Pharmacology of Seizures and Epilepsy Flashcards
AEDs (anti-epilepsy drugs) stop seizures from occuring in how many patints
- 2/3
- many stop because of SE’s
drugs used to treat epilepsy–target
- glutamate (suppress excitatory)
- GABA (enhance inhibitory)
generalized onset seizures
- absence
- myotonic, atonic, clonic
- tonic/clonic
partial onset seizures
- tonic/clonic
- simple complex
absence seizures–drugs used
- Ethosuximide
- Valproic acid
Myotonic clonic seizures–drugs used
Tonic/clonic seizures–drugs used
-Benzodiazepines–clonazepam
-Phenytoin
-Phenobarbital
-Carbamazepine (only partial onset
narrow spectrum drugs)
Simple complex seizures–drugs used
-Carbamazepine (narrow spectrum)
-Gabapentin
-Pregabalin
-Oxcarbazepine
-Lacosamide
-Tiagabine
-Vigabatrin
-Ezogabin
CGPOLTVE
Broad spectrum–drugs used (used for more than 1 type of seizure)
-Valproate
-Lamotrigine
-Topirimate
Levetiracetam
-Zonisamide
(VLTLZ)
AEDs that antagonize excitation by targeting
- NAv (voltage gated Na ion channels)
- low-threshold (T type) Ca channels
AEDs that antagonize Nav
- phenytoin
- carbamazepine
- oxcarbazepine
- lamotrigine
- zonisamide
inactivation of Nav
-channels close from inside of neuron–go into a fast inact state where they cannot be react
repolarization of new
-Na channel goes into a slow inactivated state by closing the pore from inside
prolong fast inactivation state of Nav ion channels
- phenytoin, carbamazepine
- oxcarbazepine, lamotrigine (newer)
enhance slow inactivation of Nav channels
-lacosamide
Na channels during depolarization
- resting state–activation gate closed
- open state–activation gate and inactivation gate open
- fast-inactivation state–inactivation gate closes!
Na channels during repolarization
- fast-inactivated state–inactivation gate closes
- inactivation closed state–activation gate closes
- resting state–activation gate closed
AEDs binding site of Na channel?
- at interior side of Nav channel pore
- if activation gate opens–AEDs can access pore
- if activation gate closed–AEDs cannot access pore
probability of Nav blockage proportional to?
-frequency of Nav channel opening
Nav blockers–act preferentially on?
-neurons involved in disease (neurons firing at higher frequency)
phenytoin and carbamazepine differences
-carbamazepine–binds Nav less effectively, but faster–more effective in blocking high frequency firing
Lamotrigine vs phenytoin and carbamazepine
- Nav ion channels (similar to phenytoin and carbamazepine)
- also acts on other molecular targets–voltage gated Ca channels
lacosamide–difference from other AEDs how?
- treats partial seizures
- stabilizes the slow-inactivated state (other AEDs act primarily on fast-inactivation state)
hallmark of absence seizures
-T-type Ca channels mediate 3 Hz spike and wave activiy in thalamus
Ethosuximide
only for absence seizures
- only limits excitation (Ca channel)
- Non-sedating drug!!
if ethosuximide doesnt work for absence seizures, use?
- valproate
- lamotrigine
valproate
- first line therapy
- adverse side effects (weight gain, tremor, hair loss, lethargy)
- neural tube defects in babies whose moms take it during pregnancy
Lamotrigine
- MOA on Nav ion channels–similar to phenytoin and carbamazepine
- also acts on Ca channels
Zonisamide
- sulfonamide derivative
- blocks Nav channels
- blocks T-type Ca channels
pre-synaptic modulation of GABA re-uptake or syn-drugs?
- Tiagabine–inhibits GABA reuptake
- Vigabatrin–inhibits GABA metabolism
post-synaptic modulation of GABA receptor drugs
- phenobarbital (barbiturates)
- primidone (older drug)
- bensodiazepines
phenobarbital–complications
- cause sedation
- lethal respiratory depression
- abuse and addiction potential
- needed search for better drugs (benzodiazepines)
Benzodiazepines MOA
Barbituates (phenobarbital MOA)
- bind to distinct site–allosteric change
- potentiate GABA binding–Cl channels opens with greater frequency
- bind to distinct site
- increases the duration of Cl channel opening
- toxicity–high doses are GABA independent
differential lethality of GABAa R agonists
- phenobarbital–GABA independent–lethal resp depression
- Benzodiazepine–GABA dependent
indicated for treatment of status epilepticus
-Benzodiazepines (Diazepam or Lorazepam)
Status epilepticus
- seizures occur without epilepsy due to
- drug withdrawl (AEDs, sedatives–natural disasters)
- stimulant abuse (cocaine)
- poisons
- brain tumor
- high fever
Status Epilepticus treatment
- lorazepam/diazepam
- if seizure doesnt stop, Fosphenytoin IV Na channel antagonist
clonazepam,
- benzodiazepine–drug of choice for myoclonic seizures and subcortical myoclonus
- IV or rectal
drugs with multiple MOAs
- Topirimate
- Valproic acid
Valproic acid–MOAs
- Nav channels
- T type Ca channels
- increases GABA
Topirimate–MOAs
- Nav channels
- Ligand gated Na channels (AMPA/glutamate R)
- increases GABA
- potentiates GABA Receptors
Topirimate unique MOA
-glutamate (AMPA) R antagonist!!
Gabapentin–mechanism
-voltage dependent Ca channels
Leviteracetam–mech, key points
- binds to synaptic vescicle protein SV2a–blunts glutamate release
- No CYP interaction
Pregabalin–mech, key points
multiple
100% renal clearance
Ezogabine–mech, key points
- opens voltage gated K channels
- causes urinary retention
complications with phenytoin
- zero order pharmacokinetics (dose adjustment difficult)
- induces CYP 450
- gingival hyperplasia
- Hirsutism
- hypocalcemia, osteoporosis
Complications with carbamazepine
- induces CYP450
- aplastic anemia (Rare, fatal)
- leukopenia, neutropenia, thrombocytopenia–infections,bruising
- hypocalcemia, osteoporosis
induces CYP450 drugs, effects
- carbamazepine
- phenytoin
- phenobarbital
- valproate
- CYP 450 dependent Vitamin D catabolism–decreased abs of intestinal calcium–demineralize bone (PTH mediated)
carbamazepine–induces what?
- its own metabolism (CYP450)
- have it adjust dose–loss of efficacy
carbamazepine increases clearance of?
- oral contraceptives (risk for pregnancy)
- warfarin (risk for thrombosis)
increases clearance of oral contraceptives
carbamazepine
increases clearance of warfarin
carbamazepine
drugs have mixed clearance (Renal, hepatic)
- Topiramate
- Oxcarbaxepine
- Levetiracetam
- Zonisamide
Oxcarbazepine
- analogue of carbamazepine
- fewer adverse effects–lack of formation of an active metabolite
- minimally affects CYP450
Associated with oxcarbazepine and carbamazepine
-hyponatremia
100% renal clearance drugs
-Gabapentin
-Pregabalin
(renal insufficiency requires dose adjustment)
life threatening allergic reaction –drugs
- Carbamazepine–Stevens-John syndrome, aplastic anemia
- Lamotrigin
When these 2 drugs are used together–inhibits conjugation of drugs by UGT enzymes–causes accumulation of parent drug
- Valproate
- Iamotrigine
Class D teratogens
-Valproic acid
Carbamazepine
-Phenytoin
