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1st

Generation
Carbamazepine NS
MOA - frequency-dependent and voltage-depenent blockade of inactivate Na+ channels; interaction with other ion ch and several NTs Effects - INH of post tetanic potentiation (prevents spread of seizure from epileptic focus); cerebellar vestibular stim; analgesic actions; antidiuretic actions; antidepressant actions PK - good oral BA; highly metab by CYP34A, INC metab of OCs Uses - Epilepsy (1st choice for partial seizures and gen tonic-clonic seizures; also DEC occurance of complex partial seizure; Tolerance in 10-20%); Trigeminal neuralgias; BAD; Diabetes insipidus AE- dizzines, drowsiness, blurred vision, diplopia, ataxia, neutropenia, thrombocytopenia, agranulocytosis, aplastic anemia, confusion, agitation, hallucinations, arrhythmias, HF (long Tx), water retention, liver failure, allergic rxns, NEURAL TUBE DEFECTS IN PREGOS!

Phenytoin NS
MOA - frequency-dep and voltage-dep blockade of inactivated Na+ channels Effects - INH of post tetanic potentiation (prevents spread of seizure from epileptic focus); cerebellar vestibular stim; analgesic actions, induction of hepatic microsomal enzymes PK - good oral BA; highly metab by CYP450; INH Warfarin metab; INC metab of OCs USES - EPILEPSY (1st or 2nd choice drug for partial and gen tonic-clonic seizures); Trigeminal neuralgias; cardiac arrhythmias AE CNS - nystagmus, diplopia, ataxia, dyskinesia, vertigo, tremor, hyperreWlexia, dystonic rxns, hyperactivity, sedation, drowsiness, peripheral neuropathy, encephalopathy GI - GINGIVAL HYPERPLASIA, hepatitis, hepatic necrosis, INH of folate absorption (long Tx) ENDO - hyperglycemia (b/c dec insulin secretion); Osteomalacia HEME - megaloblastic anemia (Tx w/ folate), blood dyscrasias, lymphoadenopathy Skin hyperpigmentation, hirsutism, coarsening facial features; allergic skin rxns; MALFORMATIONS IN PREGOS

Phenobarbital NS
MOA - Enhancement of GABA-mediated INH; Blockade of AMPA receptors; Direct opening of Cl- channels; Blockade of Na+ and Ca++ channels Effects - Suppression of excessive discharge of seizure focus; prevention of spread of excitation ofrom seizure focus PK - good oral BA; metab by liver; excreted by kidney, INC metab of OCs Uses - 2nd choice for parital seizures, Generalized tonic-clonic seizures, Status epilepticus AE - all AE and CI of barbiturate class; sedation, nystamus, ataxia, agitation and confuision in elderly, birth defects in PREGOS; hypoprothrombinemia (prophylaxis w/ Vit K); osteoporosis ([ix iwth Vit D); megaloblastic anemia ([ix w/ folate)

Ethosuximide NS
MOA - Blockade of voltage-sensitive T type Ca++ ch in thalamic neurons Effects - suppression of oscillating discharge of thalamic seizure focus; prevention of spread of excitation through thalamocortical and corticothalamic circuits; other brain circuits are unaffected at therapeutic con'c PK - good oral BA; metab by liver; t1/2 = 45 hrs Uses - DOC in absent seizures; earlier the Tx the greater the ef[icacy of therapy; 2nd choice drug in myoclonic and atonic seizures AEs - drowsiness, fatigue, dizziness, vertigo, ataxia, diplopia, nystagumus, restlessness, agitation, anxiety, aggressiveness, inability to con'c, leukopenia, agranulocytosis, aplastic anemia, SJ syndrome

Valproic acid BS
MOA - Blockade of inactivated Na+ ch; Blockade of NMDA rec excitation; Blockade of T type Ca++ ch; INC GABA content in brain; Opening K+ ch Effects - BROAD spectrum antiepileptic; INH CYP2C9 PK - 100% oral BA; metab by liver Uses - Epilepsy (best for myoclonic seizures; 1st line agent for tonic-clonic seizures and ABSENT seizures; effective in simple and complex partial seizures; alternative drug in infantile spasms); BAD (acute mania and prophylactic Tx); Migraine prophylaxis AE CNS - sedation, drowsiness, dizziness, tremor, ataxia, nystagmus, diplopia, dysarthria, nervousness, agitation GI - N/V, anorexia, weight gain, hyperammonemia, hepatitis HEME - Thrombocytopenia Allergic rxns; MENSTRUAL DISTURBANCES; INC risk of NTDs in PREGOS

