Clinical Pharmacy Approach: To a patient on multiple anticonvulsants for “Difficult to control’’ seizure disorder

Dharsshini. N

Group Clinical Pharmacist, Kauvery Hospital, Trichy

Case presentation

A hypothetical patient,

A 30-years-aged male
Seizure Type: Intractable refractory epilepsy, on multiple anticonvulsants

Current Medications

Drug	Dose	Frequency
T. Levetiracetam	500 mg	twice daily
T. Phenytoin	300 mg	Once daily
T. Phenobarbital	60 mg	once daily
T. Clobazam	5 mg	twice daily
T. Oxcarbazepine	300 mg	twice daily

Patient has a known history of seizure disorder for 20 years. He has been on multiple antiepileptic drugs (AED) medications for past 20 years.

Readmitted with recurrence of a seizure he attributes to missing one of the drugs the previous night. EEG during the admission had shown bilateral epileptiform discharges.

Clinical Pharmacist’s review

The use of multiple AEDs poses a risk of drug interactions including enzyme induction or inhibition, alterations in protein-binding and expression of transporter proteins ^[1]

It may result in decreased efficacy or increased toxicity of AEDs

The use of some older AEDs (e.g. carbamazepine or phenytoin), known as potent hepatic enzyme-inducers, is a major source of pharmacokinetic interactions between them and other AEDs.

Major drug interaction lead to the suboptimal serum drug levels that may lead to break- through antiepileptic activity.

Mechanism of Drug Interaction

Enzyme Induction: Phenytoin and phenobarbital induce CYP3A4 and CYP2C9 enzymes, accelerating the metabolism of oxcarbazepine and clobazam, and reducing their effectiveness.
Enzyme Inhibition: Phenytoin can reduce oxcarbazepine levels, potentially necessitating dose adjustments of oxcarbazepine to maintain therapeutic efficacy. Oxcarbazepine can increase phenytoin levels, potentially leading to toxicity. Regular monitoring of phenytoin levels is advised3.
Substrate Competition: Clobazam and its active metabolite are metabolized by CYP3A4; phenobarbital accelerates this, decreasing their levels.
Minimal Interaction: Phenytoin can decrease levetiracetam concentration in some patients. This interaction is due to phenytoin’s enzyme-inducing properties, which may enhance the metabolism of levetiracetam. However, the clinical significance of this interaction is generally considered minimal.^[2-6]

All the five drugs, that the index patient had been on, have potential drug interactions, which may lead to epileptic activity from inadequate seizure control. Phenytoin, phenobarbital and oxcarbazepine all are enzyme inducers that can reduce the serum level concentration of levetiracetam and clobazam. Dose modification or deprescribing of multiple drugs may be needed foe such patients.

Clinical Pharmacy Approach

1. Comprehensive Medication Review

Assess Drug Interactions: Review the potential interactions among the anticonvulsants. Phenytoin and phenobarbital are known to induce hepatic enzymes, which can reduce the plasma concentrations of other drugs, including oxcarbazepine and clobazam.
Evaluate Adverse Effects: Monitor for side effects such as sedation (common with phenobarbital and clobazam), cognitive impairment, and mood changes. Levetiracetam, for instance, can cause irritability and behavioral changes

2. Therapeutic Drug Monitoring (TDM): Regularly check the plasma levels of phenytoin and phenobarbital to ensure they are within the therapeutic range, adjusting doses as needed to avoid toxicity or subtherapeutic levels.

3. Individualized Pharmacotherapy:

Dose Optimization: Adjust the doses of each anticonvulsant based on efficacy and side effect profile. For instance, consider reducing phenobarbital if the patient experiences significant sedation, and closely monitor seizure control with any changes.
Pharmacogenetic Testing: If available, perform pharmacogenetic testing to identify any genetic variants that may affect drug metabolism, particularly for phenytoin.

4. Patient Education and Support: Educate the patient about the importance of adherence to the medication regimen, potential side effects, and the need for regular follow-ups. Engage in shared decision-making to improve adherence and treatment outcomes.

Suggested approach to such a patient

The patient is experiencing breakthrough seizures occasionally. Multiple medications did not achieve optimal seizure control. The seizure was difficult to control even after taking six medications

Non-invasive evaluation under video EEG is suggested.

Radiofrequency ablation can be explored for the patient.

Radiofrequency ablation (RFA) is a minimally invasive procedure used for patients with intractable partial seizures not controlled by medication. It involves advanced imaging and EEG to precisely locate the seizure focus, followed by the insertion of electrodes to deliver radiofrequency energy, destroying the abnormal brain tissue. Benefits include shorter recovery times and potential seizure control, though it carries risks such as bleeding and infection. RFA is suitable for patients with well-defined seizure foci and offers variable outcomes. Regular follow-up is essential to monitor seizure frequency and manage any complications.

Conclusion

A clinical pharmacy approach to managing patients on multiple anticonvulsants for difficult-to-control seizures involves a meticulous review of medication regimens, close monitoring of drug levels and interactions, and a focus on individualized patient care. This approach aims to optimize seizure control while minimizing adverse effects, improving the patient’s overall quality of life. To effectively manage a patient with “difficult-to-control” seizure disorder on multiple anticonvulsants such as levetiracetam, phenytoin, phenobarbital, clobazam, and oxcarbazepine, a clinical pharmacy approach must involve thorough evaluation, monitoring, and optimization of therapy. Radiofrequency ablation (RFA) offers a promising treatment option for patients with intractable partial seizures who have not responded to medications.

Reference

Zaccara, E. Perucca, Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.
Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. The Lancet Neurology. 2003;2(8):473-481.
Perucca E, Gilliam FG. Adverse effects of antiepileptic drugs. The Lancet Neurology. 2012;11(9):792-802.
Johannessen SI, Landmark CJ. Antiepileptic drug interactions – principles and clinical implications. CurrNeuropharmacol. 2010;8(3):254-267.
Löscher W, Klein P. The pharmacology and clinical efficacy of antiseizure medications: From bromide salts to cenobamate and beyond. CNS Drugs. 2021;35(9):935-963.
Patsalos PN. Drug interactions with the newer antiepileptic drugs (AEDs)—Part 2: Pharmacokinetic and pharmacodynamic interactions between AEDs and drugs used to treat non-epilepsy disorders. Clinical Pharmacokinetics. 2013;52(12):1045-1061.

Ms. Dharsshini. N
Group Clinical Pharmacist

Clinical Pharmacy Approach: To a patient on multiple anticonvulsants for “Difficult to control’’ seizure disorder

Clinical Pharmacy Approach: To a patient on multiple anticonvulsants for “Difficult to control’’ seizure disorder

Dharsshini. N

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