Neuropharm-epilepsy Introduce-from Ncbi

Neuropharmacology of Antiepileptic Drugs American Epilepsy Society

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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 P-Slide 2

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

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

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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 P-Slide 5

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

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Antiepileptic Drug Therapy

Structures of Commonly Used AEDs

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Antiepileptic Drug Therapy Structures of Commonly Used AEDs

Levetiracetam

Oxcarbazepine

Zonisamide P-Slide 8

Antiepileptic Drug Therapy Structures of Commonly Used AEDs ■

Pregabalin

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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 P-Slide 10

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

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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 P-Slide 12

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 P-Slide 13

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 P-Slide 14

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

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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

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The GABA System The GABA system and its associated chloride channel

From Engel, 1989

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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)

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The Cytochrome P-450 Enzyme System Inducers

Inhibitors

phenobarbital

erythromycin

primidone

nifedipine/verapamil

phenytoin

trimethoprim/sulfa

carbamazepine

propoxyphene

tobacco/cigarettes

cimetidine valproate P-Slide 19

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

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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 P-Slide 21

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)

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Drug Metabolizing Isozymes and AEDs AED 

CBZ  PHT  VPA  PB  ZNS  TGB 

CYP3A4 

+  + 

+       

CYP2C9 

   

  +  +  + 

CYP2C19  UGT 

   

  +     

   

    +   

 

AEDs that do not appear to be either inducers or inhibitors of the CYP system include: gabapentin, lamotrigine, tiagabine, levetiracetam, zonisamide. P-Slide 23

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

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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 P-Slide 25

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 P-Slide 26

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

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AED Inhibitors  Valproate − UDP glucuronosyltransferase (UGT)

⇑ plasma concentrations of Lamotrigine, Lorazepam − CYP2C19

⇑ plasma concentrations of Phenytoin, Phenobarbital  Topiramate & Oxcarbazepine − CYP2C19

⇑ plasma concentrations of Phenytoin  Felbamate − CYP2C19 ⇑ plasma concentrations of Phenytoin, Phenobarbital P-Slide 28

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

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Isozyme Specific Drug Interactions Category

CYP3A4

CYP2C9

CYP2C19

UGT

Inhibitor

Erythromycin Clarithromycin Diltiazem Fluconazole Itraconazole Ketoconazole Cimetidine propoxyphene Grapefruit juice

VPA Fluconazole metronidazole Sertraline Paroxetine Trimethoprim/ sulfa

Ticlopidine Felbamate OXC/MHD Omeprazole

VPA

Inducer

CBZ PHT PB felbamate Rifampin TPM OXC/MHD

CBZ PHT PB Rifampin

CBZ PHT PB rifampin

CBZ PHT PB OXC/MHD LTG (?)

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Therapeutic Index  T.I. = ED 5O% /TD 50%  “Therapeutic range” of AED serum concentrations • Limited data • Broad generalization • Individual differences P-Slide 31

Steady State and Half Life

From Engel, 1989 P-Slide 32

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. P-Slide 33

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”.

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Potential Target Range of AED Serum Concentrations AED Carbamazepine Ethosuximide Phenobarbital Phenytoin Valproic acid

Serum Concentration (mg/l) 4-12 40-100 10-40 10-20 50-100

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Potential Target Range of AED Serum Concentrations AED Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Tiagabine Topiramate Zonisamide

Serum Concentration (mg/l) 6-21 5-18 10-40 12-24 (MHD) ?? ? 4.0-25 7-40 P-Slide 36

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

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

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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 P-Slide 39

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 P-Slide 40

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

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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 P-Slide 42

Adverse Effects  Acute dose-related—reversible  Idiosyncratic— • uncommon

rare

• potentially serious or life threatening

 Chronic—reversibility and seriousness vary

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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 P-Slide 44

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

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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

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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

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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 P-Slide 48

Pharmacology Resident Case Studies

American Epilepsy Society Medical Education Program

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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.

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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.

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Case #1 – Pediatric Con’t 1. 2.

Briefly describe what characteristics are associated with Lennox-Gastaut Syndrome. What anticonvulsants are currently FDA approved for Lennox-Gastaut Syndrome?

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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.) P-Slide 53

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

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