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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 drug-
metabolizing 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