Antiepileptic Drugs Flashcards
Glutamate
- a neurotransmitter used by many excitatory neurons, e.g., NMDA, AMPA & Kainate (KA) Receptors
- Levels are increased during seizures
GABA
- a neurotransmitter used by many inhibitory neurons
- two receptor types:
1. GABAA: ionotropic
2. GABAB: metabotropic - is derived from Glutamate; the enzyme GLUTAMATE DECARBOXYLASE converts Glutamate to GABA
Drugs used in the treatment of Partial Seizures and Generalized Tonic-Clonic Seizures (GTCs)
- Phenytoin
- Carbamazepine
- Primadone
Phenytoin
Mech: blocks tetanic firing by inactivating Na channels (brings inactivation gate to closed position), and by reducing neurotransmitter release
Use:
- treat Partial Seizures and GTCs
- treat Status Epilepticus
Pharmacokinetics:
- good oral absorption (but dose dependent)
- NON-LINEAR RELATIONSHIP BETWEEN DOSE AND PLASMA LEVEL, due to shift from 1st order kinetics (at low dose) to zero order kinetics (at high dose)
- THERAPEUTIC LEVELS MUST BE MONITORED: time to peak varies from patient to patient
- highly bound to proteins and stored in fat
Toxicities:
- GINGIVAL HYPERPLASIA: overgrowth of the gums
- HIRSUTISM
- Cardiac arrhythmias with rapid infusion
- CNS depression
- Acute oral overdose: Loss of balance
Carbamazepine
Mech:
- Blocks tetanic firing by inactivating Na channels
- Reduces neurotransmitter release
- Potentiates GABA responses (inhibitory)
Uses:
- treat Partial Seizures and GTCs
- Tricyclic antidpressant for Bipolar disorder
- Treat Trigeminal disorder
Pharmacokinetics: 70% bound to protein; is itself an active metabolite
Toxicities:
- A RASH IS COMMON
- CNS: Ataxia, Diplopia, Nystagmus, Dizziness
- APLASTIC ANEMIA & blood dyscrasias
- Many drug-drug interactions
Primidone
Mech: Increases Na+ channel inactivation
- Phenobarbital (GABAa agonist) is a metabolite, but does not reach sufficient levels to be implicated in the mech
Use: Treat complex partial seizures (but now largely replaced by Phenytoin and Carbamazepine)
Pharmacokinetics:
- slow but complete absorption
- Induces hepatic enzymes
Toxicities:
- Drowsiness
- Overdose: Ataxia and Nystagmus
Adjuvant Therapies for Partial Seizures
- Gabapentin
- Lamotrigine
- Vigabatrin
- Topiramate
Gabapentin*
- Does not inactivate Na channels
Mech:
- Binds to V-G Ca+ channel subunit
- Decreases Glutamate release
- Inhibits GABA Transaminase, thereby inhibiting breakdown of GABA
Use:
- Adjuvant therapy for partial seizures
- Chronic pain management
- Not protein bound or metabolized
- Few drug-drug interactions, but interacts with Cimetidine and Aluminum/Magnesium Antacids
Lamotrigine
Mech:
- increases Na channel inactivation
- Acts on Presynaptic V-G Ca+ Channels to inhibit release of excitatory NTs
Drug-Drug Interactions:
- Phenytoin, Carbamazepine & Primadone reduce half-life
- Valproic Acid prolongs half-life
Toxicities: RASH COMMON IN CHILDREN; associated with Stevens-Johnson Syndrome
Pharmacokinetics:
- good oral absorption (but dose dependent)
- NON-LINEAR RELATIONSHIP BETWEEN DOSE AND PLASMA LEVEL, due to shift from 1st order kinetics (at low dose) to zero order kinetics (at high dose)
- THERAPEUTIC LEVELS MUST BE MONITORED: time to peak varies from patient to patient
- highly bound to proteins and stored in fat
- Vigabatrin
* does not inactivate Na+ channels
Mech: Inhibits GABA-T, thereby inhibiting breakdown of GABA (“Vi” vitalizes GABA)
Use: Treat partial seizures
Drug-Drug Interactions: Reduces plasma concentrations of Primadone
Side effect: Psychosis (rare)
Topiramate
Mech:
- Inactivates Na+ channels
- Inhibits Kainate & AMPA Receptors (Excitatory) Glutamate receptors
- Enhances action of GABA (inhibitory)
Use:
- Adjuvant therapy for partial seizures
- Anti-migraine drug
Drugs Used in Treatment of Generalized Seizures
- Valproate (Valproic Acid)
- Ethosuxamide
- Diazepam (Benzodiazepines)
Valproate (Valproic Acid)
Mech:
- blocks tetanic firing through increasing Na+ channel inactivation
- reduces transmitter release
- Reduces T-type Ca2+ channel (excitatory channel) activity, which is associated with absence seizures
- increases GABA levels by inhibiting breakdown
Use: Used against ABSENCE SEIZURES
Pharmacokinetics:
- Well absorbed, 90% protein bound – half life 9 – 18 hr
Toxicity:
- Nausea, vomiting, other GI distress
- HEPATOTOXICITY CAN BE SEVERE
Absence Seizures (Petit Mal Seizures)
- 10-45 s (maybe 100/day) with altered consciousness.
- Mild clonic spasms may occur
- Automatisms can confuse diagnosis with complex partial seizures.
- Start in childhood – patients often
suffer mental retardation - associated with T-type Ca2+ channel activity
Ethosuxamide*
Mechanism: Inhibits T-type Ca2+ channel activity in thalamic neurons
Use: against absence seizures and myoclonic seizures
Pharmacokinetics:
- Not protein bound
- Metabolized by microsomal enzymes (half life = 40 hr)
Toxicity:
- Gastric distress: pain, nausea, vomiting
- Considered safe
