Chapter 71 - Seizure & Epilepsy Flashcards
Seizure types
- Tonic - clonic: uncontrolled jerking movement
- Absent: momentary loss of awareness
Diagnostic tools
- An electroencephalogram (EEG), the most common test used to diagnose epilepsy, records electrical activity in the brain.
- An EEG can show abnormal patterns even when the patient is not having a seizure.
- Brain imaging with a CT or MRI can identify some conditions that can provoke seizures, including brain tumors or damage from a stroke.
DRUGS THAT CAN LOWER THE SEIZURE THRESHOLD
- Bupropion
- Clozapine
- Theophylline
- Varenicline
- Carbapenems (esp. imipenem)*
- Lithium*
- Meperidine*
- Penicillin*
- Quinolones*
- Tramadol*
- Acyclovir
- Cephalosporins
- lindane
- Mefloquine
- Metoclopramide
- Valacyclovir
Classification of seizure
classified into three main types based on where the seizure starts in the brain:
1) Focal seizures
- Start on one side of the brain but can spread to the other side.
- Focal seizures are further classified based on the patient’s awareness during the seizure.
- If a focal seizure results in no loss of consciousness, it is called a focal aware seizure, previously known as a simple partial seizure.
- If the patient experiences loss of consciousness, it is called a focal seizure with impaired awareness, previously known as a complex partial seizure.
2) Generalized seizures
- Start on both sides of the brain
- Patients with generalized seizures experience loss of consciousness or are unaware during the seizure event.
- Absent seizure is a type of generalized
3) Unknown onset seizures
- if the location of the beginning of the seizure is not known (e.g., the seizures are unwitnessed or occur during the night).
All seizure types can be described based on the patient’s symptoms.
motor and non motor sx
Motor symptoms include:
- Sustained rhythmical jerking movements (clonic)
- Limp or weak muscles (atonic)
- Muscle twitching (myoclonus)
- Rigid or tense muscles (tonic)
Non-motor symptoms include:
- Changes in sensation, emotions, thinking or cognition.
- Generalized seizures with non-motor symptoms are called absence seizures, which typically present as staring spells.
seizure management
- less than 2 min –> no ttmt needed
- Status epilepticus (SE) is a seizure that lasts beyond five minutes because the normal mechanisms that terminate seizures are not working.
- At 30 minutes, long-term damage can occur.
This is a medical emergency, and emergency treatment should begin with any seizure that lasts longer than five minutes.
Acute Seizure management
- Initial treatment is a benzodiazepine injection.
- Intravenous (IV) access can be difficult during a seizure; if it is not possible to connect an IV line, midazolam can be given intramuscularly (IM)
- If the patient is not receiving urgent medical care (i.e., not in a medical facility), diazepam rectal gel (DiastatAcuDial), or intranasal or buccal midazolam are non-injectable options.
- The DiastatAcuDialis given to patients (or caregivers, such as parents) who are at risk of long-lasting seizures; dispensing and counseling requirements are essential
acute seizure management
1) 0-5 minutes: Stabilization phase
- Time the seizure
- Start ECG,oxygen may be needed
- Check AED levels, electrolytes, if BG low - treat with D25-D50
2) 5-20 minutes: Initial treatment phase
If seizure continues:
- Give IV lorazepam (Ativon) or
- IM midazolam (Versed)
Alternatives if the above are not available:
- Rectal diazepam (Diastot),
- Intranasal or buccal midazolam
3) 20·40 minutes Second treatment phase
If seizure continues:
- Give regular AED: IV fosphenytoin, valproic acid, levetiracetam (phenobarbital if others are unavailable)
- If seizure lasts longer, there is no clear treatment
Diastat Acudial Dispensing
- Syringes MUST be dialed to the right dose and locked BEFORE DISPENSING.
- Syringes come in 2.5, 10 and 20 mg.
Chronic seizure management
- 1st line: AED
- AEDs should not be stopped abruptly as this can lead to seizures.
Non-drug and alternative options for chronic seizure treatment include:
- Medical marijuana {cannabis),
- A ketogenic diet,
- Vagal nerve stimulation
- Surgical intervention.
The Embrace2 smartwatch is an FDA-cleared medical device that monitors seizures in adults and children 6 years of age and older.
