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Neuropharmacology of Antiepileptic Drugs American Epilepsy Society P-Slide 1.

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Presentation on theme: "Neuropharmacology of Antiepileptic Drugs American Epilepsy Society P-Slide 1."— Presentation transcript:

1 Neuropharmacology of Antiepileptic Drugs American Epilepsy Society P-Slide 1

2 P-Slide 2 Outline n Definitions Seizure vs. Epilepsy Antiepileptic drugs n History of antiepileptic drugs (AEDs) n AEDs: Molecular and cellular mechanisms n Cellular mechanisms of seizure generation n Pharmacokinetic principles Drug metabolism enzymes AED inducers AED inhibitors AED Serum Concentrations Definitions: Therapeutic Index, Steady state Pharmacodynamic interactions n Comparative pharmacokinetics of old vs. new AEDs n Pharmacokinetics in special populations n Metabolic changes of AEDs n AEDs and drug interactions n Adverse effects Acute vs. chronic Idiosyncratic n Case Studies American Epilepsy Society 2011

3 Definitions  Seizure The clinical manifestation of an abnormal hypersynchronized discharge in a population of cortical excitatory neurons  Epilepsy: A tendency toward recurrent seizures unprovoked by acute systemic or neurologic insults American Epilepsy Society 2011 P-Slide 3

4 Antiepileptic Drug An antiepileptic drug (AED) is 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  Does not prevent the development of epilepsy in individuals who have acquired a risk for seizures (e.g., after head trauma, stroke, tumor) Goal of therapy is to maximize quality of life by eliminating seizures (or diminish seizure frequency) while minimizing adverse drug effects P-Slide 4 American Epilepsy Society 2011

5 History of Antiepileptic Drug Therapy in the U.S – bromides 1912 – phenobarbital (PB) 1937 – phenytoin (PHT) 1944 – trimethadione 1954 – primidone 1958 – ACTH 1960 – ethosuximide (ESM) 1963 – diazepam 1974 – carbamazepine (CBZ) 1975 – clonazepam (CZP) 1978 – valproate (VPA) P-Slide – felbamate (FBM), gabapentin (GBP) 1995 – lamotrigine (LTG) 1997 – topiramate (TPM), tiagabine (TGB) 1999 – levetiracetam (LEV) 2000 – oxcarbazepine (OXC), zonisamide (ZNS) pregabalin (PGB) 2008 – lacosamide (LCM), rufinamide (RUF) 2009 – vigabatrin (VGB) American Epilepsy Society 2011

6 AEDs: Molecular and Cellular Mechanisms P-Slide 6  phenytoin, carbamazepine Block voltage-dependent sodium channels at high firing frequencies Chemical formulas of commonly used antiepileptic drugs Adapted from Rogawski and Porter, 1993, and Engel, 1989 American Epilepsy Society 2011

7 AEDs: Molecular and Cellular Mechanisms P-Slide 7  barbiturates Prolong GABA-mediated chloride channel openings Some blockade of kainate receptors  benzodiazepines Increase frequency of GABA- mediated chloride channel openings American Epilepsy Society 2011

8 AEDs: Molecular and Cellular Mechanisms P-Slide 8  felbamate Blocks voltage-dependent sodium channels at high firing frequencies Modulates NMDA receptor (block) and GABA receptors (enhanced)  gabapentin Blocks calcium channels Enhances H current Suppressed presynaptic vesicle release Suppresses NMDA receptor at glycine site American Epilepsy Society 2011

9 AEDs: Molecular and Cellular Mechanisms P-Slide 9  lamotrigine Blocks voltage-dependent sodium channels at high firing frequencies Enhances H current Modulates kainate receptors  zonisamide Blocks voltage-dependent sodium channels and T-type calcium channels Mild carbonic anhydrase inhibitor Zonisamide

10 AEDs: Molecular and Cellular Mechanisms P-Slide 10  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 Modulates T-type calcium channels

11 AEDs: Molecular and Cellular Mechanisms P-Slide 11  topiramate Blocks voltage-dependent Na + 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 anhydrase  tiagabine Interferes with GABA re-uptake

