Absence seizures Tx
Ethosuximide
Atonic, myoclonic, clonic seizures Tx
Benzodiazepines, clonazepam
Tonic-clonic seisures Tx
Carbamazepine, Phenytoin, Phenobarbitol
Partial onset simple/complex seizures Tx
Gabapentin, Prebabalin, Oxcarbazepine, Lacosamide, Tiagabine, Vigabatrin, Ezogabin
Partial onset tonic-clonic seizures Tx
Carbamazepine, Phenytoin, Phenobarbital
Broad specturm (together or alone)
Valproate, Lamotrigine, Topirimate, Levetiracetam, Zonisamide
Newer drugs
All Simple/Complex partial onset + All broad spectrum EXCEPT Valproate
Good thing about newer drugs
Not hepatically metabolized, less side effects
How to use simple/complex narrow spectrum
Will each other or with older drug
Which ones are narrow spectrum?
Tonic/clonic (general onset) + Simple/complex (partial onset)
2 main things to antagonize for seizures
- Voltage-gated Na+ channels
2. Low-threshold (T-type) Ca++ channels
Absence seizures (Tx target)
Low-threshold (T-type) Ca++ channels
Drugs used to treat epilepsy target NT systems to do what 2 things?
- Slow glutamate (EAA) transmission
2. Enhance GABA (inhibitory) transmission
Phenytoin
Effect on cognitive function?
Old Limit EAA VGSC block Fast inactivation (inactivation gate) Slow recovery from inactivation Best at depolarize or high-frequency firing membranes - USE-DEPENDENT ZERO-ORDER KINETICS - Hard to dose ∆ Induces CYP enzymes (drug interactions) Tonic-clonic seizures (Narrow spectrum)
Minimal – cognition = low-frequency
Phenobarbital (Barbiturate)
Old
Enhance GABA
Like Benzodiazepines (Diazepam) BUT w/ dose-dependent lethality and side effects
DEPRESSION, sedation, lethal respiratory depression, abusive/addictive
Tonic-clonic seizures (Narrow spectrum)
Diazepam (Benzo)
Old Enhance GABA Allosterically potentiates effects of GABA transmission Lethal w/ alcohol Myotonic, atonic, clonic seizures
Ethosuximide
Old Limit EAA VGCC (Ca++) (T-type) block Absence seizures NON-SEDATING
Carbamazepine
Old Limit EAA VGSC block Fast inactivation (inactivation gate) Faster binding than Phenytoin, better at high-freq. firing - USE-DEPENDENT Tonic-clonic seizures (narrow spectrum)
Valproate
Old BOTH (limit EAA and enhance GABA) VGSC + VGCC Broad spectrum Side effects = weight gain, tremor, hair loss, lethargy, neural tube defects (mothers)
“Broad-spectrum” definition
Limits EAA AND enhances GABA
Lamotrigine
New Limit EAA VGSC block Fast inactivation (inactivation gate) Also acts on N and P-type VGCC (Ca++) in cortex Broad spectrum Toxic = STEVENS-JOHNSON SYNDROME
Topirimate
New BOTH (limit EAA and enhace GABA) VGSC + LGSC (AMPA/glutamate receptor) Potentiates GABA-A receptors Broad spectrum
Fosphenytoin
Limit EAA
Oxcarbazepine
New Limit EAA VGSC block Fast inactivation (inactivation gate) Simple/complex seizures (narrow spectrum)
Zonisamide
New
Limit EAA
VGSC block AND VGCC block (T-type)
Broad spectrum
Vigabatrin
New
Enhance GABA
GABA-T (metabolism) inhibition
Simple/complex seizures (narrow spectrum)
Tiagabine
New
Enhance GABA
GABA re-uptake inhibitor
Simple/complex seizures (narrow spectrum)
Lacosamide
New Limit EAA VGSC block SLOW INACTIVATION (activation gate) Best at PROLONGED stimuli Simple/complex seizures (narrow spectrum)
Clonazepam (Benzo)
Old
Myotonic seizures and subcortical myoclonus
Status epilepticus (IV or rectal)
2 ways to enhance GABA inhibitory transmission
- Block GABA re-uptake or metabolism
2. Potentiate GABA receptor Cl- currents
Phenobarbital vs. Benzodiazepine in GABA-A receptor agonism
Pheno - GABA-independent, can easily overdose and cause coma and respiratory depression
Benzo - GABA-dependent, much more difficult to lethally OD, will never reach respiratory depression state
Treating status epilepticus
- Benzodiazepines (Diazepam or Lorazepam)
- GABA-ergic to stop EEG bursts
- Fosphenytoin (IF SEIZURE NOT STOPPED)
- Na+ channel antagonist
Cause of status epilepticus
Abrupt withdrawal of AEDs
Diazepam vs. Lorazepam
Lorazepam - not cleared as quickly from circulation, thus can have longer-lasting effects than Valium
Status epilepticus + can’t find IV vein
Clonazepam - rectal administration
Status epilepticus definition
Repeating seizures w/o regaining consciousness in between
Drugs w/ multiple mechanisms of action
Topirimate, Valproic acid
Valproic acid vs. Topirimate
Valproic acid (OLD) = VGSC + VGCC
Topirimate (NEW) = VGSC + LGSC (glutamate receptor) + GABA-A receptor agonist
Gabapentin
Binds to VGCC
No drug interactions
Leviteracetam
Binds to PRE-SYNAPTIC glutamate vesicle
Blunts glutamate release
Well-tolerated, no CYP interaction
Ezogabine
Opens VGPC (potassium) Causes urinary retention
What is NOT used for absence seizures?
