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5. HDS Neuro Psych > Antiepileptics > Flashcards

Antiepileptics Flashcards

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1
Q

Seizure Management

A
  1. Determine if they have an epileptic syndrome
    • Provoked seizures ⇒ stop offending agent or treat underlying condition
      • ETOH withdrawal
      • Benzo withdrawal
      • DKA
      • Bupropion
      • Abx
    • Epilepsy syndrome is diagnosed
  2. Determine the epilepsy type
    • May not be possible to classify epilepsy prior to starting tx
      • Choose a medication that is indicated for both focal and generalized seizures
        • Levetiracetam
        • Valproic acid
        • Lamotrigine
        • Topiramate
        • Zonisamide
        • Phenytoin
    • If epilepsy can be classified, tx for appropriate condition
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2
Q

Generalized Epilepsy

Treatment

A
  • Absence epilepsy
    • First-line agents
      • Ethosuximide
      • Valproic acid
    • Alternatives
      • Lamotrigine, levetiracetam, or zonisamide
  • Juvenile Myoclonic Epilepsy
    • Levetiracetam
    • Valproic acid
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3
Q

Focal Epilepsy

Treatment

A
  • Strongest evidence for efficacy
  • Carbamazepine
  • Lamotrigine
  • Commonly used first-line
    • Levetiracetam
  • Same class as carbamazepine w/ more favorable side effect profile
  • Oxcarbazepine
  • Eslicarbazepine
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4
Q

Status Epilepticus

Pathophysiology

A
  • Single seizure:
    • Protein phosphorylation → ion channel opening and closing → excitatory neurotransmitter release
  • Status epilepticus proceeds to involve:
    • Endocytosis of inhibitory GABA receptors
    • ↑ Excitatory NMDA and AMPA receptors
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5
Q

Status Epilepticus

Protocol

A
  • Tx immediately with benzodiazepines
    • May immediately abort a prolonged seizure
  • Maintenance antiepileptic medications and continuous infusions of sedative medications
    • Necessary to tx SE when it no longer responds to GABA effects of benzos
    • One limitation is route of administration
      • Most pts intubated w/o oral access ⇒ drugs with IV formulations necessary
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6
Q

Antiepileptic Medications

IV Formulations

A
  • Most benzodiazepines
  • Phenobarbital
  • Valproic acid
  • Levetiracetam
  • Fosphenytoin (preferred over phenytoin with peripheral IVs)

Lamotrigine, topiramate, zonisamide, oxcarbazepine and ethosuximide are not available IV or IM.

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7
Q

Antiepileptic Medications

General MOA

A

↓ excitatory firing & ↑ inhibitory firing ⇒ ↓ initiation and propagation of seizures

Some drugs work selectively at one channel or receptor

Others have multiple mechanisms of action

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8
Q

Sodium Channels

A

Responsible for the action potential:

Depolarization @ neuronal membrane ⇒ opening of voltage-gated sodium channels ⇒ Na+ influx ⇒ further depolarization ⇒ action potential

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9
Q

Sodium Channel

Drugs

A
  • Fast-acting sodium channels are targeted by:
  • Phenytoin
  • Carbamazepine
  • Lamotrigine
  • Other antiepileptic agents
  • ⊗ Depolarization selectively during periods of hyperexcitation
  • Permit depolarization during normal neuronal transmission
  • Lacosamide ⇒ slow inactivation of sodium channels
    • ∆ Channel properties over seconds rather than milliseconds
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10
Q

T-type Calcium Channels

A
  • Implicated in absence seizures
  • Meds that reduce absence seizures via this mechanism:
    • Ethosuximide
    • Valproic acid
    • Zonisamide
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11
Q

Voltage-gated Calcium Channels

A
  • Gabapentin binds to voltage-gated calcium channels
    • ⊗ influx of Ca2+ @ presynaptic terminal ⇒ ↓ neurotransmitter release into synapse during excitation
  • Indicated for focal seizures
    • Low efficacy in epilepsy
  • Widely used to tx neuropathic pain
  • Pregabalin has a similar mech
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12
Q