12 AEDs: Molecular and Cellular Mechanisms P-Slide 12  levetiracetam Binding of reversible saturable specific binding site SV2a (a synaptic vesicle protein) Modulates kainate receptor activity 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 levetiracetam oxcarbazepine American Epilepsy Society 2011

13 AEDs: Molecular and Cellular Mechanisms  pregabalin Increases glutamic acid decarboxylase Suppresses calcium currents by binding to the alpha2-delta subunit of the voltage gated calcium channel  lacosamide Enhances slow inactivation of voltage gated sodium channels P-Slide 13 American Epilepsy Society 2011

14 AEDs: Molecular and Cellular Mechanisms  rufinamide Unclear: Possibly stabilization of the sodium channel inactive state  vigabatrin Irreversibly inhibits GABA- transaminase (enzyme that breaks down GABA) P-Slide 14 American Epilepsy Society 2011

15 Summary: Mechanisms of Neuromodulation AED Na + Channel Blockade Ca ++ Channel Blockade H-current enhance- ment Glutamate Receptor Antagonism GABA Enhance- ment Carbonic Anhydrase Inhibition PHTXX (NMDA glycine) CBZ, OXCXX (CBZ>OXC) barb, benzo X (GABA A ) ESMX VPAXXX FBMXXX (NMDA)X GBPXXX (NMDA glycine) LTGXXX (kainate) TPMXXX (AMPA,kainate)XX TGBX (reuptake) LEVX (kainate) ZNSXXX PGBX LCMX (slow inact.) RUFX VGBX (metab.) P-Slide 15 Modified from White HS and Rho JM, Mechanisms of Action of AEDs, American Epilepsy Society 2011

16 Cellular Mechanisms of Seizure Generation  Excitation (too much) Ionic: inward Na + and Ca ++ currents Neurotransmitter: glutamate, aspartate  Inhibition (too little) Ionic: inward CI -, outward K + currents Neurotransmitter: GABA P-Slide 16 American Epilepsy Society 2011

17 GABA Receptors GABA is the major inhibitory neurotransmitter in the CNS. There are 2 types of receptors: GABA A receptor Postsynaptic fast inhibition Specific recognition sites (see next slide) Inhibition mediated by CI - current GABA B receptor Postsynaptic slow inhibition Pre-synaptic reduction in calcium influx Inhibition mediated by K + current P-Slide 17 American Epilepsy Society 2011

18 GABA Receptors Diagram of the GABA A receptor From Olsen and Sapp, 1995 P-Slide 18 GABA site Barbiturate site Benzodiazepine site Steroid site Picrotoxin site American Epilepsy Society 2011

19 Glutamate Receptors Glutamate is the major excitatory neurotransmitter in the CNS. There are two major categories of glutamate receptors: Ionotropic - fast synaptic transmission AMPA / kainate: channels conduct primarily Na + NMDA: channels conduct both Na + and Ca ++ NMDA receptor neuromodulators: glycine, zinc, redox site, polyamine site Metabotropic - slow synaptic transmission 8 subtypes (mGluRs 1-8) in 3 subgroups (group I-III) G-protein linked; second messenger-mediated modification of intracellular signal transduction Modulate intrinsic and synaptic cellular activity P-Slide 19 American Epilepsy Society 2011

20 Glutamate Receptors Group I mGluRs (mGluRs 1 and 5) Primarily postsynaptic/perisynaptic Net excitatory effect (ictogenic) Couple to inositol triphosphate Long-lasting effects (epileptogenic) Group II (mGluRs 2 & 3) and group III (4,6,7,8) Primarily presynaptic Net inhibitory effect; reduce transmitter release Negatively coupled to adenylate cyclase, reduce cAMP American Epilepsy Society 2011

21 Glutamate Receptors P-Slide 21 Diagram of the various glutamate receptor subtypes and locations From Takumi et al, 1998 American Epilepsy Society 2011

