Term
Epilepsy: Seizure Classification
Partial |
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Definition
• Simple partial
• Complex partial
• Partial seizures secondarily generalized |
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Term
Epilepsy: Seizure Classification
Generalized |
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Definition
• Generalized tonic-clonic
• Absence
• Tonic
• Atonic
• Clonic and myoclonic |
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Term
| Anticonvulsants: different Mechanism of Actions |
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Definition
• Modulate voltage-gated ion channels (Na, Ca, K)
• Enhance synaptic inhibition (GABA)
• Inhibit synaptic excitation (glutamate, NMDA) |
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Term
|
Definition
So this schematic aims to provide a comprehensive overview for your anti-seizure drugs with respect to their mechanisms of action. I'd like to hone in your attention to the primary agents that we will be discussing at this time. These are the sodium channel antagonists whose main actions are at the voltage-gated sodium channels. These include phenytoin, carbamazepine, eslicarbazepine, lamotrigine, lacosamide, and zonisamide.
It has been established in clinical literature that lacosamide might have additional mechanism of action in that in patients who are refractory to the other sodium channel antagonist that we just reviewed, there are some more slower acting sodium channels that lacosamide also binds to and perhaps might be a viable option in patients who are unresponsive to the initial aforementioned sodium channel antagonists.
I'd like to hone in your view now to the agents that work mainly by action at the GABAergic terminal, either through modulation directly at the GABA receptors, namely your [? barbituritic ?] therapies or through allosteric inhibition by bonding to a non-active site of the GABA, receptor mainly the benzodiazepines and, in turn, cause an aconformational change.
Additional drug therapies that you see in the schematic includes things like gabapentin and pregabalin whose main mechanism of action includes action at the alpha 2 delta subunit of the calcium channel, thereby preventing release of neurotransmitters, which would otherwise cause excitation and subsequent seizure activity; agents like retigabine, whose main action is at potassium channels, which antagonistic activity prevents further depolarization and subsequent prevention of release of neurotransmission, otherwise which would cause seizure activity.
The next agents that are noteworthy to highlight includes levetiracetam and brivaracetam. We will, of course, go into further detail for each of these agents in subsequent slides. But it's important to get a visual representation of the site of action in the body of both of these agents. So both levetiracetam and brivaracetam act by binding to the synaptic vesicale 2A receptor, which in turn prevents the release of glutamate into the synaptic cleft and thereby inhibition of subsequent neurotransmission release and prevention of subsequent seizures that otherwise may ensue.
Additional agents that work in a different mechanism includes perampanel, phenobarbitol, and lamotrigine, whose mechanism of action has been hypothesized to surround antagonistic activity at the AMPA receptor, specifically thereby inhibition of the activity of glutamate in terms of preventing the binding of the glutamate and prevention of subsequent excitation, and ultimately prevention of seizure activity.
The final agent that is important to highlight in the schematic is valproic acid. As you can see on the bottom of the screen here, valproic acid has multiple mechanisms of action. These include increased GABAergic turnover, decrease activity of sodium channels similar to the other agents that we highlighted in terms of agonistic activity at the sodium channel receptors, and finally theorized to also antagonize NMDA receptors and subsequent prevention of excitatory neurotransmission, and further exacerbation of seizure activity or amelioration of seizure activity in patients who present with acute epilepsy. |
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Term
| Anticonvulsants: Drug Selection factors |
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Definition
• Effective against seizure type • Consider comorbid conditions • Safety
• Tolerability
• Pharmacokinetics/drug interactions • Ease of use
• Cost |
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Term
| Anticonvulsants: Drug Levels |
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Definition
-Indications for a level
• New start
• Dose adjustment
• Add or discontinue interacting medication
• Change in clearance (e.g., kidney injury)
• Suspected toxicity
• Inadequate seizure control
The therapeutic level is the level at which the patient has seizure control without medication-related adverse effects.
Treat the patient, not the number. |
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Term
| Epilepsy vs other types of seizures |
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Definition
Not necessarily; there are many other causes of seizures besides epilepsy. Epilepsy is defined as recurrent, unprovoked seizures.
