Participants 396
– First-Line Medications: Antiseizure medications (ASMs) are the cornerstone of epilepsy treatment. The choice of ASM depends on the type of epilepsy, seizure type, patient age, comorbid conditions, and potential side effects.
– Monotherapy vs. Polytherapy: Monotherapy is preferred initially. Polytherapy may be considered in refractory cases or when monotherapy fails to control seizures effectively.
– Medication Adjustment: Regular monitoring and dosage adjustments are essential to optimize treatment efficacy and minimize side effects.
Non-Pharmacological Interventions
– Dietary Therapies: The ketogenic diet, modified Atkins diet, and low glycemic index treatment can be effective, especially in children with refractory epilepsy.
– Lifestyle Modifications: Adequate sleep, stress management, and avoiding seizure triggers are crucial.
Surgical Treatments
– Candidates for Surgery: Considered for patients with drug-resistant epilepsy, especially if a focal point of seizure origination (epileptogenic zone) can be identified.
– Types of Surgery: Includes resective surgery (like temporal lobectomy), laser ablation therapy, and neurostimulation techniques (e.g., vagus nerve stimulation, deep brain stimulation).
Supportive Care
– Mental Health: Addressing comorbid conditions like depression and anxiety is important.
– Patient Education: Educating patients and families about epilepsy, treatment options, and lifestyle considerations is vital for effective management.
Pharmacotherapy of Epilepsy: First Generation Antiepileptic Drugs (AEDs)
The management of epilepsy through pharmacotherapy is central to the practice of neurology and general medicine. First-generation antiepileptic drugs (AEDs) have been foundational in the treatment of this condition. Despite the introduction of newer agents, these first-generation drugs remain highly relevant due to their established efficacy, familiarity amongst clinicians, and cost-effectiveness. This chapter focuses on a set of first-generation AEDs, namely Carbamazepine, Clonazepam, Ethosuximide, Phenobarbital, Phenytoin, Primidone, and Valproic Acid. We will explore their dosages, therapeutic drug monitoring (TDM) ranges, and clinical considerations indispensable for healthcare professionals.
Carbamazepine
– Indications: Effective for partial seizures, generalized tonic-clonic seizures, and trigeminal neuralgia.
– Pharmacokinetics: Well-absorbed, peak plasma concentrations in 4-8 hours, metabolized in the liver.
– Initial Dosing: 100-200 mg twice daily, increasing gradually every 1-2 weeks.
– Maintenance Dosing: 800 to 1200 mg/day in divided doses.
– Considerations: Auto-induction of metabolism, requiring dose adjustments.
– Side Effects: Dizziness, diplopia, ataxia, blood dyscrasias, Steven-Johnson syndrome.
– Drug Interactions: Induces cytochrome P450 enzymes.
– Contraindications and Precautions: History of bone marrow suppression, hypersensitivity to tricyclic antidepressants.
Clonazepam
– Initial Dosing: 0.5 mg/day, increasing by 0.5-1 mg every 3 days.
– Maintenance Dosing: 4 to 8 mg/day.
– Considerations: Development of tolerance, requiring smallest effective dose.
– Mechanism of Action: Enhances GABA activity.
– Indications: Absence seizures, myoclonic seizures, anxiety disorders.
– Pharmacokinetics: Peak plasma concentrations in 1-4 hours, long half-life.
– Dose Adjustments: Reduction in hepatic impairment, elderly patients.
– Side Effects: Sedation, dizziness, cognitive impairment.
– Drug Interactions: Potentiation of CNS depressants.
– Contraindications and Precautions: Caution in respiratory disease, history of substance abuse.
Ethosuximide
– Initial Dosing: 250 mg/day for children, 500 mg/day for adults.
– Maintenance Dosing: 20 mg/kg/day.
– Considerations: Primarily for absence seizures, gradual reduction if discontinued.
– Mechanism of Action: Reduces low-threshold calcium currents.
– Indications: Absence seizures.
– Pharmacokinetics: Peak levels in 3-7 hours, half-life of 40-60 hours.
– Dose Adjustments: No major adjustments for renal or hepatic impairment.
– Side Effects: Gastrointestinal disturbances, lethargy, headache.
– Drug Interactions: Minimal.
– Contraindications and Precautions: Caution in psychotic disorders.
Valproic Acid
– Initial Dosing: 10-15 mg/kg/day, increasing by 5-10 mg/kg/week.
