3561 Medical Pharmacology Anticonvulsant Tables

Excitatory AA block

Increased GABA

Hydantoins Phenytoin Fosphentoin I.V. Ethotoin Mephenytoin Immunostilbene Carbamazepine Oxcarbazepine Barbiturates Phenobarbital Primidione Mephobarbital Propofol Valproic acid Succinimides Ethosuximide Methsuximide Phensuximide Oxazolidinediones Trimethadione Benzodiazepines Lorazepam Clonazepam Clorazepate Diazepam Midazolam Carbonic hydrase inhibitors Acetazolamide 2

x x

x x

x x

x x

TC, CP, SE SE TC, CP TC,CP, JM TC,CP P-AJ TC,CF,SE TC,CP,Focal SE

Absence

Mechanisms of Action and Uses for Anticonvulsant Drugs Drug Ion Channel inhibited Na Ca Tonic, Clonic, Complex Partial

Uses1 Other Notes

NP, rarely cardiac arrythmias

Prompt and extended dose forms IM and IV form for injection

x x

x x

x?

BI, NP other Prodrug- action similar to carbamazepine LA, F LA Use in hospital settting, similar to thioenptal, facilitates glycine inhibition also. First broad spectrum anticonvulsant.

x x x x x x x x?

AK3 AK3 AK3

x?

TC,

AB AB AB AB AB

BI, NP, F, migraine

x x x x x x x? x? x? x? x? SE CP? P SE, ANY SE

Rarely used due to serious toxicity LA MY,AK, ANY F

AB ANY

May be effective after buccal administration, but can reduce respiration. Rapid tolerance Not approved for children under 16 y/o. May be useful for neuropathic pain. Irreversible GABA transaminase inhibitor. Use limited by toxicity. Blocks GABA reuptake Unique monosaccaride structure. Sulfonamide like structure, some antidepressant-like action and carbonic anhydrase action.. Synaptic inhibitor

AB x x x x x x x x x x x x x x AK3 x? P-AJ, LG P P-AJ,CP, LG, WS P-AJ, LG P-AJ P-AJ P-AJ P-AJ

CT NP NP

New Agents
Lamotrigine Gabapetin Vigabatrin Felbamate Tiagabine Topiramate Zonisamide Levetiracetam

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3561 Medical Pharmacology Anticonvulsant Tables

1. AB=Absence, AJ=Adjunctive use, AK=Akinetic, BI=Bipolar disorder, CF=Corticofocal, CP=Complex partial, psychomotor, CT=Catammenial, F=febrile, IM=impulse disorder, IS Infantile spasms, JM=Jacksonian Motor, LA=local anesthetic induced seizures, LG= Lennox- Gastaut syndrome (children), MC=Myoclonic, NP=Trigeminal neuralgia or diabetic neuropathy or post herpetic neuropathy, P=Partial seizures, SE=Status epilepticus, TC=tonic-clonic, WS Wests syndrome (children). Note: Several anticonvulsants are being used to treat 1) bipolar disorder, 2) neuralgia (& chronic pain) 3. Impulse control disorders. They may be referred to by the new name mood stablelizers. 2. Carbonic anhydrase inhibitor derived from sulfonyurea antibiotic. 3. AK=AMPA or Kinate glutamate process inhibition

Table 14-4 Adverse Reactions reported for Anticonvulsant Drugs

Drug Hydantoins Phenytoin Adverse Reactions1

Fosphentoin I.V. Ethotoin Mephenytoin Immunostilbene Carbamazepine Oxcarbazepine Barbiturates Phenobarbital Primidione Mephobarbital Propofol Valproic acid Succinimides Ethosuximide Oxazolidinediones Trimethadione Benzodiazepines Lorazepam Clonazepam Clorazepate Diazepam Midazolam Carbonic hydrase inhibitors Acetazolamide 2 New Agents Lamotrigine Gabapetin Vigabatrin Felbamate Tiagabine Topiramate Zonisamide Levetiracetam