Patients without epilepsy may have seizures for a variety of reversible causes:
Hypoglycemia
Metabolic (i.e., hyponatremia)
Fever (usually > 104 °F)
Abscess
Drug overdose/withdrawal |
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Term
| Partial Seizures and Generalized Tonic-Clonic Seizures (GTC) classic treatments |
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Definition
• Dilantin (phenytoin)
• Tegretol, Carbatrol (carbamazepine)
• Trileptal (oxcarbazepine)
• Luminal (phenobarbital)
• Depakote (valproic acid)
• Mysoline (primidone) |
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Term
| Partial Seizures and Generalized Tonic-Clonic Seizures (GTC) modern treatments |
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Definition
• Neurontin (gabapentin) • Lyrica (pregabalin)
• Topamax (topiramate) • Keppra (levetiracetam) • Vimpat (lacosamide)
• Lamictal (lamotrigine)
• Felbatol (felbamate)
• Zonegran (zonisamide)
• Gabitril (tiagabine)
• Sabril (vigabatrin)
• Onfi (clobazam)
• Banzel (rufinamide)
• Potiga (ezogabine)
• Aptiom (eslicarbazepine)
• Fycompa (perampanel)
• Briviact (brivaracetam) |
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Term
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Definition
• MOA:prolonginactivatedstateofNachannel, inhibit glutamate release, enhance GABA release
• 90%protein-bound
• TimetoSS5–7days(longerathigher concentrations)
• Therapeuticlevel:total10–20mcg/mL, free 1–2 mcg/mL
• May induce myoclonic seizures |
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Term
• Only compatible in NS
• For doses >100 mg, dilute to at least 6.7 mg/mL
• Use in-line filter if diluting unless you administer immediately
• Diethylene glycol diluent causes rate-related hypotension; administer 25 mg/min when possible, and don’t exceed 50 mg/min
• Do not give IM
• May cause phlebitis, purple glove syndrome
• Significant extravasation can be treated with hyaluronidase |
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Definition
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Term
Has ADE:
• Dose-related
• Nystagmus •
• Diplopia
• Ataxia
• Sedation
• Long-term
Coarsening of facial features
Mild peripheral neuropathy
Abnormal vitamin D metabolism
• Non-dose-related
• Gingival hyperplasia
• Hirsutism
• Rash
• Fever
• Hepatotoxicity
- Consider supplementing folic acid, calcium, active vitamin D |
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Definition
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Term
|
Definition
• Prodrugofphenytoin
• Dosedin“phenytoinequivalents”
• UnlikeIVphenytoin,norate-related hypotension, infusion-site reactions, or concern for extravasation/purple glove syndrome
• Otheradverseeffectsarethesame (including cardiotoxicity)
• Can be administered IM |
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Term
| Tegretol, Carbatrol (Carbamazepine) |
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Definition
• MOA: prolong inactivated state of sodium channel
• T1⁄2 36 hours initially, 8–12 hours with continued use
• Therapeutic level: 4–12 mcg/mL
• Dose: 400–1,200 mg/day divided q8h or q12h (q6h if suspension)
• May induce myoclonic seizures
• Inducer of liver enzymes, induces own metabolism = many drug interactions
• ↓ dose in hepatic failure |
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Term
Has ADE:
- Dose-related
• Diplopia
• Ataxia
• GI upset
• Drowsiness
• Hyponatremia
- Rare
• Aplastic anemia • Agranulocytosis • Leukopenia
- Rash(titrateslowly) • SJS/TENS
Check CBC monthly for first year, and discontinue if significant decrease in WBC or RBC.
