Anti-seizure Medications Flashcards
AE’s are common and contribute to…
Treatment failure in up to 40% of patients, due to non-adherence
Most common AE’s with ASM’s are…
Dose-dependent, predictable, and reversible
Common CNS AE’s include…
Sedation, dizziness
Blurred or double vision
Ataxia
Difficulty concentrating
Common GI AE’s include…
Nausea, vomiting
Idiosyncratic reactions from ASM’s usually develop…
Within the first few weeks of treatment; unpredictable, but uncommon/rare
An example of a hypersensitivity reaction is…
SJS, TENS
SJS/TENS is most likely to occur with…
Phenytoin
Carbamazepine
Lamotrigine
Cross-sensitvity of hypersensitivity between agents…
Is possible, due to aromatic hydrocarbon ring
Drugs with an aromatic hydrocarbon ring include…
Carbamazepine + its derivatives
Phenobarbital
Primidone
Phenytoin
Lamotrigine
ASM exposure during pregnancy has been associated with…
Major congenital malformations and neurodevelopmental delay in offspring
General measures to consider for women taking ASM’s include…
Discussing pregnancy plans prior to conception
Ensure adequate folic acid supplementation
Aim for seizure-freedom for 9-12 months prior to pregnancy
Prevention of teratogenicity may include…
Avoiding valproic acid in women of childbearing potential
Avoid polytherapy + use lowest effective dose of ASM
Avoid stopping ASM’s or switching medications during pregnancy
Be mindful of risk to baby + mom with uncontrolled seizures
Adding a new ASM will often interfere…
With the levels of an existing ASM - strong CYP inducers + inhibitors are common
Hormonal contraceptives are involved with drug interactions via…
Enzyme inducing ASM’s reduce efficacy of COC (phenytoin, carbamazepine, phenobarb, primidone). Estrogen containing contraception will reduce lamotrigene levels
Preferred contraceptives for someone on ASM is…
LGN-IUD, copper IUD, or progesterone implant
Depot-medroxyprogesterone
COC with >30mcg EE taken continuously
Therapeutic drug monitoring is available for many older ASM’s, but…
There is a poor correlation between levels and clinical efficacy
Variability in patient response + seizure type
A drug level could be drawn when…
Desired clinical response - establish individual therapeutic range
Determining magnitude of dose increase, esp. with dose-dependent PK
Signs/sx’s suggestive of ASM toxicity
Assess if alteration in PK/formulation change drug level
Unexpected change in clinical response/poor compliance expected
1st line options for focal seizures as per AAN guidelines include…
Carbamazepine + Lamotrigine
2nd line options for focal seizures as per AAN guidelines include…
Levetiracetam
VPA
Oxcarbamazepine
Zonisamide
3rd line agents for generalized motor seizures (tonic-clonic) as per NICE guidelines include…
There are no 1st/2nd line agents listed in AAN due to lack of evidence
Carbamazepine
Lamotrigine
Valproate
Topiramate
Levetiracetam
1st and 2nd line agents for generalized motor myoclonic seizures as per NICE guidelines include…
1st line: Valproate
2nd line: Levetiracetam, topiramate
Medications that NEED to be avoided in generalized motor myoclonic + absence seizures include…
Carbamazepine + derivatves
Gabapentin
Phenytoin
Tiagabine
Vigabatrin
Lamotrigine in myoclonic only
May precipitate or aggravate seizures - importance of an accurate diagnosis
1st and 2nd line medications for absence seizures as per AAN guidelines include…
1st line: ethosuximide, valproate
2nd line: lamotrigine
Most common MOA of ASM is…
Sodium channel blockers - blocking sodium ion flow in neurons alters signal transduction
ASM’s that are sodium channel blockers are…
Phenytoin
Carbamazepine + derivatives
Lamotrigine
Lacosamide
Rufinamide
Phenytoin is a ____ spectrum ASM.
