Antiseizure Drugs

The Pharmacokinetics of
Antiseizure Drugs
Antiseizure drugs are commonly used for
long periods of time
It is important to consider their
pharmacokinetics for avoiding toxicity and
drug interactions
Antiseizure drugs are well absorbed orally
and have good bioavailability

The Pharmacokinetics of
Antiseizure Drugs
Phenytoin :
The oral bioavailability is variable
Metabolism : nonlinear elimination (zero-order)
at moderate to high dose levels
The drug binds extensively to plasma protein
Interaction : the metabolism inhibited by
cimetidine, isoniazid and enhanced by inducer of
liver metabolism (sulfonamide, valproic acid

The Pharmacokinetics of
Antiseizure Drugs
Carbamazepine
Carbamazepine induces formation of liver drugmetabolizing enzymes increase metabolism of the
drug itself, & may increase the clearance of many other
anticonvulsant
The metabolism can be inhibited by propoxyphene,
valproic acid
Valproic acid
Valproic acid inhibits the metabolism of phenytoin,
phenobarbital, and lamotrigine
Hepatotoxic

The Pharmacokinetics of
Antiseizure Drugs
Gabapentine & Vigabatrin
These drugs eliminated by the kidney, largely in
unchanged form
Lamotrigine & Topiramate
Lamotrigine is eliminated via hepatic
glucoronidation
Topiramates undergoes both hepatic metabolism
and renal elimination of intact drug

Mechanism of action
The general effect : suppress repetitive action
potentials in epileptic foci in the brain
The mechanism of action of antiseizure drugs
include :
- sodium channel blockade
- GABA-related Targets
- Calcium channel blockade
- enhancing K+ channel permeability
- antagonist at some glutamate receptors

Mechanism of action
Sodium Channel Blockade
Block voltage-gate sodium channels in
neuronal membranes
Example : phenytoin, carbamazepine &
lamotrigine at therapeutic concentration;
phenobarbital and valproic acid at high
dose

Mechanism of action
GABA-Related Targets
Benzodiazepine, barbiturat, tiagabine,
gabapentin, vigabatrin
Benzodiazepin facilitate the inhibitory effects of
GABA
Barbiturat enhance the inhibitory actions of
GABA but interact with different receptor
Vigabatrin inactivate GABA transaminase (an
important enzyme in the termination of action of
GABA
Tiagabine inhibits GABA transporters in neurons
& glia

Mechanism of action
Calcium Channel Blockade
Example : ethosuximide, valproic acid
Other Mechanism
Enhancing K+ channel permeability
(valproic acid)
Antagonist at some glutamate receptors
(phenobarbital, felbamate, topiramate)

Clinical Uses
Generalized Tonic-Clonic & Partial Seizures
Valproic acid, carbamazepine, & fenitoin
are DOC for generalized tonic-clonic
seizure & partial seizure
Phenobarbital is a primary drug in infants
Absence Seizure
Ethosuximide and valproic acid are the
preferred drugs because they cause
minimal sedation

Clinical Uses
Myoclonic seizure syndromes
Valproic acid
Clonazepam, but the high doses cause
drowsiness
Status Epilepticus
Diazepam & lorazepam i.v (effective in
terminating attacks, providing short-term control)
Phenytoin i.v (for prolong therapy, because it is
less sedation)
Phenobarbital has been used in status
epilepticus, especially in children

Clinical Uses
Other Clinical Uses
Bipolar disorder (valproic acid,
carbamazepine, phenytoin, & gabapentin
Trigeminal neuralgia (carbamazepine)
Pain of neuropathic origin (gabapentin)
Migraine (phenytoin)

Toxicity
Teratogenicity (valproic acid, carbamazepin,

phenytoin)
Overdosage toxicity, include CNS depressants,
respiratory depression
(flumazenil may be used in benzodiazepine
overdose)
Fatal hepatotoxicity (valproic acid)
Skin rashes & Stevens-Johnson syndrome
(Lamotrigine)
Aplastic anemia & acute hepatic failure
(felbamate)
Withdrawal