Current Medications for Seizure Control

Transcription

1 Current Medications for Seizure Control Nabil J. Azar, M.D. Assistant Professor of Neurology Director, Clinical Neurophysiology Training Program Medical Director, Intra-operative Neuromonitoring Vanderbilt University Medical Center Nashville, TN

2 Outline General principles of antiepileptic (AED) drugs use AED selection: a. Depends on type of seizures and epilepsy syndrome b. Old vs. new AEDs c. Safety and ease of use d. Presence of other medical conditions e. Titration rate and dosing f. Special populations: - Children - Women of child bearing age - elderly Limitations of AED drug therapy

3 Goal of epilepsy treatment Seizure freedom and no side effects Efficacy and tolerability

4 Initiation of AED therapy Diagnosis: seizure type (s), epilepsy syndrome and etiology (if possible). Selection of best (or ideal) AED: - Efficacy: one AED (monotherapy) is the goal - Safety - Tolerability - Pharmacokinetic advantages - Titration rate - Dosing - Comorbidities

5 Newly treated epilepsy- outcome of AED treatment 470 patients with epilepsy who had never received AED treatment: 64% were seizure-free at follow-up Kwan & Brodie, Epilepsia 2001

6 Antiepileptic drugs (AEDs) old new Phenobarbital (Luminal) 1912 Primidone (Mysoline) Phenytoin (Dilantin) Methsuximide (Celontin) Ethosuximide (Zarontin) Clonazepam (Klonopin) Carbamazepine (Tegretol, Carbatrol) Valproate (Depakote) 1978 Coming soon: Eslicarbazepine, brivaracetam Felbamate (Felbatol) 1993 Gabapentin (Neurontin) Lamotrigine (Lamictal) Topiramate (Topamax) Tiagabine (Gabitril) Levetiracetam (Keppra) Oxcarbazepine (Trileptal) Zonisamide (Zonegran) Pregabalin (Lyrica) Vigabatrin (Sabril) Lacosamide (Vimpat) Clobazam (Onfi) Rufinamide (Banzel) Ezogabine (Potiga) 2012

7 Azar & Abou-Khalil; Sem in Neurol 2008

8 Azar & Abou-Khalil; Sem in Neurol 2008

9 Failed therapy due to lack of efficacy Option 1: substitution therapy- best if first AED has failed completely Option 2: add-on therapy- best if there has been some benefit all new AEDs

10 Questions to be answered when AEDs fail Some questions have to be asked: Is the diagnosis correct? Are we dealing with a different seizure type than we thought? are seizures non-epileptic? Are seizure medications used optimally? Is the patient taking the medication consistently? Are there other factors such as stress, sleep deprivation, alcohol, drug abuse, another medication that worsens seizures? Epilepsy may be truly resistant to medication treatment Epilepsy surgery, VNS, ketogenic diet, new drug trials

11 Advantageous combinations Advantages can be based on lack of interaction no significant interaction in either direction: gabapentin, levetiracetam, pregabalin do not significantly affect others, but have shorter half-life when added to an enzymeinducing AED: lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide Combinations with synergistic effects: Lamotrigine + valproate Levetiracetam + lamotrigine

12 Pharmacokinetic overview of old AEDs PHT CBZ VPA PHB PMD ESX CZP bioavailability >90% 75-85% >90% >90% >90% >90% >80% Protein binding 90% 75% 90% 45% <20% <10% 86% % Metabolism 95% >95% >96% 65-90% ~80% <80% Metabolism site Liver Liver Liver Liver Liver Liver Liver T1/ Enz. induction yes yes no yes yes no no Autoinduction no yes no no no no no Enz. Inhibition yes

13 Pharmacokinetic overview of new AEDs FBM GPN LTG TOP TGB LEV OXC ZNS PGB Absorption dose dependent no yes no no no no no no no bioavailability Tmax (hrs) >90% ~60% >98% >80% >89% ~100% ~1 99% 4-6* ~100% % Protein binding 25% 0% 55% 15% 96% 0% 40%* 40% 0% T1/ * Autoinduction no no slight no no no slight no no * applies to monohydroxyderivative (MHD), the main active metabolite

14 Pharmacological properties Old AEDs: - Liver induction / inhibition - Important autoinduction - High protein binding - Common blood level monitoring - Prevalent drug-drug interaction New AEDs: - No / mild liver induction / inhibition - No / mild autoinduction - Low protein binding - Less common blodd level monitoring - Minimal drug-drug interaction

15 Idiosynchratic toxicity of old AEDs PHT CBZ VPA PHB PMD ESX CZP Rash, enlarged lymph nodes, liver failure, blood abn Rash, other hypersensitivity, liver failure, blood abn Liver failure, pancreatitis (rare), blood abn Rash, connective tissue disorders, liver failure, blood Connective tissue disorders Blood abnormalitities Rash