Medical Marijuana (Cannabis)
- Cannabidiol, or CBD (Epidiolex), was the first cannabis- derived medication approved by the FDA to treat rare forms of epilepsy.
- Epidiolex does not contain tetrahydrocannabinol (THC), but there are other CBD and medical marijuana products available that contain varying amounts of THC. - Pharmacists should consider the impact of additive CNS side effects, particularly with THC-containing products (e.g., somnolence, euphoria, possible anxiety and paranoia), and the potential for drug interactions from the THC and CBD components.
Ketogenic Diet
- Pt with refractory seizures (not responding to medications).
- The diet contains high fats, normal protein and low carbohydrates (usually a 4:1 ratio of fats to combined protein and carbohydrates).
- This forces the body to break down fatty acids into ketone bodies as an energy source.
- Ketone bodies pass into the brain and replace glucose. - This elevated ketone state is called ketosis, and can lead to a reduction in seizure frequency.
Ethosuximide indication
Absence seizures
- T-Type Ca channel blocker
(i’m absent, eh though it sucks)
Main drugs to treat focal and generalized seizures
- Lamotrigine (Na)
- Levetiracetam (Ca + inc GABA)
- Topiramate (Na)
- Valproic acid (GABA)
Val leve toi cz lammo l tapi
Narrow spectrum AED
1- Carbamazepine (Na)
2- Oxcarbazepine (Na + Ca)
3- Lacosamide (Na)
4- Phenobarbital (Potentiate GABA)
5- Phenytoin (Na)
6- Fosphenytoin (Na)
Car bas ma zepine / ox car bas zepine
Lacoste
fen toi? fos fen toi?
fen barb (bread)
Pregabalin and gabapentin (Ca) are used commonly for:
not for epilepsy;
they are used to treat neuropathic pain.
AEDs dec abnormal electrical activity by either:
■ Inc GABA
■ Dec Glutamate
■ Blocking (or altering) Ca channels, which slows down or stops transmission of the electrical signal
■ Blocking Na channels, which decreases the neurons firing rate
Inc GABA
- Benzodiazepine
- Valproic Acid
- Phenobarbital (enhance/ potentiate GABA)
- Levetiracetam
Blocking (or altering) Ca channels, which slows down or stops transmission of the electrical signal
- Levetiracetam (Ca + GABA)
- Ethosuximide (T type Ca chanel blocker)
- Pregabalin/ Gabapentin (used for neuropathic pain)
- Oxcarbazepine (Ca + Na)
Blocking Na channels, which decreases the neurons firing rate
- Oxcarbazepine (Ca + Na)
- Carbamazepine
- Lamotrigine
- Phenytoin/ Fosphenytoin
- Topiramate
- Lacosamide (?)
SE of Carbamazepine. Oxcarbazepine and Eslicarbazepine
- Hyponatremia,
- rash,
- enzyme induction
SE of Gabapentin and Pregabalin
- Weight gain, peripheral edema, mild euphoria
- Used primarily for neuropathic pain
SE of Phenobarbital and Primidone (prodrug of phenobarbital)
- Sedation, dependence/tolerance/overdose risk, enzyme induction
SE of Topiramate and Zonisamide
- Weight loss, metabolic acidosis
- Nephrolithiasis and oligohidrosis/hyperthermia (in children)
what to supplement with?
Supplement with:
- ALL AEDs: calcium and vitamin D
- Women of childbearing age: folate
- Valproic acid: carnitine
- Lamotrigene & valproic acid: if alopecia develops supplement with selenium and zinc
Lamotrigine Brand
- Lamictal,
- Lamictal ODT,
- Lamictal Starter Kit,
- Lamictal XR,
- Subvenite,
- Subvenite Starter Kit-Blue, Green, Orange
Lamotrigene dosing
Initial:
- Weeks 1 and 2: 25 mg daily
- Weeks 3 and 4: 50 mg daily
- Week 5 and on: can inc by 50 mg daily every 1-2 weeks
MaintenanceDose:
300 - 400 mg daily, divide BID, unless using XR (daily)
Lamotrigene boxed warning
- Serious skin reactions, including SJS/TEN (rate of rash is greater in pediatrics than adults);
- inc risk with higher than recommended starting doses, dose escalation or when used with valproic acid
Warning & se of lamotrigene
WARNING
- Risk of aseptic meningitis,
- blood dyscrasias,
- cardiac rhythm abnormalities,
- multiorgan hypersensitivity (DRESS) reactions,
- serious rare immune system reaction [hemophagocytic lymphohistiocytosis (HLH)] that can be fatal
SIDE EFFECTS
- Alopecia (supplement selenium and zinc),
- N/V,
- somnolence,
- rash,
- tremor,
- ataxia,
- impaired coordination,
- dizziness,
- diplopia,
- blurred vision
Lamotrigene drug interactions
- Valproic acid inc lamotrigine concentrations more than two- fold. Use lower dose starter kit (blue box).
- Carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir and rifampin J,lamotrigine levels by 40%. Use the higher dose starter kit (green box).
- Oral estrogen-containing contraceptives J, lamotrigine; higher maintenance doses of lamotrigine may be needed.
levetiracetam brand
- Keppra,
- Keppra XR,
- Roweepra,
- Spritam
Tablet, ODT, oral solution, injection
Levetiracetam dose
Initial:
- 500 mg BID or
- 1,000 mg daily (XR)
Maximum:
- 3,000 mg/day
CrCI: <= 80 ml/min: dec dose
IV:PO ratio 1:1
Levetiracetam warning & se
WARNINGS
- Psychiatric reactions, including psychotic symptoms,
- somnolence, fatigue,
- suicidal behavior,
- anaphylaxis, angioedema,
- coordination difficulties,
- severe skin reactions (SJS/TEN),
- hematologic abnormalities (mainly anemias),
- inc BP,
- loss of seizure control during pregnancy
SIDE EFFECTS
Irritability, dizziness, weakness, asthenia, vomiting (children and adolescents)
NOTES
No significant drug interactions
Levetiracetam warning & se
WARNINGS
- Psychiatric reactions, including psychotic symptoms,
- somnolence, fatigue,
- suicidal behavior,
- anaphylaxis, angioedema,
- coordination difficulties,
- severe skin reactions (SJS/TEN),
- hematologic abnormalities (mainly anemias),
- inc BP,
- loss of seizure control during pregnancy
SIDE EFFECTS
Irritability, dizziness, weakness, asthenia, vomiting (children and adolescents)
NOTES
No significant drug interactions
Topiramate brand
- Topamax
- Topama Sprinkle
Topiramate extended-release
- Qudexy XR
- Trokendi XR
Capsule, extended-release capsule, tablet
- Also used for migraine prophylaxis
Topiramate dose
Initial:
- Week 1: 25 mg BID (IR) or 50 mg daily (XR)
- Weeks 2-4: inc by 25 mg BID (IR) or 50 mg daily (XR) each week
- Week 5 and on: inc by 100 mg weekly until max dose or therapeutic effect
Maximum: 400 mg/day
CrCI < 70 ml/min: dec dose by 50%
CI of topiramate
- Trokendi XR only: alcohol use 6 hours before or after dose,
- Qudexy XR only: patients with metabolic acidosis who are taking metformin
se & warning of topiramate
WARNINGS
- Hyperchloremic nonanion gap metabolic acidosis,
- oligohidrosis (reduced perspiration)/hyperthermia (mostly in children),
- nephrolithiasis (kidney stones),
- acute myopia and secondary angle- closure glaucoma,
- hyperammonemia (alone and with valproic acid),
- visual problems (reversible),
- fetal harm
SIDE EFFECTS
- Somnolence, dizziness, psychomotor slowing, difficulty with memory/concentration/attention, weight loss, anorexia, paresthesia
MONITORING
- Electrolytes (especially bicarbonate), renal function, hydration status, eye exam (intraocular pressure)
NOTES
- Topamax Sprinkle: swallow whole or open and sprinkle on a small amount of soft food (do not chew; swallow immediately)
Topiramate Drug Interactions
- Topiramate is a weak inhibitor of CYP2Cl9and inducer of CYP3A4.
- Phenytoin, carbamazepine, valproic acid and lamotrigine can dec topiramate levels.
- Topiramate can dec oral contraception effectiveness (especially doses >= 200 mg/day)
- Non hormonal contraception is recommended.
- Topiramate can dec the INR in patients on warfarin; monitor closely.
