
historical appraisal. J Toxicol Clin Toxicol. 1997;35(2):
203-9.
US Food & Drug Administration. Approved uses of
methylphenidate. [cited 2009 Jul 20]. Available from :
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
index.cfm.
Seeman P, Madras BK. Anti-hyperactivity medication:
methylphenidate and amphetamine. Mol Psychiatry
1998;3(5):386-96.
Massello W 3rd, Carpenter DA. A fatality due to the
intranasal abuse of methylphenidate (Ritalin). J Forensic
Sci 1999;44(1):220-1.
Markowitz JS, Logan BK, Diamond F, Patrick KS.
Detection of the novel metabolite ethylphenidate after
methylphenidate overdose with alcohol coingestion.
J Clin Psychopharmcol 1999;19(4):362-6.
Bailey DN. Comprehensive review of cocaethylene and
cocaine concentrations in patients. Am J Clin Pathol
1996;106(6):701-4.
U S Dr u g E n f o rc e m e n t Ad m i n i s t r a t i o n . Dr u g
information: methylphenidate. [cited 2009 Mar 14].
Available from: http://www.usdoj.gov/dea/concern/m.
html#5.
National Institute on Dr ug Abuse. InfoFacts:
methylphenidate (Ritalin). [cited 2009 Mar 14].
Available from: http://www.nida.nih.gov/pdf/infofacts/
Ritalin06.pdf.
Klein-Schwartz W, McGrath J. Poison centers'
experience with methylphenidate abuse in pre-teens and
adolescents. J Am Acad Child Adolesc Psychiatry 2003;
42(3):288-94.
Klein-Schwartz W. Abuse and toxicity of methylphenidate.
Curr Opin Pediatr 2002;14(2):219-23.
Levine B, Caplan YH, Kauffman G. Fatality resulting
from methylphenidate overdose. J Anal Toxicol 1986;
10(5):209-10.
Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J,
Gatley JS, et al. Is methylphenidate like cocaine? Studies
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
on their pharmacokinetics and distribution in the
human brain. Arch Gen Psychiatry 1995;52(6):456-63.
Department of Justice, the Government of the Hong
Kong Special Administrative Region. The Laws of Hong
Kong. Chapter 134: Dangerous Drugs Ordinance.
[cited 2009 May 1]. Available from: http://www.
legislation.gov.hk/eng/home.htm.
Schiffer WK, Volkow ND, Fowler JS, Alexoff DL,
Logan J, Dewey SL. Therapeutic doses of amphetamine
or methylphenidate differentially increase synaptic and
extracellular dopamine. Synapse 2006;59(4):243-51.
Joyce PR, Nicholls MG, Donald RA. Methylphenidate
increases heart rate, blood pressure and plasma epinephrine
in normal subjects. Life Sci 1984;34(18):1707-11.
Volkow ND, Wang GJ, Fowler JS, Molina PE, Logan J,
Gatley SJ, et al. Cardiovascular effects of methylphenidate
in humans are associated with increases of dopamine in
brain and of epinephrine in plasma. Psychopharmacology
(Berl) 2003;166(3):264-70.
Pe a r l J . A n g i n a f r o m t h e p r o p r i e t a r y u s e o f
methylphenidate. Vet Hum Toxicol 1992;34(4):334.
George AK, Kunwar AR, Awasthi A. Acute myocardial
infarction in a young male on methylphenidate,
bupropion and er ythromycin. J Child Adolesc
Psychopharmacol 2005;15(4):693-5.
Thompson J, Thompson JR. Acute myocardial
infarction related to methylphenidate for adult attention
deficit disorder. J Emerg Med 2007 Nov 14 [Epub ahead
of print].
Lange RA, Hillis, LD. Cardiovascular complications of
cocaine use. N Engl J Med 2001;345(5):351-8. Erratum
in: N Engl J Med 2001;345(19):1432.
Chan GM, Sharma R, Price D, Hoffman RS, Nelson
LS. Phentolamine therapy for cocaine-association acute
coronary syndrome (CAACS). J Med Toxicol 2006;2
(3):108-11.
Honderick T, Williams D, Seaberg D, Wears R.
A prospective, randomized, controlled trial of
benzodiazepines and nitroglycerine or nitroglycerine
alone in the treatment of cocaine-associated acute
coronary syndrome. Am J Emerg Med 2003;21(1):
39-42.