Glutamate Receptors

A
  • NMDA and AMPA are both glutamate receptors
    • Glutamate is an excitatory neurotransmitter
  • Antiepileptics will antagonize these receptors
    • Topiramate ⇒ partial anti-AMPA effect
    • Felbamate ⇒ partial anti-NMDA mechanism
      • Seldomly used d/t liver toxicity
    • Perampanel ⇒ selective NMDA antagonist
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13
Q

GABA Receptors

A
  • GABA receptors ⇒ Cl- influx at inhibitory synapses
  • Antiepileptic meds w/ GABA mediated mech. binds to receptors ⇒ prolong Cl- influx ⇒ ⊗ axonal AP & transmission at the postsynaptic membrane
  • Meds that work primarily through this mechanism:
    • Benzodiazepines
    • Phenobarbital
    • Tiagabine
    • Vigabatrin
  • Some GABA activity:
    • Topiramate
    • Valproic acid
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14
Q

Synaptic Vesicle Proteins

A
  • SV2 involved in exocytosis @ the excitatory synapse
  • SV2 inhibitors bind to the synaptic vesicle proteins ⇒ ⊗ release of excitatory neurotransmitters
    • Levetiracetam
    • Brivaracetam
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15
Q

“Older” Generation Antiepileptic Medications

Toxicities and Drug Interactions

A
  • Meds:
    • Phenobarbital
    • Phenytoin
    • Carbamazepine
  • Decline in use due to drug toxicities and drug-drug interactions
    • Phenobarbital ⇒ Liver toxicity and sedation
    • All three ⇒ induce hepatic cytochrome p450 enzymes
      • Interactions w/ other meds
      • Metabolize vitamin D ⇒ osteopenia
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16
Q

Phenytoin

Unique Adverse Effects

A
  • Long-term use:
    • Gingival hyperplasia
    • Cerebellar atrophy
    • Peripheral neuropathy
    • Lupus-like syndrome
  • Non-linear pharmacokinetics ⇒ acute toxicity is very common
    • Enzyme that metabolizes phenytoin becomes saturated @ doses very close to therapeutic dose
    • Level of phenytoin can easily become too high
      • Nystagmus, diplopia, ataxia are signs of toxicity
    • Must monitor phenytoin levels closely in many pts
  • Phenytoin IV ⇒ venous irritation and necrosis ⇒ “purple glove” syndrome w/ peripheral IV admin
    • Use Fosphenytoin for peripheral IVs
      • Water-soluble prodrug form
      • More costly but safer alternative to avoid this condition
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17
Q

Carbamazepine

A
  • Effective for focal but not generalized epilepsy
  • Low-cost agent
  • Widely used and generally well-tolerated
  • Adverse effects:
    • Weight gain
    • Somnolence
    • Stevens Johnson Syndrome
    • Cytopenias
  • Interactions:
    • Can reduce effectiveness of statins ⇒ ↑ cholesterol
    • Grapefruit juice, fluoxetine, valproic acid and some abx ⇒ ↑ carbamazepine levels
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18
Q

Stevens-Johnson Syndrome (SJS)

A
  • Medical emergency
    • Rash, fever and blistering skin lesions including mucus membranes
    • Sepsis, multiorgan failure and death in up to 10% of pts
  • Lamotrigine ⇒ most commonly associated w/ SJS
    • Very slow titration recommended to avoid developing severe complications of hypersensitivity
  • Carbamazepine ⇒ higher risk of SJS w/ HLA-B*15:02 genotype
    • Found in persons of Asian descent
  • Phenytoin and Ethosuximide can rarely cause SJS
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19
Q

Cytopenias

A

Several antiepileptic drugs can cause cytopenia:

  • Carbamazepine
    • Severe cases ⇒ aplastic anemia
  • Lamotrigine
  • Phenytoin
  • Valproic acid
    • Thrombocytopenia ⇒ hemorrhages and ↑ surgical risk