Narrow
Phenytoin place in therapy is…
Treating status epilepticus
Last line for focal seizures, NOT for absence/myoclonic seizures
Advantages to phenytoin include…
OD/BID dosing, many dosage forms
Cheap
Extensive experience
Defined therapeutic serum concentration range
Disadvantages to phenytoin include…
Substrate + broad spectrum inducer of CYP and glucuronidation - MANY drug interactions
Complicated PK, saturable kinetics (therapeutic drug monitoring necessary)
Lots of AE’s
Dose-related toxicities of phenytoin may involve…
Mainly CNS: Drowsiness, confusion, nystagmus, ataxia, slurred speech, unusual behaviour, mental changes, coma
Nausea
(Levels > 200 umol/L)
Non-dose related toxicities of phenytoin may involve…
Hirsutism, acne, gingival hyperplasia, folate deficiency, osteomalacia, hypersensitivity reactions (SJS), lupus
Carbamazepine place in therapy for seizures is…
1st line for focal onset seizures
3rd line for generalized tonic-clonic
Carbamazepine is a ____ spectrum ASM.
Narrow
Advantages of carbamazepine include…
CR/XR tablets - BID dosing
Can be used for other indications such as bipolar or neuropathic pain
Disadvantages of carbamazepine include…
Significant DI’s
Lots of AE’s
Risk of SJS + TENS
Carbamazepine has a lot of drug interactions due to…
Substrate + broad-spectrum inducer of CYP enzymes and induces its own metabolism, resulting in increased clearance and decreased half-life with continued dosing
Carbamazepine CYP inducing effect starts within ____ and ends in…
Within 24 hours, ends in 1-5 weeks. Applies to every dose increase
Dose related AE’s with carbamazepine include…
GI - N/V, constipation, dry mouth
CNS - lethargy, sedation, dizziness, blurred vision, ataxia
CV - tachycardia, hypotension, conduction abnormalities
Some idiosyncratic AE’s with carbamazepine include…
Hyponatremia
Blood dyscrasias
Rash + hypersensitivity rxns
Weight gain
Hepatic and thyroid issues
Menstrual disturbances
These lab values should be monitored with carbamazepine usage…
LFT’s + Thyroid
Renal fx
CBC with diff + platelets
Electroytes
ECG
Bone mineral density
These patients have increased risk of rash + hypersensitivity reactions with carbamazepine:
Asian ancestry + HLA-B1502
Caucasian + HLA-A3101
Chronic usage of carbamazepine may lead to…
Osteomalacia
Vitamin D deficiency
Notable drugs that will increase carbamazepine levels include…
Macrolides
Antifungals
CCB’s
Other ASM’s - valproic acid + lamotrigine
Common drugs that may decrease carbamazepine levels include…
Other ASM’s - phenytoin, phenobarbital, primidone
Notable drugs that have their serum levels decreased by carbamazepine include…
A LOT
Antipsychotics
Antidepressants
Anticoagulants
Antifungals
Estrogen/progesterone
Other ASM’s - phenytoin, valproic acid, lamotrigine
Eslicarbazepine MOA is ____, and is approved for…
Inhibition of voltage gated sodium channels - mono or adjunctive tx for focal seizures
Eslicarbazepine DI’s compared to carbamazepine is…
Less severe - still induces 3A4, but no autoinduction
Eslicarbazepine AE’s compared to carbamazepine is…
Similar, but frequency is less for all sx’s.
Eslicarbazepine severe AE includes ____ and cannot be used if…
Prolongation of PR interval - CI if 2nd/3rd degree AV block
Oxcarbazepine is a prodrug structurally related to carbamazepine, and its difference is…
Adjusted to try and reduce frequency of AE’s and severity DI’s
Lamotrigine MOA is…
Blockage of sodium channels + reducing glutamate release
Weak serotonin receptor inhibitory effect
Lamotrigine is a ____ spectrum ASM
Broad
Lamotrigine place in therapy includes…
1st line for focal seizures
3rd line for generalized motor seizures
2nd line for absence seizures
Not for myoclonic
Advantages of lamotrigine include…
Well-tolerated
Broad spectrum activity
One of the safest in pregnancy
Fewer DI’s
Good for bipolar depression
Disadvantages of lamotrigine include…
Does have clinically important DI’s
Slow titration required, not good if therapeutic levels are required quickly - risk of life-threatening rashes
Lamotrigine DI’s that are important to note include…
Other ASM’s - VPA, other enzyme-inducing ASM’s
Estrogen products
All decrease lamotrigine levels
Lamotrigine titration is usually as follows…
Week 1-2: 25mg once daily
Week 3-4: 50mg once daily
Week 5: 100mg once daily
Then increase dose by 50mg-200mg every 1-2 weeks
Common AE’s that occur with lamotrigine include…
Sedation/insomnia, headaches, nausea, dizziness
Serious but rare AE that we must monitor in lamotrigene usage includes…
Life-threatening SJS/TENS
Blood dyscrasias
85% patients on lamotrigene who experience SJS rash have prodromal symptoms, which involve…
Flu-like symptoms
The following needs to be monitored while on lamotrigine…
Baseline hepatic + renal function
Monitor for rash
CBC, LFT, SCr
Lamotrigine titration needs to be restarted if ____ days are missed, to avoid…
5 days - avoid increased risk of skin rash
Lacosamide is a newer ASM that is a ____ spectrum ASM, and is approved for ____ seizures.