S,AT,GI,TG,BC,PS,SK,VS,BD,HA,MO,ALO,OS,HT,LE,VD,SE,SX,NC,HO,MA,FV,HIR,GO,WD acute encephalopathy, lymphadenopathy, thyroid dysfunction, decreased immunoglobulins, chronic cerebellar disorder, coarsened facies, hypcalcaemia, hormonal dysfunction, connective tissue alterations, pseudolymphoma, , vasculitis, bone marrow hypoplasia., hypersensitivity reaction, myopathy. Like phenytoin. S,GI,SK, BD S,GI,SK,BD,HT,AA,LE,FV,GO, HIR, periateritis nodosa. S,AT,GI,TG(D),BC,SK,VS,BD,HA,MO,ALO,OS,HT,AA,PE,SE,MA,SJ, water retention , nephritis. S,GI,TG(C),SK (soon after starting), HA . S,AT,GI,TG(D),BC,PS,SK,VS,BD,WD,MO,ALO,OS,HT,AA,PE,VD,MA,IS,HT,SX, hyperkinesis (children), Dupuytren's contracture, frozen shoulder,and connective tissue abnormalities S,AT,GI,TG,BC,PS,SK,VS,BD,OS,LE,PE,VD,BD,SX, hyperkinesis (children), Dupuytren's contracture, frozen shoulder, connective tissue abnormalities. nd S, cardiac depression, respiratory depression. S,AT,GI,TG(D),PS,VS,BD,HA,MO,ALO,AA,HT,HO,WC+,CD (thrombocytopenia, may block platelet aggregation) pancreatitis, renal failure, tremor, encephalopathy, hyperammonemia. S,AT,GI,TG,BC,PS,SK,BD,HA,MO,DIP,LE,PE,FV. S,AT,TG(X),BC,PS,SK,,BD,ALO,LE,HO. S,AT,BC,TG(D),WD,AM. S,AT,GI,TG,BC,PS,SK,VS,WD,MO,ALO,OS,SE,AM,FV,WC+/- hypersalivation. S,AT,TG(D),BC,WD,AM. S,AT,BC,TG(D), WD,AM. GI,VS,TG(C),SK,HA,AS,NC anorexia. S,AT,GI,TG(C),PS,SK,VS,HA,WD,DIP,VD,SJ(1% children),IS, BD,SE. S,AT,GI,TG(C),BD,SK,VS,HA,WD,MO,DIP,SE,TR,WC+ and rhinitis. S,AT,BC,PS,VS,BD,HA,WC+,NC,G,AM, narrowing of visual field. S,AT,GI,TG(C),BC,PS,SK,VS,BD WD(flu-like),AA,SJ,WC+,HT,Tachycardia. S,AT,GI,TG(C), BC,PS,HA,BD,WD,MO,TR,NB,SE (non-convulsive) , speech impairment. S,AT,GI,TG(C),BC,PS,VS,BD,WD,DIP,NC,TR,AM,WC-,kidney stones,breast pain, menstrual. S,AT,GI,TG(C)BC,SK,NC,BD,NC,SJ renal tubular acidosis reported. S,AT,TG(C),BC,PS,HA,WD, infections.

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3561 Medical Pharmacology Anticonvulsant Tables

Anticonvulsant Adverse Reactions: 1.Adverse reactions in order of more frequent first. Definitions: AA=Aplastic anemia, ALO=Alopecia, AM=Amnesia, AT=Ataxia, dizziness, BC=Behavioral changes (confusion, agitation, restlessness or cognitive dysfunction), BD=Blood dyscrasias (neutropenia, thrombocytopenia or leukopenia), CDcoagulation defect or decreased platelet aggregation, DA=Dental abnormalities, DIP= Diplopia, FV=fever.GI=Gastrointestinal disturbances (nausea, vomiting, diarrhea or GI pain), GO=Gingival overgrowth, HA=Headache, HO=Hemeralopia, HT=Hepatotoxicity, IS=Insomnia, HIR=Hirsutism, LE=Lupus erythematosis syndrome, MA=Megablastic anemia, MO=Motor disturbances or dyskinesias, NC=Nerve conduction defects, paresthesias or peripheral neuropathy, OS=Osteomalacia, PE=Paradoxical excitation, PS=Psychotic reaction, (schizophreniform, mood change, depression, aggression or agitation), S=Sedation, asthenia, weakness, lethargy, fatigue, SE=Seizure exacerbation, SJ=Stevens Johnson Syndrome, SK=Skin rashes, SX=Sexual dysfunction, impotence or loss of libido, TG=Teratogenicity (A-X FDA pregnancy Class), TR=Tremor, VD= Vitamin deficiency (folate, vitamins D,K), VS=Visual disturbance, WC= Weight change (+=gain,-=loss), WD=Withdrawal reaction.