Consider screening for HLAB 1502. |
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Definition
| Tegretol, Carbatrol (Carbamazepine): Adverse Effects |
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Term
| Trileptal (Oxcarbazepine) |
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Definition
• MOA: prolongs inactivated state of sodium channel
• Active 10-hydroxy metabolite (MHD)
• T1⁄2 1–2 hours, metabolite 8–12 hours
• Therapeutic level: 7.5–20 mcg/mL (MHD)
• Dose: 300–1,200 mg/day divided q12h
• May induce myoclonic seizures |
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Term
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Definition
• MOA: enhance inhibitory processes and inhibit excitatory processes through sodium, calcium, and chloride channels, GABA receptors
• T1⁄2 75–125 hours
• Therapeutic level: 10–40 mcg/mL
• Load 10–3 0mg/kg, maintenance 1–3 mg/kg divided q8h or q12h
• Induces liver enzymes = many drug interactions
• Decrease dose in hepatic failure
• May worsen absence seizures |
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Term
Has ADE:
• Sedation
• Cognitiveproblems • Ataxia
• Hyperactivity
• Stupor
• Coma
Avoid when drowsiness very problematic or if there is abuse potential |
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Definition
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Term
|
Definition
• MOA: modifies release of GABA, reduces glutamate release
• Dose: 900–3,600 mg divided q8h
• ↓ dose and extend interval in renal failure
• May induce myoclonic seizures
• Minimal drug interactions
• Absorption ↓ as doses ↑ (divide large doses) |
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Term
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Definition
• Active enantiomer of gabapentin
• More predictable pharmacokinetics: linear response in plasma levels to ↑ dose
• Dose: 150–600 mg divided q12h
• Schedule V |
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Term
Has ADE:
• Somnolence
• Dizziness
• Ataxia
• Weight gain
• Peripheral edema
• Hypotension |
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Definition
| Neurontin (Gabapentin) and Lyrica (Pregabalin) |
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Term
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Definition
• MOA: inhibit sodium channels, potentiate inhibitory effect of GABA, reduce glutamate receptor activation
• Dose: 25–200 mg divided q12h
• Moderate drug interactions→ dose-related
-carbonic anhydrase inhibitor→ monitor serum bicarbonate |
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Term
Has ADE:
Dose-related
• Metabolic acidosis
• Weight loss
• Somnolence
• Fatigue
• Dizziness
• Cognitive slowing
• Paresthesias
• Nervousness
• Confusion
Rare
• Acute myopia
• Glaucoma
• Urolithiasis
• Hypothermia |
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Definition
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Term
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Definition
• MOA: affects vesicular release of GABA and glutamate
• No need to monitor levels
• Achieve steady state in two days
• Dose: 500–3,000 mg divided q12h
• Minimal drug interactions
• Available as IR and ER tablet, oral solution, injection
• 100% bioavailable |
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Term
Has ADE:
• Somnolence • Asthenia
• Ataxia
• Agitation
• Anxiety
• Psychosis
Avoid in patients with history of psychiatric disorder |
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Definition
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Term
|
Definition
• MOA: affects vesicular release of GABA and glutamate
- Similar mechanism to levetiracetam with higher binding affinity to SV2A
• No need to monitor levels
• Achieve steady state in two days
• Dose:500–3,000 mg divided q12h
• Minimal drug interactions
• Available as IR and ER tablet, oral solution, injection
• 100% bioavailable |
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Term
Has ADE:
• Somnolence • Asthenia
• Ataxia
• Agitation
• Anxiety
• Psychosis (less incidence vs. levetiracetam)
- May be considered in patients intolerant of levetiracetam |
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Definition
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Term
|
Definition
• MOA: preferentially affects slow inactivation of sodium channels; binds to CRMP-2, which may have neurotrophic effects
• Dose: 200–400 mg divided q12h
• No need to monitor levels
• Available IV and PO
• Minimal protein binding, minimal drug interactions |
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Term
Has ADE:
• Dizziness • Headache • Nausea
• Diplopia
• Prolonged PR interval
-Titrate slowly to avoid dizziness |
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Definition
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Term
AJ takes phenytoin 300 mg extended-release capsule three times a day. Her total phenytoin level is 9 mcg/ml.
What is the therapeutic range for phenytoin?
What additional information do you need to interpret the level? |
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Definition
Therapeutic range: 10–20 mcg/ml
This patient is slightly outside of that range. However, if she is experiencing no side effects and no seizures, this could be an appropriate level for this individual patient.
