Antiepileptic drugs kinetics exam 4

define a seizure

sudden change in behavior caused by electrical hypersynchronization of neuronal networks in the cerebral cortex

What is epilepsy

two unprovoked seizures occurring more than 24 hours apart

What is status epilepticus

failure of the mechanisms responsible for seizing termination or by the initiation of mechanisms, which lead to abnormally prolonged seizures after 5 minutes

What is always the initial therapy when a patient presents with an active seizure

benzodiazepine

most AEDs require

titration

What are some indications for obtaining a drug level?

1. initiating therapy

2. uncontrolled seizures despite high doses

3. seizures in a previously controlled patient

4. documentation of toxicity

5. assessment of adherence

6. after dose changes

7. concomitant drugs added or removed

describe the bioavailability of carbamazepine

highly bioavailable

Describe the protein binding of carbamazepine

highly protein bound to albumin

what is special about carbamazepine's elimination

induces its own metabolism

the more carbamazepine a patient takes, the ________ its half life becomes

shorter

What is the metabolite of carbamazepine

CBZE

What is true of CBZE

1. anti-epileptic

2. neurotoxic

What is repsonsible for clearing carbamazepine

CYP3A4

CYP3A4 inhibitors will _________ carbamazepine serum concentrations

increase

CYP3A4 inducers will _________ carbamazepine serum concentrations

decrease

What happens when carbamazepine is taken with valproate

CBZE builds up and can be toxic

What may occur in about 40% of patients taking carbamazepine

diurnal fluctuations

Why does diurnal fluctuation happen with carbamazepine

changes in protein binding, metabolism, and mild anticholinergic effects that decrease absorption in the GI tract

What time of day should carbamazepine be taken and why?

at bedtime because serum levels and CNS toxicity may increase gradually throughout the day

time to steady state of carbamazepine depends on....

half-life and completion of autoinduction

_______ of carbamazepine are recommended to ensure that concentrations are always _______

troughs, above the lower end of the therapeutic range

troughs of carbamazepine should be measured _________

weekly while titrating to the desired maintenance dose

What is the common carbamazepine target

4-8 mg/L

when giving a loading dose of carbamazepine, you target a concentration of ______ within ______

4mg/L within 1-2 hours

What medication allows for the fastest oral loading dose of any AED

carbamazepine

What is an appropriate way to load carbamazepine (in monotherapy)

8mg/kg followed by maintenance dose in 12 hours

what electrolyte abnormality can cause seizures

hyponatremia

second generation ADEs have ________

more predictable pharmacokinetics

Select what is generally true of second generation ADEs

1. oral absorption tends to be complete

2. concomitant administration of food slows absorption but does not reduce it

3. protein binding is less prominent

4. elimination is first order

What second generation ADE is related to carbamazepine

oxcarbazepine

What is the titration of oxcarbazepine

increase by 600 mg weekly

Drug concentration of oxcarbazepine are...

not readily available

What dose adjustment is necessary for oxcarbazepine

50% dose reduction if GFR < 30mL/min

the adverse effects of oxcarbazepine are similar to ________ but _________

similar to carbamazepine but decreased frequency and severity

neurological adverse reactions are notes with oxcarbazepine in which instances

1. high doses

2. fast up-titration

3. during conversion to monotherapy

___________ of oxcarbazepine is responsible for its AED activity

the active metabolite

_________ undergoes __________ to produce its active metabolite ________

oxcarbazepine, arylketone reduction, MHD

MHD, the active metabolite of ___________, is inactivated more quickly when taken with ____________

oxcarbazepine, taken with carbamazepine, phenobarbital, and phenytoin

Lamotrigine should be dose adjusted in

liver impairment

What is true of lamotrigine

autoinduction when monotherapy decreases half life by 25%

3 multiple choice options

What is true of the titration of lamotrigine

must be up-titrated slowly

What is the most common adverse reaction with lamotrigine

morbilliform rash

If a patient taking lamotrigine develops a ____________, the agent should be __________

marbilliform rash, stopped immedietly and not rechallenged

Which agents will induce lamotrigine metabolism

1. carbamazepine

2. phenytoin

3. phenobarbital

4. primidone

Which agents will inhibit lamotrigine metabolism and the agent should therefore be titrated slower than usual