CBC recommended when starting and periodically during tx

20
Q

Metabolic Toxicities

A
  • Oxcarbazepine and carbamazepine ⇒ hyponatremia
    • Potentiate seizures
    • Monitor sodium
  • Valproic acid
    • Insulin resistance
    • Hyperammonemia
    • Hepatotoxicity
    • Pancreatitis
    • Monitor LFTs
  • Topiramate and Zonisamide
    • Weak carbonic anhydrase inhibitors
      • Can worsen renal stones
      • Inadequate perspiration (oligohydrosis)
      • Acidosis in extreme cases
    • Both have a sulfa component ⇒ idiosyncratic rxn of acute angle glaucoma
      • Zonisamide contraindicated in pts with a known sulfa allergy
21
Q

Oral Contraceptive Pills (OCPs)

Interactions

A
  • Antiepileptics can ↑ OCPs metabolism via hepatic enzymes ⇒ unwanted pregnancies
    • ↓ Estrogens and progestins
      • Carbamazepine
      • Oxcarbazepine
      • Phenytoin
      • Phenobarbital
      • Eslicarbazepine
      • Rufinamide
    • ↓ Estrogens
      • High doses of Topiramate
    • ↓ Progestins
      • Lamotrigine
      • Perampanel
  • ± ↓ lamotrigine or valproate efficacy d/t ↑ glucuronidation by UGT enzymes by OCPs
22
Q

Protein-binding

A
  • BBB prevents protein-bound drugs from affecting the CNS
  • % of drug bound to protein is important
  • Drugs that competitively bind to protein ⇒ ∆ free fraction of drug
  • Low protein states (ex. Malnutrition) ⇒ ∆ effectiveness of the drug
  • Highly protein bound
    • Phenytoin
    • Valproic acid
    • Phenobarbital
    • Clonazepam
  • Valproic acid ⇒ competitive binding agent ⇒ displaces other drugs ⇒ ↑ free levels of phenytoin and phenobarbital when used concomitantly
  • Minimal to no protein-binding
    • Levetiracetam
    • Gabapentin
    • Ethosuximide
    • Lacosamide
23
Q

Antibiotic / Antifungal

Effects

A
  • Doxycycline ⇒ ↓ carbamazepine levels
    • Carbamazepine ⇒ ↓ doxycycline levels via enzyme induction
  • Macrolides (ex. Erythromycin) ⇒ ↑ carbamazepine levels
  • Ciprofloxacin ⇒ ↓ Phenytoin levels
    • Also potentiates seizures
  • Isoniazid and azole antifungals ⇒ ↑ phenytoin levels
24
Q

Warfarin

Effects

A

Warfarin metabolized by cytochrome p450 system

Starting or ↑ dose of phenytoin, carbamazepine, or phenobarbital ⇒ ↓ effect of warfarin ⇒ thrombus formation

Discontinuing these meds for pts on warfarin ⇒ ↑ warfarin effect ⇒ ↑ risk of bleeding

25
Q

Pregnancy

Effects

A

Hormone levels and ↑ GFR during pregnancy ⇒ ↓ levels of some antiepileptic meds

Need close monitoring during pregnancy

26
Q

Teratogenicity

A

Major concern when tx females of childbearing potential

  • Many antiepileptics have an unknown risk of fetal malformations
  • Drugs with known risks:
    • Valproic acid ⇒ highest risk of fetal malformations
      • Neural tube defects → spina bifida
      • Related to folate mechanism
      • Supplementation with folic acid recommended for all women
      • Low IQ in children born to mothers taking valproate
    • Lamotrigine ⇒ considered low risk
      • Still a risk of cleft lip and palate
  • Using a single agent recommended to minimize fetal risk during pregnancy
  • Neonatal hemorrhage d/t drug-related Vitamin K deficiency
    • Hepatic enzyme inducers such as phenytoin
    • Not seen when Vit K routinely given to newborns
  • Breastfeeding is recommended
    • Despite some drugs being detected in breastmilk
27
Q