Metabolism and Drug Interaction for Anticonvulsant Drugs Drug T1/2(h)/ Tpeak(h) Phase I, Oxidative (P450) metabolism
ind 3A4,. s CYP2C9, s CYP2C19 Phase II Metabo lism (UGT) Decre ase oral contra ceptiv es

Other drug interactions

Hydantoins Phenytoin

Non-linear, 624, Tpeak 3-12h.

Fosphentoin I.V. Ethotoin Mephenytoin Immunostilbene Carbamazepine

Non-linear, onset 10-60 min. 3-9, non-linear 7, AM1 25-65, chronic 12-17, (AM) 1 Tpeak 4-8 9 (AM-MHD) 1 Tpeak 3-13 53-140, Tpeak 24 ind 1A2, 3A4 groups, s. for 3A4. mild inducer 3A4, inh CYP2C19. ind P450, PBREM2 (CYP:2ABC,3A4, 6A, s 3A4, CYP2C9, s CYP2C19) Ind 3A4 group

Many, phenytoin metabolism is capacity limited, increases sedative effects, inc LiCO3 tox, inc meperidine tox., displace warfarin binding, increases acetaminophen toxicity, ibuprofen may increase P. toxicity, AEDs4, decrease theophylline, decrease haloperidol etc. Like phenytoin. Hepatic metabolism. Hepatic metabolism, active metabolite. Many, Increases sedative effects, MAOI, Inhibiters of 3A4 inc CBZ blood levels:isoniazid, propoxyphene, fluoxetine, valproic acid, anticoagulants, acetaminophen, s ME. 45% renal, 45% hepatic metabolism, interactions with 3A4 substrates and inducers. Many, increased sedative effects, decrease anticoagulants ,beta blockers, digitalis, other AED4, theophylline, etc.

Oxcarbazepine Barbiturates Phenobarbital

Primadione

Valproic acid

5-15 (AM) 1 metabolite PEMA 10-18 phenobarbital (53-140), Tpeak 3 5-20, Tpeak 1-4

Acetazolamide decreases P, CBZ reduces P, Phenytoin may increase P, nicotinamide decreases P, Succinimides decrease P. Rifampin decreased V levels, salicylate displace bound V, CBZ interactions, clonazepam (induced absences), CNS depressants (increased sedation), diazepam, inh ethosuximide, lamotrigine, phenytoin metabolism, inhibits urea synthesis.

May inhibit metabolism of some 3A4 substrates, s. CYP2C9, s. CYP2C19, s3A4, s. CYP4B1 s. 3A4.

s. UGT

Succinimides Ethosuximide

.40(15-72), Tpeak 3-7

E increases hydantoins, E. decreases phenobarbital and primadione, E changes valproate levels.

New Agents

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3561 Medical Pharmacology Anticonvulsant Tables

Anticonvulsant Actions at the GABA Synapse

Presynaptic terminal GABAA receptor GABA Cl

Postsynaptic neuron

GABA SSA

Vigabatrin inhibits
SSA

GABA

Tiagabine blocks reuptake

glial cell

benzodiazepine's facilitate

GABA Uptake Transporter

GABA T

Lamotrigine

33h,Tpeak 1.44.8

Gabapetin Vigabatrin Felbamate

5-7, Tpeak 2-3 4-7, Tpeak 0.752. 20-23, Tpeak1-4

s + inh, 3A4, inh dihydrofolate reductase, dose adjustment needed if cotherapy with CYP3A4 inducer. s, 3A4.

