Review of Anticonvulsant Medications: Traditional and Alternative Uses. Andrea Michel, PharmD, CACP

Review of Anticonvulsant Medications: Traditional and Alternative Uses Andrea Michel, PharmD, CACP

Objectives Review epidemiology of epilepsy Classify types of seizures Discuss non-pharmacologic and pharmacologic treatment options for epilepsy Outline common adverse reactions and prevalent drug-drug interactions associated with anticonvulsant medications Highlight important considerations for special patient populations with epilepsy State appropriate plan for anticonvulsant medication therapy discontinuation

Epilepsy

Definition Central nervous system disorder in which brain activity becomes abnormal, causing seizures or periods of unusual behavior, sensations, and sometimes loss of awareness Epilepsy diagnosis requires: History of >2 seizures at least 24 hours apart OR 1 seizure with significant risk of recurrence (e.g. recent stroke, brain structure abnormality, abnormal electroencephalography (EEG))

Prevalence in the US 3 Million adults & 470,ooo children 1.2% of population Epidemiology CDC: Epilepsy Data and Statistics. Accessed 9/2018. https://www.cdc.gov/epilepsy/data/index.html.

Causes Mechanical birth injuries, head trauma, tumors, stroke Metabolic electrolyte disturbances, hypoglycemia Genetic Influence familial neonatal seizures, juvenile myoclonic epilepsy (JME) Other fever, infectious disease

Causes Drugs Recreational drugs Carbapenems Meperidine Local anesthetics Metoclopramide Theophylline Tricyclic antidepressants Anticonvulsant therapy: carbamazepine, phenytoin, phenobarbital

Diagnosis Medical History Physical and Neurological Exam Lab tests Electroencephalogram (EEG) Magnetic resonance imaging (MRI)

Classification of Seizures

Focal seizure Focal Seizure One hemisphere of the brain Unilateral, asymmetric movements Associated with an aura Other terms: simple partial seizure, complex partial seizure, secondarily generalized seizure

Generalized seizure Generalized seizure Begins simultaneously in both brain hemispheres Types of generalized seizures: 1. Absence 2. Myoclonic 3. Tonic-clonic 4. Clonic 5. Tonic 6. Atonic

Unknown onset seizure Unknown seizure Reserved for seizures that are unwitnessed Occur while patient is asleep Observers cannot provide an adequate description

Status epilepticus Status Epilepticus Seizure that lasts >20 minutes OR >2 seizures with incomplete recovery of consciousness between episodes Medical emergency Up to 20% mortality rate

Treatment of Epilepsy

Treatment Non-Pharmacologic Surgical Procedures Vagus Nerve Stimulation Dietary Restrictions Pharmacologic Anticonvulsant medication therapy

Anticonvulsant Therapy

Treatment algorithm DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 9 th ed. Figure 40-1.

First Line Treatment of New-Onset Epilepsy for Patients > 13YO National Institute for Health and Care Excellence (NICE). Epilepsies: Diagnosis and Management. Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Neurology Jul 2018;81:74-81.

Adverse Effects Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Neurology Jul 2018;81:74-81.

Adverse Effects Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I:: Treatment of new-onset epilepsy. Neurology Jul 2018;81:74-81.

Drug Selection Serious adverse effects rapid discontinuation required Drug reaction with eosinophilia and system symptoms (DRESS) Stevens-Johnson syndrome (SJS) Toxic epidermal necrolysis (TEN)

Pharmacogenomic Considerations Drug Selection Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Neurology Jul 2018;81:74-81.

Drug Selection Drug Interactions!

Metabolism and Monitoring Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Neurology Jul 2018;81:74-81.

Interactions of Non-AEDs Ryan, M. Neurology: ACCP Updates in Therapeutics 2013: The Pharmacotherapy Review and Recertification Course. Lenexa, KS. 2013: 1-194-195.

Drug Selection Alternative indications Mood stabilization related to bipolar disorder: valproate, carbamazepine, and lamotrigine Neuropathic pain & postherpetic neuralgia: gabapentin and pregabalin Migraine prophylaxis: valproate and topiramate Essential tremor: primidone Trigeminal neuralgia: carbamazepine Anxiety: phenobarbital

Adjunct Therapy Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Neurology Jul 2018;81:74-81.

Adjunct Therapy Ryan, M. Neurology: ACCP Updates in Therapeutics 2013: The Pharmacotherapy Review and Recertification Course. Lenexa, KS. 2013: 1-194-195.

Special Populations

Elderly Pharmacokinetic changes in aging population may affect therapy 1. Carbamazepine: Decreased clearance 2. Phenytoin: Decreased protein binding if renal failure or hypoalbuminemic 3. Valproic acid: Decreased protein binding 4. Diazepam: Increased half-life 5. Lamotrigine: Decreased clearance 6. Seizure medications with renal elimination must be adjusted based on CrCl

Women s Health Reproductive years: Match best drug for seizure type Monotherapy, if possible Discuss possible decrease in hormonal contraceptive effectiveness if appropriate Ideal to be seizure free for at least 9 months before pregnancy Folic acid 1 mg daily

Women s Health During pregnancy: Avoid valproic acid monotherapy or polytherapy during 1st trimester Avoid use of seizure medication polytherapy throughout complete pregnancy Avoid use of phenytoin, carbamazepine, and phenobarbital, if possible Lamotrigine has a lower relative risk of congenital malformations

Treatment discontinuation

Treatment discontinuation Consider withdrawal of anticonvulsants: Remain seizure-free for 2 or more years Control obtained with 1 drug Normal neurologic examination EEG normalized with seizure medication treatment No history of seizure relapse after drug withdrawal Withdraw 1 drug at a time Taper over several months Common regimen: reduce the dose by 1/3 for 1 month, reduce by another 1/3 for 1 month, and then stop

Other Considerations

Sexual Dysfunction Reported in 30-60% of men and women with epilepsy Mechanism: Induction of CYP isoenzymes to increase testosterone metabolism Increased hepatic synthesis of sex hormone-binding globulin Induction of aromatase; conversion to testosterone and estradiol Dysfunction associated with: carbamazepine, phenobarbital, phenytoin, pregabalin, topiramate, zonisamide Improved functioning with: lamotrigine and oxcarbazepine

Bone Health Osteopenia and osteoporosis reported in 38-60% in tertiary epilepsy clinics Increased risk based on treatment duration Evidence that all seizure medications likely contribute Treatment: Vitamin D (4000 IU/day for adults and 2000 IU/day for children)

Twice the risk of suicidal behavior or ideation for patients receiving seizure medications No difference between type of antiepileptic drug or age group Suicidality In 2008, FDA required warning and medication guide for all seizure medications

Questions?