Anticonvulsants Flashcards by Andrew Braaten

Anticonvulsant Mechanisms (GABA)

 Goal is to increase GABA activity

 Block GABA re-uptake -Tiagabine
 Inhibit GABA metabolism - Vigabatrin
 Stimulate GABAa receptors - Benzos and barbs
 Binds synaptic vesicular protein SV2A - Levetiracetam

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Anticonvulsants Mechanism (Glutamate)

 The goal is to decrease excitatory glutamate activity
 Common targets: voltage-gated Na+and
Ca++ channels
• Phenytoin, ethosuximide

 Other targets: SV2A, K+channels, NMDA and AMPA
receptors

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Phenytoin (Dilantin®); Fosphenytoin (Cerebyx®) - MoA

Prolongs inactivation of Na+channels; decreases glutamate activity

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Phenytoin (Dilantin®); Fosphenytoin (Cerebyx®) - Uses

Partial seizures, generalized tonic-clonic seizures

• Not effective for absence seizures

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Phenytoin (Dilantin®); Fosphenytoin (Cerebyx®) - Pharmacokinetics

•Not water soluble -> not injected
• Fosphenytoin (Cerebyx®) - injectable form
• Elimination is 1st order at low doses
• Zero order at therapeutic at higher doses; Small
changes in dose/elimination can cause big changes in
plasma levels

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Phenytoin (Dilantin®) - Drug Interactions

Drugs that alter CYP450’s

* Metabolized by, induces, and inhibits CYP450’s

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Phenytoin (Dilantin®) - Side Effects

• Nystagmus, diplopia, ataxia, sedation 
• Gingival hyperplasia
• Long-term:
  Coarsening of facial features
  Mild peripheral neuropathy
  Abnormal Vitamin D metabolism
• Skin rash - discontinue use (risk of SJS)
• Pregnancy category D

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Carbamazepine (Tegretol®) - MoA

• Blocks Na+channels; decreases glutamate activity
• Inhibits NE release and reuptake; May potentiate
GABA action

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Carbamazepine (Tegretol®) - Uses

Drug of choice for partial seizures
Generalized tonic-clonic seizures
Bipolar disorder
Trigeminal Neuralgia

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Carbamazepine (Tegretol®) - Pharmacokinetics

Induces CYP450’s (3A4);lots of drug interactions

* Induces own metabolism

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Carbamazepine (Tegretol®) - Drug Interactions

• Increases metabolism of multiple anticonvulsants,
haloperidol and oral contraceptives
• Metabolism increased by: phenobarbital, phenytoin
• Metabolism inhibited by: cimetidine, fluoxetine,
valproic acid

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Carbamazepine (Tegretol®) - Side Effects

• Diplopia, ataxia, GI upset, drowsiness
• Aplastic anemia and agranulocytosis
• Stevens Johnson Syndrome - More common in
patients with a certain HLA allele (HLA-B1502); should
be screened for HLA-B1502
• Pregnancy category D

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Lamotrigine (Lamictal®) - MoA

• Inactivation of Na+channels; decreases glutamate
activity
• May also inhibit Ca++channels

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Lamotrigine (Lamictal®) - Uses

• Partial seizures
• May be effective against myoclonic and absence
seizures in children
• Bipolar disorder

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Lamotrigine (Lamictal®) - Pharmacokinetics

• Inducers of CYP450s (phenytoin, carbamazepine,
phenobarbital) will increase metabolism
• Half-life doubled by valproic acid

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Lamotrigine (Lamictal®) - Side Effects

• CNS -Dizziness, headache, diplopia, ataxia, &
somnolence
• GI -nausea and vomiting
• Skin rash and Stevens-Johnson syndrome

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Topiramate (Topamax®) - MoA

Blocks Na+channels; decreases glutamate activity

• Also has some activity at Ca2+ channels
• Potentiates GABA receptors and inhibits glutamate
receptor
• May inhibit spread of seizures

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Topiramate (Topamax®) - Uses

Partial and generalized tonic-clonic seizures
May also be effective for absence seizures
Migraine prevention

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Topiramate (Topamax®) - Pharmacokinetics

May increase metabolism of contraceptives

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Topiramate (Topamax®) - Side Effects

Dizziness, sedation, nervousness, confusion

• Acute myopia/glaucoma

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Levetiracetam (Keppra®) - MoA

Binds synaptic vesicular protein (SV2A)

• Appears to decrease glutamate and increase GABA
release

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Levetiracetam (Keppra®) - Uses

Partial, myoclonic, and tonic-clonic

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Levetiracetam (Keppra®) - Pharmacokinetics

• Oral absorption is rapid; peak blood concentrations in
1-2h
• ½ life of 6-8h; longer in elderly

Minimal drug interactions

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Levetiracetam (Keppra®) - Side Effects

• Dizziness, somnolence, ataxia, and asthenia

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Phenobarbital (Luminal®) - MoA

* Prolongs opening of chloride channel at GABA receptor | * Alters Na+and Ca2+conductance at high concentrations

