Epilepsy II Flashcards
What are the factors that influence ASM choice?
- Seizure type and epilepsy syndrome
- focal or generalised onset
- whether the drug requires rapid titration (e.g. lamotrigine and topiramate require slow titration), carbamazepine undergoes autoinduction. - Co-medication and co-morbidity
- migraine: add valproate, depression: levetiracetam with caution
- drug-drug interactions: patients on HIV immunosuppressants
- route of elimination: liver or renal impairment
- special population: administer lamotrigine or levetiracetam for women of childbearing potential only. - Patient’s lifestyle and preference
- National/institutional
- guidelines
- costs, financial subsidy
Which medications to give for new onset, focal onset epilepsy?
- phenytoin (possible teratogenicity)
- sodium valproate (avoid use in pregnancy)
- carbamazepine
- levetiracetam
- lamotrigine (can be administered to elderly)
- topiramate (possible cognitive effect and teratogenicity)
- gabapentin (can be used in elderly)
- oxcarbamazepine
Which medications are first-line for new onset, focal onset epilepsy?
carbamazepine, lamotrigine, oxcarbazepine, sodium valproate, levetiracetam
Examples of refractory medications for new onset, focal onset epilepsy
- clobazem
- pregabalin
Which medications to give for new onset, GTC epilepsy?
- lamotrigine
- valproate
- carbamazepine
- topiramate
Which medications are first-line for new onset, GTC epilepsy?
lamotrigine, valproate, carbamazepine
Examples of refractory medications for new onset, GTC epilepsy
clobazem, levetiracetam
Drug treatment dose for phenytoin
300-400mg max
5-7mg/kg/day
Drug treatment dose for sodium valproate
600-2000mg
or 20-30mg/kg/day (max 60mg/kg/day)
Drug treatment dose for carbamazepine
800-1200mg
Drug treatment dose for phenobarbitone
60-180mg
Drug treatment dose for lamotrigine
100-200mg
Drug treatment dose for topiramate
200-400mg
Drug treatment dose for levetiracetam
1000-3000mg
Pharmacokinetics of 1st generation ASMs
Drugs: carbamazepine, phenobarbitone, phenytoin and valproate
- all highly protein bound (lowest is phenobarbitone, at ~50%)
- all are 100% hepatically cleared (except for phenobarbitone, 75%)
- all have drug-drug interactions
Pharmacokinetics of 2nd generation ASMs
- Gabapentin
- non protein-bound, completely renally eliminated, no interactions - Pregabalin
- non protein-bound, largely renally eliminated, no interactions - lamotrigine
- half protein-bound, completely hepatically eliminated, few drug-drug interactions - levetiracetam
- few are protein bound, majority renally eliminated, no drug-drug interactions - topiramate
- few are protein bound, 30-55% renally eliminated, dose-dependent DDI - clobazem
- largely protein bound, largely renally eliminated, DDI
Effects of drug metabolism: first generation ASMs
Potent enzyme inducers (CYP, UGTs)
- carbamazepine
- phenytoin
- phenobarbital
Potent enzyme inhibitor (CYP, UGTs)
- valproate
No effect on CYPs
- ethosuximide
Effects of drug metabolism: second generation ASMs
No effects on CYP:
- gabapentin, levetiracetam, pregabalin
Moderate inducer:
- topiramate
What are deinduction mechanisms?
- Drugs that are metabolized by the affected enzymes may require dose adjustment.
- When an enzyme inducing ASM is discontinued – the enzymatic activity returns to baseline
Issues with enzyme-inducing ASMs
- DDIs
- antidepressants and antipsychotics
- immunosuppressive therapy
- antiretroviral therapy
- chemotherapeutic agents - Reproductive hormones, sexual function, oral contraceptives in women
- Sexual function and fertility in men
- Bone health
- Vascular risk
Phenytoin characteristics
- Bioavailability, F = 1
- Complete absorption, but slow
- Reduced at higher doses > 400mg/dose
- Reduced by NGT and feeds interaction (space out 1-2 hours between feeds and dosing) - Highly albumin bound
- Low albumin -> increases free phenytoin
- Affected by uremia, other drugs - Zero order kinetics
- Concentration increment is NOT proportional to dose increment. - Capacity-limited clearance
- Clearance is dependent on concentration
- Clearance will decrease with increasing concentration
Valproate characteristics
- Complete oral bioavailability
- Highly albumin bound
- Saturable protein binding within therapeutic range
- Decreased protein binding with higher dose
- Higher free fraction of drug with low albumin - Total valproic acid concentrations increase in a nonlinear fashion with dosage increases
- Displacement by endogenous compounds (uremia, hyperbilirubinemia)
- Competition for binding: phenytoin, warfarin, NSAIDs
Carbamazepine characteristics
- High bioavailability
- Highly protein bound
- Almost completely metabolized by CYP3A4
- Undergoes autoinduction (induces its own metabolism)
- Maximum autoinduction usually occurs 2-3 weeks after dose initiation. - Clearance increase and half-life shorten -> carbamazepine concentration decline and stabilize in accord with new clearance and half-life.
- Do not start with desired maintenance dose at the first dose, but gradually increase over the few weeks
What are some dose-plasma concentration-related adverse effects
- CNS: somnolence, fatigue, visual disturbances, nystagmus, ataxia
- GI: Nausea, vomiting (carbamazepine, valproate)
- Psychiatric: behavioural disturbances (levetiracetam)
- Cognition: usually speech literacy (topiramate)
- Adverse effects usually more pertinent at higher concentrations.