Brand names:
1- Valproic acid
2- Valproate sodium
3- Divalproex
1- Depakene: Capsule, syrup
2- Oepacon: IV
3- Depakote, Depakote ER, Depakote Sprinkle,
- Depakote: delayed-release (DR) tablet
- Depakote ER- extended-release (ER) tablet
- Depakote Sprinkle- capsules can be opened and sprinkled on food
Also used for bipolar disorder and migraine prophylaxis
Dosing of valproic acid
Initial:
- 10-15 mg/kg/day
Maximum:
- 60 mg/kg/day
Therapeutic Range:
- 50-100 mcg/ml (total level)
If the albumin is low (< 3.5 g/dl), the true valproic acid level will be higher than it appears - adjust with
the same formula used for phenytoin.
DR and ER formulations are not bioequivalent, inc total daily dose 8-20% when converting from DR to ER tablets
Boxed Warning of valproic acid
Hepatic failure:
- Usually during first 6 months of therapy,
- Children < 2 years old and patients with mitochondrial disorders [mutations in mitochondrial DNA polymerase gamma gene (POLG)] are at inc risk;
- fetal harm (neural tube defects and dec IQ scores); pancreatitis
CI of Valproic Acid
- Hepatic disease,
- Urea cycle disorders,
- Prophylaxis of migraine in pregnancy,
- Known POLG-related disorder or suspected if < 2 years of age
how to treat hyperammonemia caused from valproic acid?
Treat with carnitine in symptomatic adults only
what to supplement with if a pt had alopecia cz of valproic acid
selenium & zinc
what to monitor with valproic acid
- LFTs (baseline and frequently in the first 6 months),
- CBC with differential,
- Platelets
Valproic acid drug interations
- Valproic acid is an inhibitor of CYP2C9 (weak) and a substrate of CYP2Cl9and 2El (minor).
- Valproic acid can i levels of lamotrigine, phenobarbital, phenytoin, warfarin and zidovudine.
- Salicylates displace valproic acid from albumin {i levels).
- Carbapenem antibiotics can J,the levels of valproic acid.
- Estrogen-containing hormonal contraceptives can dec valproic acid levels.
- Use caution with valproic acid and lamotrigine due to risk of serious rash; use lower starting dose of lamotrigine and titrate slowly.
- Use with topiramate can lead to hyperammonemia with or without encephalopathy.
Carbamazepine brand names
- Tegretol
- Tegretol XR
- Carbatrol
- Epitol
Capsule, tablet, chewable, oral suspension
- Equetro - for bipolar disorder
- Also used for trigeminal neuralgia
Carbamazepine dose
Initial:
- 200 mg BID (or divided QID for suspension)
Maximum:
- 1,600 mg/day (some patients can require more)
Therapeutic Range:
- 4-12 mcg/ml
Boxed warning of carbamazepine
- Serious skin reactions, including SJS/TEN:
- Patients of Asian descent should be tested for HLA-B*1502 allele prior to initiation; if positive for this allele, carbamazepine cannot be used (unless benefit clearly outweighs risk);
- Aplastic anemia and agranulocytosis; discontinue if significant myelosuppression occurs
CI of carbamazepine
- Myelosuppression,
- Hypersensitivity to TCAs,
- Use of MAO inhibitors within past 14 days,
- Use with nefazodone or non-nucleoside reverse transcriptase inhibitors (NNRTls) that are substrates of CYP3A4
Risk of developing a hypersensitivity reaction can be inc in patients with
The variant HLA-A*3101 allele
Warning with carbamazepine
- Multiorgan hypersensitivity (DRESS) reactions
- Hyponatremia (SIADH)
- Hypothyroidism
- Mild anticholinergic effects
- Cardiac conduction abnormalities
- Liver damage
- Fetal harm
SE with carbamazepine
- Dizziness,
- drowsiness,
- ataxia,
- N/V,
- pruritus,
- photosensitivity,
- blurred vision,
- rash,
- inc LFTs,
- alopecia
Monitoring with carbamazepine
- CBC with differential and platelets prior to and during therapy,
- LFTs,
- rash,
- eye exam,
- thyroid function tests,
- electrolytes (especially Na),
- renal function
- Monitor levels within 3-5 days of initiation and after 4 weeks due to autoinduction
NOTE: - Enzyme inducer, autoinducer - dec level of other drugs and itself
Drug interaction with carbamazepine
- Carbamazepine is an autoinducer and will dec its own levels.
