Clinical Toxicology

ISSN: 1556-3650 (Print) 1556-9519 (Online) Journal homepage: http://www.tandfonline.com/loi/ictx20

Cardiovascular toxicity with levetiracetam

overdose

Colin B. Page, Ahmed Mostafa, Ana Saiao, Jeffrey E. Grice, Michael S. Roberts
& Geoffrey K. Isbister

To cite this article: Colin B. Page, Ahmed Mostafa, Ana Saiao, Jeffrey E. Grice, Michael S.
Roberts & Geoffrey K. Isbister (2016) Cardiovascular toxicity with levetiracetam overdose,
Clinical Toxicology, 54:2, 152-154, DOI: 10.3109/15563650.2015.1115054

To link to this article: http://dx.doi.org/10.3109/15563650.2015.1115054

View supplementary material

Published online: 22 Jan 2016.

Submit your article to this journal

Article views: 40

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ictx20

Download by: [Penn State University] Date: 27 January 2016, At: 20:42
 CLINICAL TOXICOLOGY, 2016
VOL. 54, NO. 2, 152–154
http://dx.doi.org/10.3109/15563650.2015.1115054

BRIEF COMMUNICATION

Cardiovascular toxicity with levetiracetam overdose

Colin B. Pagea,b,c, Ahmed Mostafad,e, Ana Saiaoa, Jeffrey E. Griced, Michael S. Robertsd,f and Geoffrey K. Isbistera
a
Clinical Toxicology Research Group, University of Newcastle, Newcastle, Australia; bSchool of Medicine, University of Queensland, Brisbane,
Australia; cEmergency Department, Princess Alexandra Hospital, Brisbane, Australia; dTherapeutics Research Centre, Translational Research
Institute, University of Queensland, Brisbane, Australia; ePharmaceutical Chemistry Department, Helwan University, Helwan, Egypt; fSchool of
Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia

ABSTRACT ARTICLE HISTORY

Objective: To describe the cardiovascular toxicity and pharmacokinetics of levetiracetam in Received 13 July 2015
overdose. Case Report: A 43-year-old female presented 8 h post ingestion of 60–80 g of Revised 25 October 2015
levetiracetam with mild central nervous system depression, bradycardia, hypotension and oliguria. Accepted 27 October 2015
Her cardiovascular toxicity transiently responded to atropine and intravenous fluids. A bedside Published online 22 January
echocardiogram demonstrated normal left and right ventricular contractility. Despite her 2016
Downloaded by [Penn State University] at 20:42 27 January 2016

cardiovascular toxicity and oliguria, she had normal serial venous lactates and renal function; KEYWORDS
and made a complete recovery over 48 h. Her levetiracetam concentration was 463 mcg/ml 8 h post Anticonvulsant;
ingestion (therapeutic range 10–40 mcg/ml) and her concentration–time data best fitted a one- CNS/psychological; heart
compartment model with first-order input and an elimination half-life of 10.4 h. Discussion:
Levetiracetam in large ingestions appears to cause bradycardia and hypotension that is potentially
responsive to atropine and intravenous fluids. Based on a normal echocardiogram, the mechanism
for this effect may be levetiracetam acting at muscarinic receptors at high concentration. The
pharmacokinetics of levetiracetam in overdose appeared to be similar to therapeutic levetiracetam
dosing.