Remember to treat the patient, not the number. |
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Term
LM is an 18-year-old woman with a new diagnosis of epilepsy. She has been experiencing partial seizures and has never been treated with an antiseizure medication before.
What medication would you choose? Explain your rationale. |
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Definition
Things to consider when selecting an anticonvulsant:
What medications are effective for partial seizures?
Recommended as first-line therapy?
Which of those medications have the most favorable side effect profile?
Is she on birth control?
Are there comorbid conditions? |
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Term
SF is a 37 yom with refractory epilepsy. He has been on many different antiseizure regimens in the past, but was recently started on oxcarbazepine and lacosamide, which have significantly reduced his seizure frequency.
How would you monitor this regimen? |
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Definition
| Monitor seizure frequency, electrolytes, neurologic status, and, for oxcarbazepine, drug levels. |
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Term
|
Definition
- Generalized tonic-clonic: same as partial
- Absence
• Ethosuximide (ETS)
• Valproic acid
• Clonazepam
• Lamotrigine
• Topiramate
- Myoclonic
• Valproic acid
• Benzodiazepines • Zonisamide
• Levetiracetam
- Atonic
• Valproic acid
• Lamotrigine
• Benzodiazepines • Felbamate |
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Term
| May exacerbate myoclonic seizures: |
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Definition
• Phenytoin
• Carbamazepine • Oxcarbazepine • Gabapentin
• Pregabalin |
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Term
| May exacerbate absence seizures: |
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Definition
• Phenobarbital • Primidone
• Vigabatrin |
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Term
|
Definition
• Use:absence
• MOA: selective inhibition of calcium channels
• Therapeutic Level:50–100mcg/mL
• Dose:500–1,500 mg divided q8h or q12h
• Minimalprotein-binding
• Minimal drug interactions, except valproic acid decreases ethosuximide metabolism |
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Term
Has ADE:
• GI distress
• Lethargy
• Fatigue
• Headache
• Dizziness
• Hiccup
• Euphoria
• Psychosis |
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Definition
|
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Term
|
Definition
• Use: atonic
• MOA: selective NMDA receptor inhibition, potentiates GABA receptor response
• Therapeutic level: 30–100 mcg/mL
• Dose: 1,200–3,600 mg divided q8h or q6h |
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Term
Has ADE:
(rare): • Aplastic anemia
• Severe hepatitis |
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Definition
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Term
|
Definition
• Use: absence, generalized tonic-clonic, partial, myoclonic, atonic
• MOA: selective inactivation of sodium and calcium channels
• Therapeutic level: 3 mcg/mL
• Immediate-release and extended-release formulations available |
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Term
Has ADE:
Common
• Dizziness
• Headache
• Diplopia
• Nausea
• Somnolence
Rare
• Skin rash including TENS/SJS
• Hepaticfailure • Renalfailure
• DIC
• Arthritis
-Reduce risk of rash through slow titration schedule |
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Definition
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Term
| Depakote, Depakene (Valproic Acid) |
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Definition
• Use: absence, GTC, partial, myoclonic, atonic
• MOA: prolong inactivated state of sodium channels, ↑ GABA
• 90% protein-bound
• Liver enzyme inhibitor = many drug interactions
• Therapeutic level: 50–100 mcg/mL
• Load 15–45 mg/kg, maintenance 15–60 mg/kg divided q8h–q12h
• Oral solution, sprinkle caps, extended-release tablets, injection |
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Term
Has ADE:
Frequent
• GI distress
• Sedation
• Fine tremor
• Weight gain
• Increased appetite
• Hair loss
• Hyperammonemia (consider l-carnitine supplementation)
Rare
• Hepatotoxicity
• Thrombocytopenia
- Check LFTs every three months for one year; discontinue if LFTs or ammonia increase >2 x ULN |
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Definition
| Depakote, Depakene (Valproic Acid) |
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Term
|
Definition
• Use: myoclonic
• MOA: acts on sodium, calcium channels
• Minimal protein-binding, drug interactions
• Dose: 100–600 mg daily
• Sulfonamide |
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Term
Has ADE:
drowsiness, cognitive impairment, confusion, poor concentration, rash including TENS/SJS |
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Definition
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Term
|
Definition
• MOA: potentiates GABA response
• Adverse effects: sedation, respiratory depression (high doses)
• Usually reserved for acute management of actively seizing patient due to tachyphylaxis
-Ativan (lorazepam), Versed (midazolam), Valium (diazepam) |
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Term
| LM has developed an allergy to ethosuximide. What other treatment options are available to treat his absence seizures? |
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Definition
| Valproic acid, lamotrigine, topiramate. |
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Term
| Convulsive Status Epilepticus |
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Definition
, there is a tiered approach based on several recommendations in the clinical literature.