22 AEDs: Molecular and Cellular Mechanisms Overview  Blockers of repetitive activation of sodium channels:  phenytoin, carbamazepine, oxcarbazepine, valproate, felbamate, lamotrigine, topiramate, zonisamide, rufinamide, lacosamide  GABA enhancers (direct or indirect): barbiturates, benzodiazepines, carbamazepine, valproate, felbamate, topiramate, tiagabine, vigabatrin  Glutamate modulators: Phenytoin, gabapentin, lamotrigine, topiramate, levetiracetam, felbamate  T-calcium channel blockers: ethosuximide, valproate, zonisamide P-Slide 22 American Epilepsy Society 2011

23 AEDs: Molecular and Cellular Mechanisms Overview  N- and L-calcium channel blockers: lamotrigine, topiramate, zonisamide, valproate  H-current modulators: gabapentin, lamotrigine  Blockers of unique binding sites: gabapentin, levetiracetam, pregabalin, lacosamide  Carbonic anhydrase inhibitors: topiramate, zonisamide P-Slide 23 American Epilepsy Society 2011

24 Epilepsy Trivia This epilepsy medication was discovered by accident. It was used as a solvent in studies on a drug that was being investigated as an anticonvulsant. It turned out that similar, substantial improvement was seen in both the placebo group and the "active" drug group. What drug am I? P-Slide 24 American Epilepsy Society 2011

25 Epilepsy Trivia This epilepsy medication was discovered by accident. It was used as a solvent in studies on a drug that was being investigated as an anticonvulsant. It turned out that similar, substantial improvement was seen in both the placebo group and the "active" drug group. What drug am I? valproic acid P-Slide 25 American Epilepsy Society 2011

26 Pharmacokinetic Principles  Absorption: entry of drug into the blood Essentially complete for all AEDs Exception = gabapentin with saturable amino acid transport system. Timing varies widely by drug, formulation and patient characteristics Generally slowed by food in stomach (carbamazepine may be exception) Usually takes several hours (important for interpreting blood levels) P-Slide 26 American Epilepsy Society 2011

27 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 27 American Epilepsy Society 2011

28 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) P-Slide 28 American Epilepsy Society 2011

29 The Cytochrome P-450 Isozyme System  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 29 American Epilepsy Society 2011

30 Drug Metabolizing Isozymes and AEDs AEDCYP3A4CYP2C9CYP2C19UGT CBZ+ PHT++ VPA++ PB+ ZNS+ TGB+ OXC++ LTG+ TPM++ LCM+ P-Slide 30 American Epilepsy Society 2011

31 AED Inducers: The Cytochrome P-450 Enzyme System  Increase clearance and decrease steady-state concentrations of other substrates  Results from synthesis of new enzyme or enhanced affinity of the enzyme for the drug  Tends to be slower in onset/offset than inhibition interactions P-Slide 31 American Epilepsy Society 2011

32 AED Inducers: The Cytochrome P-450 Enzyme System  Broad Spectrum Inducers: phenobarbital - CYP1A2, 2A6, 2B6, 2C8/9, 3A4 primidone - CYP1A2, 2B6, 2C8/9, 3A4 phenytoin - CYP2B6, 2C8/9, 2C19, 3A4 carbamazepine - CYP1A2, 2B6, 2C8/9, 2C19, 3A4  Selective CYP3A Inducers: oxcarbazepine - CYP3A4 at higher doses topiramate - CYP3A4 at higher doses felbamate - CYP3A4  Tobacco/cigarettes - CYP1A2 P-Slide 32 American Epilepsy Society 2011

33 AED Inhibitors: The Cytochrome P-450 Enzyme System  Decrease clearance and increase steady-state concentrations of other substrates  Competition at specific hepatic enzyme site, decreased production of the enzyme, or decreased affinity of the enzyme for the drug  Onset typically rapid and concentration (inhibitor) dependent  Possible to predict potential interactions by knowledge of specific hepatic enzymes and major pathways of AED metabolism P-Slide 33 American Epilepsy Society 2011

