5. HDS Neuro Psych > Antiepileptics > Flashcards

Antiepileptics Flashcards

(47 cards)

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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

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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

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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

Study These Flashcards
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

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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

Study These Flashcards
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

Study These Flashcards
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
Pregnancy Effects
**Hormone levels** and **↑** **GFR** during pregnancy ⇒ ↓ levels of some antiepileptic meds Need close monitoring during pregnancy
26
Teratogenicity
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
Antiepileptics in Children
* 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
Neuropsychiatric Comorbidities
_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
Kidney and Liver Disease
* **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
Cannabis
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
Drugs Table
32
Ethosuximide
* 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
Gabapentin
* 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
Levatiracetam
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
Lamotrigine
* 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
Phenytoin
(“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
Carbamazepine
(“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
Oxcarbazepine
* 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
Rufinamide
(Rarely mentioned in notes) * Indications: * Lennox-Gastuat syndrome (form of childhood epilepsy) * MOA: * Sodium channels * Interactions: * ↓ Estrogens and progestins (OCPs)
40
Eslicarbazepine
(Rarely mentioned in notes) * Indications: * Focal or generalized sz * Temporal Lobe Epilepsy * MOA: * Sodium channels * Interactions: * ↓ Estrogens and progestins (OCPs)
41
Lacosamide
* Indications: * Focal sz * MOA: * Slowly activated sodium channels * Pharmacokinetics/Pharmacodynamics: * Minimal to no protein-binding * AE: * Dizziness/syncope * Prolonged PR interval * Interactions: * None
42
Valproic acid | (Divalproex)
* 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
Topiramate
* 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
Zonisamide
* 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
Phenobarbital
(“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
Benzodiazepines | (Lorazepam, diazepam, clonazepam)
* Indications: * Focal or generalized * MOA: * GABA-A * Pharmacokinetics/Pharmacodynamics: * Highly protein bound * AE: * Sedation * Respiratory depression * Interactions: * Serotonin syndrome
47
Vigabatrin
(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
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