Lorazepam, diazepam, midazolam are recommended initially as preferred therapies, and selection of either agent is based on patient-specific factors and established IV access. Phenytoin, phosphenytoin, valproic acid, or levetiracetam may be considered subsequently if patients continue to have ongoing seizures. Phenobarbitol or lacosamide may then be considered in refractory cases. And then phenobarbital or lacosamide optimization might also be considered in patients who continue to have seizures. And then subsequently, continued infusion anesthetics, either benzodiazepines or agents with a more desirable mechanism of action. That's a little different than the conventional therapies might ensue. |
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Term
Status Epilepticus
Available IV: |
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Definition
• Lorazepam
• Diazepam
• Midazolam
• Phenytoin/Fosphenytoin
• Phenobarbital
• Valproic acid
• Levetiracetam
• Lacosamide
• Propofol
• Ketamine |
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Term
| Emergency Seizure Management |
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Definition
• Position person on their side to prevent aspiration.
• Prevent injury: move dangerous objects or move patient away from dangerous environment.
• Place pillow or jacket under their head if possible.
• Call 911 if seizure persists >five minutes.
• Do not hold them down.
• Do not place anything in their mouth, including medications. |
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Term
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Definition
• FDA reported increased risk of suicidality: 1 in 500
• All anti-seizure medications include a black box warning regarding this risk
• Medication guides must be dispensed for all anti-seizure medications per FDA REMS program |
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Term
Women With Epilepsy (WWE)
Reduce effectiveness of oral contraceptives: |
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Definition
• Carbamazepine
• Oxcarbazepine
• Phenytoin
• Phenobarbital
• Topiramate >200 mg/day |
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Term
| Do not interact with oral contraceptives: |
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Definition
• Gabapentin
• Lamotrigine
• Levetiracetam |
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Term
|
Definition
• If seizure-free, can consider discontinuing medications
• Use a single agent
• Use lowest effective dose
• Avoid valproic acid, phenytoin, and phenobarbital if possible |
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Term
|
Definition
• Weigh risk of seizure occurrence against risk of continued use of anti-seizure medication
• Any changes to regimen should be undertaken with great caution
• Monitor drug levels frequently |
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Term
WWE
Supplement folic acid daily in pregnancy for three months prior to conception if possible, especially for: |
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Definition
• Phenytoin
• Carbamazepine
• Phenobarbital
• Primidone
• Valproic acid |
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Term
| Withdrawal of Anti-Seizure Medication |
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Definition
• No standard recommendation
• May be considered if patient has been seizure-free for at least 2–5 years
• Generalized tonic-clonic and partial seizures are more likely to relapse
• Longer duration of disease and abnormal EEG increase risk of relapse |
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Term
|
Definition
• Mayormaynotbeprecededbyaura
• Commonsymptomsinclude:
- Nausea/vomiting
- Phonophobia
- Photophobia
- Visualdisturbancesincludinghemianopsia,speech disturbances
• Severeunilateralheadachelastinghourstodays
• Oftendescribedasthrobbingpainthatworsens with activity |
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Term
| Migraine: Pathophysiology |
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Definition
• Extravasation of plasma and plasma proteins leads to edema and pain
• Sensitization of trigeminal nerve causes normally innocuous stimulus to be perceived as painful |
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Term
|
Definition
• Consistent use of NSAIDs may cause medication overuse headache
• Concomitant conditions such as depression may worsen headaches
