9/29 Anti-epileptics - Ryazanov Flashcards
anti epileptic drugs based on type of seizure
black = representative
red = popular today
partial seizures
drugs
phenytoin
carbamazepine
valproate
lamotrigine
topiramate
lacosamide
generalized tonic-clonic
(grand mal)
drugs
phenytoin
carbamazepine
valproate
levetiracetam
topiramate
absence
(petit mal)
drugs
ethosuximide
valproate
myoclonic
drugs
phenobarbital
valproate
levetiracetam
status epilepticus
drugs
phenobarbital
lorazepam
major mechanisms of anti-seizure drugs
- decrease Glu excitatory transmission
- increase GABA-mediated inhibition (either pre or postsynaptic)
- modification of ionic conductances
- inhibition of sustained, repetitive firing of neurons via promotion of inactivated state of voltage-activated Na channels
- inhibition of voltace-activated Ca channels
molecular targets for antiseizure drugs acting at excitatory (glu) synapse
1. VG Na channels
- phenytoin
- carbamazepine
- lamotrigine
- lacosamide
2. VG Ca channels
- ethosuximide
- lamotrigine
- gabapentin
- pregabalin
3. K channels : retigabine
4. SVA2 synaptic vesible proteins : levetiracetam
5. CRMP-2 (collapsin response mediator protein 2) : lacosamide
6. AMPA receptors
- phenobarbital
- topiramate
- lamotrigine
7. NMDA receptors : blocked by felbamate
molecular targets for GABA-mediated synaptic inhibition
1. GABA transporters (esp GAT1, tiagabine)
2. GABA-transaminase (GABA-T, vigabatrin)
3. GABA-a receptors (benzodiazepines)
4. GABA-b receptors
might also be mediated by “nonspecific” targets like VG ion channels and synaptic proteins
example: GABA-a inhibition
benzodiazepines and barbiturates : GABAa receptor mediated inhibition
- increases inflow of Cl ions into cell → hyperpolarization
- inhibits postsyn cell
drug action:
Na channel inactivation
goal: inhibition of high-freq firing of neurons
how?
reduce ability of Na channels to recover from inactivation, i.e. prolong inactivation of Na channels
- inactivation achieved by inactivation gate
ex. carbamazepine, phenytoin, topiramate, lamotrigine, valproate, zonisamide
drug action:
VG Ca channel inhibition
goal: reduce pacemaker current underlying thalamic rehythm in spikes/waves seen in gen absence seizures
how?
inhibit T-type Ca channels
ex. valproate, ethosuximide
drugs used for partial seizures/generalized tonic-clonic seizures
phenytoin
carbamazepine
valproate
barbiturates
phenytoin
- alters Na, K, Ca conductance and membrane potentials
- decreases synaptic release of glu and enhances release of GABA
distribution: highly bound to plasma proteins (90%)
- incr proportion of free/active in newborns, hypoalbunimenia, uremic pts
metabolism: hepatic metabolism to active metabolites, excreted in urine
- half life 12-36 hours
- low conc: first order kinetics. 5-7 days to reach steady state
- tx range: non-linear relationship of dosage and pl concentration
drug interactions:
- protein-binding drugs can increase free phenytoin
- phenytoin can induce microsomal enzymes resp for metabolism of drugs (OCPs)
fosphenytoin is IV precursor to phenytoin
phenytoin toxicity
general tox: diplopia, ataxia, gingival hyperlasia, hirsutism, neuropathy
long term use toxicity:
- coarsening of facial features
- mild periph neuropathy: diminished deep tendon reflexes in lower extremities
- serum folic acid, thyroxine, vitK may decrease
- abnormal vitD metabolism → osteomalacia
carbamazepine
primary drug for tx of partial, tonic-clonic seizure
chemically related to tricyclic antidepressants
mechanism: limits repetitive firing of APs evoked by sustained depolarization by slowing rate of recovery of VG Na channels (from inactivated state)
carbamazepine
PK
drug interactions
limited aqueous solubility
many anti-seizure drugs can increase conversion to active metabolites [via CYP450s]
- induces CYP2C, CYP3A, UGT → enhances metabolism of other drugs (ex. OCPs)
absorption: slow, erratic following oral admin
drug interactions:
- phenobarbital, phenytoin, valproate can increase metabolism of carbamazepine via induction of CYP3A4
- may enhance biotransformation of phenytoin
