10-22 Epilepsy PHARM Flashcards
Phenobarbital –Use –MOA –Metab –Toxicity
Use: Effective for all seizure types except absence. Can be given PO or IV. IV form very useful in status epilepticus.
Mechanism: GABA agonist. Opens chloride channel. Produces hyperpolarization.
Metabolism: Long half life (100 hours). Can be given PO or IV. Needs to be loaded. Hepatic metabolism. Hepatic enzyme inducer.
Toxicity: Hyperactivity in children. Sedation in adults. Joint and connective tissue problems.
Dose: 60-180mg daily
Phenytoin –Use –MOA –Metab –Toxicity
Use: Effective against all seizure types except absence. Better for focal and secondarily generalized seizures than for primary generalized ones.
Mechanism: Blocks voltage-gated Na+ channels.
Metabolism: Can be given PO or IV. Poorly absorbed PO in children. Has ZERO-ORDER kinetics at high doses because of enzyme saturation. Hepatic metabolism. Variable half- life (6-24 hours). Hepatic enzyme inducer.
Toxicity: Gingival hyperplasia, osteomalacia, ataxia. Need to supplement calcium, vitamin D, vitamin K, and folate.
Dose: 200-500mg daily.
Ethosuximide
Use: only for absence seizures
Mechanism: Blocks T-type Calcium Channels
Metabolism: Only oral preparation. Has good GI absorption. 1⁄2 life 24-48 hours. Mild hepatic enzyme inducer. Hepatic metabolism
Toxicity: Sedation, GI distress, occasional behavioral changes. (surprisingly well-tolerated in kids)
Dose: 200-600mg daily, in divided doses.
Benzos
Use: Effective against all seizure types. Tolerance develops rapidly (months). Drugs of choice for status epilepticus, alcohol withdrawal symptoms and alcohol withdrawal seizures. Good sedatives and anxiolytics.
Mechanism: Agonists at the GABA receptor.
Carbamazepine
Use: Excellent for focal and secondarily generalized seizures. Less effective for primary generalized seizures. Also a mood stabilizer for bipolar disorder. Works for neuropathic pain and trigeminal neuralgia.
Mechanism: Na+ channel blockade.
Metabolism: Only has oral preparation. 1⁄2 life 12 hours. Hepatic metabolism. Hepatic enzyme inducer. Levels increased by Calcium channel blockers, and macrolide antibiotics.
Toxicity: Blurred vision, sedation; uncommonly: neutropenia & hyponatremia; commonly: weight gain.
Dose: 400-1600 mg daily, in divided doses.
Valproate
Use: Very wide spectrum of efficacy. Works for all seizure types. Also used for migraine and bipolar disorder.
Mechanism: Not well understood. May block Na+ channels. Probably also affects GABA levels, Ca++, and K+ conductances.
Metabolism: Oral and IV preparation. Half Life ~15 hours. Hepatic metabolism. Not a major enzyme inducer.
Toxicity: GI upset, weight gain, menstrual problems, hair loss, low platelet count, hepatic encephalopathy sometimes but not always associated with elevated ammonia levels and carnitine deficiency.
Dose: 500-3000mg daily in divided doses.
Gabapentin
Use: effective against partial and secondarily generalized seizures. Not good for primary generalized seizures. Also a good anxiolytic, sedative, and anti-spasmodic. Works well for peripheral neuropathy and other painful states.
Mechanism: Increases GABA levels in the brain. May have other mechanisms.
Metabolism: PO preparation only. Short 1⁄2 life (6 hours). Well absorbed, except at very high doses. Not metabolized and excreted in the urine. Few drug interaction. Not an enzyme inducer.
Toxicity: sedation, particularly in the elderly. Occasional GI distress, and pedal edema. (no drug interactions)
Lamotrigine
Use: Broad spectrum efficacy against all seizure types. Also works for bi-polar disorder, and neuropathic pain.
Mechanism: Blocks Na+ channels. Blocks release of glutamate.
Metabolism: Only an oral preparation Renally excreted after hepatic glucoronidation. Not a major enzyme inducer. 1⁄2 life of 24 hours.
Toxicity: Allergic rash 5-10% (can progress to Stevens-Johnson Syndrome—>mucositis—>death). Other problems minor. Not sedating. May cause insomnia.
Dose: 200-600mg daily. in divided doses.
Topiramate
Use: Broad spectrum of efficacy, but not particularly good for absence. Good for migraine prevention. Some use in neuropathic pain. Causes weight loss.
Mechanism: Multiple mechanisms. Na+ channel blockade, GABA agonist, glutamate antagonist.
Metabolism: Some hepatic metabolism, but mainly renal clearance without change. 1⁄2 life of 24 hours. Only an oral preparation. Not a hepatic enzyme inducer.
Toxicity: Sedation, aphasia, parasthesias, kidney stones.
Levetiracetam
Use: Broad spectrum of use for focal and generalized seizures. Equivalent IV or PO dosing. Favorite anti-epileptic drug in hospitals.
Mechanism: Controversial, blocks Ca++ channels, but probably has other effects as well.
Metabolism: 2/3 excreted renally unchanged. Some enzymatic hydrolysis by liver and RBCs to inactive metabolites. Not protein- bound. Not an enzyme inducer.
Toxicity: Cognitive and behavioral problems.
Targets, MOAs of AEDs w/ examples
- Na+ channel (MOA: common depol. pathway for szs) blockade—phenytoin, carbamazepine, valproate, topiramate, and lamotrigine
- Ca2+ channel blockade (MOA depols neuron)—know most about ethosuximide MOA (blocks T-type Na+ channels in thalamus)…absence szs have 3Hz spike involving cortico-thalamic loop
- glutamate antagonists [open Na+ and Ca2+ channels—>depol] —lamotrigine (blocks release), topiramate (gutamate antagonist)
- GABA agonists [Cl- channels—> hyperpol] —barbiturates (prolong opening) benzos (incr freq of opening); also topiramate
Absorption of AEDs generally
usually complete (except gabapentin: has saturable gut transporter)
—takes several hrs (implications for blood level testing and acute TX)
—all but cbz slowed by food
Thadani recommends measuring serum conc.
so yeah
REVIEW: Therapeutic Index
TD_50/ED_50
toxic/effective
Elimination of AEDs generally
mostly hepatic metab* w/ renal excretion
—metab ∆s over time (cbz auto-induction, enzyme induct or inhib by other cmpds)
—variable between pts
- uses P450 (mostly CYP2C9, C19, & 3A4) and/or UGT then glucuronidation
- *just use epocrates and remember that LEVETIRACETAME does not induce or inhibit