• Encourage patients to maintain headache diary to identify triggers and objectively evaluate improvement or worsening of headaches |
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Term
| Migraine: Acute Treatment |
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Definition
• Triptans
• Ergot alkaloids
• NSAIDs
• Miscellaneous (lidocaine, haloperidol, valproic acid) |
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Term
|
Definition
• MOA: serotonin 1D/1B agonists which inhibit vasodilation
• Contraindicated in patients with coronary artery disease or with angina
• Avoid Amerge (naratriptan) and Relpax (eletriptan) in severe renal or hepatic impairment; Frova (frovatriptan) in patients with peripheral vascular disease; Zomig (zolmitriptan) in patients with Wolff-Parkinson-White syndrome |
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Term
has ADE:
-dizziness, muscle weakness, neck pain, paresthesias |
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Definition
|
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Term
|
Definition
| Axert (almotriptan), Relpax (eletriptan), Frova (frovatriptan), Amerge (naratriptan), Maxalt (rizatriptan), Imitrex (sumatriptan), Zomig (zolmitriptan) |
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Term
| Ergot Alkaloids: Dihydroergotamine |
|
Definition
• MOA:
• Activation of 5-HT1D receptors located on intracranial blood vessels, including those on arteriovenous anastomoses è vasoconstriction
• Activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release |
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Term
Has ADE:
• Nausea and vomiting (often requires premedication),
• Diarrhea,
• Drowsiness,
• In overdose, prolonged vasospasm, bowel infarction, hallucinations, drowsiness
-• Avoidwithin24hoursoftriptanadministration,in patients with symptomatic coronary artery disease, pregnancy, or lactation |
|
Definition
Ergot Alkaloids: Dihydroergotamine
-PK:onset15–30minutes,duration3–4hours |
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Term
|
Definition
• Aspirin, ibuprofen, naproxen, indomethacin, diclofenac
• Often coadministered with caffeine |
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Term
| Miscellaneous treatments for headaches |
|
Definition
- Metoclopramide, especially if significant nausea/vomiting
- Refractory migraine:
• Lidocaine infusion
• Haloperidol infusion
• Valproic acid rapid IVP • Peripheral nerve block |
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Term
| FL is a 29-year-old female who experiences migraine headaches approximately 1x every week. She has tried over-the-counter Tylenol and Excedrin migraine with no relief. Imitrex (sumatriptan) was prescribed at her last visit, but it only provided minimal relief. What is your plan for FL? |
|
Definition
Excedrin® Extra Strength, Excedrin® Migraine: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg
Could trial another triptan like Zomig.
Ergots may be an alternative, but toxic.
Ensure that she is not overusing NSAIDs.
Candidate for prophylaxis. |
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Term
Migraine: Prophylaxis
• Indications for prophylaxis: |
|
Definition
• Frequent migraines which interfere with ADLs
• Migraines that are resistant to treatment
• Contraindications to effective acute migraine treatments |
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Term
| migraine prophylaxis agents |
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Definition
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|
Term
Migraine: Prophylaxis
• First in class: |
|
Definition
Erenumab-aooe (Aimovig)
• Approved in 2018, several others currently under review
• Selective calcitonin gene-related peptide (CGRP) antibody
• Dose: 70 mg once monthly SubQ injection
• Reduce migraine frequency up to 50%
• Potential for antibody development (up to 6% incidence) |
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Term
| FL (a 29-year-old female) would like to trial pharmacologic prophylaxis of her migraines. Her BMI is 18 and she has long-standing asymptomatic hypotension at baseline. What agent would you recommend? |
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Definition
Topamax may exacerbate weight loss, need to monitor.
Metoprolol, propranolol may exacerbate hypotension.
Valproic acid is teratogenic (18 years old).
Frova only appropriate for menstrual migraines.
Butterbur is an option.
How about erenumab-aooe? |
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