* more frequent and occur in lower concentrations for patients receiving ASM combination therapy.
How to reduce occurrence and severity of dose-plasma concentration-related adverse effects?
- Initiating therapy at a low dose, and slowly increasing the dose.
- Avoiding large dosage changes
- Restricting therapy to one drug only (if clinically feasible)
- Adjusting the administration schedule
» Administration of largest dose at bedtime
» Dividing a daily dose into smaller doses given more frequently
» Use of sustained-release formulations
» Reducing the total daily dose
What are some examples of idiopathic/hypersensitivity-related adverse effects?
Rare (<0.1%)
- Blood dyscrasia (aplastic anemia, granulocytosis) (phenytoin and carbamazepine)
- Hepatotoxicity (first generation ASMs: phenytoin, valproate, carbamazepine)
- Pancreatitis (sodium valproate)
- Lupus-like reaction
- Dermatitis
- Stevens-Johnson syndrome (carbamazepine, phenytoin and lamotrignine)
What are the long-term, non-dose ASM-related therapy side effects?
- Neurological
» Encephalopathy: phenytoin, phenobarbitone
» Peripheral neuropathy: phenytoin, carbamazepine and phenobarbitone - Gastrointestinal
» Sodium valproate (increased weight gain), topiramate (weight loss) - Hematological: Blood dyscrasias, megaloblastic anemia
- Neonatal congenital defects
» Associated with phenytoin, phenobarbitone and topiramate
» Valproate – cognition - Suicidal ideation
» All of the key drugs, except phenytoin
»No changes to therapy without first discussing with physician
» Requires close monitoring of symptoms
What is the hypersensitivity reaction, and its risk management strategies?
- Rash is a common side effect
- Could be Stevens-Johnson syndrome, or just a macropapular rash.
- can be caused by: carbamazepine, phenytoin, lamotrigine
- Risk management strategies:
1. Pharmacogenetic testing: carbamazepine
» Strong association between carriage of HLA-B 1502 and risk of carbamazepine-induced SJS.
» Relevant for Han Chinese and other Asian ethnic groups.
- Follow dosing guidelines: lamotrigine
- Identify potential cross-sensitivity reactions (ASMs with aromatic rings)
Cross-sensitivity reaction associated with aromatic ASMs
- mechanisms by which ASMs induce skin reactions is unclear.
- main hypotheses: ASMs with an aromatic ring can form an arene-oxide intermediate
- become immunogenic through interactions with proteins or cellular macromolecules
- in the event if an individual is allergic to an aromatic ASM, he may switch to a non-ringed ASM, or continue with the ringed ASM if symptoms are deemed mild, and epilepsy severe, subject to close monitoring.
Common side effects and other known side effects of levetiracetam
Common side effects: somnolence, dizziness, asthenia, coordination difficulties, headache
Other known side effects: irritability, aggression
Why is it important to conduct therapeutic drug monitoring for ASM?
- To establish an individual’s therapeutic range
• “Reference range” may not be effective for all due to interindividual variability.
• Plasma ASM levels correlate much better with clinical effects than dose. - To assess lack of efficacy
• Some individuals may be fast metabolizers, may have adherence issues.
• Need to decide if choice of drug and dosing is right for a particular patient in achieving long-term seizure control.
• Doses tend to be prophylactic, seizures occur at irregular intervals. - Assess for potential toxicity
• Concentration-dependent adverse effects, slow metabolizers, renal or hepatic impairment - To assess loss of efficacy (breakthrough seizures)
• Drug interactions, changes in physiology or formulation
Special populations: women of childbearing age
- Receive counselling on importance of early discussion on family planning
- Cannot prescribe teratogenic drugs
- Use of oral contraceptives
» Potent enzyme inducers may render OC ineffective, alternative methods required.
» For patients on lamotrigine, OC may lower lamotrigine concentrations, resulting in breakthrough seizures.
Special populations: pregnancy and lactation
- Women with epilepsy should be referred to specialist care for pre-conception counselling.
- Taking ASM is not an absolute contraindication to breastfeeding
- All breastfeeding women on ASM should be encouraged to breastfeed, and receive support from healthcare professionals.
Can ASM be discontinued?
o Drug discontinuation can be considered after a minimum of two years without a seizure.
o Longer for patients who are at increased risk of seizure recurrence.
o Discuss with family members and caregivers
o Drug tapering schedule should be individualized.
o Patients are considered free from epilepsy if: they have not experienced seizure for 10 years, and have remained off-medicine for 5 OR if they suffered from age-dependent epilepsy syndrome and are now past the given age.
What is the definition of status epilepticus?
o Constant state of epilepsy
o Need to act within 5 mins, else seizure will be prolonged, need to act within 30 mins, else there will be long-term consequences to the seizures.
Treatment algorithm for status epilepticus
- First 5 mins: stabilize the seizure, time the seizure onset, check vital signs etc. Collect finger stick glucose (hypoglycemia may cause seizure)
- 5-20 mins: prescribe benzodiazepine as the initial therapy of choice
- IV diazepam, midazolam, lorazepam, if not: rectal diazepam, IV phenobarbital - 20-40 mins:
- Phenytoin, valproate, or levetiracetam - 40-60 mins (if patient is still seizing):
- No clear guidelines on what to use, but can give anesthetic agents like thiopental, midazolam, propofol.