valproic acid

Topiramate has a ________

wider safety profile

topiramate needs dosage adjustment in

GFR < 70mL/min

What is true of the adverse reaction profile of topiramate

high incidence of CNS adverse reactions

When is a patient most likely to experience CNS related adverse effects when on topiramate

rapid upward titration

Other than CNS effects, what can be seen with topiramate

metabolic acidosis

Topiramate concentrations are significantly reduced when used with

1. phenytoin

2. carbamazepine

3. phenobarbital

Which AED distributes into red blood cells

zonisamide

zonisamide should be avoided in patients with

sulfonamide allergy

What adverse effects are seen with zonisamide

1. dose related CNS effects

2. metabolic acidosis

3. renal stones

With doses of Zonisamide over __________, distribution is greatly __________ due to __________

> 800mg/day, altered, saturable binding

What is true of the AUC and Cmax of zonisamide

increase disproportionally compared to therapeutic doses because erythrocytes become saturated

The pro of using zonisamide is

faster titration schedule

what is important to remember when dosing zonisamide

time to Cmax is delayed by food

What is the #1 antiepileptic drug

levetiracetam

What is true of dosage adjustments with levetiracetam

should be renally adjusted

What is the mechanism of levetiracetam

exact mechanism is truly unknown

The elimination of levetiracetam is

exclusively extrahepatically

Loading dose of levetiracetam provides

fast achievement of serum concentrations

What is the recommended loading dose of levetiracetam

20-60mg/kg

What is the MD of levetiracetam

500-3000mg daily divided into 2 doses

What CYP metabolizes lacosamide

CYP2C19

What are the dosage adjustments needed with lacosamide

renal and hepatic

3 multiple choice options

Common adverse effects of lacosamide are

dose related CNS symptoms

Use caution with lacosamide in

patients with underlying heart disease

what agent should be used with caution in patients with underlying heart disease

lacosamide

why is timing of treatment with seizures so important

changes in receptor trafficking and neuropeptide expression

what happens to the efficacy of benzodiazepines the longer a seizure persists

reduced efficacy

Why are benzodiazepines less effective the longer a seizure persists

GABA internalization occurs during prolonged status epilepticus

_________ is internalized in a seizure, but __________ is inducted

GABA, NMDAR

What occurs from the NMDAR induction in prolonged status epilepticus

enhanced excitability and increased intracellular calcium decreases GABA receptors

Neurotransmitter receptor modification from prolonged seizures results in ________

modified GABA and glutamate receptors which mimics the composition of an immature brain where excitation predominates over inhibition

Which of the following can you utilize a loading dose

carbamazepine

3 multiple choice options

which is IV

fosphenytoin

1 multiple choice option

_____ mg of fosphenytoin = 1mg of phenytoin

1.5mg

Phenytoin equivalent dose =

fosphenytoin dose (mg) / 1.5

absorption of phenytoin is impacted by

impacted by food

phenytoin rapidly distributes where

into the brain

phenytoin kinetics are

capacity limited

in phenytoin, small dose increases can

lead to huge/disproportionate increases in concentration

What is the therapeutic range of phenytoin

10-20 mg/L

What is the free phenytoin therapeutic level

1-2 mg/L

What is the therapeutic total phenytoin concentration

10-20 mg/L

What is the active form of phenytoin responsible for efficacy and side effects

free

1 multiple choice option

Lower albumin results in

higher free phenytoin

What is the corrected phenytoin equation

phenytoin observed / (albumin x 0.25) + 0.1

When should the binding affinity of albumin with phenytoin be considered

CrCl < 25 ml/min

When do you obtain a peak phenytoin concentration

obtained 2 hours after administration of the loading dose

What is the loading dose equation for phenytoin

(Vd x actual body weight x target Cp) / (F)(S)

What is the s of phenytoin

0.92

What is the loading dose of fosphenytoin

20mg PE/kg

What is the max infusion rate of phenytoin

50 mg/min

What is the max infusion rate of fosphenytoin

150 mg/min

why is fosphenytoin IV preferred over phenytoin

1. does not contain propylene glycol

2. no filter required

3. max infusion rate of 150mg/min

A consideration with using fosphenytoin instead of phenytoin is

it takes several minutes for conversion

An oral loading dose of phenytoin is....

NOT for status epilepticus