Neuropharmacology of Antiepileptic Drugs American Epilepsy Society

Definitions  Seizure: the clinical manifestation of an abnormal synchronization and excessive excitation of a population of cortical neurons  Epilepsy: a tendency toward recurrent seizures unprovoked by acute systemic or neurologic insults

Antiepileptic Drug  A drug which decreases the frequency and/or severity of seizures in people with epilepsy  Treats the symptom of seizures, not the underlying epileptic condition  Goal—maximize quality of life by minimizing seizures and adverse drug effects

History of Antiepileptic Drug Therapy in the U.S.  1857 - Bromides  1912 - Phenobarbital  1937 - Phenytoin  1954 - Primidone  1960 - Ethosuximide

History of Antiepileptic Drug Therapy in the U.S.  1974 - Carbamazepine  1975 - Clonazepam  1978 - Valproate  1993 - Felbamate, Gabapentin  1995 - Lamotrigine  1997 - Topiramate, Tiagabine  1999 - Levetiracetam  2000 - Oxcarbazepine, Zonisamide

Antiepileptic Drug Therapy Structures of Commonly Used AEDs Chemical formulas of commonly used old and new antiepileptic drugs Adapted from Rogawski and Porter, 1993, and Engel, 1989

Antiepileptic Drug Therapy Structures of Commonly Used AEDs

Antiepileptic Drug Therapy Structures of Commonly Used AEDs Levetiracetam Oxcarbazepine Zonisamide

Antiepileptic Drug Therapy Structures of Commonly Used AEDs Pregabalin

Cellular Mechanisms of Seizure Generation  Excitation (too much) Ionic-inward Na+, Ca++ currents Neurotransmitter: glutamate, aspartate  Inhibition (too little) Ionic-inward CI-, outward K+ currents Neurotransmitter: GABA

AEDs: Molecular and Cellular Mechanisms  Phenytoin, Carbamazepine Block voltage-dependent sodium channels at high firing frequencies  Barbiturates Prolong GABA-mediated chloride channel openings Some blockade of voltage-dependent sodium channels  Benzodiazepines Increase frequency of GABA-mediated chloride channel openings

AEDs: Molecular and Cellular Mechanisms  Felbamate May block voltage-dependent sodium channels at high firing frequencies May modulate NMDA receptor via strychnine-insensitive glycine receptor  Gabapentin Increases neuronal GABA concentration Enhances GABA mediated inhibition  Lamotrigine Blocks voltage-dependent sodium channels at high firing frequencies May interfere with pathologic glutamate release

AEDs: Molecular and Cellular Mechanisms  Ethosuximide Blocks low threshold, “transient” (T-type) calcium channels in thalamic neurons  Valproate May enhance GABA transmission in specific circuits Blocks voltage-dependent sodium channels  Vigabatrin Irreversibly inhibits GABA-transaminase

AEDs: Molecular and Cellular Mechanisms  Topiramate Blocks voltage-dependent sodium channels at high firing frequencies Increases frequency at which GABA opens Cl- channels (different site than benzodiazepines) Antagonizes glutamate action at AMPA/kainate receptor subtype Inhibition of carbonic anydrase  Tiagabine Interferes with GABA re-uptake

AEDs: Molecular and Cellular Mechanisms  Levetiracetam Binding of reversible saturable specific binding site Reduces high-voltsge- activated Ca2+ currents Reverses inhibition of GABA and glycine gated currents induced by negative allosteric modulators  Oxcarbazepine Blocks voltage-dependent sodium channels at high firing frequencies Exerts effect on K+ channels  Zonisamide Blocks voltage-dependent sodium channels and T-type calcium channels

AEDs: Molecular and Cellular Mechanisms Pregabalin Increases neuronal GABA Increase in glutamic acid decarboxylase Decrease in neuronal calcium currents by binding of alpha 2 delta subunit of the voltage gated calcium channel

The GABA System The GABA system and its associated chloride channel From Engel, 1989

Pharmacokinetic Principles  Absorption: entry of drug into the blood Essentially complete for all AEDs (except gabapentin) Timing varies widely by drug, formulation, patient characteristics Generally slowed by food in stomach (CBZ may be exception) Usually takes several hours (importance for interpreting blood levels)

