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Anticonvulsants

Anticonvulsants. Spectrum of action. Generalized, focal motor, partial seizures: threat with carbamazepine , phenytoin , valproic acid, lamotrigine , phenobarbital Generalized absence seizures: treat with ethosuximide , valproic acid, lamotrigine , but NOT carbamazepine

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Anticonvulsants

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  1. Anticonvulsants

  2. Spectrum of action • Generalized, focal motor, partial seizures: threat with carbamazepine, phenytoin, valproic acid, lamotrigine, phenobarbital • Generalized absence seizures: treat with ethosuximide, valproic acid, lamotrigine, but NOT carbamazepine • Complex childhood seizures: treat with benzodiazepine, valproic acid, or unusual Rx (egketogenic diet, ACTH) • Status epilepticus therapy • 1. Airway, breathinq, circulation support • 2. IV glucose • 3. IV benzodiazepine (lorazepam or diazepam) (possible coma side effect and need for mechanical vent) • 4. IV phenytoin or fosphenytoin (slow admin to avoid bradycardia and arrhythmia) • 5. IV phenobarbital • 6. Midazolam or general anesthesia

  3. Pharmacology of Anti-Convulsants • Anticonvulsants reduce uncontrolled neural electrical activity. • They are more selective than ​anesthetics, which suppress both paroxysmal and normal activity. • Anticonvulsants are teratogens, and also may alter metabolism of birth control pills or endogenous ​hormones. This can lead to unwanted pregnancies or ovarian dysfunction. • 70% of children eventually discontinue anticonvulsants without problems.

  4. The primary targets of anticonvulsants are GABA and glutamate receptors. • Drugs that act via GABA receptors are the most powerful but have severe sedating side effects. • Drugs that act via glutamate protect against excitotoxicity but have severe cognitive side effects. • **Too much glutamate or too little GABA activity at synaptic receptors causes seizures.

  5. Common seizure types are generalized/focal motor, or partial with complex behavior. • ​All anticonvulsants are effective. Anticonvulsants will target the most active neurons. • Uncommon seizure types are absence seizures. These are made worse by carbamazepine

  6. General side effects of anticonvulsants • Teratogenic, • spinabifida, • antagnoizes folic acid • Induces metabolism of birth control pills • Altered endogenous hormone metabolism, • ovarian dysfunction • May increase oxygen free radicals • Decrease epoxidehydrolase activity -> less oxidative detoxification of anticonvulsant metabolites

  7. Anticonvulsants that increase GABA activity • Phenobarbital and Mysoline. • Mysolineis actually converted to Phenobarbital and PEMA, which are ​both barbiturate anticonvulsants metabolized in the liver. They increase GABA activity. • ​All barbiturates cause cognitive dulling and behavioral side effects

  8. Phenobarbital • MOA: barbiturate (inc GABA/BZ receptor function) • PK: long t1/2, liver metabolism to active metabolites • ADR: cognitive dulling, behavioral side effects

  9. Mysoline • MOA: prodrug of phenobarbital and PEMA -> barbiturate effects • PK: long t1/2, liver metabolism to active metabolites • ADR: cognitive dulling, behavioral side effects

  10. Sodium Channel Blockers • Phenytoin • Cabamezapine • Lamotrigine

  11. Phenytoin • Phenytoin is hydroxylated in the liver by saturableMichaelis-Menton kinetics. ​At low levels this metabolism is first-order. At high levels it is zero-order • MOA: voltage-gated Na channel blocker -> inhibits sustained repetitive firinq • PK: saturable liver metabolism • ADR:littlesedation, at high levels causes ataxia and nystagmus, "purple glove", gum hypertrophy, hirsutism

  12. Fosphenytoin • Prodrugof phenytoinwithout as much peripheral side effects

  13. Carbamazepine • inhibits sustained repetitive firing by blocking sodium channels. ​Hyperpolarizes membranes. • It is metabolized in the liver to an epoxide. • MOA: voltage-gated Na channel blocker -> inhibits sustained repetitive firinq • ADR: Makes generalized absence seizures worse • PK: sustained release extends short t1/2

  14. Lamotrigine • MOA: blocks Na channels associated with presynapticGlurelease • PK: Half-life is hugely prolonged by valproic acid. • ADR: few cognitive side effects, rarely causes a severe skin rash

  15. Valproic acid • MOA: Na channel blocker, enhance GABA/BZ receptors, • Rx all types of seizures • ADR: fatal hepatic necrosis in children <2yo especially if on a 2nd anticonvulsant, few cognitive side effects

  16. Valproic Acid blocks sodium channels, which boosts GABA activity. • Very good widely used drug. • ​Has a simple fatty acid structure, and is metabolized in the liver. • ​Slows metabolism (prolongs half-life) of Phenobarbital and Lamotrigine. • ​**Can cause fatal hepatic necrosis, especially in children on multiple anticonvulsants.

  17. Benzodiazepine • MOA: enhance GABA/BZ receptor function • 1st line Rx for status epilepticus • Tiagibine blocks GABA reuptake.

  18. Treating Status Epilepticus • Status epilepticus • 30 minutes of continuous seizing, • or >2 seizures without conscious recovery. • Can damage brain and organs. • Therapy includes airway support, IV glucose, Phenytoin. • If needed, graduate to Phenobarbitals, then anesthesia.

  19. summary • Barbituate -> Enhance GABA/BZ receptor • Benzodiazepine -> Enhance GABA/BZ receptor • Carbamazepine-> Blocks Na channel • Ethosuximide-> Blocks Ca channel • Lamotrigine-> Blocks Na channel • Phenytoin-> Blocks Na channel • Tiagabine-> Blocks GABA reuptake • Topiramate-> Blocks Glu receptor and Na channel • Valproicacid -> Blocks Na channel, enhances GABA receptor • Vigabatrin-> Blocks GABA breakdown

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