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Pharmacotherapeutics > Epilepsy II > Flashcards

Epilepsy II Flashcards

1
Q

What are the factors that influence ASM choice?

A
  1. 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.
  2. 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.
  3. Patient’s lifestyle and preference
  4. National/institutional
    - guidelines
    - costs, financial subsidy
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2
Q

Which medications to give for new onset, focal onset epilepsy?

A
  • 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
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3
Q

Which medications are first-line for new onset, focal onset epilepsy?

A

carbamazepine, lamotrigine, oxcarbazepine, sodium valproate, levetiracetam

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4
Q

Examples of refractory medications for new onset, focal onset epilepsy

A
  • clobazem

- pregabalin

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5
Q

Which medications to give for new onset, GTC epilepsy?

A
  • lamotrigine
  • valproate
  • carbamazepine
  • topiramate
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6
Q

Which medications are first-line for new onset, GTC epilepsy?

A

lamotrigine, valproate, carbamazepine

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7
Q

Examples of refractory medications for new onset, GTC epilepsy

A

clobazem, levetiracetam

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8
Q

Drug treatment dose for phenytoin

A

300-400mg max

5-7mg/kg/day

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9
Q

Drug treatment dose for sodium valproate

A

600-2000mg

or 20-30mg/kg/day (max 60mg/kg/day)

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10
Q

Drug treatment dose for carbamazepine

A

800-1200mg

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11
Q

Drug treatment dose for phenobarbitone

A

60-180mg

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12
Q

Drug treatment dose for lamotrigine

A

100-200mg

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13
Q

Drug treatment dose for topiramate

A

200-400mg

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14
Q

Drug treatment dose for levetiracetam

A

1000-3000mg

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15
Q

Pharmacokinetics of 1st generation ASMs

A

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
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16
Q

Pharmacokinetics of 2nd generation ASMs

A
  1. Gabapentin
    - non protein-bound, completely renally eliminated, no interactions
  2. Pregabalin
    - non protein-bound, largely renally eliminated, no interactions
  3. lamotrigine
    - half protein-bound, completely hepatically eliminated, few drug-drug interactions
  4. levetiracetam
    - few are protein bound, majority renally eliminated, no drug-drug interactions
  5. topiramate
    - few are protein bound, 30-55% renally eliminated, dose-dependent DDI
  6. clobazem
    - largely protein bound, largely renally eliminated, DDI
17
Q

Effects of drug metabolism: first generation ASMs

A

Potent enzyme inducers (CYP, UGTs)

  • carbamazepine
  • phenytoin
  • phenobarbital

Potent enzyme inhibitor (CYP, UGTs)
- valproate

No effect on CYPs
- ethosuximide

18
Q

Effects of drug metabolism: second generation ASMs

A

No effects on CYP:
- gabapentin, levetiracetam, pregabalin

Moderate inducer:
- topiramate

19
Q

What are deinduction mechanisms?

A
  • 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
20
Q

Issues with enzyme-inducing ASMs

A
  1. DDIs
    - antidepressants and antipsychotics
    - immunosuppressive therapy
    - antiretroviral therapy
    - chemotherapeutic agents
  2. Reproductive hormones, sexual function, oral contraceptives in women
  3. Sexual function and fertility in men
  4. Bone health
  5. Vascular risk
21
Q

Phenytoin characteristics

A
  1. 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)
  2. Highly albumin bound
    - Low albumin -> increases free phenytoin
    - Affected by uremia, other drugs
  3. Zero order kinetics
    - Concentration increment is NOT proportional to dose increment.
  4. Capacity-limited clearance
    - Clearance is dependent on concentration
    - Clearance will decrease with increasing concentration
22
Q

Valproate characteristics

A
  1. Complete oral bioavailability
  2. Highly albumin bound
    - Saturable protein binding within therapeutic range
    - Decreased protein binding with higher dose
    - Higher free fraction of drug with low albumin
  3. Total valproic acid concentrations increase in a nonlinear fashion with dosage increases
  4. Displacement by endogenous compounds (uremia, hyperbilirubinemia)
  5. Competition for binding: phenytoin, warfarin, NSAIDs
23
Q

Carbamazepine characteristics

A
  1. High bioavailability
  2. Highly protein bound
  3. Almost completely metabolized by CYP3A4
    - Undergoes autoinduction (induces its own metabolism)
    - Maximum autoinduction usually occurs 2-3 weeks after dose initiation.
  4. Clearance increase and half-life shorten -> carbamazepine concentration decline and stabilize in accord with new clearance and half-life.
  5. Do not start with desired maintenance dose at the first dose, but gradually increase over the few weeks
24
Q

What are some dose-plasma concentration-related adverse effects

A
  1. CNS: somnolence, fatigue, visual disturbances, nystagmus, ataxia
  2. GI: Nausea, vomiting (carbamazepine, valproate)
  3. Psychiatric: behavioural disturbances (levetiracetam)
  4. Cognition: usually speech literacy (topiramate)
  5. Adverse effects usually more pertinent at higher concentrations.
    * more frequent and occur in lower concentrations for patients receiving ASM combination therapy.
25
Q

How to reduce occurrence and severity of dose-plasma concentration-related adverse effects?

A
  • 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
26
Q

What are some examples of idiopathic/hypersensitivity-related adverse effects?

A

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)
27
Q

What are the long-term, non-dose ASM-related therapy side effects?

A
  • 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
28
Q

What is the hypersensitivity reaction, and its risk management strategies?

A
  • 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.
  1. Follow dosing guidelines: lamotrigine
  2. Identify potential cross-sensitivity reactions (ASMs with aromatic rings)
29
Q

Cross-sensitivity reaction associated with aromatic ASMs

A
  • 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.
30
Q

Common side effects and other known side effects of levetiracetam

A

Common side effects: somnolence, dizziness, asthenia, coordination difficulties, headache

Other known side effects: irritability, aggression

31
Q

Why is it important to conduct therapeutic drug monitoring for ASM?

A
  1. 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.
  2. 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.
  3. Assess for potential toxicity
    • Concentration-dependent adverse effects, slow metabolizers, renal or hepatic impairment
  4. To assess loss of efficacy (breakthrough seizures)
    • Drug interactions, changes in physiology or formulation
32
Q

Special populations: women of childbearing age

A
  • 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.
33
Q

Special populations: pregnancy and lactation

A
  • 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.
34
Q

Can ASM be discontinued?

A

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.

35
Q

What is the definition of status epilepticus?

A

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.

36
Q

Treatment algorithm for status epilepticus

A
  1. First 5 mins: stabilize the seizure, time the seizure onset, check vital signs etc. Collect finger stick glucose (hypoglycemia may cause seizure)
  2. 5-20 mins: prescribe benzodiazepine as the initial therapy of choice
    - IV diazepam, midazolam, lorazepam, if not: rectal diazepam, IV phenobarbital
  3. 20-40 mins:
    - Phenytoin, valproate, or levetiracetam
  4. 40-60 mins (if patient is still seizing):
    - No clear guidelines on what to use, but can give anesthetic agents like thiopental, midazolam, propofol.

Pharmacotherapeutics (28 decks)

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