Phenobarbital (Luminal®) - Uses

* Partial seizures | * Generalized tonic-clonic seizures

Phenobarbital (Luminal®) - Drug Interactions

Induction of CYP450’s increases metabolism of Phenytoin and carbamazepine

Gabapentin (Neurontin®) - MoA

GABA analog; May augment GABA release

Gabapentin (Neurontin®) - Uses

Adjunct for partial and generalized tonic-clonic seizures * Neuropathic pain * Bipolar disorder (off label)

Gabapentin (Neurontin®) - Pharmacokinetics

• 1st order elimination; Excreted unchanged by the kidney • Short half-life, taken 3 times/day

Gabapentin (Neurontin®) - Side Effects/Precautions

Sleepiness, dizziness, ataxia, fatigue, tremor, headache Pregnancy Category C

Gabapentin (Neurontin®) - Drug Interactions

Negligible

Pregabalin (Lyrica®) - MoA

 GABA analog – structurally related to GABA  Binds to alpha-2-delta subunit of voltage-gated calcium channels inhibiting excitatory neurotransmitter release

Pregabalin (Lyrica®) - Uses

 Used for generalized anxiety disorder  Other uses: neuropathic pain, fibromyalgia, post- operative pain

Pregabalin (Lyrica®) - Metabolism

negligible so little adverse drug interaction (relative to other anticonvulsants); ½ life about 6 hrs.

Pregabalin (Lyrica®) - Side Effects

Peripheral edema, dizziness, fatigue, weight gain, xerostomia, ataxia, blurred vision, GI disturbances, etc.

Pregabalin (Lyrica®) - Contraindications

Teratogenic

Tiagabine (Gabitril®) - MoA

Inhibits reuptake of GABA (GAT-1); Enhances GABA activity

Tiagabine (Gabitril®) - Uses

Adjunct treatment for partial seizures

Tiagabine (Gabitril®) - Pharmacokinetics

• Short half-life (5-8h) which is shortened by CYP450 inducers • Few drug interactions

Tiagabine (Gabitril®) - Side Effects

* Nervousness, difficulty concentrating, depression * Dizziness, tremor, rash (rare, but stop drug) * Pregnancy Category C

Vigabatrin (Sabril®) - MoA

Irreversibly inhibits GABA transaminase (GABA-T); decreases GABA metabolism and enhances activity

Vigabatrin (Sabril®) - Uses

Refractory complex partial seizures • Infantile spasm (West’s syndrome)

Vigabatrin (Sabril®) - Pharmacokinetics

½ life of 6-8h but drug effects are prolonged and do not correlate with plasma levels

Vigabatrin (Sabril®) - Side Effects

* Visual field problems/retinal damage | * Agitation, confusion

Ethosuximide (Zarontin®) - MoA

• Inhibits low-threshold (T-type) Ca2+ channels • Inhibits ‘pacemaker’ for rhythmic cortical discharge

Ethosuximide (Zarontin®) - Uses

Drug of choice for absence seizures

Ethosuximide (Zarontin®) - Pharmacokinetics

Metabolized by liver | • Variable half-life of 18-72h

Ethosuximide (Zarontin®) - Side Effects

GI irritation, lethargy, fatigue, headache, dizziness • Hiccup • Stevens Johnson syndrome very rare

Ethosuximide (Zarontin®) - Drug Interactions

Metabolism inhibited by valproic acid

Valproic acid (Depakene®) - MoA

Blocks Ca2+ channels and Na+channels •May enhance GABA activity

Valproic acid (Depakene®) - Uses

Absence and general tonic-clonic seizures (“mixed” seizures) •Bipolar disorder •Prophylaxis of migraine

Valproic acid (Depakene®) - Pharmacokinetics

* Absorption is prolonged by food; ½ life of 9-18h | * Inhibits its own metabolism at low doses

Valproic acid (Depakene®) - Side Effects

Nausea, abdominal pain, heartburn, weight gain, sedation, tremor, alopecia • Hepatotoxicity - Monitoring liver function is recommended • Pregnancy category D - Increased risk of Spina Bifida

Valproicacid (Depakene®) - Drug Interactions

• Inhibits metabolism of phenytoin, phenobarbital, | carbamazepine

Clonazepam (Klonopin®) - MoA

- Benzodiazepine Stimulates GABA receptor and enhances GABAergic inhibition

Clonazepam (Klonopin®) - Uses

Absence seizures, myoclonic seizures and infantile spasms (West Syndrome)

Clonazepam (Klonopin®) - Side Effects

Sedating –tolerance develops * Tolerance to anti-seizure effect may develop * Pregnancy category D

Diazepam (Valium®) and Lorazepam (Ativan®) - Uses

Drug of choice for status epilepticus

Diazepam (Valium®) and Lorazepam (Ativan®) - MoA

Stimulates GABA channel

Diazepam (Valium®) and Lorazepam (Ativan®) - Pharmacokinetics

Administered IV or rectally

Diazepam (Valium®) and Lorazepam (Ativan®) - Precuations

Pregnancy category D

Anticonvulsants Flashcards

(62 cards)