Clonazepam BS
A benzodiazepine some selectivity for seizures and long-acting. MOA increase the frequency of the GABA A activated Cl- channels. Uses - second line drug in partial and generalized seizures (including absence, myoclonic seizures, infantile spasms nad Lennox-Gastaut syndrome). Tolerance can occur after 1-6 months. An adjunct therapy for partial seizures. AEs: drowsiness, lethargy. Cognitive effects.

2nd Generation
Oxcarbazepine NS
Prodrug that results in less potent enzyme inducer Uses - monotherapy or adjunct therapy for partial seizures

Gabapentin/Pregabalin NS
MOA - unknown PK - intestinal absorption by L-amino acid carrier protein; elim by kidney; oral admin Uses - 2nd choice or adjenct for partial and tonic-clonic seizures; essential tremor; neuropathic pain AE - fatigue, drowsiness, dizziness, ataxia; WITHDRAWAL RXNS

Ezogabine NS
MOA - Targets neuron speci[ic voltage-gated K channels to dampen neuronal hyperexcitability. Uses - Adjunct treatment in drug resistant partial seizures.

Lamotrigine BS
MOA - volt and freq. dep blockade of Na+ ch; Blockade of volt-gated Ca++ ch PK - good oral BA; metab by glucuronidation (INH by valproate --> INC plasma con'c) Uses - 1st choice for simple and complex partial seizures, tonic-clonic seizures; 2nd choice form absent, myoclonic, and infantiie seizures; migraine prophylaxis AE - drowsiness, dizziness, fatigue, ataxia, diplopia; gen skin rash; S-J syndrome

Levetiracetam BS
MOA - unknown Uses - 1st or 2nd choice for parial and tonic-clonic and myoclonic seizures AE - drowsiness, fatigue, dizziness, ataxia

Topiramate BS
MOA - Blockade of voltage-gated Na+ and Ca++ ch; potentiation of inhibitory effects of GABA at GABA-A receptors; blockade of AMPA glutamate receptors; INH of CA PK - good oral BA; 50% elim by kidney; DEC OC plasma levels Uses - 1st or 2nd choice for simple and complex partial, tonic-clonic, myoclonic, atonic, infantile seizures; Lennox-Gastaut syndrome; Migraine prevention AE - drosiness, dizziness, fatigue, ataxia, aphasia, nystagmus, parethesias; ocular HTN, CA glaucoma, metab acidosis, PPT renal calculi CI - glaucoma, COPD, nephrolithiasis, porphyria

Felbamate BS
MOA - Blockade of NMDA glutamate receptors; potentiation of GABA responses Uses - 2nd choice drug for atonic seizures, Lennox-Gastaut syndrome AEs - drowsiness, dizziness, fatigue HA; APLASTIC ANEMIA AND SEVERE HEPATITIS

Zonisamide BS
MOA - Blockade of Na+ channels, Blockade of T type Ca++ ch; Enhancement of GABAergic transmissiion, INH of glutamatergic transmission Uses - 2nd choice of adjunct for Partial and tonic clonic seizures, myoclonic seizures AEs - drowsiness, dizziness, HA, irritability, allegic rxns (sulfa drug), somnolence, anorexia, hyperthermia and oligohydrosis in children