- Carbamazepine is a strong inducer of many enzymes (CYP1A2,2Cl9, 2C8/9, 3A4) and P-glycoprotein (P-gp).
- It will dec the levels of many drugs, including other seizure medications, aripiprazole, levothyroxine, warfarin and hormonal contraceptives.
- Use of an alternative, non- hormonal contraceptive is recommended.
- Carbamazepine is a major CYP3A4substrate; inhibitors will inc carbamazepine levels and inducers will dec carbamazepine levels. Do not use with nefazodone or NNRTls.
- Carbamazepine suspension should not be taken with other liquid medications (especially chlorpromazine) or diluents, as precipitates can form.
Lacosamide brand name
- Vimpat
- C-v
Tablet, oral solution, injection
Lacosamide dosing
Initial:
- 50-100 mgBID
Maximum:
- 400 mg/day
CrCI< 30 ml/min: maximum dose is 300 mg/day
IV:PO ratio 1:1
Lacosamide warning, SE, Monitoring
WARNINGS
- Prolongs PR interval and inc risk of arrhythmias;
- Obtain an ECG prior to use and after titrated to steady state in patients with or at risk of cardiac conduction problems;
- Multiorgan hypersensitivity (DRESS) reactions,
- syncope,
- dizziness,
- ataxia
SIDE EFFECTS
- Dizziness, headache,
- diplopia, blurred vision,
- ataxia, tremor, euphoria
MONITORING
ECG (baseline and at steady state) in at-risk patients
Lacosamide DDI
Lacosamide is a substrate of CYP2Cl9 (minor), 2C9
(minor), 3A4 (minor) and an inhibitor of CYP2Cl9 (weak). Caution with inhibitors of CYP2Cl9, 2C9 and 3A4 as they can inc lacosamide levels.
Caution with medication that prolong PR interval:
- B blockers
- CCB
- Digoxin
due to risk of bradycardia & AV block
oxcarbazepine brand names
- Trilleptal: Tablet,oral suspension
- Oxtellar XR: Extended-release tablet
Oxcarbazepine dosing
Initial:
- 300 mg BlD (Trilleptal);
- 600 mg daily (Oxtellar XR)
Maximum:
2,400 mg/day
CrCI < 30 ml/min: start 300 mg daily
Carbamazepine to oxcarbazepine dose conversion:
1.2-1.5x carbamazepine dose
Oxcarbazepine CI
Hypersensitivity to eslicarbazepine
WARNING:
- inc risk for serious skin reactions (SJS/TEN),
- consider screening patients of Asian descent for HLA-B*1502 prior to initiating therapy,
- multi organ hypersensitivity (DRESS) reactions,
- hypersensitivity reactions to carbamazepine have
25 - 30% cross-sensitivity to oxcarbazepine
- Hyponatremia,
- hypothyroidism,
- potential worsening of seizures
SIDE EFFECTS
- Somnolence, dizziness,
- N/V, abdominal pain,
- diplopia,
- visual disturbances,
- ataxia, tremor
MONITORING
- Serum Na levels, especially during first 3 months of therapy,
- thyroid function,
- CBC
NOTES
- Trilleptal oral suspension: must be used within 7 weeks once original container is opened
- XR tablet: take on empty stomach 1 hour before or 2 hours after a meal
Phenobarbital
C-IV
Tablet, oral solution, elixir, injection
dose:
Initial:
- 50-100 mg BID or TID
Therapeutic Range:
- 20-40 mcg/ml (adults)
- 15-40 mcg/ml (children)
CONTRAINDICATIONS
- Severe hepatic impairment,
- dyspnea or airway obstruction,
- previous addiction to hypnotics,
- intra arterial administration
WARNING:
- Habit-forming,
- respiratory depression,
- fetal harm,
- paradoxical reactions including hyperactive or aggressive behavior (in acute pain and pediatric patients),
- hypotension when given IV,
- serious skin reactions (SJS/TEN)
SIDE EFFECTS
- Physiological dependence, tolerance, hangover effect,
- somnolence, cognitive impairment,
- dizziness, ataxia, depression,
- folate deficiency
MONITORING
LFTs, CBC with differential
NOTES
Primidone is a prodrug of phenobarbital
Phenobarbital DDI
- Phenobarbital (and primidone, which is the prodrug) is a strong inducer of most enzymes, including CYP1A2, 2C8/9, 3A4 and P-gp.
