Drugs for Seizure Disorders Flashcards
Anticonvulsants
tx seizure disorders
- excessive, random discharge of neurons in brain
- imbalance between excitatory and inhibitory systems
Partial seizures
No loss of consciousness localized to specific area -elementary symptamology- cortical focal -complex symptomatology- psychomotor -increasing electrical activity at a focu followed by synch of the surrounding neurons, abnormal firing can then spread to adjacent neurons
Generalized siezures
always involves loss of consciousness
- tonic clonic
- absence
- status epilepticus
Tonic clonic (grand mal) siezures
focal seizure activity in one hemisphere spreads throughout the brain
-generalized seizure
Absence (petit mal) seizure
generalized seizure
- brief interruptions of consciousness manifested as motionless staring
- school aged children
- abnormal synch of thalamocortical and cortical cells, activation of T-type calcium channels that are normally active during sleep
Status epilepticus (absence or tonic clonic)
generalized seizures
5 min w/o regaining consciousness
med emergency
MOA
1) Prolong inactivation of Na channels- reduce ability of neurons to fire at high frequency (phenytoin, carbamazzepine, valproic acid, lacosamide, lamotrigine, topiramate, zonisamide)
2) Enhance GABA-ergic activity- inc receptor response to neurotransmitter (barbs, benzos) or inc synaptic activity of GABA (tiagabine, levetiracetam)
3) Inhibit T-type Ca+ channels (active during sleep, efficacious for absence seizures) (ethosuximide, valproic acid, trimethadione)
4) Other- dec excitatory neurotransmission by binding to subunits of voltage gated Ca channels within CNS; enhance K+ channel opening (gabapentin, pregabalin, ezogabine)
Benzos- Diazepam
Bind to BZ site on GABA receptor and inc affinity of GABAa receptors for GABA- inc likelihood of Cl channel opening
Drug of choice for tx of status epilepticus (iv)
Effective for tonic clonic and absence seizures but only for 2-3 weeks due to tolerance to anticonvulsant effects
Barbiturates
Bind to barbiturate binding site on GABAa receptor- inc Cl ion channel flux by inc channel opening time
-Dec glutametergic neurotransmission
Phenobarbital- tonic clonic seizures, very sedating, abrupt withdrawal can precipitate status epilepticus, induces microsomal enzymes, possible teratogen
can lead to stevens-johnson syndrome
Primidone
- Converted to phenobarbital and then phenylethylmalonamid (All three are active)
- frequently effective in pts not responding to phenytoin or phenobarbital (combo with phenytoin but NOT with phenobarbital)
- drowsiness, ataxia, nausea, vomiting, rash, diplopia, blood dyscrasias, impotence
Hydantoins
- Phenytoin (ethotoin, fosphenytoin, mephenytoin)
- Prolongs inactivation of Na channels, decreases glutamate release
- Tonic clonic and partial seizures drug of choice
- generally less sedating than barbs
- numerous drug interactions- highly bound to plasma proteins, induces P450s and other enzymes increasing metabolism and can lead to vit D deficiency
- metabolism- first order, hepatic metabolic capacity saturates in therapeutic concentration range (changes to zero order), small dose increases- large changes in drug concentration and toxicity
Side effects of hydantoins
- diplopia, ataxis, drowsiness, nausea vomiting, rashes
- hirsutism, hyperplasia of gums, megaloblastic anemia, teratogenic (fetal hydantoin syndrome), coarsening of facial features, osteomalacia
Valproid acid
- broad spectrum
- inc Na channel inactivation, inhibit T type Ca channels, enhances GABA transmission, modifies AA metabolism
- tonic clonic seizures
- idiosyncratic hepatotoxicity (esp in children <2 yo or taking multiple drugs- fatal)
- sedation uncommon
- SE: pancreatitis, nausea, vomiting, diplopia,
- IV for status epilepticus
- P450 inhibitor- inhibits metabolism of other drugs!!!
Which anticonvulsant is a p450 inhibtor
valproic acid
Carbamazepine
- partial seizures
- relatively safe and nontoxic
- diplopia, ataxia, drowsiness, not typically sedating, induces microsomal enzymes
- blood dyscrasias
Oxcarbazepine
much lower half life than carbamazepine
-no blood dyscrasias
fewer drug interactions
-partial seizures
Lamotrigine
Inc inactivation of Na channels
- inhibit T type Ca channels and decrease glut release
- nausea, diplopia, rashes, sedation, headache, dizziness
- valproic acid increases 1/2 life, so reduce dose if given in combo
- partial or possibly absence seizures
- add on or monotherapy
Topiramate
- add on, now used as monotherapy
- inc inactivation of Na channels, enhances GABA and dec glut activity
- partial, generalized tonic clonic, maybe absence seizures
- sedation, mental dulling, parasthesia, dec serum bicarb (met acidosis)
- teratogenic
- decrease efficacy of oral contraceptives
Levitiracetam
Modifies synaptic release of GABA (and glutamate) by binding to synaptic vesicular protein SV2A
-not metabolized by P450
SE: agitation, nausea, drowsiness, asthenia, muscle weakness
-Partial seizures monotherapy or add on
Lacosamide
enhances slow inactivation of Na channels
-partial seizures
monotherapy or add on
Gabaptenin/Pregabalin
- add ons
- pregabalin more potent
- dec glutamate release by binding to voltage gated Ca channels containing alpha-beta subunit (also augment GABA release)
- refractory partial seizures when used in combo with other drugs (carbamazepine or phenytoin)
Tiagabine
Inhibits GABA reuptake
Add on for partial and tonic clonic seizures
Zonisamide
Add on for partial seizure
Inc inactivation of Na channels (maybe also Ca channels)
Not metabolized by P450
Drowsiness, anorexia
Ezogabine
Add on for partial seizure
-K channel facilitator
Perampenel
AMPA glutamate receptor antagonist
add on for partial seizure
Eslicarbazepine
-pro drug
add on for partial seizures
voltage gated Na channel blocker
Ethusuximide
Drug for absence seizures
Inhibit T type Ca channels
-drug of choice
SE: GI upset, lethargy, headache
pts may develop tonic clonic seizures, often administered with primidone or phenytoin
Other drug for absence seizures
Valproic acid -inhibits T type Ca channels Drug of choice Also effective in tonic-clonic seizures Idiopathic hepatotoxicity
Also- methsuximide, lamotrigine, trimethadione, clonazepam
Black box warning on anticonvulsants
inc risk of suicidal behavior or ideation when used in tx of epilepsy, psych disorders, other conditions
Other uses for these drugs- bipolar disorder
carbamazepine
valproic acid
lamotrigine
Migraine prophylxis
valproic acid
topiramte