Narrow, but maybe broad spectrum - approvaed for focal seizures
MOA of lacosamide is also…
Slow inactivation of voltage-gated sodium channels, inhibiting repetitive neuronal firing
Lacosamide has few DI’s, but notably…
Has no contraceptive interactions
Lacosamide AE’s are similar to other sodium channel blockers, which include…
CNS - dizziness, headache, ataxia, fatigue, diplopia, nystagmus, tremor
GI - nausea, vomiting, diarrhea
Serious AE’s with lacosamide include…
Hypersensitivity skin reactions
Dose-dependent prolongation in PR interval, 1st degree AV block, afib/flutter
Skin rxn thought to be cross-reactive with other agents
Clobazam’s MOA is…
This is a BZD
Bind to GABA receptors to facilitate increased endogenous GABA binding activity
Clobazam is a ____ spectrum ASM
Broad
Clobazam place in therapy is…
3rd/4th line, or adjunct tx. for most seizure types. (both focal + generalized - including myoclonic, atonic)
Compared to other BZD’s, clobazam is less likely…
To develop tolerance
BZD’s are usually not well-suited for chronic management due to rapid development of tolerance - this one is less likely
Advantages of clobazam include…
Broad-spectrum
Rapid onset
OD/BID dosing, cheap
Few DI’s
Disadvantages of clobazam include…
Possible tolerance (but less likely than other BZD’s)
Potential for abuse + dependence
Needs to be weaned off to avoid withdrawal, if stopping
In general, if we are stopping ASM’s, we should ____, because…
Taper - stopping immediately may worsen seizures
Going from “seizure protective” to “no protection”
Primary AE’s with clobazam include…
CNS effects - drowsiness, dizziness, ataxia, reduced concentration
Some people develop tolerance
With clobazam, we should monitor…
Level of sedation
Respiratory depression (especially with concurrent opioids)
MOA of phenobarbital is…
Bind to GABA receptors to prolong the activity of GABA
Phenobarbital is a ____ spectrum ASM
Narrow
Phenobarbital place in therapy is…
Not listed in AAN.
4th line for focal seizures and 3rd line for generalized TC seizures as per ILAE
Declining use due to AE’s and DI’s
Advantages with phenobarbital include…
OD dosing, due to long half-life
Cheap
Disadvantages with phenobarbital include…
Substrate + broad-spectrum inducer of various CYP enzymes and glucuronidation = many DI’s
Prominent sedation
Lethality in overdose
Notable AE’s with phenobarbital include…
CNs effects - sedation
Rash
Decreased vitamin D, folic acid
Hepatotoxicity
If someone were to take phenobarbital, we would monitor…
Serum levels (target therapeutic range available)
LFT’s + renal function
CBC’s
MOA of topiramate is…
Combination
Blocks sodium channels
Enhances GABA
Antagonizes AMPA glutamate receptors
Weakly inhibits carbonic anhydrase
Topiramate is a ____ spectrum ASM
Broad
Topiramate place in therapy is…
4th line for focal seizures (AAN)
3rd line for generalized tonic-clonic seizures (AAN)
2nd line for myoclonic seizures (NICE)
3rd line for absence seizures (NICE)
GABA is the major ____ neurotransmitter, involved in seizure activity
Inhibitory
One advantage with topiramate is that it may assist with…
Migraine prophylaxis
Weight loss
Alcohol dependence
Topiramate is generally not well tolerated due to the multitude of AE’s, such as…
CNS - drowsiness, dizziness, paresthesias, decreased concentration + cognition
Nausea, diarrhea
Renal stones, metabolic acidosis
Weight loss
Glutamate is the major ____ neurotransmitter, thought to increase seizure activity
Excitatory
MOA of perampanel is…
AMPA (Glutamate) receptor antagonist
Place in therapy of perampanel is…
Adjunctive tx of generalized tonic-clonic seizures, may also help with adjunctive tx with focal seizures
Perampanel is a ____ spectrum ASM
Broad
Common AE’s with perampanel include…
CNS - dizziness, drowsiness, fatigue, ataxia, abnormal gait, irritability
