L9 Anticonvulsants Flashcards
What is a seizure?
Where do they generally originate?
Seizures are abnormal discharges of electrical activity if cerebral neurons.
Generally originate in the cerebral cortex.
What is a partial seizure?
What are the 3 types of partial seizures?
Partial seizures begin focally in a cortical site and may spread
- Simple partial: jerking, lasting 20 seconds, preservation of consciousness
- Complex partial: impairment of consciousness < 2 min, automatic movements, originate in temporal lobe
- Partial with secondary generalized tonic-clonic: originates as partial and develops into tonic-clonic, loss of consciousness, muscle contractions alternating with relaxation
What is a generalized seizure?
What are the 3 types of generalized seizures?
Involves both hemispheres from the outset
- Tonic-clonic (grand mal): loss of consciousness, muscle contractions
- Absence (petit mal): staring, cease activity, <30 secs
- Myoclonic: brief shock-like muscle contraction
What is the main mechanism behind seizure generation?
What is the mechanism behind a partial seizure vs. an absence seizure?
Seizures are thought to be a result of under-activity of GABAergic neurons or over-activity of glutamate transmission.
Partial seizure: neurons fire at a very high frequency. Inhibited by drugs which reduce the ability of Na+ channels to recover from inactivation after an action potential to decrease rapid firing.
Absence seizure: characterized by generalized spike-and-wave discharges at 3Hz, orginating from the thalamus. Due to the T-type Ca++ voltage gated channel. Inhibited by drugs that block this channel
Which drugs block prolong the inactivation of the voltage-gated Na+ channel and decrease release of glutamate?
Phenytoin, carbamazepine, lamotrigine, valproic acid
Which drugs block the thalamic low threshold T-type Ca++ current?
What type of seizure would this treat?
Ethosuximide and Valproic acid
Treats absence seizures
What drugs enhance GABA activity and increase hyperpolarization of neurons by opening Cl- channels?
Phenobarbital and benzos
The increase in inhibitory GABA activity protects against generalized and partial seizures
How successful is seizure treatment? What are some general treatment principles with the anticonvulsants?
What are the main side effects of the antiseizure medications?
Treatment is completely successful in about 50% of patients. Best to initiate therapy with single drug and switch if it is not effective. Combining drugs is more likely to cause complications.
Monitoring plasma drug levels is frequently done to optimize dosage
Side effects: CNS sedation, hepatic damage, aplastic anemia
Which of the antiseizure drugs induce cytochrome p450?
phenytoin, carbamazepine, phenobarbital
Phenytoin
Block sustained high-frequency repetitive firing of neurons by prolonging inactivation of the Na+ channel.
Effective in partial seizures and generalized tonic-clonic.
No CNS depression, not very sedating
What are some significant pharmacokinetic properties of phenytoin?
Fosphenytoin is the water-soluble prodrug that can be used parenterally
Highly (90%) plasma protein bound
Narrow therapeutic range
Metabolism saturated at therapeutic concentrations, so addition of other drugs metabolized by same enzymes may inhibit phenytoin metabolism significantly, increasing concentration
What drug does phenytoin inhibit the metabolsm of?
Warfarin concentration goes way up if combined with phenytoin
What drug increases the metabolis of phenytoin?
Carbamazepine
What are signs of phenytoin toxicity?
Nystagmus
Ataxia and double vision
Sedation at high levels
Gingival hyperplasia and hirsuitism
Coarsening of facial features, mild peripheral neuropathy
Abnormal Vit D metaboism and inhibition of Ca++ absorption leads to osteomalacia
Skin rash-discontinue
Pregnancy category D
Carbamazepine
Blocks Na+ channels, decreases neurotransmitter release
Mood stabilizer: effective in bipolar
DOC: partial seizures, widely used for tonic-clonic as well
Effective at high doses for trigeminal neuralgia
Not very sedating normally
Carbamazepine increases the metabolism of…
phentoin, valproic acid, ethosuximide, clonazepam, haloperidol, oral contraceptives, primidone
These drugs increase the metabolism of carbamazepine.
Phenobarbital, phenytoin, valproic acid
These drugs inhibit the metabolism of carbamazepine
Cimetidine, fluoxetine, isoniazid, erythromycin
What is the big worrisome side effect of carbamazepine?
What are some other signs of toxicity?
Steven Johnson Syndrome: dangerous and potentially fatal necrolysis skin reaction
More common with HLA-B 1502 allele: most common in asian ancestry
Other signs of toxicity: double vision, ataxia, GI upset, drowsiness at high doses, idosyncratic blood dyscrasias (most commom in elderly treated for trigeminal neuralgia)
Pregnancy category D-not used
Topiramate
Blocks voltage dependent Na+ channels, enhances GABAa currents and limits glutamate receptor activation
Can be effective against ALL types of seizures
Used for West’s syndrome and Lennox-Gestaut syndrome
Used for biopolar and binge eating disorder
Migraine prophylaxsis
Excreted unchanged in the urine 20-30 hr half-life
What are the unique side effects of Topiramate?
acute myopia and glaucoma-stop drug immediately
Cognitive impairment, nervousness, confusion
Dizziness, fatigue, sedation, paresthesias
Lamotrigine (Lamictal)
inactivates voltage dependent Na+ channels
May also act on N and P/Q type Ca++ channels as works in absence seizures
Decreases glutamate release
Used in partial seizures, myoclonic and absence in children
Used in bipolar
What are the signs of Lamotrigine toxicity?