Introduction On arrival she had a Glasgow Coma Scale (GCS) of 14 (verbal

Levetiracetam is a newer anticonvulsant approved as anticon-
vulsant therapy in children and in adults.[1] Its mechanism of
action is unknown but is unrelated to the actions of other
anticonvulsants in that it does not affect voltage dependent
sodium channels, gamma-amino butyric acid (GABA) transmis-
sion or affinity for GABA and glutamate receptors.[2] Its
pharmacokinetics therapeutically are well described with
rapid absorption, complete bioavailability with 66% of the
ingested dose renally excreted unchanged with a half-life of 6–
8 h.[3] Most reports in overdose report its toxicity as mild
central nervous system (CNS) depression, both in children and
adults.[4–11] There are no reports of cardiovascular toxicity.
Here we report a large ingestion of levetiracetam with serial
serum concentrations that resulted in cardiovascular toxicity.
Case report
A 43-year-old female presented 8 h after an overdose of 60–80
1000 mg tablets of levetiracetam (KeppraÔ; immediate release
preparation), 20 tablets of paracetamol/codeine combination
product (500 mg/30 mg) and an unknown quantity of alcohol.
Her past medical history included epilepsy on levetiracetam
1000 mg twice a day and asthma on inhaled salbutamol and
beclomethasone last taken 12 h prior to presentation.
4) with a heart rate (HR) of 45 beats per minute (bpm) and a
blood pressure (BP) of 86/57. She had a normal respiratory rate,
oxygen saturations on air of 97% and the rest of her clinical
examination was normal. Her serum glucose was 4.4 mmol/l (N
3.5–7.8) and her electrocardiogram (ECG) showed a sinus
bradycardia of 42 bpm.
She was administered 1.2 mg of atropine as a once only
dose and three litres of 0.9% saline. Her HR and BP transiently
increased to 80 bpm and 111/57 mmHg respectively, before
falling back to 40 bpm and 88/62 mmHg, 90 min later. Despite
her bradycardia and systolic hypotension she remained well
perfused with normal capillary return and a normal venous
blood gas lactate of 2.1 mmol/l. Her paracetamol concentration
was 41 mg/l at 8 h post ingestion (non-toxic) and her baseline
full blood count and biochemistry including electrolytes, renal
and liver function were normal. A serum ethanol level also
taken on admission was 32 mmol/l or 0.147 g/dl.
Overnight her GCS improved to 15. She remained brady-
cardiac (HR 38–55 bpm) and hypotensive (BP 88/56). Serum
glucose 13 h post ingestion was 3.7 mmol/l and 50 ml 50%
glucose was administered. Three hours later her serum glucose
was 3 mmol/l and 10% dextrose was commenced for 3 h. The
urine output was low at 22–50 ml/h despite intravenous fluid
administration with a positive fluid balance of 5 l over the first
12 h of her admission. The following day a bedside

CONTACT Colin B. Page cpage@bigpond.net.au Emergency Department, Princess Alexandra Hospital, Brisbane, Australia
Supplemental data for this article can be accessed http://dx.doi.org/10.3109/15563650.2015.1115054.