These two drugs can J,the levels of many drugs metabolized by these enzymes. - Phenobarbital and primidone cant hormonal contraceptive levels significantly.
Use of an alternative, non-hormonal contraceptive is recommended.
Phenytoin brand names
- Dilantin,
- Dilantin lnfatabs,
- Phenytek
Capsule, chewable, oral suspension, injection (IV only)
Fosphenytoin brand names
- Cerebyx,
- Sesquient
Injection (IV/IM)
Prodrug of phenytoin
Phenytoin/ Fosphenytoin dose
Loading dose:
- 15-20 mg/kg
Maintenance dose:
- up to 300-600 mg/day
Fosphenytoin is dosed in phenytoin equivalents (PE):
1 mg PE = 1 mg phenytoin
(fosphenytoin 1.5 mg = 1 mg PE)
IV:PO ratio 1:1
Therapeutic Range:
- 10-20 mcg/ml (total level)
- 1-2.5 mcg/ml (free level)
Phenytoin/ fosphenytoin BBW
- Phenytoin IV administration rate should not exceed 50 mg/minute and
- Fosphenytoin IV should not exceed 150 mg PE/minute or 2 mg PE/kg/min (use the slower rate);
- if given faster, hypotension and cardiacarrhythmias can occur
CI Phenytoin/ fosphen
Previous hepatotoxicity due to phenytoin
warning with phen/fosphenytoin
- Extravasation (leading to purple glove syndrome, characterized by edema, pain and bluish discoloration of the skin, which can sometimes lead to tissue necrosis),
- avoid phenytoin in patients with a positive HLA-B*1502 and in patients who have had a severe rash with carbamazepine,
- multi organ hypersensitivity (DRESS) reactions,
- fetal harm,
- bradycardia,
- inc risk of serious skin reactions (SJS/TEN),
- fraction of unbound (free) drug is higher with renal or hepatic failure or dec albumin,
- blood dyscrasias,
- caution in cardiac disease, hepatic and renal impairment,
- hypothyroidism
phen/fosphenytoin SE, monitoring
Dose-related (toxicity):
- Nystagmus, ataxia, diplopia/blurred vision, slurred speech, dizziness, somnolence, lethargy, confusion
Chronic:
- Gingival hyperplasia,
- hair growth,
- hepatotoxicity,
- skin thickening (children),
- morbilliform rash (measles-like),
- peripheral neuropathy,
- inc BG,
- metallic taste,
- connective tissue changes,
- enlargement of facial features (lips}
MONITORING
- Serum phenytoin concentration,
- LFTs,
- CBC with differential
IV: continuous cardiac (ECG,BP,HR) and respiratory monitoring
!!! adjust phenytoin dose for low doses of albumin
phen/fosphen DDI
- Phenytoin and fosphenytoin are strong inducers of several enzymes, including CYP2B6, 2Cl9, 2C8/9, 3A4, Pgp and UGTlAl; they are substrates of CYP2Cl9 (major), 2C9 (major) and 3A4 (minor).
- Phenytoin and fosphenytoin can dec the concentration of many drugs including other AEDs, contraceptives and warfarin.
- Use of an alternative, non-hormonal contraceptive is recommended with chronic phenytoin.
- Both have high protein binding and can displace other highly protein-bound drugs or be displaced by other highly protein-bound drugs, causing an inc in levels that can lead to toxicity.
phen/ phenytoin administration
IV Phenytoin
- Do not exceed 50 mg/minute (slow infusion)
- Monitor BP, respiratory function and ECG
- Requires a filter
- Dilute in NS, stable for 4 hours, do not refrigerate
NG-tube Phenytoin
- Enteral feedings (e.g.,tube feeds) dec phenytoin absorption
- Hold feedings 1-2 hours before and after administration
IV Fosphenytoin
- Do not exceed 150 mg PE/minute
- Monitoring same as above
- Lower risk of purple glove syndrome than phenytoin
