Antiepileptics Flashcards
Seizure Management
-
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
-
Provoked seizures ⇒ stop offending agent or treat underlying condition
-
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
- Choose a medication that is indicated for both focal and generalized seizures
- If epilepsy can be classified, tx for appropriate condition
- May not be possible to classify epilepsy prior to starting tx
Generalized Epilepsy
Treatment
-
Absence epilepsy
- First-line agents
- Ethosuximide
- Valproic acid
- Alternatives
- Lamotrigine, levetiracetam, or zonisamide
- First-line agents
-
Juvenile Myoclonic Epilepsy
- Levetiracetam
- Valproic acid
Focal Epilepsy
Treatment
- Strongest evidence for efficacy
- Carbamazepine
- Lamotrigine
-
Commonly used first-line
- Levetiracetam
- Same class as carbamazepine w/ more favorable side effect profile
- Oxcarbazepine
- Eslicarbazepine
Status Epilepticus
Pathophysiology
-
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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Status Epilepticus
Protocol
-
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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Antiepileptic Medications
IV Formulations
- 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.
Antiepileptic Medications
General MOA
↓ excitatory firing & ↑ inhibitory firing ⇒ ↓ initiation and propagation of seizures
Some drugs work selectively at one channel or receptor
Others have multiple mechanisms of action
Sodium Channels
Responsible for the action potential:
Depolarization @ neuronal membrane ⇒ opening of voltage-gated sodium channels ⇒ Na+ influx ⇒ further depolarization ⇒ action potential
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Sodium Channel
Drugs
- 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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T-type Calcium Channels
- Implicated in absence seizures
- Meds that reduce absence seizures via this mechanism:
- Ethosuximide
- Valproic acid
- Zonisamide
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Voltage-gated Calcium Channels
-
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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Glutamate Receptors
-
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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GABA Receptors
- 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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Synaptic Vesicle Proteins
- 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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“Older” Generation Antiepileptic Medications
Toxicities and Drug Interactions
-
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
Phenytoin
Unique Adverse Effects
-
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
- Use Fosphenytoin for peripheral IVs
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Carbamazepine
- 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
Stevens-Johnson Syndrome (SJS)
- 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
Cytopenias
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
Metabolic Toxicities
-
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
-
Weak carbonic anhydrase inhibitors
Oral Contraceptive Pills (OCPs)
Interactions
-
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
- ↓ Estrogens and progestins
- ± ↓ lamotrigine or valproate efficacy d/t ↑ glucuronidation by UGT enzymes by OCPs
Protein-binding
- 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
Antibiotic / Antifungal
Effects
-
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
Warfarin
Effects
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
Pregnancy
Effects
Hormone levels and ↑ GFR during pregnancy ⇒ ↓ levels of some antiepileptic meds
Need close monitoring during pregnancy
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
-
Valproic acid ⇒ highest risk of fetal malformations
- 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
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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
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
-
Meds used as mood stabilizers for pts with bipolar disorder:
-
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
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
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
Drugs Table
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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
Gabapentin
- Indications:
- Focal sz
- MOA:
- Voltage-gated calcium channels
- Pharmacokinetics/Pharmacodynamics:
- Renally excreted
- Lower doses for renal insufficiency
- Minimal to no protein-binding
- Renally excreted
- AE:
- Weight gain
- Interactions:
- None
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
- High rate of psychiatric side effects
- Interactions:
- OCPs ⇒ ↓ lamotrigine efficacy d/t ↑ glucuronidation by UGT enzymes
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
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
- Interactions w/ other meds
- Ciprofloxacin ⇒ ↓ Phenytoin levels
- Also potentiates seizures
- Isoniazid and azole antifungals ⇒ ↑ phenytoin levels
- ↓ Estrogens and progestins (OCPs)
- Induces hepatic cytochrome p450 enzymes
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
- Interactions w/ other meds
- 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)
- Induces hepatic cytochrome p450 enzymes
Oxcarbazepine
- Indications:
- Focal sz
- Used as mood stabilizers for pts with bipolar disorder
- MOA:
- Sodium channels
- Pharmacokinetics/Pharmacodynamics:
- None
- AE:
- Hyponatremia
- Potentiates seizures
- Hyponatremia
- Interactions:
- ↓ Estrogens and progestins (OCPs)
- High doses ⇒ ↑ phenytoin levels
Rufinamide
(Rarely mentioned in notes)
- Indications:
- Lennox-Gastuat syndrome (form of childhood epilepsy)
- MOA:
- Sodium channels
- Interactions:
- ↓ Estrogens and progestins (OCPs)
Eslicarbazepine
(Rarely mentioned in notes)
- Indications:
- Focal or generalized sz
- Temporal Lobe Epilepsy
- MOA:
- Sodium channels
- Interactions:
- ↓ Estrogens and progestins (OCPs)
Lacosamide
- Indications:
- Focal sz
- MOA:
- Slowly activated sodium channels
- Pharmacokinetics/Pharmacodynamics:
- Minimal to no protein-binding
- AE:
- Dizziness/syncope
- Prolonged PR interval
- Interactions:
- None
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
- Neural tube defects → spina bifida
- Low IQ in children born to mothers taking valproate
- Interactions:
- OCPs ⇒ ↓ valproate efficacy d/t ↑ glucuronidation by UGT enzymes
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
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
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
- Interactions w/ other meds
- ↓ Estrogens and progestins
- Induces hepatic cytochrome p450 enzymes
Benzodiazepines
(Lorazepam, diazepam, clonazepam)
- Indications:
- Focal or generalized
- MOA:
- GABA-A
- Pharmacokinetics/Pharmacodynamics:
- Highly protein bound
- AE:
- Sedation
- Respiratory depression
- Interactions:
- Serotonin syndrome
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