Antiepileptics in Children

A
  • Pediatric drug dosing must be used for all antiepileptic agents
  • Target mg/kg differing among newborns and infants
  • Phenobarbital ⇒ neonates
  • ACTH, adrenal corticosteroids, vigabatrin ⇒ infants
28
Q

Neuropsychiatric Comorbidities

A

Significant overlap of antiepileptic and psychiatric meds:

  • Pts w/ bipolar disorder & epilepsy are not uncommon ⇒ using one med to tx both preferred
    • Meds used as mood stabilizers for pts with bipolar disorder:
      • Carbamazepine
      • Lamotrigine
      • Oxcarbazepine
      • Valproic acid
    • Therapeutic dose for epilepsy may be higher than to tx mood fluctuations
  • All antiepileptic meds have a warning for ↑ suicidality, including mood stabilizers
    • Counsel pts about poss. mood changes
  • Levetiracetam ⇒ high rate of psychiatric side effects
    • Irritability
    • Depression
    • Psychosis
  • Migraine, essential tremor and neuropathic pain disorders can be tx w/ antiepileptic meds
29
Q

Kidney and Liver

Disease

A
  • Renal impairment
    • May need special dosing for some antiepileptic medications
    • Mostly renally excreted ⇒ gabapentin and levetiracetam
      • Use a lower dose in chronic renal insufficiency
      • Post-dialysis dosing is best ⇒ avoid rapid w/d of the drug and w/d seizures
  • Hepatic impairment
    • Risk of hepatotoxicity ⇒ Valproic acid and phenobarbital
    • Levetiracetam preferred
30
Q

Cannabis

A

Epilepsy is one of the approved dx for medical marijuana

Risk/benefit ratio is high, esp. for smoking marijuana

  • Synthetic forms of marijuana (ex. K-2)
    • Can cause seizures
  • Δ9-Tetrahydrocannabidiol (THC)
    • Antiepileptic action at CBD1 and CBD2 receptors
    • THC’s effects are mixed ⇒ in some cases may trigger seizures
  • Cannabidiol (CBD)
    • Unknown MOA for epilepsy
    • May be related to GABA
    • FDA approved oral CBD oil for severe and refractory forms of generalized epilepsies
    • CBD can interact with other meds including antiepileptic medications via the cytochrome p450 system
31
Q

Drugs Table

A
32
Q

Ethosuximide

A
  • Indications:
    • Absence seizures
  • MOA:
    • T-type calcium channels
  • Pharmacokinetics/Pharmacodynamics:
    • Minimal to no protein-binding
  • AE:
    • Nausea
    • SJS (rare)
    • Aplastic anemia (rare)
  • Interactions:
    • None
33
Q

Gabapentin

A
  • Indications:
    • Focal sz
  • MOA:
    • Voltage-gated calcium channels
  • Pharmacokinetics/Pharmacodynamics:
    • Renally excreted
      • Lower doses for renal insufficiency
    • Minimal to no protein-binding
  • AE:
    • Weight gain
  • Interactions:
    • None
34
Q

Levatiracetam

A

Levatiracetam

  • Indications:
    • Focal and generalized sz
  • MOA:
    • Synaptic vesicle 2A protein (SV2A)
  • Pharmacokinetics/Pharmacodynamics:
    • Minimal to no protein-binding
    • Mostly renally excreted ⇒ preferred in hepatic impairment
  • AE:
    • High rate of psychiatric side effects
      • Irritability
      • Depression
      • Psychosis
  • Interactions:
    • OCPs ⇒ ↓ lamotrigine efficacy d/t ↑ glucuronidation by UGT enzymes
35
Q

Lamotrigine

A
  • Indications:
    • Focal and generalized sz
    • Used as mood stabilizers for pts with bipolar disorder
  • MOA:
    • Sodium channels
  • Pharmacokinetics/Pharmacodynamics:
    • None
  • AE:
    • Most commonly associated w/ SJS
    • Cytopenias
    • Considered low risk during pregnancy
      • Still a risk of cleft lip and palate
  • Interactions:
    • Level dec. in pregnancy
    • Level inc. by valproate
36
Q