ß 2016 Taylor & Francis


echocardiogram demonstrated normal left and right ventricu-
lar contractility, which was dynamic in nature with a comment
that this can be seen in states of peripheral vasodilatation. Her
HR (37–55 bpm), BP (82/54–95/61 mmHg) and urine output
(22–30 ml) continue to remain low, but serial venous lactates
and renal function were normal. Her repeat ethanol level was
undetectable. Approximately 36 h post ingestion her BP started
to increase followed by an ncrease in HR and urine output 6 h
later. On discharge (48 h post ingestion) her HR was 60 bpm
with a blood pressure of 142/81.
Six serum samples were available and levetiracetam
concentrations were measured (see Appendix 1 in the
Supplemental Material). On admission 8 h post ingestion the
concentration was 462.5 mg/L (Figure. 1). A one-compartment
model with first order input adequately described the timed
concentration data, with absorption coefficient, 1.32 h 1,
volume of distribution, 75 l and an elimination half-life of
10.4 h (see Appendix 2 in the Supplemental Material).
Downloaded by [Penn State University] at 20:42 27 January 2016
Discussion
We report a large levetiracetam overdose with bradycardia and
hypotension, with no significant end organ effects or
hypoperfusion. A pharmacokinetic analysis found that the
concentration-time profile was similar to that of therapeutic
doses with a half-life of about 10 h.
Figure. 1. (A) Serum levetiracetam concentrations (observed) with modeled
(predicted) time concentration curve for 70 g. (B) Patients reported range of
ingested dose (60 & 80g).
CLINICAL TOXICOLOGY 153
Cardiovascular toxicity has not previously been described
with levetiracetam in overdose. The time course of the patient’s
bradycardia and hypotension indicated that this was a toxic
effect of her levetiracetam overdose. Her regular medications,
co-ingested paracetamol/codeine combination product and
ethanol are not expected to contribute to the cardiovascular
toxicity seen in this patient. The bedside echocardiogram
suggests that the hypotension could be secondary to a
combination of bradycardia and reduced systemic vascular
resistance (SVR), as the ventricular function was normal.
One possible explanation for the toxicity seen in this case is
increased muscarinic activity. Stimulation of M2 muscarinic
receptors leads to bradycardia and stimulation of M3 muscar-
inic receptors will cause peripheral vasodilatation and both will
lead to hypotension. Although muscarinic receptors are
present in the ventricle, they are thought to only be important
in the presence of beta adrenergic agonists,[12] therefore
stroke volume or ventricular contractility should not be
affected, which was the case in our patient. In an animal
model of pilocarpine-induced seizures, levetiracetam has been
shown to have agonist-like activity at the M2 receptor.[13] In
higher concentrations it is possible that levetiracetam has an
effect on the other muscarinic receptor subtypes. Possible
support for this mechanism in our patient for a combined M2
(bradycardia) and 3 (reduced SVR) effect was the nature of the
resolving levetiracetam toxicity whereby the hypotension
started to resolve prior to the bradycardia resolving. We are
unable to explain the lack of other M3 effects, e.g.,
bronchoconstriction.
Our patient also developed hypoglycaemia. Glucose homeo-
stasis is influenced by muscarinic receptors, which regulate
both insulin, and glucagon release from pancreatic alpha and
beta cells respectively. It is possible that the actions of
levetiracetam at the muscarinic receptors lead to a disruption
of glucose homeostasis. The patient also consumed alcohol,
which impairs gluconeogenesis, and this may on its own
explain the hypoglycaemia.[14]
Our patient presented at 8 h post ingestion and so
we only have a predicted peak levetiracetam concen-
tration of approximately 800 mcg/ml. The first level in
our patient was 463 mcg/ml at 8 h post ingestion.
Serum levetiracetam levels in overdose have been
previously reported, with concentrations of 596 mcg/ml
6 h post-overdose of 45 g[8] and a concentration of
400 mcg/ml (therapeutic reference range 10–40 mcg/ml)
6 h post overdose of 30 g.[15] In the second case,
three timed concentrations were reported and a half-
life of 5.1 h was estimated assuming first order
elimination kinetics.[15] In our case, we found that a
first order input and first order elimination model best
fitted the data with a half-life of 10.4 h, which is
similar to known pharmacokinetics in therapeutic use
(6–8 h).
This report describes cardiovascular toxicity associated with
a levetiracetam overdose. Levetiracetam appears to cause
bradycardia and hypotension that is potentially responsive to
atropine and intravenous fluids. The mechanism of this effect
may involve levetiracetam acting at M2 and M3 muscarinic
receptors at very high concentrations.
 154 C. B. PAGE ET AL.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding information
The study was supported by an NHMRC Program Grant
(1055176). CBP is supported by a QEMRF Research
Fellowship. GKI is supported by an NHMRC Senior Research
Fellowship ID1061041, MSR is supported by an NHMRC Senior
Principal Research Fellowship ID1002611.
References
[1] Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy.
Drugs. 2011;71:489–514.
[2] Deshpande LS, Delorenzo RJ. Mechanisms of levetiracetam
in the control of status epilepticus and epilepsy. Front Neurol.
2014;5:11.
[3] Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin
Downloaded by [Penn State University] at 20:42 27 January 2016
Pharmacokinet. 2004;43:707–724.
[4] Awaad Y. Accidental overdosage of levetiracetam in two children
caused no side effects. Epilepsy Behav. 2007;11:247.
[5] Özkale Y, Özkale M, Saygi S, et al. Long-term accidental
overdose of levetiracetam in an infant. J Child Neurol.
2014;29:959–961.
[6] Larkin TM, Cohen-Oram AN, Catalano G, et al. Overdose with
levetiracetam: a case report and review of the literature. J Clin
Pharm Ther. 2013;38:68–70.
[7] Chayasirisobhon S, Chayasirisobhon WV, Tsay CC. Acute levetirace-
tam overdose presented with mild adverse events. Acta Neurol
Taiwan. 2010;19:292–295.
[8] Miller SN, Punja M, Meggs WJ. Asymptomatic presentation of
overdose of levetiracetam with highest reported serum level.
Clinical Toxicol. 2014; 52: 811 (abstract).
[9] Bodmer M, Monte AA, Kokko J, et al. Safety of non-therapeutic
levetiracetam ingestions-a poison center based study.
Pharmacoepidemiol Drug Saf. 2011;20:366–369.
[10] Wills B, Reynolds P, Chu E, et al. Clinical outcomes in newer
anticonvulsant overdose: a poison center observational study. J Med
Toxicol. 2014;10:254–260.
[11] Lewis JC, Albertson TE, Walsh MJ. An 11-year review of levetiracetam
ingestions in children less than 6 years of age. Clinical Toxicol.
2014;52:964–968.
[12] Brodde OE, Michel MC. Adrenergic and muscarinic receptors in the
human heart. Pharmacol Rev. 1999;51:651–690
[13] Oliveira AA, Nogueria CRA, Nascimento VS, et al. Evaluation of
levetiracetam effects on pilocarpine-induced seizures: cholinergic
muscarinic system involvement. Neurosci Lett. 2005;385:184–188.
[14] Lieber CS. Medical disorders of alcoholism. N Engl J Med.
1995;333:1058–1065
[15] Barrueto F , Williams K, Howland MA, et al. A case of levetiracetam
(Keppra) poisoning with clinical and toxicokinetic data. J Toxicol Clin
Toxicol. 2002;40:881–884.