34 AED Inhibitors: The Cytochrome P-450 Enzyme System  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  Grapefruit juice: CYP3A4 P-Slide 34 American Epilepsy Society 2011

35 Therapeutic Index  T.I. = ED 5O% /TD 50%  “Therapeutic range” of AED serum concentrations Limited data Broad generalization Individual differences P-Slide 35 American Epilepsy Society 2011

36 Steady State and Half Life From Engel, 1989 P-Slide 36 American Epilepsy Society 2011

37 AED Serum Concentrations  Serum concentrations are useful when optimizing AED therapy, assessing adherence, or teasing out drug-drug interactions.  They should be used to monitor pharmacodynamic and pharmacokinetic interactions.  Should be done when documenting a serum concentration when a patient is well controlled. P-Slide 37 American Epilepsy Society 2011

38 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”. P-Slide 38 American Epilepsy Society 2011

39 Potential Target Range of AED Serum Concentrations AED Serum Concentration (µg/ml) carbamazepine ethosuximide phenobarbital phenytoin (10-20) valproic acid primidone P-Slide 39 American Epilepsy Society 2011

40 Potential Target Range of AED Serum Concentrations AEDSerum Concentration (µg/ml) gabapentin4 -16 lamotrigine levetiracetam oxcarbazepine (MHD) pregabalin tiagabine topiramate zonisamide felbamate P-Slide 40 American Epilepsy Society 2011

41 Admixture and Administration of Injectable AEDs P-Slide 41 AEDDosage/Rate of Infusion fosphenytoin (Cerebyx®) Status epilepticus: Loading Dose: mg PE/kg IV (PE = phenytoin equivalent) Non-emergent: Loading Dose: mg PE/kg IV or IM ; MD: 4-6 mg PE/kg/day IV or IM Infusion Rate: Should not exceed 150 mg PE/minute levetiracetam (Keppra®) >16 y/o. No Loading Dose mg/day in 2 divided doses. Dose can be increased by 1000 mg/day ever 2 weeks up to a maximum dose of 3000 mg/day Infusion Rate: Dilute in 100 ml of normal saline (NS), lactated ringers (LR) or dextrose 5% and infuse over 15 minutes phenytoin (Dilantin®) Loading Dose: mg/kg; up to 25 mg/kg has been used clinically. Maintenance Dose: 300 mg/day or 5-6 mg/kg/day in 3 divided doses, IM not recommended; dilute in NS or LR, DO NOT MIX WITH DEXTROSE, do not refrigerate, use within 4 hrs. Use inline micron filter Infusion Rate: Should not exceed 50 mg/min; elderly/debilitated should not exceed 20 mg/min valproic acid (Depacon®) No Loading Dose; mg/day in 1-3 divided doses Infusion Rate: Administer over 60 minutes (<= 20 mg/min); rapid infusion over 5-10 minutes as mg/kg/min lacosamide (Vimpat®) No Loading Dose; maintenance dose mg/day in 2 divided doses Infusion Rate: IV formulation is 10 mg/ml, can be administered with or without diluents over minutes American Epilepsy Society 2011

42 Comparative Pharmacokinetics Of Traditional AEDs DrugAbsorptionBinding %Eliminationt ½ (hrs) Cause Interactions CBZ % H * 6-15Yes PB % H72-124Yes PHT % H ** 12-60Yes VPA % H6-18Yes P-Slide 42 * autoinduction ** non-linear H = hepatic R = renal Problems with traditional AEDs: Poor water solubility Extensive protein binding Extensive oxidative metabolism Multiple drug-drug interactions American Epilepsy Society 2011

43 Pharmacokinetics Of Newer AEDs P-Slide 43 DrugAbsorptionBindingElimination T ½ (hrs) Cause Interactions? GBP≤ 60%0%100% R5-9No LTG100%55%100% H18-30No LEV~100%<10%66% R4-8No TGB~100%96%100% H5-13No TPM≥80%15%30-55% R20-30Yes/No Potential advantages of newer AEDs: Improved water solubility….predictable bioavailability Negligible protein binding….no need to worry about hypoalbuminemia Less reliance on CYP metabolism…perhaps less variability over time American Epilepsy Society 2011