, s. UGT, weak

Valproic acid inhibits metabolism of L, 90% hepatic elimination.

Tiagabine Topiramate Zonisamide Levetiracetam

7-9, Tpeak 1-2 21, Tpeak 2 63, Tpeak 2-6 7, Tpeak 1

ind 3A4, (but less than CBZ), CYP2C19, non P450 metabolism, F inc. s 3A4 (possibly CYP1A2, 2C9, 2C19, 2D6), weak ind 3A4, inh P450, s 3A4, , inh CYP2C19 s CYP3A4

possibl e

100% renal elimination. Not metabolized by liver. Renal elimination. Alters phenytoin levels. Duration determined by rate of resynthesis of GABA-Transaminase. 50% hepatic, 50% renal elimnination, phenytion dec. F, F inc phenobarbital, phenobarbital decreases F, CBZ decreases F, F decreases CBZ, F increases valproic acid but not reverse. F increases methsuximide active metabooite. High protein binding; Valproate displaces T; T sl. dec. valproate; valproate dec. T; PB, CBZ or Phenytoin dec T, dose adjustment needed if cotherapty with CYP3A4 inducer. Increases sedative effectss, renal>hepatic elimination, carbonic anhydrase inhibitors. Decreases digoxin. No interactions with AED's4, >90% hepatic. 66% renal, Non hepatic metabolism, No interactions with AED's4.

1. AM-drug has active metaboloite(s). 2. Drug Interactions: s=substrate,ind= inducer, inh=inhibitor, 3A4= cytochrome P450-CYP3A4, AA=antiacid, UGT=uridine diphosphate glucurosyl transferase, ME=microsomal epoxide hydrolase. PBREM nuclear induction via phenobarbital responsive enhancer module. Many substrates of CYP3A4 may be altered by inducers including oral contraceptives, digoxin, anticoagulants, HMG-CoA reductase inhibitors, lipid soluble vitamin (D and K), etc. 3. nd=no data or not done yet. 4. AED=Anti Epileptic Drug

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3561 Medical Pharmacology Anticonvulsant Tables

Drug Interactions for Phenytoin (MZ=induces mocrosomal enzymes, reduces other drug effect IS=increased sedation by combination IA=increased anticonvulsant blood level, Inhibit metabolism of anticonvulsant LT=lower seizure threshold by combination BA=block anticonvulsant absorption) Acetaminophen MZ Acyclovir (Acyclovir reduced phenytoin conc) Alfentanil IS Amiodarone IA Antacids BA Barbiturates-complex response possible Busulfan-MZ Calcium Carbonate BA Calcium Salts BA Carbamazepine Cardiac glycosides MZ Chloramphenicol IA Cimetidine IA Clonazepam MZ Corticosteroids MZ Cyclosporine MZ Disopyramide MZ dicoumarol MZ Disulfiram IA Dopamine-hypotension and death after adding phenytoin in cardiac pateint Doxorubicin decreased phenytoin conc. Doxycycline MZ enteral feedings BA Estazolam MZ Estrogens MZ Ethanol IS Felodipine MZ Fentanyl MZ Fluconazole IA Fluoxetine IA Folic Acid, Vitamin B9 reduce anti convulsant effect food General Anesthetics increased risk of hepatoxicity with phenytoin) Ginger, Zingiber officinale reduced antiarrhythmic effect H1-blockers-IS Isoniazid, INH IA Itraconazole MZ Leucovorin Levobupivacaine MZ

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3561 Medical Pharmacology Anticonvulsant Tables