Phenytoin

A

(“Older” generation antiepileptic)

  • Indications:
    • Focal and generalized sz
    • Not absence or myoclonic
  • MOA:
    • Sodium channels
  • Pharmacokinetics/Pharmacodynamics:
    • Highly protein bound
    • Non-linear pharmacokinetics ⇒ acute toxicity very common
      • Saturates metabolic enzyme @ doses very close to therapeutic dose
      • Must monitor phenytoin levels closely in many pts
  • AE:
    • Cytopenias
    • Osteopenia
    • SJS (rare)
    • Long-term use:
      • Gingival hyperplasia
      • Cerebellar atrophy
      • Peripheral neuropathy
    • Phenytoin via peripheral IV ⇒ phlebitis and necrosis ⇒ “purple glove” syndrome
      • Use Fosphenytoin for peripheral IVs
      • Water-soluble prodrug form
  • Interactions:
    • Induces hepatic cytochrome p450 enzymes
      • Interactions w/ other meds
        • Warfarin levels
      • Metabolizes vitamin D ⇒ osteopenia
    • Ciprofloxacin ⇒ ↓ Phenytoin levels
      • Also potentiates seizures
    • Isoniazid and azole antifungals ⇒ ↑ phenytoin levels
    • ↓ Estrogens and progestins (OCPs)
37
Q

Carbamazepine

A

(“Older” generation antiepileptic)

  • Indications:
    • Focal sz
    • Used as mood stabilizers for pts with bipolar disorder
  • MOA:
    • Sodium channels
  • Pharmacokinetics/Pharmacodynamics:
    • None
  • AE:
    • Osteopenia
    • Weight gain
    • Somnolence
    • Hyponatremia
    • Hepatotoxicity
    • Leukopenia
    • Aplastic anemia (rare)
    • Stevens Johnson Syndrome
      • Higher risk of SJS w/ HLA-B*15:02 genotype (Asian descent)
  • Interactions:
    • Induces hepatic cytochrome p450 enzymes
      • Interactions w/ other meds
        • Warfarin levels
      • Metabolizes vitamin D ⇒ osteopenia
    • Can reduce effectiveness of statins ⇒ ↑ cholesterol
    • Grapefruit juice, fluoxetine, valproic acid and some abx ⇒ ↑ carbamazepine levels
    • Macrolides (ex. Erythromycin) ⇒ ↑ carbamazepine levels
    • Doxycycline ⇒ ↓ carbamazepine levels
      • Carbamazepine ⇒ ↓ doxycycline levels via enzyme induction
    • ↓ Estrogens and progestins (OCPs)
38
Q

Oxcarbazepine

A
  • Indications:
    • Focal sz
    • Used as mood stabilizers for pts with bipolar disorder
  • MOA:
    • Sodium channels
  • Pharmacokinetics/Pharmacodynamics:
    • None
  • AE:
    • Hyponatremia
      • Potentiates seizures
  • Interactions:
    • ↓ Estrogens and progestins (OCPs)
    • High doses ⇒ ↑ phenytoin levels
39
Q

Rufinamide

A

(Rarely mentioned in notes)

  • Indications:
    • Lennox-Gastuat syndrome (form of childhood epilepsy)
  • MOA:
    • Sodium channels
  • Interactions:
    • ↓ Estrogens and progestins (OCPs)
40
Q

Eslicarbazepine

A

(Rarely mentioned in notes)

  • Indications:
    • Focal or generalized sz
    • Temporal Lobe Epilepsy
  • MOA:
    • Sodium channels
  • Interactions:
    • ↓ Estrogens and progestins (OCPs)
41
Q