The Cytochrome P-450 Enzyme System Inducers Inhibitors phenobarbital erythromycin primidone nifedipine/verapamil phenytoin trimethoprim/sulfa carbamazepine propoxyphene tobacco/cigarettes cimetidine valproate

The Cytochrome P-450 Enzyme System  Substrates (metabolism enhanced by inducers): steroid hormones theophylline tricyclic antidepressants vitamins warfarin (many more)

The Cytochrome P-450 Isozyme System  The enzymes most involved with drug metabolism  Nomenclature based upon homology of amino acid sequences  Enzymes have broad substrate specificity, and individual drugs may be substrates for several enzymes  The principle enzymes involved with AED metabolism include CYP2C9, CYP2C19, CYP3A4

Drug Metabolizing Enzymes: UDP- Glucuronyltransferase (UGT)  Important pathway for drug metabolism/inactivation  Currently less well described than CYP  Several isozymes that are involved in AED metabolism include: UGT1A9 (VPA), UGT2B7 (VPA, lorazepam), UGT1A4 (LTG)

Drug Metabolizing Isozymes and AEDs AEDs that do not appear to be either inducers or inhibitors of the CYP system include: gabapentin, lamotrigine, tiagabine, levetiracetam, zonisamide.

Enzyme Inducers/Inhibitors: General Considerations  Inducers: Increase clearance and decrease steady-state concentrations of other substrates  Inhibitors: Decrease clearance and increase steady-state concentrations of other substrates

Pharmacokinetic Principles  Elimination: removal of active drug from the blood by metabolism and excretion Metabolism/biotransformation — generally hepatic; usually rate-limiting step Excretion — mostly renal Active and inactive metabolites Changes in metabolism over time (auto-induction with carbamazepine) or with polytherapy (enzyme induction or inhibition) Differences in metabolism by age, systemic disease

AED Inducers: General Considerations  Results from synthesis of new enzyme  Tends to be slower in onset/offset than inhibition interactions  Broad Spectrum Inducers: Carbamazepine Phenytoin Phenobarbital/primidone  Selective CYP3A Inducers: Felbamate, Topiramate, Oxcarbazepine

Inhibition  Competition at specific hepatic enzyme site  Onset typically rapid and concentration (inhibitor) dependent  Possible to predict potential interactions by knowledge of specific hepatic enzymes and major pathways of AED metabolism

AED Inhibitors  Valproate  Topiramate & Oxcarbazepine  Felbamate UDP glucuronosyltransferase (UGT)  plasma concentrations of Lamotrigine, Lorazepam CYP2C19  plasma concentrations of Phenytoin, Phenobarbital  Topiramate & Oxcarbazepine  plasma concentrations of Phenytoin  Felbamate CYP2C19  plasma concentrations of Phenytoin, Phenobarbital

Hepatic Drug Metabolizing Enzymes and Specific AED Interactions  Phenytoin CYP2C9 CYP2C19 Inhibitors: valproate, ticlopidine, fluoxetine, topiramate, fluconazole  Carbamazepine CYP3A4 CYP2C8 CYP1A2 Inhibitors: ketoconazole, fluconazole, erythromycin, diltiazem  Lamotrigine UGT 1A4 Inhibitor: valproate

Isozyme Specific Drug Interactions

Therapeutic Index  T.I. = ED 5O% /TD 50%  “Therapeutic range” of AED serum concentrations Limited data Broad generalization Individual differences

Steady State and Half Life From Engel, 1989

AED Serum Concentrations  In general, AED serum concentrations can be used as a guide for evaluating the efficacy of medication therapy for epilepsy.  Serum concentrations are useful when optimizing AED therapy, assessing compliance, or teasing out drug-drug interactions.  They should be used to monitor pharmacodynamic and pharmacokinetic interactions.

AED Serum Concentrations  Serum concentrations are also useful when documenting positive or negative outcomes associated with AED therapy.  Most often individual patients define their own “ therapeutic range” for AEDs.  For the new AEDs there is no clearly defined “therapeutic range”.