– Maintenance Dosing: 20 to 60 mg/kg/day.
– Considerations: Hepatotoxicity risk, liver function monitoring.
– Mechanism of Action: Increases GABA, suppresses neuronal firing.
– Indications: Absence, myoclonic, tonic-clonic seizures.
– Pharmacokinetics: Rapid absorption, peak in 1-4 hours, highly protein-bound.
– Dose Adjustments: Reduced in liver impairment.
– Side Effects: Gastrointestinal disturbances, tremor, weight gain.
– Drug Interactions: Inhibits metabolism of many drugs.
– Contraindications and Precautions: Hepatic disease or dysfunction.
Phenobarbital
– Initial Dosing: Adults: 1-3 mg/kg/day; Children: 3-5 mg/kg/day.
– Maintenance Dosing: Adults: 60-180 mg/day; Children: 3-6 mg/kg/day.
– Considerations: Once-daily dosing, sedative effects.
– Mechanism of Action: Potentiates GABA, inhibits glutamate activity.
– Indications: Various seizure types.
– Pharmacokinetics: Slow absorption, long half-life (75-120 hours).
– Dose Adjustments: Adjustments in hepatic impairment, elderly.
– Side Effects: Sedation, cognitive impairment, dependence.
– Drug Interactions: Induces cytochrome P450 enzymes.
– Contraindications and Precautions: Acute intermittent porphyria, hypersensitivity to barbiturates.
Phenytoin
– Initial Dosing: Loading dose of 15-20 mg/kg, then 4-6 mg/kg/day.
– Maintenance Dosing: Max 300 mg/day in divided doses.
– Considerations: Non-linear kinetics, careful monitoring required.
– Mechanism of Action: Blocks voltage-gated sodium channels.
– Indications: Partial and tonic-clonic seizures.
– Pharmacokinetics: Variable absorption, nonlinear kinetics.
– Dose Adjustments: Monitoring in hepatic impairment, elderly.
– Side Effects: Nystagmus, ataxia, gingival hyperplasia, hirsutism.
– Drug Interactions: Numerous due to liver enzyme effects.
– Contraindications and Precautions: Hypersensitivity to phenytoin or hydantoins.
Primidone
– Initial Dosing: Start with 100-125 mg at bedtime, increasing by 125 mg every 3 days.
– Maintenance Dosing: 750 mg to 1.5 g/day in divided doses.
– Considerations: Metabolized to phenobarbital, requires monitoring.
– Mechanism of Action: Metabolized to phenobarbital and PEMA.
– Indications: Partial and generalized tonic-clonic seizures.
– Pharmacokinetics: Gastrointestinal absorption, liver metabolism.
– Dose Adjustments: Reduced dose in elderly, caution in renal/hepatic impairment.
– Side Effects: Similar to phenobarbital.
– Drug Interactions: CNS depressants, liver enzyme induction.
– Contraindications and Precautions: Similar to phenobarbital.
Therapeutic Drug Monitoring (TDM)
– Carbamazepine: 4-12 µg/mL
– Clonazepam: 20-70 ng/mL
– Ethosuximide: 40-100 µg/mL
– Phenobarbital: 15-40 µg/mL
– Phenytoin: 10-20 µg/mL
– Primidone (and phenobarbital): 5-12 µg/mL (primidone), 15-40 µg/mL (phenobarbital)
– Valproic Acid: 50-100 µg/mL
Clinical Considerations
– Dosing Within Recommended Ranges: Efficacy and safety, individual variability.
– Outside Recommended Ranges: Subtherapeutic risk, supratherapeutic toxicity.
– Dose Adjustments: Based on patient response and side effects, co-medications.
– Personalized Approach: Pharmacogenomics, comorbidity considerations.
– Practical Aspects of Dose Adjustment: Gradual titration, monitoring for side effects.
– Drug Interactions: Vigilance for interactions, including over-the-counter drugs.
– Counseling and Education: Importance of adherence, potential side effects.
– Adjustment in Special Populations: Considerations for pregnant women, elderly, renal/hepatic impairment.
– Emergency Situations: Management of status epilepticus with AEDs.
Pharmacotherapy of Epilepsy – Second Generation Antiepileptic Drugs
With the evolution of epilepsy management, second-generation antiepileptic drugs (AEDs) have emerged as pivotal agents due to their advanced pharmacological profiles and patient-friendly characteristics. This chapter delves into the clinical application of these newer AEDs, including Topiramate, Zonisamide, Felbamate, Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine, and Tiagabine. These agents are lauded for their broad therapeutic indices, minimal side effects, and fewer drug interactions, marking a significant advancement from their first-generation counterparts.