GI - vomiting, nausea
Skin rash
Pain (MSK, arthralgia, myalgia, back pain)
Black box warning on perampanel is…
CNS + Irritability AE’s may lead to…
Psychiatric and behavioural reactions - aggressive behaviour and homicidal thoughts
Appears to be dose-dependent
Valproic acid MOA is…
Increasing GABA activity through several mechanisms
Modulates sodium, calcium, and potassium channels
Divalproex compared to valproic acid…
Has better GI tolerance
VPA is a ____ spectrum ASM
Broad - option for practically all seizure types
Divalproex place in therapy includes…
2nd line - focal seizures
3rd line - generalized tonic-clonic
3rd line - myoclonic
1st line - absence
Advantages with divalproex include…
Very broad spectrum - useful for other psychiatric + neurologic conditions
Low risk of rash, no cross-reactivity
Disadvantages with divalproex include…
Inhibition of CYP enzymes - many potential DI’s
Well known teratogen
May contribute to metabolic syndrome
Lamotrigine and valproic acid have a key drug interaction in that…
Lamotrigine concentrations are increased by ~50%, so we have to decrease lamotrigene dose by 50%
Notable side effects of valproic acid include…
GI: N/V/D, constipation, anorexia
CNS: Tremor, sedation, ataxia, dizziness
Thrombocytopenia
Hair loss/thinning, weight gain, amenorrhea
Some serious adverse effects of valproic acid include…
Increased transanimases, LDH; hepatotoxicity
Pancreatitis
Hyperammonemia
Leukopenia
Skin rash (increased with lamotrigene usage)
With chronic usage of valproic acid, the following may occur…
Weight gain (up to 8-14kg)
Menstrual disturbances; PCOS
Alopecia
The following should be monitored with valproic acid usage…
Sedation
Rash
CBC, platelets, and LFT’s
Ammonia levels (unexplained lethargy, confusion, vomiting)
Valproate levels
How often should valproate levels be tested?
2-4 days after a dose change or an interacting drug is started, then in 1-2 weeks to ensure stability
Then PRN
Therapeutic range of valproic acid is…
350-700 micromol/L of total valproic acid; guideline only and needs to be individualized
Valproic acid levels should be taken…
At a steady state trough level; 3-4 days after initial therapy
Or at suspected s/sx’s of valproic acid toxicity
MOA of levetiracetam is…
Full mechanism unclear - binds to synpatic vesicle protein SV2A in presynaptic terminal to modulate NT release
Levetiracetam is a ____ spectrum ASM.
Broad
Levetiracetam’s place in therapy for seizure management is…
2nd line for focal
3rd line for generalized TC seizures
2nd line or adjunct tx for myoclonic seizures
Advantages of levetiracetam include…
Different MOA, easy to be added
No significant DI’s (COC still affected)
Very-well tolerated, low risk of rash
Can be titrated rapidly with loading doses
Disadvantages of levetiracetam include…
Psychiatric/behavioural prbolems may limit therapy
Renal dosing adjustments necessary
Common AE’s with levetiracetam include…
CNS - sedation most common
GI
Behavioural/psychiatric symptoms
Mood swings - agitation, aggression, anxiety, depression
Rare AE’s with levetiracetam include…
Decrease in WBC’s
SJS, TEN
Monitoring with levetiracetam can include…
CBC’s, if clinically indicated
Renal function
Brivaracetam’s MOA is…
Same as levetiracetam - binds to SVA2 protein
Brivaracetam is considered a ____ spectrum ASM.
Broad
So far, brivaracetam is approved for…
Adjunctive tx for focal seizres, not controlled with 1st line ASM’s
Brivaracetam AE’s are similar to levetiracetam, except for…
Lower risk of psychiatric disturbance (clinically, may still be similar)
Low risk of bronchospasm or angioedema
IN GENERAL, broad-spectrum ASM’s are…
Often effective at treating focal AND generalized seizures
IN GENERAL, narrow-spectrum ASM’s are…
Used primarily for focal seizures