Why?
Phenytoin and Carbamazepine
Both of these are good for HIGH-FREQUENCY firing seizures, via blocking VGSC
Treating absence seizures = blocking VGCC
Complications of phenytoin
Zero-order pharmacokinetics
- Hard to adjust dose
Induces CYP enzymes
- Drug-drug interactions, etc.
Toxicities of phenytoin
GINGIVAL HYPERPLASIA
Hirsutism
Hypocalcemia
Osteoporosis
How would patient present with carbamazepine toxicity?
Leukopenia/neutropenia, thrombocytopenia –> infections, bruising (APLASTIC ANEMIA)
Major cause of drug-drug interactions between AEDs
Hepatic CYP enzyme inductions
Osteoporosis in phenytoin/carbamazepine/phenobarbital/valproic acid CHRONIC USE toxicity
- P450-induced vitamin D catabolism
- Reduced vitamin D levels
- Decreased absorption of intestinal Ca++
- Compensatory PTH release
- PTH –> bone demineralization
Patient on carbamazepine (or phenytoin) for 2 weeks starts to show recurrence of seizures. Explanation?
Fix?
CYP induction –> reduced efficacy
Increase dose
Carbamazepine + Oral Contraceptive
Increased CYP clearance of OC –> 4-fold OC failure rate –> risk for pregnancy
Carbamazepine + Oral Anti-coagulant (ex. warfarin)
Increased CYP clearance of drug –> risk for RAPID coagulation –> A/V thrombosis
Ginkgo supplements/nuts + anticonvulsants
CYP2C19 induction by ginkgo –> increased clearance of anticonvulsants
Fixing CYP drug-drug interactions
NEW AEDs
How do new AEDs prevent such CYP induction?
50% renal clearance
Drug structure does not allow for CYP conversion into TOXIC metabolites
10,11-CBZ epoxide
Toxic metabolite of carbamazepine
Patient on oxcarbazepine or carbamazepine complains of hyponatremia
Why?
Increased responsiveess of collecting tubules to ADH (SIADH) –> increased water retention –> diluted blood –> hyponatremia
Gabapentin and Pregabalin
100% renal clearance (no CYP)
Renal insufficiency requires dose adjustment
Patient taking Lamotrigine presents with a rash
Risk factor for this?
Stevens-Johnson syndrome = side effect
- Life-threatening allergic reaction
Taking Valproic acid as well
Lamotrigine and Valproic acid
Inhibit conjugation of other drugs by UGT enzymes –> accumulation of parent drug
Adverse effects:
Levetiracetam
NONE
Adverse effects:
Oxcarbazepine
Hyponatremia (elderly), rash
Adverse effects:
Tiagabine
Stupor
Adverse effects:
Topiramate
Nephrolithiasis (kidney stone)
Open angle glaucoma
Hypohidrosis
Adverse effects:
Zonisamide
Rash
Renal calculi
Hypohidrosis
Carbamazepine warnings
Allergic reaction (S-J syndrome) Aplastic anemia
Lamotrigine warning
Allergic reaction (S-J syndrome)
Teratogenic drugs
Valproic acid
Carbamazepine
Phenytoin