epilepsy 4 Flashcards
what are the clinically desired properties of the ideal AED?
does not require monitoring of plasma concentrations
does not induce or inhibit hepatic metabolising
enzymes
is not involved in adverse drug interactions
well tolerated with no long-term safety problems
can be conveniently taken once or twice a day
how should pharmacological treatment be initiated?
should only be after confirmed diagnosis of
epilepsy & generally after a second epileptic seizure
should be by or on the recommendation of a
specialist
should be after consultation between the patient,
family or carer and the specialist
choice of AED should normally be based on the
presenting epilepsy syndrome
what are the commonly used AEDs?
Carbamazepine Sodium Valproate Levetiracetam Lamotrigine Phenytoin Clonazepam Zonisamide Clobazam Pregabalin Phenobarbital Topiramate
how do you initiate monotherapy?
Use a first-line drug for the seizure type
Start at a low dose
Gradually increase the dose until seizures stop (or
adverse effects develop)
Adjust drug dose to the minimal effective AED dosage
or optimal maintenance dosage
Monitor AED response in terms of seizure frequency,
epileptic discharges & adverse effects
how do you initiate sequential monotherapy?
If seizures remain uncontrolled with maximum
tolerated dose of initial first-line drug
Review the diagnosis, underlying aetiology & compliance
Start low dose of another first-line drug for seizure type
Gradually increase dosage until seizures stop
Start gradual tapering off & withdrawal of first drug
adverse effects of drug change can be correctly attributed
ensures patient is not exposed to suboptimal doses of both drugs
at any time
what are some of the advantages of monotherapy?
High efficacy
complete seizure control in most (~70%) of patients
Better tolerated than multiple drug therapy
Easy management
enables assessment of efficacy/safety of individual drugs
Simple
facilitates / encourages better patient compliance
No adverse AED interactions
Cost-effective
when would you use comination/polytherapy?
in chronic epilepsy
reserved for patients with continued seizures in spite of
first, second or third monotherapy with maximum
tolerated doses
benefits only 10-15% of patients
what may AED combinations lead to?
infra-additive (antagonistic)
additive, or
supra-additive (synergistic) interactions
how should you initiate polytherapy?
Establish optimal dose of baseline AED
Add drug with different or multiple mechanism(s) or
mode(s) of action
Titrate new AED slowly and carefully
Be prepared to reduce dose of baseline/original AED
Replace less effective drug, if response still poor
Try a range of different duotherapies
Add third drug, if seizure control is still sub-optimal
what methods are there for improving complicance?
Adequate & clear information about AED treatment
its role, efficacy, limitations, possible side-effects, etc
Drug therapy
monotherapy –simplify regimen, introduce drugs slowly
Aide-memoire
Drug wallet, regular remainders, cues, etc
Reinforcement at regular clinic follow-up visits
what are the possible outcomes with pharmacological management?
remission with further AEDS
continuing seizures
remission with first aed
What are the clinically relevant drug interactions that are likely?
AED combination or polytherapy
Co-medication due co-morbidity
Most AEDs have narrow therapeutic window
AED induction or inhibition of major hepatic drug
metabolising enzymes
Most AEDs are themselves substrates of hepatic
metabolising enzymes
what is the main MOA of AED interactions?
Hepatic metabolising enzyme induction
Cytochrome P450 enzymes –CYP1A2, CYP2C9,
CYP2C19 & CYP3A4
Glucuronyl transferases (GT)
Epoxide hydrolases
Leads to rapid clearance of substrate drugs
May lead to build-up of active / toxic metabolites
Major inducer AEDs –CBZ, PHY, PHB & PRI
what are some of the clinical consequences of AED enzyme induction?
Impact on other AEDs during Polytherapy
Polytherapy with major inducers (CBZ, PHY, PHB & PRI)
leads to increased metabolic clearance & reduced serum
levels of
valproic acid, lamotrigine, tiagabine*, ethosuximide,
topiramate, oxcarbazepine, zonisamide, felbamate &
benzodiazepines
For example
serum levels of SVP may be reduced by ~50-75%
serum levels of lamotrigine may be reduced by >50%
what impact would other drug have during co-medication? with warfarin
Co-administration of major inducers (CBZ, PHB & PRI)
with warfarin leads to
increased metabolic clearance & reduced serum levels of
warfarin
Net effect:
decreased prothrombin time & reduced anticoagulant effect
need to increase dose of warfarin (sometimes by up to ~10x)
More complex interaction between PHY & warfarin
decrease, increase or biphasic anticoagulant effect