Topiramate (Topamax, Trokendi XR)
– MOA: Topiramate modulates neuronal activity primarily by blocking voltage-dependent sodium channels and enhancing GABAergic inhibition.
– nitial Dosing: Start with 25-50 mg nightly for one week, increasing by 25-50 mg increments weekly.
– Maintenance Dosing: Typically ranges from 200 to 400 mg/day in two divided doses.
– Extended-Release (XR) Formulation: Approved for patients aged 6 and older, starting at lower doses and titrating to a maximum recommended TDD of 400 mg; however, up to 1,600 mg has been used in special circumstances like status epilepticus.
– Considerations: Slow titration is necessary to minimize side effects such as cognitive dulling.
– Therapeutic Monitoring: While TDM ranges are not strictly defined, clinical monitoring for efficacy and side effects is recommended.
– Zonisamide:
– MOA: Zonisamide stabilizes neuronal membranes and reduces neuronal hyper-synchronization by blocking voltage-dependent sodium and T-type calcium channels.
– Initial Dosing: Begin with 100 mg daily; increase by 100 mg increments every two weeks.
– Maintenance Dosing: Effective doses are usually 300 to 600 mg/day in one or two divided doses.
– Considerations: Requires adequate hydration to prevent kidney stones.
– Therapeutic Range: Aim for plasma levels of 10-40 mcg/mL, adjusting the dose to achieve the best balance between efficacy and side effects.
– Felbamate:
– MOA: Felbamate modulates synaptic transmission through actions at the NMDA receptor and inhibitory effects on voltage-gated sodium channels.
– Initial Dosing: 1200 mg/day in three to four divided doses.
– Maintenance Dosing: Can be increased by 1200 mg increments at weekly intervals to 3600 mg/day max.
– Considerations: Due to serious adverse effects, including aplastic anemia and hepatotoxicity, it is reserved for severe refractory epilepsy.
– Gabapentin:
– MOA: Gabapentin binds to the α2δ subunit of voltage-gated calcium channels, reducing calcium influx and subsequent neurotransmitter release.
– Initial Dosing: Start with 300 mg three times a day.
– Maintenance Dosing*: Can be increased up to a maximum of 1800-3600 mg/day based on response and tolerability.
– Considerations: Renal function should be considered when dosing; dose adjustments are necessary in patients with renal impairment.
– Lamotrigine:
– MOA: Lamotrigine acts by inhibiting voltage-sensitive sodium channels, leading to stabilization of neuronal membranes and inhibition of repetitive neuronal firing.
– Initial Dosing: For patients not taking valproic acid, begin with 25 mg daily for two weeks, followed by 50 mg daily for two weeks, then increase by 50-100 mg every 1-2 weeks.
– Maintenance Dosing: Maintenance doses generally range between 100 to 200 mg/day in one or two divided doses.
– Considerations: If used with valproic acid, start at a lower dose and titrate slowly to avoid rash, including the life-threatening Stevens-Johnson syndrome.
– Levetiracetam:
– MOA: Levetiracetam exerts its effects by binding to the synaptic vesicle protein SV2A, which is thought to modulate neurotransmitter release.
– Initial Dosing: Start with 500 mg twice daily.
– Maintenance Dosing: Maintenance dose typically ranges from 1000 to 3000 mg/day, divided into two doses.
– Considerations: It has a favorable side effect profile, but behavioral side effects should be monitored.
– Therapeutic Range: Target plasma levels of 4-20 mcg/mL, with dose adjustments made in consideration of other antiseizure medications that may affect lamotrigine levels.
– Oxcarbazepine:
– MOA: Oxcarbazepine and its active metabolite, monohydroxy derivative (MHD), block voltage-sensitive sodium channels, stabilizing hyperexcitable neuronal membranes.
– Initial Dosing: Begin with 300 mg twice daily.
– Maintenance Dosing: May be increased to achieve a dose of 600 to 2400 mg/day.
– Considerations: Hyponatremia is a potential side effect; monitor sodium levels, especially in the elderly or in those with cardiac or renal conditions.
– Therapeutic Range: Target plasma levels of 3-35 mcg/mL, with dose adjustments made in consideration.
