3.4 Antiepileptics Flashcards
absence seizures
ethosuximide first, then valrpoate and clonazepam
myclonic seizures
valproate and clonazepam
febriel seizures
diazepam
status epilepticus
lorazepam or diapepam, fosphenytoin or phenytoin, alt. phenoboarbital
simple partial siaures
phenytoin, carbamazepine, alt penobarbital, primidone,
complex partial seizures
phenytoin, carbamazepine, alt. Primidone
loldes nonsedative antiseizure drug
phenytoin
penytoin action
blocks Na channels in their inactivated state (prolonging it) and slows its rate of recovery, prevents seizure propagation
Na channel acts in
resting(channed doesn_t move - activation (M) gate closed, inactivate gate opnes) open/activated (activation gate opens, sodium moves), inactivated (after deopolarizaiton inactivation (H) gate closes and channel blocked)
phenytoin other mechanism
at very high concentrations, phenytoin can block voltage dependent Ca cannels and interfere with the release of excitatory neurotransmitters
phenytoin is not a
not a generalized CNS depressant however, produces some degree of drowsiness and lethargy without producing hypnosis
Phenytoin absorption
slow and veriable
Phenytoin kinetics
non-linear (follows zero order kinetic elimination) – disproportiate increases with every inc in dose
phenytoin half life
12 to 24hrs at therapuetic dose but then at high dose it will be 60 hrs
Phenytoin daility dose
daily dose can produce large increases in the plasma concentration resuling in toxicity —->NEEDS PLASMA MONITORING (therapeutic range is 10-20ug/mL)
Phenytoin and enzyme induction
inducers of CYP450 like most antiepileptics
Status epilepticus and Phenytoin
given in the IV form of fosphenytoin, a produrg bc it has better pharmacokinetic and toxicity profile
Dose related toxicity to Phenytoin
CNS depression (lethargy, fatigue, drowsiness, nystagmus, ataxia, diplopia), gingival hyperplacia (gum hypertrophy***very imp) – occurs in about 20% of all pts during chronic therapy due to altered collagen metabolism, can be minimized with good oral hygien (Ca blockers can also casue gingival hyperplasia), hirsutism, coarsing of facial features occur in young pts (unpleasant in women), acne, megaloblastic anemia (pehnytoing interferes with folate absorption and increases its excretion), Aplastic anemia (immune -mediated–check CBC –they are succeptible to infection), behaviour changes (confusion, hallucination, drowsiness), osteomalacia (phenytoin desensitized target tissues to Vit D and interferes with Ca metabolism), inhibition of ADH release and inhib of insulin release (hyperglycemia, glycosuria–>hypovelemia), in pregnancy (teratogenic effect) –fetal hydantoin syndrom) cleft lip, cleft palate, growth retardation, microcephaly (possibly due to an epoxide metabolite of phenytoin)
Phenytoin is an inducer so
it induces metabolism of other anti-epileptics, anticoagulatns, oral contraceptives (steroids), levodopa, Vit D,
Inhibition of the metabolism of Phenytoin
chloramphenicol, dicumarol, cimetidine, sulfonamides
therapeutic uses of phenytoin
generalized tonic-clonic seizures, partial seizures (both simple and complex), status epilepticus (IV fosphenytoin), trigeminal neuralgia (occasionally)
fosphenytoin
prodrug of phytoin, rapily converted to pheytoin in plasma, IV can be used as a substute for phenytoin
fosphenytoin compared with phenytoin
fosphenytoin allows more rapid loading, IM adminsitration and IV administration with minimal vascular erosion –Phenytoin sodium should never be give IM as it can cause tissue damage and necrosis. Fosphenytoin can be used to control seizures during neurosurgery and status epilepticus
carbamazepine
prolongs the inactivated Na channel (identical to phenytoin) and inhibits high freq repetitive firing in neurons
carbamazepine absorption
slow oral abs
carbamazepine metabolism
metabolized in liver by oxidation –epoxide derivative (active metaboliet leading ot toxicity)
carbamazepine inducer
enzyme inducer of CYP450–auto induction
carbamazepine t 1/2
10 to 20hrs, reduced with repeated used
adverse effects of carbamazepine
dialational hypnatremia (due to inc ADH secretion), exfoliative dermatitis (unique to carbamazepine), fetal malformations (teratogenic) cleft lip, palate, spinabifida (more classic)
therapuetic uses of carbamazepine
partial/generalized epilepsy, trigeminal neuralgia (neuropathic pain), maniac depressive psychosis (bipolar disorder)
carbamazepine contraindications
should not be sued for pts with absence seizures bc it amy cause an inc in seizures, the mechanisms underlying carbamazepine aggravation of absence seizures are uncertain but are thought to involve enhancement of neuronal activity withing thalamocortical circuity
Oxcarbazepine