44 Pharmacokinetics Of Newer AEDs P-Slide 44 DrugAbsorptionBindingElimination T ½ (hrs) Cause Interactions? ZNS80-100%40-60%50-70% H50-80No OXC100%40%100% H5-11Yes/No LCM100%<15%60% H13No RUF85%35%100% H6-10Minor VGB100%0%R7-8Yes/No American Epilepsy Society 2011

45 Pharmacodynamic Interactions  Wanted and unwanted effects on target organ Efficacy - seizure control Toxicity - adverse effects (dizziness, ataxia, nausea, etc.) P-Slide 45 American Epilepsy Society 2011

46 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 46 American Epilepsy Society 2011

47 Pharmacokinetic Factors in Pediatrics  Neonate - often lower per kg doses Low protein binding Low metabolic rate  Children - higher, more frequent doses Faster metabolism P-Slide 47 American Epilepsy Society 2011

48 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  Return to pre-pregnancy conditions rapidly (within 2 weeks) after delivery P-Slide 48 American Epilepsy Society 2011

49 Metabolic Changes of AEDs  Febrile Illnesses ↑ metabolic rate and ↓ serum concentrations ↑ serum proteins that can bind AEDs and ↓ free levels of AED serum concentrations  Severe Hepatic Disease Impairs metabolism and ↑ serum levels of AEDs ↓ serum proteins and ↑ free levels of AED serum concentrations Often serum levels can be harder to predict in this situation P-Slide 49 American Epilepsy Society 2011

50 Metabolic Changes of AEDs  Renal Disease ↓ the elimination of some AEDs gabapentin, pregabalin, levetiracetam  Chronic Renal Disease ↑ protein loss and ↑ free fraction of highly protein bound AEDs It may be helpful to give smaller doses more frequently to ↓ adverse effects phenytoin, valproic acid, tiagabine, vigabatrin P-Slide 50 American Epilepsy Society 2011

51 Effects of Dialysis  Serum concentrations pre/post dialysis can be beneficial in this patient population  Bolus dosing of AEDs is sometimes recommended in this situation P-Slide 51 American Epilepsy Society 2011

52 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 Important note about oral contraceptives (OCPs): OCP efficacy is decreased by inducers, including: phenytoin, phenobarbital, primidone, carbamazepine, and higher doses of topiramate and oxcarbazepine OCPs and pregnancy significantly decrease serum levels of lamotrigine. P-Slide 52 American Epilepsy Society 2011

53 Isozyme Specific Drug Interactions P-Slide 53 American Epilepsy Society 2011

54 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 lacosamide P-Slide 54 American Epilepsy Society 2011

55 Pharmacokinetic Interactions: Possible Clinical Scenarios Be aware that drug interactions may occur when there is the: addition of a new medication when an inducer/inhibitor is present. addition of inducer/inhibitor to an existing medication regimen. removal of an inducer/inhibitor from chronic medication regimen. P-Slide 55 American Epilepsy Society 2011

56 Adverse Effects  Acute dose-related: reversible  Idiosyncratic Uncommon - rare Potentially serious or life threatening   Chronic: reversibility and seriousness vary P-Slide 56 American Epilepsy Society 2011

57 Acute, Dose-Related Adverse Effects of AEDs  Neurologic/psychiatric: most common  Sedation, fatigue  All AEDs, except unusual with LTG and FBM  More pronounced with traditional AED  Unsteadiness, incoordination, dizziness  Mainly traditional AEDs  May be sign of toxicity with many AEDs  Tremor - valproic acid P-Slide 57 American Epilepsy Society 2011

58 Acute, Dose-Related Adverse Effects of AEDs (cont.)  Paresthesia (topiramate, zonisamide)  Diplopia, blurred vision, visual distortion (carbamazepine, lamotrigine)  Mental/motor slowing or impairment (topiramate)  Mood or behavioral changes (levetiracetam)  Changes in libido or sexual function (carbamazepine, phenytoin, phenobarbital) P-Slide 58 American Epilepsy Society 2011