16 Old AEDs: most problematic adverse effects PHT CBZ VPA PHB PMD ESX CZP Sedation, gum swelling Sedation, fatigue Sedation, weight gain, hair loss, hormonal changes Sedation, slow thinking, lower IQ Sedation, slow thinking Gastrointestinal malaise Sedation, constipation, tolerance

17 Idiosynchratic toxicity of new AEDs FBM GPN LTG TPM TGB Aplastic anemia, liver failure - Skin rash acute angle-closure glaucoma, oligohydrosis - LEV - OXC Rash ZNS Rash, oligohydrosis

18 New AEDs: most problematic adverse effects FBM GPN, PGB LTG TPM TGB LEV OXC ZNS GI upset, headache, insomnia Weight gain, myoclonus Insomnia Speech disorder, behavior changes, kidney stones Confusion, dizziness Irritability, nightmares Low sodium (hyponatremia) Behavioral changes, kidney stones

19 Tolerability - cognitive profiles of new AEDs Best - Lamotrigine - Gabapentin - Levetiracetam - Oxcarbazepine - Pregabalin - Lacosamide - Ezogabine Intermediate - Tiagabine - Zonisamide Worst - Topiramate

20 Prevalence of comorbidity Depression (50%) Bipolar disorder (10%) Panic attacks 50 % Migraine: 25 % Sleep disturbances: >25% Restless leg syndrome: 10 % Obesity 30 % Spasticity: cerebral palsy, multiple sclerosis Peripheral neuropathy Chronic pain syndromes

21 Nonepileptic indications Azar & Abou-Khalil, Sem in Neurol 2008

22 How other medical conditions influence our choice Migraine: valproate, topiramate(? for levetiracetam, zonisamide) Bipolar disease: lamotrigine, valproate(? gabapentin, topiramate, oxcarbazepine) Obesity: topiramate, zonisamide, felbamate Obesity + migraine: topiramate Peripheral neuropathy, chronic pain syndromes: pregabalin, gabapentin

23 Titration rates: initiation at therapeutic doses Rapid titration: - Most of old AEDs - Felbamate - Gabapentin - Zonisamide - Levetiracetam * - Pregabalin - Lacosamide * Slow titration: - Lamotrigine - Topiramate - Tiagabine - Vigabatrin - Ezogabine * Available in intravenous form

24 Special considerations in Children General rules: - Avoid sedating AEDs because of comorbid disorders (autism, mental retardation ) - Go slower and lower Specifics: - Rash with lamictal is more serious - Psychosis with keppra is more common - Oligohydrosis with topamax and zonegran more lethal - Fulminant liver failure with depakote is more likely (2 years<) Nadkarni et a; Neurology 2005 Bryant & Dreifuss; Neurology 1996 Pellock & Brodie; Epilepsia 1997

25 Women of childbearing potential Infertility: more common than normal population Reproductive and sexual dysfunction: Deapkote causing PCOS reversible with lamotrigine Oral contraceptive pills (OCP): - Lowered efficacy by enzyme inducing AEDs; PHB, PHT, CBZ, PMD, TPM (>200 mg) and OXC (>900 mg) - estradiol (OCP, pregnancy) lowers efficacy of lamotrigine Developmental abnormalities in exposed fetus: VPA has the highest risk (7-8 %) especially in polytherapy and high dosages, followed by CBZ and PHT (5-6 %). Some new AEDs appear safer in event of unexpected pregnancy (ex: LTG, OXC,? LEV?, TPM?, ZNS?) Folic acid (1-4 mg daily) Lofren et al; Epilepsy Res 2007 Artama et al; Neurology 2005

26 Special considerations in the elderly General rules: - Avoid sedating AEDs because of comorbid disorders (polytherapy, dementia ) - Go slower and lower: respond better to low doses - Avoid enzyme-inducing and highly protein-bound AEDs (i.e AEDs) - Anaylze blood levels with caution (ask for free levels) - Use extended release formulation (especially with CBZ, VPA) - Use new AEDs Specifics: - Hyponatremia with trileptal is common (especially when taking diuretics) - Reversible Parkinsonism with chronic VPA is not rare - Renal calculi with TPM and ZNS are more likely - Osteopenia and osteaporosis with PB, PHT and CBZ are very common Armaon et al; Neurology 1996 Perucca et al; Epilepsy Res 2006 Saetre et al; Epilepsia 2007

27 New versus old AEDs- summary Old - Established efficacy - Poor tolerability: more sedation - Safety issues - Fast titration - Major interactions - Blood level monitoring - Disrupt hormonal milieu - Reduce bone density New - Similar efficacy - Better tolerability - Better safety - Slower titration - Less interactions - More expensive - Less teratogenicity - High in breast milk

28 Limitations of AED therapy Treats the symptoms or seizures and not the disease or epilepsy Does not prevent the development or progression of epilepsy Does not cure epilepsy We need drugs with: - Better efficacy and tolerability - Prevent epilepsy - Reverse the process of epileptogenesis