– Tiagabine:
– MOA: Tiagabine increases GABA levels by selectively inhibiting the reuptake of GABA into presynaptic neurons.
– Initial Dosing: Start with 4 mg daily, usually given with food.
– Maintenance Dosing: The dose can be increased by 4-8 mg at weekly intervals; usual maintenance dose is 32 to 56 mg/day in divided doses.
– Considerations: Should be used with caution in patients with a history of absence seizures as it can potentially exacerbate this type of seizure.
– Therapeutic Range: Target plasma levels of 0.02-0.2 mcg/mL, with dose adjustments made in consideration of other antiseizure medications.
Therapeutic Drug Monitoring (TDM)
While second-generation AEDs typically require less monitoring than first-generation drugs, TDM can still be an important tool in specific clinical situations to ensure therapeutic efficacy and avoid toxicity.
– When to Monitor:
– With the initiation of therapy to establish a baseline.
– When reaching a stable dose to confirm therapeutic levels.
– In the case of suspected noncompliance, toxicity, or lack of efficacy.
– When drug-drug interactions are a concern.
– In special populations (e.g., pregnancy, renal/hepatic dysfunction).
Clinical Application and Personalization
The application of second-generation AEDs should be tailored to the individual patient, considering factors like seizure type, comorbidities, concomitant medications, and individual patient preferences and tolerability.
– Titration and Adjustment:
– The titration schedule should be adjusted based on the patient’s response and the presence of side effects. Slow titration may be necessary for those with a history of medication sensitivity.
– Dose adjustments may be necessary in response to changes in seizure frequency or severity, side effects, or changes in the patient’s weight or metabolic rate.
– Side Effect Management:
– Educate patients to report any cognitive, behavioral, or mood changes.
– Assess for more common side effects such as fatigue, dizziness, and weight changes.
– Monitor for rare but serious side effects, such as rash with lamotrigine or metabolic acidosis with topiramate.
– Special Considerations:
– In women of childbearing potential, discuss the potential teratogenic risks of AEDs and the need for effective contraception.
– Regularly review the need for continued therapy, especially in patients who have been seizure-free for significant periods.
– Consider the impact of AEDs on bone health, particularly with long-term use, and discuss preventive measures such as supplementation and lifestyle modifications.
Pharmacotherapy of Epilepsy – Third Generation Antiepileptic Drugs
In the ever-evolving landscape of epilepsy treatment, third-generation antiepileptic drugs (AEDs) stand out for their novel mechanisms of action, targeted efficacy, and improved safety profiles. These drugs have been developed to address the limitations of earlier generations, such as drug-drug interactions and side effects, with the goal of delivering personalized care to patients with epilepsy. This chapter introduces third-generation AEDs, discussing their clinical significance, and providing detailed insights into pharmacokinetics, dosing, and therapeutic monitoring. Emphasis is placed on the importance of integrating these modern AEDs into comprehensive care plans tailored to the unique needs of each patient.
Lacosamide (Vimpat)
– Mechanism of Action: Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, which stabilizes hyperexcitable neuronal membranes and inhibits repetitive neuronal firing.
– Dosing Guidelines:
– Initial Dosing: Begin with 50 mg twice daily, which can be increased to 100 mg twice daily after one week.
– Maintenance Dosing: The typical maintenance dose ranges from 200 to 400 mg per day, divided into two doses.
– Therapeutic Monitoring:
– Regular clinical monitoring is advised for efficacy and side effects, with dose adjustments as needed based on clinical response.
– While there is no well-defined therapeutic plasma concentration range, monitoring may be useful in cases of potential drug interactions, side effects, or changes in seizure control.
– Clinical Considerations:
– Lacosamide is generally well-tolerated, with dizziness and headache being the most common side effects.
– It has a low potential for drug-drug interactions, making it a suitable option for polytherapy.
– Cardiac conduction abnormalities have been noted; therefore, caution is advised in patients with known cardiac conduction problems.
Rufinamide (Banzel)
– Mechanism of Action: Rufinamide is thought to limit the sustained repetitive firing of sodium-dependent action potentials, which is a common characteristic of epileptic networks.
– Dosing Guidelines:
– Initial Dosing: For patients over 17 years, start with a total daily dose of 800-1600 mg, divided into two doses.
– Maintenance Dosing: Adjusted based on therapeutic response and tolerability, up to a maximum recommended daily dose of 3200 mg.