Three Major Categories for Pharmacotherapy: MOA Limit repetitive firing by promoting inactivated state of voltage-gated Na + channels. Excitatory ion channel. Enhance GABA-mediated synaptic inhibition. Inhibitory Cl- ion channel. Inhibition of voltage-activated Ca2+ channels associated with T-type Ca2+ currents. Other: Opens K+ channels and stabilizes the electrical currents, NMDA antagonist Drugs that Work on Reducing the Rate of Na+ Channels Recovery from Inactivation: Neurons can no longer fire at high frequency Drugs that work on simple partial, complex partial and partial with secondary generalized tonic-clonic seizures Carbamazepine, phenytoin, valproic acid ( 1st generation) Lamotrigine, topiramate and zonisamide ( 2nd gen) Drugs that Enhance GABA Inhibition: Raise the Seizure Threshold Benzodiazepines and barbiturates enhance GABA A receptors, enhances Cl- flow and hyperpolarizes the membrane. They work on both partial and tonic-clonic seizures. At high doses can be used for status epilepticus, drugs may also inhibit high frequency firing. Tiagabine inhibits GABA transporter site preventing reuptake back into the presynaptic cell. Drugs Effective Against Generalized-Onset: Absence Seizure There is a presence of thalamic and neocortical discharge of 3/sec generalized spike and wave discharges. T-type Ca2+ channels inhibited by Ethosuximide, valproic acid effective on absence seizures. When do you start treating? Treatment is indicated after at least two unprovoked seizures. After the first, if warranted by abnormal EEG discharges, abnormal neurological exam or other structural abnormality thought responsible for the seizure. First Line Drugs for Partial Seizures Advantages/Disadvantages Carbamazepine high evidence for efficacy, low cost, mood stabilizer/ enzyme inducer, high interaction potential, hyponatremia in elderly. Gabapentin non-enzyme inducer, no interactions, effective in neuropathic pain/ low evidence of efficacy (except in the elderly), weight gain. Lamotrigine high level of efficacy also in the elderly, non- enzyme inducer, effective mood stabilizer (bipolar depression) / slow titration, allergic reaction, drug interactions . Levetiracetam- high level of evidence for efficacy, rapid titration, non-enzyme inducer, no significant interactions/ psychiatric adverse effects. Oxcarbazepine low potential for enzyme induction, lower risk of rashes then carbamazepine/ higher risk of hyponatremia then carbamazepine, reduces blood conc of oral contraceptives.

Phenobarbital extensive experience, low cost, once-daily dosing/ enzyme inducer, high interaction potential, cognitive and behavioral effects Phenytoin high level of evidence of efficacy, rapid titration, extensive experience, low cost, once-daily dosing possible/ complicated PK, enzyme inducer, high interaction potential, cosmetic adverse effects Topiramate effective for migraine prophylaxis, low potential for enzyme induction/ slow titration, cognitive adverse effects Valproate rapid titration, mood stabilizer/ enzyme inhibitor, some interaction potential, weight gain, teratogenic potential

First Line Drugs for Generalized Seizure Advantages/ Disadvantages Lamotrigine non-enzyme inducer, effective in bipolar depression/ slow titration; dose requirements influenced by valproate, enzyme inducers and estrogen-containing contraceptives; can aggravate myoclonic seizures in some patients Levetiracetam non-enzyme inducer, no significant interactions, rapid titration/ psychiatric adverse effects Topiramate effective for migraine prophylaxis, low potential for enzyme induction/ slow titration, cognitive adverse effects Valproate best evidence for efficacy, rapid titration/ enzyme inhibitor, some interaction potential, weight gain, teratogenic potential Other Seizures Absence seizures: ethosuximide, valproate and lamotrigine. Myoclonic convulsions: valproic acid and levetiracetam. Status epilepticus: prolonged seizure, any type (>30mins). Emergency. Give IV: lorazepam or diazepam followed by phenytoin, phenobarbital or valproate. Attend to airway and cardiovascular stability Dosing Gradual dose titration. Improves CNS tolerability and reduces the risk of idiosyncratic adverse effects. Measure serum concentration based on individual response. Dose with the least amount of sedation as possible maintaining blood levels. Dose based on symptoms. Seizures begat seizures, make changes if the seizures are not controlled. If efficacy diminishes, consider changes in enzymes review for drug interactions and adjust the dose. Refractory seizures: 30% Long Term Prognosis Excellent for most children with seizures, particularly if they are cryptogenic/ idiopathic (unknown origin). Long-term mortality increased in childhood-onset epilepsy, especially for those not in remission. With uncontroled Sz, an increased risk in epilepsy-related deaths and sudden unexplained death.