L9 Anticonvulsants Flashcards by Amanda Gittelman

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.

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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

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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

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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

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Which drugs block prolong the inactivation of the voltage-gated Na+ channel and decrease release of glutamate?

Phenytoin, carbamazepine, lamotrigine, valproic acid

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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

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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

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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

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Which of the antiseizure drugs induce cytochrome p450?

phenytoin, carbamazepine, phenobarbital

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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

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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

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What drug does phenytoin inhibit the metabolsm of?

Warfarin concentration goes way up if combined with phenytoin

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What drug increases the metabolis of phenytoin?

Carbamazepine

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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

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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

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Carbamazepine increases the metabolism of…

phentoin, valproic acid, ethosuximide, clonazepam, haloperidol, oral contraceptives, primidone

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These drugs increase the metabolism of carbamazepine.

Phenobarbital, phenytoin, valproic acid

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These drugs inhibit the metabolism of carbamazepine

Cimetidine, fluoxetine, isoniazid, erythromycin

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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