Lec 44 Antiepileptic Drugs Flashcards
What are the main types of seizures?
- partial = begin locally
- –> simple
- –> complex
- –> sexondarily generalized
- generalized with or without convulsions
- –> absence
- –> myoclonic
- –> tonic
- –> clonic
- –> tonic-clonic
- –> atonic
What is use of narrow-spectrum anti-epileptic drugs?
- effective in partial seizures [including secondarily generalized]
- less effective in primary generalized tonic-clonic seizures
- not useful for myoclonic or absence
What is use of broad spectrum anti-epileptic drugs?
- effective in partial
- effective in generalized [primary or secondary]
use narrow-spectrum or broad spectrum drugs for myoclonic or absence seizures?
broad spectrum!!! narrow spectrum not useful and may even worsen
Why are some particular brain regions more likely to become epileptic foci?
- because of intrinsic burst firing or automaticity characteristics of the cell types
- because of close packing of neurons in sheets
What are some anti-epileptic drugs that inhibit Na channels?
- carbamazepine
- lamotrigine
- phenytoin
- topiramate
- valproate
What is first line drug of choice for simple focal seizure?
carbamazepine
What is first line drug of choice for complex focal seizure?
carbamazepine
What are the 3 first line options for generalized tonic-clonic seizure?
- phenytoin
- carbamazepine
- valproic acid
phrase for remembering the 4 broad spectrum anti-epileptics we need to learn?
Lamb values a top clone
- lamotrigine
- valproate
- topiramate
- clonazepam
What is the first line for absence seizures?
ethosuximide
What is the first line of acute vs prophylaxis status epilepticus?
prophylaxis = phenytoin acute = benzodiazepines
Which Na channels are likely to be inhibited first by AEDs?
preferentially inhibit channels that are open with high freq/burst firing
What is mech of action of benzodiazepines?
- increase activity of GABA-A receptors
What is mech of phenobarbital [barbiturate]?
- increase activity of GABA-A receptors
What is mech of topiramate?
blocks NA channels AND increases GABA-A receptor action
What is mech of action tiagabine?
increases synaptic levels of GABA by blocking GABA reuptake
What is mech of action gabapentin?
- may increase release of GABA
- may also inhibit high voltage activated Ca channels or Na channels
What is function of T-type Ca channels? what type of epilepsy are they associated wtih?
- exist in thalamocortical neurons and involved in generating sleep spindles
excess firing through T-type Ca leads to absence seizure
Which 4 types of drugs can be used to treat absence epilepsy?
- ethosuximide = first line
- valproate
- lamotrigine
- clonazepam = less used
What drug inhibits N/P type Ca channels?
lamotrigine
When do you start treatment for status epilepticus? What is initial treatment?
treat ASAP to protect against neuronal damage
initial = benzodiazepine [lorazepam, etc] PLUS fosphenytoin or phenytoin to prevent recurrence
What are refractory treatments for status epilepticus if cannot be controlled with standard benzo + phenytoin?
- give phenobarbital or valporate IV
- if not controlled in 1 hr, give general anesthesia
What is induction of elimination?
if drug A increases expression of enzyme –> drug B is eliminated at higher rate
What is competition of elimination?
drug A and B are substrates for same enzyme
if drug A has higher affinity for enzyme –> drug B elimination is slowed
What is inhibition of elimination?
drug A is an inhibitor, not a substrate, for the enzyme so slows elimination of drug B
What type of enzymes usually involved in drug interactions due to altered elimination?
usually Phase 1 cyp450 enzymes
Which 3 anti-epileptic drugs are notable CYP450 inducers? which specific isoform primarily?
- phenytoin
- carbamzepine
- phenobarbitol
primarily = 3A4 –> ~1/2 of all drugs metabolized by CYP450 isoforms are metabolized by 3A4
What happens if you give carbamazepine and phenytoin?
- decreased carbamazepine [increased metabolism]
- variable change in phenytoin level
What happens if you give valproate and phenobarbital?
increased phenobarbitol [inhibited metabolism]
What happens if you give valproate and lamotrigine?
increased lamotrigine [due to competition for phase 2 enzyme]
What happens if you give valproate and clonazepam?
may precipitate absence status epilepticus
Which drug is an inhibitor of CYP450 enzymes?
valproate
What is stevens-johnson syndrome?
- malaise + fever followed by rapid onset erythematous/purpuric macules [oral/ocular/genital], skin lesions progress to epidermal necrosis and sloughing
What 5 drugs associated with hypersensitivity/ stevens-johnson syndrome?
- phenytoin
- carbamazepine
- lamotrigine
- ethosuximide
- phenobarbital
What 4 drugs associated with teratogenicity?
- phenytoin
- carbamazepine
- phenobarbital
- valproate
What 5 drugs associated with cognitive slowing?
- topiramate
- phenobarbital
- carbamazepine
- phenytoin
- valproate
What 2 drugs most likely to cause increase in seizure activity?
phenytoin
tiagabine
Which AED associated with gingival hyperplasia?
phenytoin
What is fosphenytoin? use?
- ester prodrug of phenytoin
- higher aqueous solubility
- use IV for emergency treatment for seizure and during surgery
What is therapeutic window for phenytoin? pharmacokinetics?
- non-linear pharmacokinetics in therapeutic window
- narrow therapeutic window [10-20 ug/mL] 30 = toxic
Is steady state conc [Css] for phenytoin proportional to dose?
NO!
Are pharmacokinetics constant or variable between pts treated with phenytoin?
VARIABLE!
What is equation for rate of elimination [V] of a drug?
V = Vmax *C / [Km + C]
What is equation for rate of elimination [V] of a drug under first order kinetics?
C «< Km so
V = Vmax C / [Km + C]
== C Vmax/ Km
so Clearance is constance Vm/Km with changes in C
What is equation for rate of elimination [V] of a drug under zero order kinetics?
C»_space; Km so
V = Vmax *C / [Km + C]
== Vmax * C/C == Vmax
*clearance rate decreases as C increases since Vmax is a function of C
What 3 antiepileptics can also be used to treat bipolar disorder?
- valproate
- carbamazepine
- lamotrigine
What antiepileptic is first line for trigeminal neuralgia?
- carbamazepine
What antiepileptic is also used to treat peripheral neuropthy + post-herpetic neuralgia
- gabapentin
What 2 anti-epileptics also used for migraine prevention?
- topiramate
- valproate
What types of seizures are benzodiazepines used to treat?
- status epilepticus [1st line acute]
- –> esp lorazepam
- also clonazepam used absence and myoclonic/atonic
What types of seizures is ethosuximide used to treat?
first line for absence seizures only
What type of seizures is phenytoin used to treat?
- partial
- first line for tonic-clonic
- first line for prophylaxis of status epilepticus
What type of seizures is tiagabine used to treat?
focal only [simple and complex]
What type of seizures is lamotrigine used to treat?
- focal [simple + complex]
- tonic-clonic
- absence
What type of seizures is valproic acid used to treat?
- focal simple + complex
- tonic-clonic
- absence
Which anti-epilepsy drugs are primarily eliminated by renal?
- gabapentin and topiramate
- all the rest are primarily hepatic
