Anti-Seizure Flashcards
What is the mechanism of action of PHENYTOIN and CARBAMAZEPAM?
Binds to Na+ voltage gated channels -> Prolongs its INACTIVATION (Prolonging refractory period) -> INHIBITS high frequency neuronal firing and reduces neuronal excitability -> DECREASES PRE-SYNAPTIC RELEASE OF GLU
What is the mechanism of action of ETHOSUXIMIDE? (used for generalized ABSENCE seizures)
T-Type Ca2+ Channel Blocker - Reduces Ca2+ Influx -> Reduces PACEMAKER CURRENT underlying thalamic waves and spikes seen in Generalized absence seizures
Name the 3 mechanisms of anti-seizure drugs
1) REDUCE Glu-mediated excitatory transmission
2) ENHANCE GABA-mediated inhibitory transmission (either presynaptic or post-synaptic)
3) MODIFY Ionic Conductance - PROMOTE inactivated state of voltage-gated Na+ (Delay refractory period and inhibit sustained, repetitive neuronal firing) and INHIBIT voltage-gated Ca2+
What are the proposed mechanisms of action of PHENOBARBITOL (used for myoclonic seizures and status epilepticus)? (2)
- Blocks Na+ and Ca2+ conductance -> Decreasing pre-synaptic release of Glu
- Binds to GABA(A)R -> Enhances the opening of the Cl- channel -> Hyperpolarization -> Decreases neuronal excitability
What is the shared mechanism of action of BENZODIAZAPENES + BARBITURATES?
Binds and ENHANCES the activity of GABA(A)R [Cl- channel] -> Increased frequency of opening Cl- channel = GREATER Cl- Influx = Hyperpolarization = Lower neuronal excitability
What specific drug is used ONLY for ABSENCE SEIZURES?
ETHOSUXIMIDE
Which representative/conventional drugs are used to treat PARTIAL SEIZURES (Both simple, complex)?
PHENYTOIN
CARBAMAZEPINE
VALPROATE
Which representative/conventional drugs are used to treat GENERALIZED TONIC-CLONIC (Grand mal) SEIZURES?
PHENYTOIN CARBAMAZEPINE VALPROATE PRIMIDONE PHENOBARBITAL
Which representative/conventional drugs are used to treat GENERALIZED ABSENCE (PETIT MAL) SEIZURES?
ETHOSUXIMIDE
VALPROATE
CLONAZEPAM
Which representative/conventional drugs are used to treat GENERALIZED MYOCLONIC SEIZURES?
PHENOBARBITOL
VALPROATE
CLONAZEPAM
Which representative/conventional drugs are used to treat GENERALIZED STATUS EPILEPTICUS?
PHENOBARBITOL
DIAZEPAM
FOSPHENYTOIN
Which representative/conventional drugs are used to treat PARTIAL seizures that evolved into GENERALIZED tonic-clonic seizure?
PHENYTOIN
CARBAMAZEPINE
VALPROATE
PRIMIDONE
What is the toxicity of NEW DRUG- FELBAMATE? (2)
- Aplastic Anemia
2. Hepatic failure
What is the toxicity of NEW DRUG GABAPENTIN? (4)
1-3. Nystagmus + Dizziness + Ataxia
4. Sedation
Which two drugs can have a chronic toxicity of Stevens-Johnson Syndrome?
CARBAMAZEPINE
LAMOTRIGINE
What is the prodrug of phenytoin designed for PARENTERAL (IV, or IM) routes? (used for status epilepticus)
FOSPHENYTOIN - Phosphate group attached to the N of phenytoin
What is the toxicity of NEW DRUG - LAMOTRIGINE? (5)
1-3. Nausea + Dizziness + Ataxia
- Rash
- Rare Stevens-Johnson Syndrome
PHARMACOKINETICS: Of the 3, which two drugs are highly bound to plasma proteins?
PHENYTOIN
VALPROATE
PHARMACOKINETICS: CARBAMAZEPINE
Describe absorption, distribution (peak levels), metabolism, and elimination.
ABSORPTION - Slowly but well absorbed orally
DISTRIBUTION - Reaches peak levels from 6-8hrs
METABOLISM - 10,11- epoxide is the active metabolite
ELIMINATION - half life is 8-12hrs in TREATED pts and 36hrs in NORMAL pts
PHARMACOKINETIS: VALPROATE
Describe absorption, metabolism, and elimination
ABSORPTION: Well absorbed from several formulations
METABOLISM: Extensively metabolized by UGT enzymes and beta-oxidation
ELIMINATION: Half-life is 9-16hrs
DRUG INTERACTIONS: PHENYTOIN (3)
- Induces MICROSOMAL Enz -> Induces greater metabolism of other drugs such as ORAL CONTRACEPTIVES
- Induces CYP3A4 -> Induces greater metabolism of other anti-seizures (CARBAMAZEPINE/ PHENOBARBITOL/ VALPROATE)
- Competes with VALPROATE for protein binding sites -> Inhibits PHENYTOIN metabolism -> INCREASE in free phenytoin
DRUG INTERACTIONS: CARBAMAZEPINE (1)
- Induces CYPs and UGT -> Enhances metabolism of other drugs (e.g. ORAL CONTRACEPTIVES + other Anti-seizures such as VALPROATE/ PHENYTOIN/ PHENOBARBITOL)
DRUG INTERACTIONS: VALPROATE (2)
- **INHIBITS PHENYTOIN / PHENOBARBITOL/ LAMOTRIGINE/ LORAZEPAM Metabolism - unlike phenytoin and carbamazepine
- Competes with Phenytoin for protein binding sites (albumin) -> Inhibits Phenytoin metabolism -> INCREASE in free phenytoin
PHARMACOKINETICS: PHENYTOIN
Describe absorption, metabolism, and elimination.
ABSORPTION - Formulation dependent
METABOLISM - No active metabolites
ELIMINATION - Dose-dependent (half-life = 12-36hrs)
What is the toxicity of CARBAMAZEPINE?
(1-7. Mentioned in Class
8-12. Chronic Effects - Table)
1-4. Nausea + Diplopia + Dizziness + Ataxia
5-7. Headache + Hyponatremia + Rash
8-12. CHRONIC EFFECTS: Cognitive Dysfunction + Drowsiness + Rare occurrence of severe blood dyscrasis + Stevens-Johnson Syndrome (Han Chinese) + Potential Teratogenicity
What is the toxicity of VALPROIC ACID?
(1-6. - pointed out in class)
(7-10. - in 2 tables)
1-6. Nausea (Transient)+ Anorexia (Transient) + Weight gain (Chronic) + Tremor + Acute Pancreatitis + Hyperammonia
7-10. Drowsiness + Hair loss + Teratogenicity (neural tube defects) + Hepatotoxicity (infants)/Inhibition of Hepatic Drug Metabolism
What is the toxicity of PHENYTOIN?
(1-6. General Toxicity
7-11. Chronic Toxicity)
1-6. Nystagmus + Diplopia + Ataxia + Gingival Hyperplasia + Hirsutism + Neuropathy
7-11. COARSENING of facial features + OSTEOMALACIA (VitD metabolism abnormalities) + Peripheral neuropathy (hyporeflexia) + Induction of Hepatic Drug Metabolism + Sedation