– Therapeutic Monitoring:
– TDM is not routinely performed for rufinamide, but plasma level monitoring may be considered in special situations, such as when drug interactions are suspected or in cases of refractory epilepsy.
– Clinical Considerations:
– Rufinamide is approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome, a severe form of childhood-onset epilepsy.
– The side effect profile includes headache, dizziness, and fatigue, with a risk of QT shortening on the electrocardiogram, necessitating caution in patients with cardiac risk factors.
Eslicarbazepine Acetate (Aptiom)
– Mechanism of Action: Eslicarbazepine acetate works by blocking voltage-gated sodium channels, thereby stabilizing hyperexcitable neuronal membranes and preventing repetitive neuronal firing.
– Dosing Guidelines:
– Initial Dosing: The recommended starting dose is 400 mg once daily, which can be increased to 800 mg once daily after one week based on the patient’s response.
– Maintenance Dosing: Depending on the patient’s response and tolerability, the dose can be adjusted up to a maximum of 1200 mg once daily.
– Therapeutic Monitoring:
– Although routine TDM is not typically necessary, monitoring may be helpful in situations of potential drug interactions, during pregnancy, or in instances of altered metabolic capacity.
– Clinical Considerations:
– Eslicarbazepine acetate is generally well-tolerated, with dizziness, somnolence, and nausea as the most common side effects.
– It has a reduced potential for drug-drug interactions and is often used as monotherapy or adjunctive therapy for focal seizures.
Perampanel (Fycompa)
– Mechanism of Action: Perampanel is a selective non-competitive antagonist of the AMPA glutamate receptor on postsynaptic neurons, which reduces excitatory neurotransmission.
– Dosing Guidelines:
– Initial Dosing: The initial dose is usually 2 mg per day taken orally at bedtime, which can be titrated upwards based on response and tolerability.
– Maintenance Dosing: Maintenance doses typically range from 4 to 12 mg per day, adjusted in increments of 2 mg per week.
– Therapeutic Monitoring:
– Perampanel does not usually require TDM, but plasma levels may be checked in special circumstances, such as when unexpected side effects occur or if adherence is in question.
– Clinical Considerations:
– The drug’s most notable side effects include dizziness, fatigue, irritability, and a risk of behavioral and psychiatric adverse events.
– Due to its long half-life and potential for significant central nervous system-related side effects, cautious titration and close monitoring for mood changes or aggression are recommended.
Brivaracetam (Briviact)
– Mechanism of Action: Brivaracetam binds to the synaptic vesicle protein 2A (SV2A) in the brain, similar to levetiracetam, but with a higher affinity, which may modulate neurotransmitter release and reduce seizure propagation.
– Dosing Guidelines:
– Initial Dosing: For adults, the starting dose is typically 50 mg twice daily, which can be adjusted based on seizure control and tolerability.
– Maintenance Dosing: The usual maintenance dose ranges from 50 to 200 mg per day, divided into two doses.
– Therapeutic Monitoring:
– Routine TDM is not typically indicated for brivaracetam. Monitoring may be useful in specific clinical scenarios, such as during dose adjustments or in the presence of potential drug interactions.
– Clinical Considerations:
– Side effects can include somnolence, fatigue, dizziness, and, less commonly, behavioral changes.
– Brivaracetam may offer an alternative for patients who have experienced psychiatric side effects with levetiracetam, although caution is still advised.
Cannabidiol (Epidiolex)
– Mechanism of Action: Cannabidiol, a derivative of Cannabis sativa, is believed to have multiple actions, including modulation of the endocannabinoid system, although its exact antiepileptic mechanisms are not fully understood.
– Dosing Guidelines:
– Initial Dosing: The starting dosage is 2.5 mg/kg taken twice daily, which can be doubled after one week to achieve a dose of 5 mg/kg twice daily.
– Maintenance Dosing: If further seizure reduction is needed, the dose may be increased in weekly increments of 2.5 mg/kg twice daily, up to a recommended maximum dosage of 10 mg/kg twice daily.
– Therapeutic Monitoring:
– Monitoring of plasma levels of cannabidiol is not generally required; however, levels of concomitant AEDs may need to be monitored due to potential interactions.
– Clinical Considerations:
– Its side effect profile includes diarrhea, somnolence, appetite changes, and potential liver enzyme elevations, necessitating regular monitoring of liver function.
– Cannabidiol is specifically approved for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravetsyndrome, and tuberous sclerosis complex, expanding the therapeutic options for these challenging epilepsy syndromes.