Management of Drug-induced Seizures

Many drugs in overdose can induce seizures. Drugs known to cause seizures in overdose include sympathomimetics (e.g. amphetamines, cocaine, methylphenidate), antidepressants (e.g. amitriptyline, citalopram, fluoxetine), anticholinergics (e.g. atropine, hyoscine), antihistamines (chlorpheniramine, diphenhydramine), and antimicrobials (e.g. imipenem/ cilastatin, isoniazid).^[1,2] Seizures occur as a result of an imbalance between inhibitory and excitatory neurotransmitters. This may be due to either an increase of excitatory neurotransmitters and/or decrease of inhibitory neurotransmitters.^[3] Drug-induced seizures are distinct in that they result from diffuse neuronal excitability and not from a single epileptic focus in the brain.^[3] A suitable treatment approach would therefore be to increase the inhibitory neurotransmitter effects of gamma-aminobutyric acid (GABA) to overcome the drug-induced diffuse excitatory effects. For this reason benzodiazepines are the first-line antiseizure drugs of choice for drug-induced seizures, similar to the management of status epilepticus.

However, phenytoin should not be used for further treatment of drug-induced seizures. Phenobarbital should preferably be used.

Why is phenobarbital the preferred second-line agent?

• Phenobarbital (also known as phenobarbitone) is recommended as further treatment for drug-induced seizures since it potentiates the effect of GABA, similar to the benzodiazepines. Phenobarbital binds to a different site on the GABA receptor than benzodiazepines, prolonging the duration of the chloride channel opening with chloride influx, and ultimately increasing the inhibitory neurotransmitter effects. Benzodiazepines increase the frequency of chloride channel opening, and the addition of phenobarbital to benzodiazepines can act synergistically to potentiate the inhibitory effects of GABA^[3]

Why should phenytoin not be used in drug-induced seizures?

• Phenytoin inhibits voltage-gated sodium channels increasing the threshold of depolarization and subsequently the propagation of electrical potentials from a single epileptic focus.^[4] Phenytoin is considered to be less effective in reducing diffuse neuronal excitability or increasing the seizure threshold in patients presenting with drug-induced seizures.^[3] In addition, phenytoin is associated with adverse cardiovascular effects such as dysrhythmias and hypotension. Phenytoin could therefore potentially exacerbate the cardiovascular toxicity associated with many drugs when taken in overdose.^[4]  

Management of drug-induced seizures

1. Manage and secure airway, breathing, and circulation according to basic principles
2. Exclude immediate, reversible causes of seizures, such as electrolyte abnormalities and hypoglycaemia
3. 1^st line treatment: Benzodiazepines 

• Lorazepam 
  - Dose: 4 mg IV at a rate of 2 mg/minute^[5] 
  - Repeat dose if required. Maximum dose 8 mg over 12 hours

If lorazepam is not available, consider:

• Midazolam
  - Dose: 10 mg, IM/IV, slow IV injection at a rate of approximately 1 mg over 30 seconds
  - Repeat once after 5–10 minutes if necessary^[6,7] 

OR

• Diazepam
  - Dose: 10 mg, IV, not faster than 2 mg/minute, repeat once after 5–10 minutes if necessary^[6]

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Note:
Where isoniazid-induced seizures are suspected, administer pyridoxine (vitamin B6) immediately

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• Pyridoxine
  - Dose: Estimate the isoniazid ingestion and give an equivalent pyridoxine dose up to a maximum of 5 g pyridoxine. If the ingested quantity of isoniazid is unknown, administer 5 g immediately. Repeat the pyridoxine dose if necessary^[8]
  - Pyridoxine is usually available as 25 mg tablets. The required dosage (e.g. 200 tablets = 5 g if unknown isoniazid amount) can be crushed, mixed with water, and administered via a nasogastric tube. Parenteral vitamin B preparations containing vitamin B6 may be available in the private sector and access should be discussed with the Clinical Pharmacologist on call.

4. 2^nd line treatment: 

• Phenobarbital
  - Dose: 15 – 20 mg/kg IV at a rate no faster than 100 mg/min^[5]
  - Maximum dose 1 000 mg–1 500 mg

5. Drug-induced seizures not responding to 1^st and 2^nd line treatments: 

• Consider intubation and ventilation
• Propofol
  - Loading dose: 1–2 mg/kg IV
  - Maintenance dose: 1.2 mg/kg continuous IV infusion

Contact the Clinical Pharmacologist on call as needed for assistance.  All drug-induced seizures are serious adverse events and we encourage reporting via the Clinical Pharmacologist on call.

References:

1. Murphy K, Delanty N. Drug-induced seizures: General principles in assessment, management and prevention. CNS Drugs 2000;14(2):135–146. https://doi.org/10.2165/00023210-200014020-00004
2. Reichert C, Reichert P, Monnet-Tschudi F, et al. Seizures after single-agent overdose with pharmaceutical drugs: Analysis of cases reported to a poison center. Clin Toxicol 2014;52(6):629–634. https://doi.org/10.3109/15563650.2014.918627 
3. Chen HY, Albertson TE, Olson KR. Treatment of drug-induced seizures. Br J Clin Pharmacol 2016;81(3):412–419. https://doi. org/10.1111/bcp.12720
4. Shah AS, Eddleston M. Should phenytoin or barbiturates be used as second-line anticonvulsant therapy for toxicological seizures. Clin Toxicol 2010;48(8):800–805. https://doi.org/10.3109/15563650.2010.521506 
5. South African Medicines Formulary (SAMF), 13th edition. 2020.
6. National Department of Health. Standard Treatment Guidelines and Essential Medicines List for South Africa [Internet]. 2019. https://doi.org/10.1128/AAC.03728-14 
7. Dormicum® [Internet]. 2019
8. AfriTox [Internet].

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