Dizziness, headache, double vision
Nausea, somnolence
Skin rash-discontinue
Dermatitis can be life-threatening in children
Pregnancy category C
Phenobarbital and Primidone
Prolongs opening of Cl- channel at GABAa receptor
Used for partial and generalized tonic-clonic seizures
Causes drowsiness and CNS depression
Contraindicated in porphyria
Do not use in pregnancy
Gabapentin and Pregabalin
GABA analogs, does not act on GABA receptors, may augment GABA release
Blocks N-type Ca++ channels, inhibiting glutamate release
Adjunct tx. for partial and tonic-clonic
Widely used for neuropathic pain
Pregabalin-used for fibromyalgia
High doses for antiseizure, lower doses for pain
Excreted by kidney-few drug interactions
Short half-lives
Levetiracetam (Keppra)
Binds to synaptic vesicular protein (SV2A): reduces glutamate release, increases GABA release
Used for tx of partial, myoclonic, and tonic-clonic seizures
Minimal drug interactions-not metabolized by cytochrome p450
Tiagabine (Gabatril)
Inhibits uptake of GABA, prolonging inhibitory action of GABA and potentiating tonic inhibition in the brain
Used in adjunct tx of partial seizures
Highly protein bound
Vigabatrin (Sabril)
Irreversible inhibitor of GABA transaminase, which breaks down GABA in synaptic cleft
Increases GABA levels and tonic inhibition in brain
Approved for refractory adult complex partial seizures and for infantile spasm
30-40% of patients experience irreversible constriction of visual field and/or retinal damage
Pre-existing mental illness is contraindication-agitation and confusion may occur
Ethosuximide (Zarontin)
DOC for absence seizures
Blocks T-type Ca++ channels: which are part of pacemaker current that generates rhythmic cortical discharge in thalamic neurons thought to cause absence seizures
Given twice per day to decrease GI side effects
What is the one significant drug interaction of Ethosuximide?
Valproic acic decreases its clearance
Valproic Acid
DOC if both absence and tonic-clonic seizures occur
First line of tx in bipolar disorder with mixed episodes and rapid cycling
Blocks Na+ channels and high-frequency repetitive firing
Decreases NMDA stimulation
Increases synthesis of GABA
Also useful in myoclonic, atonic, and partial seizures
Severe toxicity possible-still widely used drug
What are the significant drug interactions of Valproic acid?
Inhibits own metabolism at low doses
Phenytoin (displaces from plasma proteins and increases concentration)
Inhibits metabolism of phenytoin, carbamazepine, lamotrigine, and phenobarbital
What are effects of Valproic acid toxicity?
Most common: nausea, vomiting, abdominal pain, heartburn
Fine tremor, weight gain, increased appetite, hair loss
Hepatotoxicity: worse under 2 or taking other meds
Contraindicated in liver disease- > 50 deaths in US due to liver damage
Black box warning for pancreatitis
Do not use in pregnancy-birth defects
Clonazepam
Benzo-used in absence seizures
Effective for myoclonic and infantile seizures as well
Sedation is common
Pregnancy category D
Diazepam (Valium) and Lorazepam (Ativan)
DOC: status epilepticus, administer IV
Status epilepticus causes death in 20% patients
Should not be given in pregnancy except if absolutely necessary
What is Stevens-Johnson Syndrome?
Hypersensitivity reaction consisting of erythema multiforme, arthritis, nephritis, CNS abnormalities, and myocarditis
Discontinue use!
Rare
What drugs are most likely to cause Stevens-Johnson syndrome?
Phenytoin, fosphenytoin
Phenobarbital, primodine
Lamotrigine
Ethosuximide
Valproic acid
What anticonvulsants should be avoided in pregancy, but are category C and may be used if necessary?
Lamotrigine
Gabapentin
Topiramate
Tiagabine
If you are worried about suicide with anticonvulsants, which two drugs would you want to give?
Carbamazepine and Valproate
No data for phenytoin
What drugs are used for partial and generalized tonic-clonic seizures?
Phenytoin
Carbamazepine
Gabapentin
Levetiracetam
Lamotrigine
Topiramate
Tiagabine
Phenobarbital
Valproic acid
What drugs are used for absence seizures?
Ethosuximide
Valproic acid
Clonazepam
What drugs are used for myoclonic seizures?
Levetiracetam
Valproic acid
What drugs are used for atonic seizures?
Valproic acid
Lamotrigine
What drugs are used in infantile spasms?
Corticosteroids
Topiramate
Clonazepam
What drugs are used in Status Epilepticus?
Diazepam or lorazapem iv: most effective
Phenytoin iv
Phenobarbital iv
