5 Oct 2015
Lotfi El Bahri
Job Title
Figure 1. ECG showing cardiac conduction disturbances.
Lamotrigine (Lamictal, GlaxoSmithKline), a phenyltriazine compound – 1,2,4–triazine-3,5-diamine, 6- (2,3-dichlorophenyl) is a second-generation antiepileptic drug used for the treatment of partial and generalised seizures as well as bipolar affective disorder in human medicine1.
Lamotrigine (LTG) is prescribed for oral administration as regular, chewable dispersible, orally disintegrating, and extended-release tablets1,2. Retrospective case series from 2003 to 2012, have studied the clinical manifestations of humans exposed to LTG in overdose3. LTG toxicity was associated with minor to moderate neurologic effects and/or cardio toxicity symptoms to some degree in the majority of patients3,4. Rare serious effects have been reported3,4.
A review of the American Society for the Prevention of Cruelty to Animals’ database from 2003 to 2011 identified 138 LTG cases involving 128 dogs and 10 cats5. Eight of the 138 animals (6%) died due to the exposure5.
Pets can accidentally ingest medications for their human owners. Ingestion of LTG by pets is a life-threatening emergency and veterinarians should be aware of the high toxicity of this human medication to pets6.
LTG is a weak basis (pKa 5.7), lipid soluble (logP 2,4)1,7. The pharmacokinetics of LTG is linear, and can be described as a one-compartment model8,9.
Following oral administration, LTG is rapidly and completely absorbed from the gastro-intestinal tract with negligible first-pass effect1,7. The absolute oral bioavailability is 98% and is unaffected by food1,7. The peak plasma concentration occurs at one or one-and-a-half hours with the immediate-release formulations and four to 11 hours with the extended-release formulations1,2,6. Serum concentrations of LTG increase in direct proportion to the dose ingested8,9.
In the blood, LTG is approximately 55% bound to serum proteins1,7. The mean apparent volume of distribution ranges from 0.9L/kg to 1.3L/kg1,7. LTG binds to melanin and it could accumulate in melanin-rich tissues (eye and pigmented skin)1.
LTG distributes into saliva in humans10, salivary LTG concentrations being on average 0.4 to 0.5 that of serum concentrations, which makes saliva an interesting sample to perform toxicological analysis10. LTG crosses the placenta in rabbits1.
In dogs, LTG is metabolised in the liver predominantly to a LTG-2-N-methyl1. This metabolite causes severe cardiac disturbances in a dose-dependent manner1.
Only trace amounts (0.14%) of the LTG-2-N-methyl have been found in human urine1,9,11. LTG is also metabolised in dogs by glucuronic conjugation at the two-position of the triazine ring (2-N-LTG glucuronide)12.
Elimination of LTG is essentially renal, with 94% of the drug excreted through the urine and 2% excreted in the faeces1,13. Mean plasma elimination half-life (t1/2β) is 22.8 hours to 37.4 hours on single oral dose administration13. The pharmacokinetics of LTG is not affected by renal impairment13.
LTG inhibits voltage-sensitive sodium channels, thereby stabilising presynaptic neuronal membranes that may result in a decreased release of the excitatory amino acid neuro-transmitters (glutamate and aspartate)1,8.
LTG may have also potassium channel-blocking actions by bindings to hERG (human Ether-a-gogo-Related Gene) potassium channels14. hERG encodes the cardiac rapid delayed rectifier ion potassium current, IKr, in atrial and ventricular myocytes14,15,16,17. LTG inhibits the current IKr, which is crucial for repolarisation of cardiac action potentials16,17.
The oral median lethal doses (LD50) of LTG are 245mg/kg and 205mg/kg in mice and rats respectively1,7.
In dogs, doses of 3.4mg/kg of LTG induce lethargy and somnolence6. Cardiac signs are generally not seen until the exposure dose is more than 20mg/kg6. Doses more than 40mg/kg induce seizures and life-threatening signs such as arrhythmias6.
Cats may be more sensitive because of their low capacity of glucuronide formation. A cat developed bradycardia and ventricular extrasystoles (ventricular premature complexes) after ingesting a dose of 5mg/kg6. In humans, ingestion of LTG higher than 15g can be fatal8.
In dogs, LTG is extensively metabolised to a major metabolite cardiotoxic LTG-2-N-methyl1.
In case of LTG poisoning, intraventricular conduction could be delayed resulting in prolonged electrocardiographic parameters: PR interval, QRS complex, QT interval (Figure 1). In acute poisoning, the effects of cardiac sodium channel blockade are consistent with widening of QRS complex18. Hypokalaemia induces prolongation of the PR interval. Potassium channel blockade results a prolonged QT interval14,17. Prolongation of the QT interval is associated with high risk for ventricular arrhythmias, torsade de pointes and sudden death. Treatment with phenytoin or phenobarbital, which inhibit hERG potassium channels and induce QT prolongation, contribute to the increased risk of ventricular arrhythymias19.
Clinical signs of toxicosis most commonly occur within four hours after exposure and are delayed up to 12 hours with the extended-release products5,6. The common reported clinical signs include5,6,18,20,21:
An ECG (Figure 1) shows cardiac conduction disturbances:
Laboratory values indicate hypokalaemia, hypomagnesaemia and metabolic acidosis6,8. Death is due to cardiac arrhythmia.
The diagnosis of LTG intoxication is based on the history of exposure, rapid onset of significant clinical signs such as CNS depression, seizures and cardiac disturbances. Toxicological diagnosis is based on analysis of vomits, blood, urine and saliva. Kidneys and liver can also be used to verify the presence of LTG in tissue collected postmortem.
The presence of LTG can be confirmed by various analytical methods: gas chromatography-mass spectrometry (GC/MS), liquid chromatography-mass spectrometry (LC/MS), liquid chromatography-tandem mass spectrometry (LC/MS/MS), homogenous enzyme immunoassay9,11,22,23.
There is no specific antidote. Management of LTG poisoning is listed in Table 11,6,24-29. In human medicine, intravenous lipid emulsion is a potential antidote for the treatment of acute poisoning by lipophilic cardiotoxic drugs that did not respond to standard therapies. The dosage recommended for dogs and cats is adapted from human literature.