Lacosamide

A
  • Indications:
    • Focal sz
  • MOA:
    • Slowly activated sodium channels
  • Pharmacokinetics/Pharmacodynamics:
    • Minimal to no protein-binding
  • AE:
    • Dizziness/syncope
    • Prolonged PR interval
  • Interactions:
    • None
42
Q

Valproic acid

(Divalproex)

A
  • Indications:
    • Focal and generalized sz
    • Used as mood stabilizers for pts with bipolar disorder
  • MOA:
    • GABA
    • T-type calcium channels
    • Sodium channels
  • Pharmacokinetics/Pharmacodynamics:
    • Highly protein bound
    • Competitive binding agent ⇒ displaces other drugs
      • ↑ free levels of phenytoin and phenobarbital
  • AE:
    • Thrombocytopenia
    • Insulin resistance
    • Weight gain
    • PCOS
    • Hyperandrogenism
    • Hyperammonemia
    • Hepatotoxicity (Monitor LFTs)
    • Pancreatitis
    • Tremor
    • Highest risk of fetal malformations
      • Neural tube defects → spina bifida
        • Related to folate mechanism
        • Supplementation with folic acid recommended for all women
    • Low IQ in children born to mothers taking valproate
  • Interactions:
    • OCPs ⇒ ↓ valproate efficacy d/t ↑ glucuronidation by UGT enzymes
43
Q

Topiramate

A
  • Indications:
    • Focal and generalized
  • MOA:
    • GABA
    • AMPA receptors
    • Sodium channels
    • Weak carbonic anhydrase inhibitor
  • Pharmacokinetics/Pharmacodynamics:
    • None
  • AE:
    • Weight loss
    • Cognitive side effects
    • Paresthesias
    • Weak carbonic anhydrase inhibitor
      • Renal stones
      • Inadequate perspiration (oligohydrosis)
      • Acidosis (extreme cases)
    • Acute angle glaucoma (idiosyncratic rxn of sulfa component)
  • Interactions:
    • High doses ⇒ ↓ Estrogens
44
Q

Zonisamide

A
  • Indications:
    • Focal and generalized sz
  • MOA:
    • T-type calcium channels
    • Sodium channels
    • Weak carbonic anhydrase inhibitor
  • Pharmacokinetics/Pharmacodynamics:
    • None
  • AE:
    • Weight loss
    • Cognitive side effects
    • Weak carbonic anhydrase inhibitor
      • Renal stones
      • Inadequate perspiration (oligohydrosis)
      • Acidosis (extreme cases)
    • Acute angle glaucoma (idiosyncratic rxn of sulfa component)
  • Interactions:
    • Contraindicated w/ sulfa allergy
45
Q

Phenobarbital

A

(“Older” generation antiepileptic)

  • Indications:
    • Focal and generalized myoclonic
    • Not absence
    • Preferred in neonates
  • MOA:
    • GABA-A
  • Pharmacokinetics/Pharmacodynamics:
    • Highly protein bound
      • AE:
    • Osteopenia
    • Sedative
    • Hepatotoxicity
    • Cytopenias
    • Contractures
  • Interactions:
    • Induces hepatic cytochrome p450 enzymes
      • Interactions w/ other meds
        • Warfarin levels
      • Metabolizes vitamin D ⇒ osteopenia
    • ↓ Estrogens and progestins
46
Q

Benzodiazepines

(Lorazepam, diazepam, clonazepam)

A
  • Indications:
    • Focal or generalized
  • MOA:
    • GABA-A
  • Pharmacokinetics/Pharmacodynamics:
    • Highly protein bound
  • AE:
    • Sedation
    • Respiratory depression
  • Interactions:
    • Serotonin syndrome
47
Q

Vigabatrin

A

(Rarely mentioned in notes)

  • Indications:
    • Refractory seizures
    • Infantile spasms
      • ACTH, adrenal corticosteroids, and vigabatrin
  • MOA:
    • GABA degrading enzyme (GABA transaminase)
  • Pharmacokinetics/Pharmacodynamics:
    • No protein binding

5. HDS Neuro Psych (46 decks)

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