Potential Target Range of AED Serum Concentrations (mg/l) Carbamazepine 4-12 Ethosuximide 40-100 Phenobarbital 10-40 Phenytoin 10-20 Valproic acid 50-100

Potential Target Range of AED Serum Concentrations (mg/l) Gabapentin 6-21 Lamotrigine 5-18 Levetiracetam 10-40 Oxcarbazepine 12-24 (MHD) Pregabalin ?? Tiagabine ? Topiramate 4.0-25 Zonisamide 7-40

AEDs and Drug Interactions  Although many AEDs can cause pharmacokinetic interactions, several agents appear to be less problematic.  AEDs that do not appear to be either inducers or inhibitors of the CYP system include: Gabapentin Lamotrigine Pregabalin Tiagabine Levetiracetam Zonisamide

Pharmacodynamic Interactions  Wanted and unwanted effects on target organ Efficacy — seizure control Toxicity — adverse effects (dizziness, ataxia, nausea, etc.)

Pharmacokinetic Interactions: Possible Clinical Scenarios Be aware that drug interactions may occur when:  Addition of a new medication when inducer/inhibitor is present  Addition of inducer/inhibitor to existing medication regimen  Removal of an inducer/inhibitor from chronic medication regimen

Pharmacokinetic Factors in the Elderly  Absorption — little change  Distribution decrease in lean body mass important for highly lipid-soluble drugs fall in albumin leading to higher free fraction  Metabolism — decreased hepatic enzyme content and blood flow  Excretion — decreased renal clearance

Pharmacokinetic Factors in Pediatrics  Neonate—often lower per kg doses Low protein binding Low metabolic rate  Children—higher, more frequent doses Faster metabolism

Pharmacokinetics in Pregnancy  Increased volume of distribution  Lower serum albumin  Faster metabolism  Higher dose, but probably less than predicted by total level (measure free level)  Consider more frequent dosing

Adverse Effects  Acute dose-related—reversible  Idiosyncratic— uncommon rare potentially serious or life threatening  Chronic—reversibility and seriousness vary

Acute, Dose-Related Adverse Effects of AEDs  Neurologic/Psychiatric – most common Sedation, fatigue Unsteadiness, uncoordination, dizziness Tremor Paresthesia Diplopia, blurred vision Mental/motor slowing or impairment Mood or behavioral changes Changes in libido or sexual function

Acute, Dose-Related Adverse Effects of AEDs (cont.)  Gastrointestinal (nausea, heartburn)  Mild to moderate laboratory changes Hyponatremia (may be asymptomatic) Increases in ALT or AST Leukopenia Thrombocytopenia  Weight gain/appetite changes

Idiosyncratic Adverse Effects of AEDs  Rash, Exfoliation  Signs of potential Stevens-Johnson syndrome Hepatic Damage Early symptoms: abdominal pain, vomiting, jaundice Laboratory monitoring probably not helpful in early detection Patient education Fever and mucus membrane involvement

Idiosyncratic Adverse Effects of AEDs  Hematologic Damage (marrow aplasia, agranulocytosis) Early symptoms: abnormal bleeding, acute onset of fever, symptoms of anemia Laboratory monitoring probably not helpful in early detection Patient education

Long-Term Adverse Effects of AEDs  Neurologic: Neuropathy Cerebellar syndrome  Endocrine/Metabolic Effects Vitamin D – Osteomalacia, osteoporosis Folate – Anemia, teratogenesis Altered connective tissue metabolism or growth  Facial coarsening  Hirsutism  Gingival hyperplasia

Pharmacology Resident Case Studies American Epilepsy Society Medical Education Program

Pharmacology Resident Case Studies  Tommy is a 4 year old child with a history of intractable seizures and developmental delay since birth.  He has been tried on several anticonvulsant regimens (i.e., carbamazepine, valproic acid, ethosuximide, phenytoin, and phenobarbital) without significant benefit.

Case #1 – Pediatric Con’t  Tommy’s seizures are characterized as tonic seizures and atypical absence seizures and has been diagnosed with a type of childhood epilepsy known as Lennox-Gastaut Syndrome.

Case #1 – Pediatric Con’t Briefly describe what characteristics are associated with Lennox-Gastaut Syndrome. What anticonvulsants are currently FDA approved for Lennox-Gastaut Syndrome?

Case #1 – Pediatric Con’t 3. Tommy is currently being treated with ethosuximide 250 mg BID and valproic acid 250 mg BID. The neurologist wants to add another anticonvulsant onto Tommy’s current regimen and asks you for your recommendations. (Hint: Evaluate current anticonvulsants based on positive clinical benefit in combination therapy and adverse effect profile.)

Case #1 – Pediatric Con’t 4. Based on your recommendations above, what patient education points would you want to emphasize?