- may lower conc of other anti-seizure drugs (ex. valproate)
carbamazepine
adverse effects
- drowsiness, blurred vision, diplopia, headache, dizziness, ataxia, nausea/vomiting
- mild leukopenia, hyponatremia common
- high dose? thrombocytopenia
- high dose/rapid escalation → rash
- Asian pts: carbamazepine-induced Stevens-Johnson syndrome
myoclonic seizure drugs
valproic acid
mechanism:
- inhibits sustained repetitive firing via prolonged recovery of VG Na channels (in inactivated state), possibly small reductions in T-type Ca currents
- increases amount of GABA recovered from brain
- in vitro: can stimulate activity of GABA synthetic enzyme, inhibit GABA degradation enzymes
valproic acid
PK
drug interactions
absorbed rapidly/completely after oral admin
peak conc: 1-4 hours
usually about 90% bound to pl protein initially (fraction drops as concentration is incr)
maybe carrier-mediated transport in/out of CSF
metabolism: UGT, beta-ox
- half life approx 15 hr
drug interactions:
- inhibits metabolism of phenytoin and phenobarbital, lamotrigine, lorazepam
- can displace phenytoin and other drugs from albumin
valproate toxicity
- transient GI sx: anorexia, nausea, vomiting
- CNS sx: sedation, ataxia, tremor
- chronic use: rash, alopecia, stim of appetite → weight gain
- dose-related tremor, hair thinning/loss, platelet drop, thrombocytopeia
- hepatic fx: elevation of hepatic transaminases in plasma
- acute pancreatitis, hyperammonemia
- teratogenic effects like neural tube defects
absence seizure drugs
ethosuximide:
mechanism
drug interactions
toxicity
reduces low threshold T-type Ca current
- T-type Ca channels implicated in pacemaker current in thalamic neurons that generate the rhythmic cortical discharge of absence seizure
drug interactions
- valproic acid can decrease ethosuximide clearance and cause higher steady-state conc
toxicity
- common: gastric distress (pain, nausea, vomiting)
- transient lethargy or fatigue
- urticaria/skin rxns (Stevens-Johnson syndrome, systemic lupus erythematosus, eosinophilia, etc)
status epilepticus drugs
phenobarbital
mechanism
low tox, low cost
mechanism: unknown
- enhancement of inhibitory processes
- suppression of high-freq firing neurons through action on Na conductance and Ca currents (L-, N-type)
- enhances GABA receptor mediated current (prolongs Cl current)
- depression of excitatory responses (glu release)
phenobarbital
PK
absorption:
- oral abs is slow but complete
- 40-60% bound to plasma proteins; similarly bound in tissues, incl brain
- up to 25% eliminated by pH-dep renal excretion unchanged
metabolism:
- CYP enzymes: mainly CYP2C9 (also CYP2C19 and CYP2E1)
drug interactions:
- induces UGT enzymes, CYP2C, CYP3A
phenobarbital
toxicity
- sedation, but tolerance can be developed
- nystagmus and ataxia (excessive dosage)
- irritability and hyperactivity in children
- agitation and confusion in elderly
- scarlatiniform or morbilliform rash (and maybe other manifestations of drug allergy) in 1-2% of patients
- megaloblastic anemia during chronic phenobarbital tx of epilepsy (responds to folate, osteomalacia, high dose vitD)
anti seizure drugs:
duration of tx
usually cont’d for at least 2 years
after 2 years, consider tapering/discontinuing tx if pt is seizure free
high risk after discont:
- EEG abnormalities
- structural lesions
- abnormal neuro exam
- hx of freq seizures or medically refractory seizures prior to control
drugs for epilepsy in infancy
Primidone and phenobarbital limited due to learning issues
issues with gabapentin
v high dose needed to achieve improvement in seizure control
- used mainly down the road as adjunctive tx
adverse effects: somnolence, dizziness, ataxia, headache, tremor
felbamate issues
causes aplastic anemia, severe hepatitis (acute hepatic failure) at high rates
- 3rd line drug for refractory cases
lamotrigine
can cause toxic epiderman necrolysis and Stevens Johnson syndrome
ped pts at high risk of rash, maybe potentially life threatening dermatitis (1-2% pts)
adverse effects: dizziness, headache, diplopia, nausea, somnolence, skin rash
topiramate
see lecture