is a prodrug whose actions are similar to those of carbamazepine, with improved toxicity profile. Oxc dos not produce the epoxide metabolite wich is largely responsible for the adverse effects of carbamazepine. Less potent inducer of hepatic microsomal enzymes than carbamazepine. antiseizure efficacy and is comparable with that of carbamazepine, phenytoin and valproic acid
disadvantage of oxcarbazepine
more reports of hyponatremia with oxcarbazepine, eps in pts at risk
Phenobarbital
has specific anticonvulsant action at low dose – GABA a facilitatory action, anti glutamate action (those medated by activation of AMPA rec), Ca entry reduction, at high dos also blocks Na conductance like phenytoin
phenobarbital kinetics
long half life, enzyme induction, increases porphyrin synthesis - contraindicated in porphyrias, tolerance and dependence
barbiturates toxidity
hangover effect, impairment of finemotor skills, tolarance (PK and PD) and dependenc (physical and psychological)
primidone
this drug is also metabolized to phenobarbital and the main action is through it—M/a like phenobarbital also resembles pheytoin M/a
valproate (sodium valproate)
antiseizure properties discovered serendispitously, broad spectrum anticonvulsant, effective in Manic depressive psychosis and acute mania, and migrane
valproate mechanism of action
prolongs inactivation of Na channel (simialr to pehytoing and carbamazepien) hence blocks sustained high-freq repetitive firing of neurons, inhibition of degredation of gaba by inhibiting GABA transaminase, blocks t-type Ca channels
valproate abs
good, metabolize d by liver
valproate inhibition
enzyme inhibitor inhibitng CYP450
divalproex sodium
a combination of sodium valproate and valproic acid, is reduced to valproate when reaches GIT, better GI tolerance hence preferred by pts
adverse effects of valproate
gi eefcts (nausea, vomiting, abdominal pain and heart burn) and alopecia, hepatotoxicity (from toxic metabolites) Idiosyncracy) –> severe (may be fatal) Liver function test should be done in the first 6 to 12 monts of therapy, thromocytopenia and inhibition of platelet aggregation causes bleeding (idiosyncrasy), rashes, pancreatitis, neural tube defects (spinabifida -teratogenic), stimulation of appetiteld
valproate therapeutic uses
broad spectrum antiepileoptic, generalized and partial seizures, absence seizures (second choice), myoclonic seizures, MDP and acute mania (bipolar disorder) migraine prophylaxis
benzodiazepienes for antiepileptics
lorazepam, diazepam, clonazapam
conazepam
absence and myoclonic seizures
status epileptic benzos
lorazepam, diazepam
benso disadvantages
sedation and tolerance with long term use
ethosuximide
primary action on thalamic neurons which are involved in absence seizures, acts by supression of T type Ca channles
Ethosuximide acts by
suppression of the T Ca curren (primarily in thalamic neurons)
Ethosuximide is used in
absence seizures
Ethosuximide adverse effects
GI disturbances (Nausea and vomiting ; 40%) fatigue dizziness and agranulocytosis (RARE)
Phensuximide and methsuximide
congerners with limited utility, used in absence seizures, Phensuximide is generally less effective and Methsuximide is more toxic than Ethosuximide
Gabapentin
analog of Gaba, precise mechanism of action is not known but increases gaba effects by altering gaba metabolism and inc gaba levels in brain (does not bind with gaba receptors)
gabapentin use
partial refractory seizures, neuropathic pain (cush as post herpetic neuralgia), A/E most common –Fatigue, somnolence, dizziness and atxia
pregabalin
analog of gabapentin, binds to voltage gated Ca channel and reduces release of excitatory neurotransmitters (such as glutamate, NE, substance P, and calcitonin gene-related (CGRP))
Adjunct antiepiletics
gabapentin, pregabalin, felbamate, lamotrigine, vigabatrin, tiagabine, topiramate
pregabalin use
used to treat partial seizures and also approved fo use in treating post herpetic neuralgia and diabetic peripheral neuropathy
pregabalin majro adverse effects
dizziness, dryness of mouth, blurred vision, somnolence, ataxia, weight gain
felbamate
broad spectrum of anticonvulsant action, has multiple propsoed mechanisms (block voltage Na channels, block NMDA glut rec, block Ca channels, potentiation of Gaba actions
felbamate risks
aplastic anemia and hepatic failure, reserved for use in refractory epilepsis (particulary Lennox-Gastaut syndrome)
Lamotrigine
blocks Na channels, high voltage-dependent Ca channels, effective in a wide variety of seizure disorders (partial seizures, generalized seizures, absence seizures, Lennox gastaut syndrome) approved in bipolar disorder
Lamotrigine half-life
