Antiepileptics Flashcards
1
Q
Seizure Management
A
-
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
2
Q
Generalized Epilepsy
Treatment
A
-
Absence epilepsy
- First-line agents
- Ethosuximide
- Valproic acid
- Alternatives
- Lamotrigine, levetiracetam, or zonisamide
- First-line agents
-
Juvenile Myoclonic Epilepsy
- Levetiracetam
- Valproic acid
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
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
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
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.
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
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
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
10
Q
T-type Calcium Channels
A
- Implicated in absence seizures
- Meds that reduce absence seizures via this mechanism:
- Ethosuximide
- Valproic acid
- Zonisamide
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
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
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
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
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
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
- Use Fosphenytoin for peripheral IVs
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
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
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
-
Weak carbonic anhydrase inhibitors
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
- ↓ Estrogens and progestins
- ± ↓ 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
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
