Pharmacology and pharmacokinetics - Vanderbilt University Medical

68 Pages·2013·5.71 MB·English

Pharmacology and
pharmacokinetics
Bassel Abou-Khalil, M.D.
Vanderbilt University
Pharmacology and Pharmacokinetics
Mechanisms of drug actions
n
Pharmacokinetic principles, illustrate PHT
n
Pharmacokinetic interactions
n
Liver, renal disease, hemodialysis
n
Changes through the ages
n
AED main mechanisms of action
Na channel blocking
n
Enhancing GABA
n
Glutamate receptor antagonism
n
Blocking high voltage activated calcium channels
n
Blocking T- calcium channels
n
Binding Alpha-2-delta subunit of voltage-activated
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calcium channels
Binding synaptic vesicle protein SV2A
n
K-channel opening
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Na channel blocking

Enhancement of fast inactivated state- blocking of
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sustained repetitive firing:
Phenytoin, carbamazepine, oxcarbazepine, lamotrigine,
n
rufinamide
Selective enhancement of slow inactivation of
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voltage-gated sodium channels
Lacosamide
n
Multiple mechanisms, including effect on sodium
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channels
Valproate, felbamate, topiramate, zonisamide
n
Fast versus slow inactivation of
VGSC
Fast inactivation occurs on a time scale of
n
milliseconds.
Slow inactivation occurs over the time course of
n
seconds to minutes.
involves modification of the shape of the sodium
n
channel

ARS
SAE Question
All but one of the following AEDs block sodium
channels as their main mechanism of action
A- carbamazepine
B- lamotrigine
C- levetiracetam
D- phenytoin
E- lacosamide
ARS
SAE Question
All but one of the following AEDs block sodium
channels as their main mechanism of action
A- carbamazepine
B- lamotrigine
C- levetiracetam
D- phenytoin
E- lacosamide
Enhancing GABA
n Irreversible inhibition of GABA transaminase: vigabatrin
n Inhibition of GABA reuptake at the synapse: tiagabine
n Prolongation of GABA-mediated chloride channel
openings: phenobarbital
n Increased frequency of GABA-mediated chloride channel
openings: benzodiazepines, topiramate (different binding
site- also increases GABA levels in the brain by MRS)
Enhancing GABA transmission in specific circuits: valproate
n
Enhancing GABA-elicited Cl − currents: felbamate
n
Several AEDs are associated with acute elevation of brain
n
GABA by MRS after single doses: 70% for topiramate, 48%
with gabapentin.