24-35h, decreases by carbamazepine and phenytoin, increases by >50% by valproate, dosages should be reduced if given with valproate
Lamotrigine adverse effects
hepatotoxicity, stevens-Johnson Syndrome
vigabatrin
a gamma vinyl analog of GABA, irreversible inhibitor of Gaba transaminase, used in infantile spasms and partial epilepsy
Adverse effects of vigabatrin
visual field defects (must undertake baseline visual test), asthenia, depression, and psychosis
Tiagabine
inhibits gaba uptake into the neuron by blocking the gaba transporter
tiagabine
used for partial epilepsy
tiagabine adverse effects
dizziness, astenia, nervousness, tremor, diarrhea, and depression (mild to moderate in severity and transient)
Topiramate
broad-spectrum anticonvulsant, delays the recovery of the inactivated Na channels, enhances Gaba activity by binding to the Gaba receptor, blocks the activation of AMPA receptors
Topiramate use
used as add on therapy for partial seizures
Topiramate adverse effects
ataxia, fatigue, nervousness and memory dysfunction (thinking abnormally, word-finding difficulties), acute myopia, glaucoma, and renal stones
Levetiracetam
binds to the synaptic vesicular protein SV2A, may modify the synaptic release of glutamate and Gaba through action on vesicular function
Levetiracetam use
in refractory partial epilepsy, myoclonic seizures, and primary generalized tonic-clonic seizures in adults and children. Somnolence, asthenia, dizziness, and ataxia are the adverse effects
Zonisamide
sulfonamide derivtive, prolongs the inactivated state of Na channel, inhibits Ca T currents, add on thereapy for partial and generalized seizures
Zonisamide adverse effects
drowsiness, fatigue and coordination difficulties (most common)
Acetazolamide
carbonic anhydrase inhibitor, used for seizures during menses (catamenial epilepsy) and absence seizures
what is the drawback to acetazolamide
tolerance in the drawback
Status epilepticus
an emergency and must be treated immediately, refers to continuous seizures or repetitive, discrete seizures with impaired consciousness. Anticonvulsant therapy should then begin without delay
Status epilepticus management
to attend to any acute cardiorespiratory problems or hyperthermia, establish venous access, to perform a brief medical and neurologic examination
3 most commonly used classes fo drugs for the initial treatment of status epilepticus
benzodiazepines (IV diazepam/IV Lorazepam), Hydantoins (IV Fosphenytoin/IV Phenytoin), Barbitu
Pregnancy and Epilepsy
Phenytoine, Carbamazepine, Valproate, Lamotrigine, and phenobarbital have been associated with teratogenicity, however the potential harm of uncontrolled seizures on the mother and fetus is considered greater than the teratogenic effects of antiepileptic drugs
current recommendation for pregnant women
pregnant women be maintained on effective drug therapy, when possible it is prudent to have the pt on montherapy at the lowest effective does, especially during the first trimester, also folate supplementation and Vit K supplementation
folate supplementation
pt should also take folate (1 to 4 mg/d) since the antifolate effects of anticonvulsants are thought to play a role in the development of neural tube defects)
vit K supplementation
oral vit K in the last 2 weeks of pregnancy and vit K at birth to the neonate
Contraception and AEDs
special care should be taken when prescribing antiepileptic medications for women who are taking oral contraceptive agents. Carbamazepine, phenytoin, phenobarbital, and topiramate can significantly decrease the effects of oral contraceptives via enzyme induction na dother mechanisms. pt should be advised to consider alternative forms of contraception
Withdrawla of AEDS
best treatable seizures - childhood seizures, consider withdrawal if complet control of seizures at least for 2 years, slow withdrawal withing 12 months, rapid withdrawal leads to status epilepticus, recurrance rate of seizures is 40%
AED therapuetic strateges
AEDs treatment individualization is most important, specifically different pt groups (eg children, women of child bearing potential, and the elderly) may be better suited to receive one AED than another, Anti-epileptic drugs are most effective and have the least adverse effects when they are used as monotherapy. the drug should not be abruptly withdrawn in controlled seizures as seizures may occur on withdrawal, hence the initial drug should not be discontinued prior to the substitution of an alternative drug, some antiepileptic drugs have teratogenic potential (needs reduction or termination of therapy during pregnancy or planned pregnancy; however, maternal sezures also present significant risk to the fetus. TDM - very effective and important in maximizing the treatment and minimizing the adverse effects