Levodopa MZ Lidocaine MZ Methadone MZ Mexiletine MZ Neuromuscular blockers-Antagonize blockers Omeprazole (high dose om) IA Oral contraceptives MZ Paroxetine variable effect Propoxyphene IA Quinidine MZ Rifampin LT, increased phenytoin metabolism Salicylates Displace Pheyntoin from protein binding Sirolimus MZ Sucralfate BA Sulfamethizole IA Tacrolimus MZ Theophylline, MZ Aminophylline Thyroid hormones MZ Tramadol MZ, IS, LT Trimethoprim IA Valproic Acid, Divalproex Sodium, IA and displace protein binding Vinca alkaloids LT Vitamin D analogs MZ Warfarin MZ Zaleplon MZ Drug Interactions for Carbamazepine Acetaminophen MZ Alfentanil MZ Barbiturates MZ Bupropion MZ Cimetidine IA Clarithromycin IA Clozapine MZ Corticosteroids MZ Cyclosporine MZ Dacarbazine, DTIC Dalfopristin; Quinupristin IA Danazol IA Diltiazem IA Doxycycline MZ Erythromycin IA Estazolam MZ Estrogens MZ Felodipine MZ Fentanyl MZ

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3561 Medical Pharmacology Anticonvulsant Tables

Fluconazole IA Fluoxetine IA Fluvoxamine IA food (grapefruit juice) IA Haloperidol MZ Isoniazid, INH Inhibit CBZ clearance Itraconazole IA Ketoconazole IA Levobupivacaine MZ Lithium-sometimes ataxia, lethargy, hyperreflexia, tremor with combo Loratadine IA Loxapine IS Monoamine oxidase inhibitors (MAOIs)- hyperpyrexia, hypertensive crisis, convulsions, or death Maprotiline IS Metronidazole IA Miconazole IA Molindone IS Nefazodone IA Neuromuscular blockers MZ niacin, vitamin B3 IA Nifedipine MZ Olanzapine MZ (CYP1A2) Oral contraceptives MZ Phenothiazines IS Phenytoin (Interaction) Pimozide IS Pioglitazone possible IA Primidone (Interaction) Propoxyphene IA Quinidine MZ Rifampin-increases phenytion metabolism Sirolimus MZ Terfenadine ? displace CBZ fro prot binding. Theophylline, Aminophylline MZ Thyroid hormones MZ Tramadol MZ, LT Tricyclic antidepressants MZ Troleandomycin IA Valproic Acid, Divalproex Sodium (interaction) Verapamil IA, or MZ Warfarin MZ Xanthines-MZ Zaleplon MZ Drug interations for Valproic Acid

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3561 Medical Pharmacology Anticonvulsant Tables

Antacids (Increased absorption) Aspirin, ASA (increased bleeding) Barbiturates (increase phenobarbital blood levels, increased drowsiness) Carbamazepine (decreases valproic acid blood levels, increases cabamazepine active metabolite) Cholestyramine-May inhibit absorption of valproic acid Clonazepam-(may increase absence status attact, but may not) Diazepam (displaces bound diazepam and decrease diazepam Vd and Cl) Ethanol (increase CNS depression) Ethosuximide (may alter blood levels) Felbamate (may increase valproate blood levels) Haloperidol (increase CNS depression, decrease seizure thresholds) Heparin ( may increase bleeding) Isoniazid, INH (may block metabolism of valproate, increasing its toxicity) Lamotrigine (both drugs may have altered blood levels) Loxapine (increase CNS depression, decrease seizure thresholds) Monoamine oxidase inhibitors(MAOIs) (increase CNS depression, decrease seizure thresholds) Maprotiline(increase CNS depression, decrease seizure thresholds) Nonsteroidal antiinflammatory drugs (NSAIDs) (increased bleeding) Phenothiazines-(increase CNS depression, decrease seizure thresholds) Phenytoin (complex interation, monitor blood levels) Primidone (increase phenobarbital blood levels, increased drowsiness) Rifampin (increased valporate clearance) Temozolomide (valproate decreases it clearance) Thrombolytic Agents (increased bleeding) Tricyclic antidepressants (increase CNS depression, decrease seizure thresholds) Warfarin (increased bleeding) Zidovudine, ZDV (valproic acid clearance reduced 38%) Drug Interactions for Ethylsuximide Ethanol Haloperidol Loxapine Monoamine oxidase inhibitors (MAOIs) Maprotiline Molindone Phenobarbital Phenothiazines Phenytoin Pimozide Primidone Tricyclic antidepressants Valproic Acid, Divalproex Sodium

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