59 Acute, Dose-Related Adverse Effects of AEDs (cont.)  Gastrointestinal (nausea, heartburn)  Mild to moderate laboratory changes  Hyponatremia: carbamazepine, oxcarbazepine  Increases in ALT or AST  Leukopenia  Thrombocytopenia P-Slide 59 American Epilepsy Society 2011

60 Acute, Dose-Related Adverse Effects of AEDs (cont.)  Weight gain/appetite changes valproic acid gabapentin pregabalin vigabatrin  Weight loss topiramate zonisamide felbamate P-Slide 60 American Epilepsy Society 2011

61 Idiosyncratic Adverse Effects of AEDs  Rash, exfoliation  Stevens-Johnson syndrome More common in lamotrigine patients receiving valproate and/or aggressively titrated.  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 P-Slide 61 American Epilepsy Society 2011

62 Stevens-Johnson Syndrome P-Slide 62 sary%20Clinical%20Images/Stevens_Johnson-28.jpg American Epilepsy Society 2011

63 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 Felbamate aplastic anemia approx. 1:5,000 treated patients Patient education P-Slide 63 American Epilepsy Society 2011

64 Long-Term Adverse Effects of AEDs  Endocrine/Metabolic Effects  Osteomalacia, osteoporosis (Vit D deficiency or other)  carbamazepine  barbiturates  phenytoin  oxcarbazepine  valproate  Teratogenesis (folate deficiency or other)  barbiturates  phenytoin  carbamazepine  valproate (neural tube defects)  topiramate (cleft lip/cleft palate)  Altered connective tissue metabolism or growth (facial coarsening, hirsutism, gingival hyperplasia or contractures)  phenytoin  phenobarbital  Neurologic  Neuropathy  phenytoin  carbamazepine  Cerebellar degeneration  phenytoin  Sexual Dysfunction (polycystic ovaries et al.)  phenytoin  carbamazepine  phenobarbital  primidone P-Slide 64 American Epilepsy Society 2011

65 Gingival Hyperplasia Induced by Phenytoin P-Slide 65 New Eng J Med. 2000:342:325. American Epilepsy Society 2011

66 After Withdrawal of Phenytoin P-Slide 66 New Eng J Med. 2000:342:325. American Epilepsy Society 2011

67 Trabecular Bone P-Slide 67 American Epilepsy Society 2011

68 AED Hypersensitivity Syndrome  Characterized by rash, systemic involvement  Arene oxide intermediates - aromatic ring  Lack of epoxide hydrolase  Cross-reactivity phenytoin carbamazepine Phenobarbital oxcarbazepine  Relative cross reactivity - lamotrigine P-Slide 68 American Epilepsy Society 2011

69 AED Hypersensitivity P-Slide 69 American Epilepsy Society 2011

70 Epilepsy Trivia This famous person with epilepsy held the papal throne from 1846 thru Who am I? P-Slide 70 American Epilepsy Society 2011

71 Epilepsy Trivia This famous person with epilepsy held the papal throne from 1846 thru Who am I? Pope Pius IX P-Slide 71 American Epilepsy Society 2011

72 Pharmacology Resident Case Studies P-Slide 72 American Epilepsy Society Medical Education Program American Epilepsy Society 2011

73 Case #1 - Pediatric  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. P-Slide 73 American Epilepsy Society 2011

74 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. P-Slide 74 American Epilepsy Society 2011

75 Case #1 – Pediatric Con’t 1.Briefly describe what characteristics are associated with Lennox-Gastaut Syndrome. 2.What anticonvulsants are currently FDA approved for Lennox-Gastaut Syndrome? P-Slide 75 American Epilepsy Society 2011

76 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 76 American Epilepsy Society 2011

77 Case #1 – Pediatric Con’t 4. Based on your recommendations above, what patient education points would you want to emphasize? P-Slide 77 American Epilepsy Society 2011


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