Anticonvulsants

Pathophysiology

Carbamazepine is a tetracyclic compound that bears a structural similarity to tricyclic antidepressants, which accounts for some of its clinical features in overdose. It blocks pre-synaptic voltage-gated sodium channels in the central nervous system (CNS) as well as blocking N-methyl D-aspartate (NMDA) and adenosine receptors. It has a slow rate of dissolution and thus is erratically and incompletely absorbed. Its metabolism is further complicated by the fact that carbamazepine induces its own metabolism with therapeutic use; therefore individuals who are on carbamazepine therapy tend to have less toxic symptoms that those who are naive. With continual therapeutic dosing, the half-life of carbamazepine is 12 to 17 hours; however, in overdose, much longer half-lives are reported. This is likely due to ongoing absorption, impaired elimination or a combination of the two.

Clinical features

The clinical features are neurological, cardiovascular and anticholinergic. Vomiting is a common feature with acute overdose. Clinical features may include altered mental status, dysarthria, ataxia and seizures. Coma with respiratory depression can occur with severe toxicity. Cardiovascular toxicity includes sinus tachycardia, hypotension, myocardial depression and conduction disturbances such as atrioventricular block and QRS complex prolongation. Carbamazepine has anti-cholinergic properties in high concentrations and can impair gut motility, leading to prolonged absorption over many hours. This is further compounded in the treatment of overdose with sustained-release formulations of carbamazepine.

Investigations

Patients presenting following carbamazepine overdose should have a blood sugar level, paracetamol level and electrocardiogram (ECG) performed as part of routine management. Furthermore, serum carbamazepine levels can be utilized both to confirm diagnosis as well as for therapeutic and prognostic applications. Carbamazepine concentrations offer guidance as to resolution of toxicity as well as indication for other therapies such as dialysis or haemoperfusion. Neurological effects start to occur above 10 mg/L (50 μmol/L). Significant toxicity including cardiac arrhythmias/conduction abnormalities usually occurs above 45 mg/L (200 μmol/L).

Patients should have 6-hourly carbamazepine concentrations tested in order to monitor the clinical course. Furthermore, ingestions of more than 50 mg/kg require close monitoring in a resuscitation bay, as such patients are at risk of developing coma calling for intubation; however, they rarely develop cardiac conduction abnormalities.

Treatment

Supportive care with particular attention to the airway is essential to the appropriate management of patients with significant carbamazepine toxicity. Appropriate lines and monitoring should be utilized, as would be expected with other unwell patients.

With regard to specific treatments,

• 1.

  Management of CNS effects: Seizures and agitation secondary to anti-cholinergic effects should be managed with benzodiazepines.

• 2.

  Decontamination: Activated charcoal should be considered for patients who have taken a significant overdose (20 mg/kg) who present early and without symptoms. If patient is drowsy and ingestion is significant, activated charcoal (50 g) should be given only in an intubated patient with a radiologically confirmed nasogastric tube.

• 3.

  Enhancement of elimination: Carbamazepine undergoes enterohepatic circulation; therefore multiple-dose activated charcoal (MDAC) (50 g initially, then 25–50 g q4h) is recommended for patients with coma. This should be continued until the development of ileus, evidence of obstruction or clinical improvement (resolution of coma). Usually two to four doses are given before ileus occurs.

• 4.

  Cardiovascular effects: In the event of a ventricular dysrhythmia secondary to sodium channel blockade, though rare, a bolus of 1 mmol/kg sodium bicarbonate 8.4% is recommended.

• 5.

  Extracorporeal elimination may have a role in severe toxicity. Intermittent haemodialysis is the preferred method; however, if that is not available, intermittent haemoperfusion or continuous renal replacement therapy is a suitable alternative. Extracorporeal elimination is recommended in the following circumstances :

  • Multiple seizures refractory to other treatments

  • Life-threatening dysrhythmias or hypotension requiring inotropic support

  • Prolonged coma greater than 48 hours

  • Severe toxicity with rising or persistently elevated carbamazepine levels despite MDAC and supportive care

A suspected paediatric ingestions of 20 mg/kg or greater should be observed in hospital for at least 8 hours or longer if presenting at night. Adult patients who are clinically well at 8 hours following ingestion do not require any further monitoring or sedation.

Patients with evidence of toxicity should be admitted to hospital, with those presenting with coma managed in a high-dependency or intensive care unit.

Pathophysiology

Phenytoin blocks voltage-dependent sodium channels and reduces neuronal hyper-excitability; thus it is indicated in seizure disorders. It is slowly and erratically absorbed after oral overdose and, as a result, clinical toxicity and peak serum concentrations may be delayed by 1 to 2 days. Furthermore, its elimination half-life is also prolonged in overdose, as phenytoin undergoes hepatic metabolism via zero-order kinetics, which is saturable. Individuals with genetic polymorphism at cytochrome P450 2C9 are known to have particularly prolonged elimination half-lives and may require additional treatment to achieve resolution of toxicity.

Phenytoin toxicity can be either acute (i.e. intentional overdose) or chronic. The latter presentation is often one of gradual onset of symptoms in patients taking therapeutic phenytoin where there may have been a dosing error or drug interaction.