Newer Anticonvulsants

The newer anticonvulsant agents include: Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine, Pregabalin, Tiagabine, Topiramate and Vigabatrin. These are generally less toxic in overdose causing sedation and non-specific neurological symptoms and patients do well with supportive care.

Toxic Mechanism:

Broadly speaking these drugs potentiate GABA neurotransmission either by enhancing the release of GABA or inhibiting GABA re-uptake at the receptor. There are other mechanisms, some proven and some that remain unclear which gives each of these drugs unique properties.

• Lamotrigine: It is a voltage-gated sodium channel blocking drug leading to the stabilisation of neuronal membranes. It also blocks calcium channels and weakly 5-HT3 receptors which is thought to be responsible for the inhibition of glutamate in the ventral straitum.
• Levetiracetam: has a more novel mechanism of action. It has been proposed that is binds to the synaptic vesicle protein SV2A thus reducing the amount of vesicles released at neuronal synapses.
• Oxcarbazepine: Like carbamazepine acts as a sodium channel blocker thus stabilising hyper excitable neuronal membranes.
• Pregabalin: Although an analogue of GABA it does not bind directly to GABA. It modifies the GABA channels, increasing the density of transporter proteins and increasing the rate of functional GABA transport. This is done via the alpha2-delta subunit. These subunits in the spinal cord are responsible for calcium dependent release of pro-nociceptive neurotransmitters, it is thought that pregabalin disrupts this transmission resulting in its benefit in neuropathic pain. Gabapentin works along a similar mechanism but appears to affect the calcium currents after chronic dosing and not in the acute stages.
• Tiagabine: is a GABA reuptake inhibitor
• Topiramate: This has a wide range of actions on voltage-gated sodium channels, high-voltage-activated calcium channel, GABA-A receptors and carbonic anhydrase receptors. The addition of carbonic anhydrase receptors may be responsible for the drug to potentiate a metabolic acidosis and calcium phosphate kidney stones.
• Vigabatrin: is an irreversible suicide inhibitor of GABA transaminase, the enzyme responsible for the catabolism of GABA.

Toxicokinetics: 

• Well absorbed orally
• Most undergo hepatic metabolism to inactive metabolites and are really excreted
• Of note, gabapentin absorption from the GI tract is saturable in high doses and thus limits its toxic effects in overdose.

Resuscitation:

• Attention to ABC, if there is a reduced GCS or an unprotected airway or respiratory depression, intubation and ventilation will need to be performed.
• Seizures: IV benzodiazepines incrementally dosed every 5 minutes to effect.
  • Check the patient is not in a dysrhythmia
  • Can be managed with benzodiazepines (varying doses in the textbooks, easy method is 0.1mg/kg IV for lorazepam (max 4mg) / midazolam (max 10mg) / diazepam (max 10mg). Or…
  • Lorazepam 0.1mg/kg max 4mg
  • Diazepam 0.15mg/kg max 10mg
  • Midazolam 0.2mg/kg max 10mg

Risk Assessment

• Most overdoses produce mild and transient CNS symptoms only (see below).
• Symptoms usually occur within 2 hours and resolve within 24 hours.
• Coma and seizures can occur but are rare. If a patient is in a coma then other agents need to be considered e.g. carbamazepine, valproic acid or barbiturates (levels can be obtained for these drugs).
• Children: Unintentional ingestion is benign and children only need assessment in hospital if symptoms develop.
• Clinical features:
  • Gabapentin: Nausea, vomiting, tachycardia, hypotension, drowsiness
  • Lamotrigine: Ataxia, nystagmus, slurred speech, drowsiness, transient intraventricular conduction delay (rare) and seizures (rare).
  • Levetiracetam: Agitation, decreased GCS, coma and respiratory depression
  • Oxcarbazepine: Mild to moderate sedation (although similar to carbamazepine structurally is much less toxic in overdose)
  • Pregabalin: Drowsiness
  • Tiagabine: Decreased GCS, coma and respiratory depression
  • Topiramate: Ataxia, sedation, coma, seizures, hypotension and metabolic acidosis. The non-anion gap metabolic acidosis is secondary to the carbonic anhydrase inhibition and may persist for 7 days. It is of little significance.
  • Vigabatrin: Drowsiness and delirium

Supportive Care

• General supportive care
• Monitor for urinary retention
• If intubated consider FASTHUGSINBED Please

Investigations

• Screening: 12 lead ECG, BSL, Paracetamol level
• Specific:
  • EUC and VBG (NAGMA with topiramate)
  • Specific drug levels are not readily available nor clinically useful

Decontamination:

• Routinely not recommended due to the rapidity of GI absorption, however, if the patient is intubated 50 g (1 g/kg in a child) of activated charcoal can be given via a nasogastric tube to prevent any ongoing absorption.

Enhanced Elimination

• Not clinically useful

Antidote

• None available

Disposition

• Children only require assessment and observation if they become symptomatic otherwise they can remain at home.
• Patients who are asymptomatic 6 hours post ingestion are medically fit for discharge. Discharge should not occur over night.
• Those who develop symptoms will require the appropriate treatment and level of observation. Most symptoms resolve within 24 hours.

Additional Resources and References:

Additional Resources:

• Tox seizures – Tox conundrum 023

References:

• Fischer JH, Barr AN, Rogers SL, Fischer PA, Trudeau VL. Lack of serious toxicity following gabapentin overdose.  Neurology 1994; 44(5):982-9833.
• Klein-Schwartz W, Shepherd JG, Gorman S et al. Characterization of gabapentin overdose using a poison center case series. Journal of Toxicology-Clinical Toxicology 2003; 41(1):11-15.
• Lofton AL, Klein-Schwartz W.  Evaluation of lamotrigine toxicity reported to poison centers.  Annals of Pharmaotherapy 2004; 38:1811-1815.
• Murray L et al. Toxicology Handbook 3rd Edition. Elsevier Australia 2015. ISBN 9780729542241
• Traub JS, Howland MA, Hoffman RS et al. Acute Topiramate Toxicity. Journal of Toxicology-ClinicalToxicology 2003; 41(7):987-990.
• Wade JF, Dang CV, Nelson L et al.  Emergent complications of the newer anticonvulsants.  Journal of Emergency Medicine 2008; Aug 30 [Epub ahead of press].
• Wisniewski M, Lukasek-Glebocka  M, Anand JS. Acute topiramate overdose – clinical manifestations. Clinical Toxicology 2009; 47:317-320.