Antiepileptics Flashcards
Why is TDM needed
Avoid toxicity
Optimize dose and therapeutic response
Detect changes in pharmacokinetics
Monitor compliance
AED classification
Classical : phenytoin, phenobarbital, carbamazepine, valproate
Newer : lamotrigine, levetiracetam
Inducers of CYT P450
Phenytoin
Phenobarbital
Carbamazepine
Definition of epilepsy
Brain disorder with aberrant neuronal firing
Abnormal neuronal activity presents as strange sensation, behavior or convulsions with or without LOC
Recurrent (>2) seizures unprovoked by systemic or acute neurological insults
Classification of seizures
LOC?
Y- generalized
N- change in consciousness? Y- complex partial, N- simple partial
Seizure pathhysiology
Due to imbalance between excitation and inhibition
Excitation- inward flow of Na and Ca2, and glutamate
Inhibition- inward flow of chloride, outward flow of K, and GABA
Function of GABA
Binds and stimulates GABA-A receptor Increases conductance Influx of chloride causing membrane hyperpolarization Increase threshold for developing AP Inhibitory effect
General MOA of AEDs?
Affect ion conduction: Prolongs Na channel inactivation Increases GABAergic transmission via Cl channels Glutamate receptor antagonism Inhibition of calcium current
Factors in choosing AED
Seizure - classification
Patient - age, comorbidities, lifestyle, pregnancy risk, preference
Drug - PK profile, interactions, adverse effects, cost, efficacy
Drugs that inhibit atonal transmission
Phenytoin
Carbamazepine
Valproate
Lamotrigine
Drugs that cause potentiation of GABA receptor
Benzodiazepines - increase Cl channel openings
Phenobarbital - prolongs Cl channel openings and decreases some Na channel openings
Drugs that act at the excitatory synapse
Gabapentin
Levetiracetam
Which are the pleotropic AEDs and activity
Valproate - increase GABA , inhibit Na channels, augment K channels
Lamotrigine - inhibit Na channels, interfere with glutamate release, inhibit calcium channels
ARVs and epilepsy?
Phenytoin and carbamazepine = enzyme-inducing - potential reaction with ARVs –> change to lamotrigine or valproate
If RVD+ and of child bearing age, lamotrigine»_space;> valproate
Phenytoin drug characteristics
MOA: Inhibit Na generation –> inhibit AP generation
Highly bound to plasma proteins
Adverse effects: CNS sedation, gum hyperplasia, hirsuitism, skin rash/ hypersensitivity
Interactions: displaced from plasma proteins by valproate. Induces CYT P450
Zero order kinetics - saturable metabolism
Carbamazepine drug characteristics
MOA: Inhibits Na channels, inhibits high frequency
Adverse effects: Diplopia and ataxia, idiosyncratic skin reaction, agranulocytosis and aplastic anemia
Interactions: stimulates own metabolism, induces microsomes enzymes
Lamotrigine drug characteristics
MOA: inhibits Na channels, Ca channels and glutamate release
Adverse effects: CNS sedation (less), dermatitis (–> fatal)
Interactions: induces CYT P450, levels increased by valproate and decreased by carbamazepine, phenytoin and phenobarbital
Phenobarbital drug characteristics
MOA: increases GABA-A receptor opening time
Adverse effects: CNS sedation, skin rash if allergic, tolerance and physical dependence
Interactions: CNS depression, induces CYT p450
Valproate drug characteristics
MOA: increases GABA transmission, inhibits Na channels, opens K channels
Highly plasma protein bound
Adverse effects: increases liver enzymes, brith defects
Interactions: displaces phenytoin, inhibits CYT p450
Benzodiazepine drug characteristics
MOA: increases frequency of GABA -A receptors
Adverse effects: CNS sedation, tolerance and dependence
Interactions: increases action of other CNS depressants
Definition of status epilepticus
5 minutes or more continuous
A. Clinical or EEG seizure activity or
B. Recurrent seizure activity without recover between seizures
Management of status epilepticus
Start Rex immediately : BDZs –> phenytoin (20 mg/kg IV diluted in 0.9%NS)–> phenobarbital (20-30 mg/kg)–> RSI with propofol (2-5mg/kg) or thiopental sodium
ABCs
Check blood glucose
Check electrolyte and anticonvulsant levels
Epilepsy in pregnancy
Valproate - highest teratogenic risk
Folate supplementation before pregnancy
PK changes in pregnancy therefore adjust dose
Goals of therapy
Control seizures Restore quality of life Restore neuronal function Minimize drug adverse effects Identify and avoid precipitating factors
