Lesson 4.4. Anti-Seizures

Epilepsy

a disorder where there are recurrent seizures unprovoked by identifiable causes

Seizure

symptom for disturbed electrical activity in the brain

Absence (petit mal)

3 Generalized seizures:

• brief loss of awareness (blank stare)

• postseizure amnesia but with no loss of motor activity

Myoclonic seizures

3 Generalized seizures:

• no loss of consciousness and involves short seizure duration

Tonic-Clonic (grand mal)

3 Generalized seizures:

• bilateral muscular jerking

• loss of consciousness

• tonic-clonic spasms

Simple

Partial seizures:

• affects an entire hemisphere or a lobe within a hemisphere of the brain.

Complex

Partial seizures:

• temporal/psychomotor seizures

• mistaken for psychotic behavior

ion channel or receptor function

Mechanism of Action:

• Anti-seizure drugs alter __________________________ to promote synaptic inhibition or modulate synaptic excitation.

Ureides

OLD AGENTS:

• class of drugs and their derivatives with a similar pharmacophore

hydantoins, barbiturates, oxazolidinediones, succinimides

Ureides includes:

Ureide Pharmacophore

Barbiturate

Hydantoin

oxazolidinedione

Succinimide

Phenytoin and Fosphenytoin

Drugs under Hydantoins

bulky C5

Structure Activity Relationship of Hydantoins:

1. ________________ is optimal for activity (at least 1)

2. Phenytoin has a ________________ giving it maximal activity.

1 = ?

5,5-diphenyl

Structure Activity Relationship of Hydantoins:

1. ________________ is optimal for activity (at least 1)

2. Phenytoin has a ________________ giving it maximal activity.

2 = ?

disodium phosphate

Structure Activity Relationship of Hydantoins:

1. Fosphenytoin is a ____________________ ester of phenytoin

2. ____________ soluble

3. better stability for _______________

1 = ?

water

Structure Activity Relationship of Hydantoins:

1. Fosphenytoin is a ____________________ ester of phenytoin

2. ____________ soluble

3. better stability for _______________

2 = ?

parenteral administration

Structure Activity Relationship of Hydantoins:

1. Fosphenytoin is a ____________________ ester of phenytoin

2. ____________ soluble

3. better stability for _______________

3 = ?

generalized seizures, partial seizures, status epilepticus

use of Hydantoins

CYP 2C9

Metabolism of Hydantoins:

1. ____________________ catalyzed aromatic hydroxylation

2. ____________________

3. ______________

1 = ?

glucuronidation

Metabolism of Hydantoins:

1. ____________________ catalyzed aromatic hydroxylation

2. ____________________

3. ______________

2 = ?

sulfation

Metabolism of Hydantoins:

1. ____________________ catalyzed aromatic hydroxylation

2. ____________________

3. ______________

3 = ?

Phenytoin

can induce CYP 3A4 levels increasing the risk of drug-drug interaction

Phenytoin Structure

Fosphenytoin Structure

Trimethadione

drugs under oxazolidinedione

Oxazolidinedione

Oxygen replaces the first nitrogen in Hydantoins

no bulky C5

Structure Activity Relationship of Oxazolidinedione:

1. has ____________ groups

2. eliminates activity for grand mal, but increases activity for _____________________

3. _______________________ limits therapeutic applications

1 = ?

petit mal (absence seizure)

Structure Activity Relationship of Oxazolidinedione:

1. has ____________ groups

2. eliminates activity for grand mal, but increases activity for _____________________

3. _______________________ limits therapeutic applications

2 = ?

high toxicity

Structure Activity Relationship of Oxazolidinedione:

1. has ____________ groups

2. eliminates activity for grand mal, but increases activity for _____________________

3. _______________________ limits therapeutic applications

3 = ?

Trimethadione Structure

Ethosuximide

Succinimide Drugs

absence seizure (petit mal)

Succinimide is a drug of choice for _______________________

no C3 bulky

Structure Activity Relationship for Succinimide:

1. has ________________ group

2. replaced the -O- (in oxazolidinedione) with ________

3. ______ with retained activity

1 = ?

-CH2

Structure Activity Relationship for Succinimide:

1. has ________________ group

2. replaced the -O- (in oxazolidinedione) with ________

3. ______ with retained activity

2 = ?

safer

Structure Activity Relationship for Succinimide:

1. has ________________ group

2. replaced the -O- (in oxazolidinedione) with ________

3. ______ with retained activity

3 = ?

~20%

Metabolism of Succinimide:

1. __________ excreted unchanged

2. CYP ____________

1 = ?

3A4 and 2E1

Metabolism of Succinimide:

1. __________ excreted unchanged

2. CYP ____________

2 = ?

Structure of Succinimide

Valproic acid

2-propylpentanoic acid and is used for both grand and petit mal

hepatotoxicity and teratogenicity

2 rare side effects that limits the use of Valproic acid

promotes GABA transmission

Mechanism of Action of Valproic Acid:

1. ________________________ by inhibiting GABA metabolism

2. ________________________________, decreasing excessive neuronal firing

1 = ?

blocks Voltage Gated Sodium Channel

Mechanism of Action of Valproic Acid:

1. ________________________ by inhibiting GABA metabolism

2. ________________________________, decreasing excessive neuronal firing

2 = ?

Valproic Acid Structure

Carbamazepine

drugs under Iminostilbene

tricyclic antidep (TCAs)

Carbamazepine are derivatives of:

Carbamazepine Structure

Carbamazepine

prototype iminostilbene used for grand mal and partial seizures

2 phenyl groups

Structure Activity Relationship of Carbamazepine:

1. ________________ are essential for activity

2. ______________________ can be substituted at C10 = less potent but active

1 = ?

keto, hydroxy, or acetate ester

Structure Activity Relationship of Carbamazepine:

1. ________________ are essential for activity

2. ______________________ can be substituted at C10 = less potent but active

2 = ?

blocks Voltage Gated Sodium Channels

Mechanism of Action of Carbamazepine:

• _____________________ resulting to inactivation of excessive neuronal firing

Gabapentin and Pregablin

Drugs under GABA Analogs

Structure of Gabapentin

Structure of Pregablin

modulates Ca+2 influx by regulating VGCC

Mechanism of Action of GABA Analogs:

• ________________________________ resulting activation of glutamic acid decarboxylase (GAD) resulting to glutaminergic neurotransmission inhibition.

minimal

Metabolism of GABA Analogs:

Structure of Phenyltriazine

Lamotrigine

drugs under Phenyltriazine

Phenyltriazine

useful for both grand mal, petit mal, and partial seizures for adults

blocks both VGSC and VGCC

Mechanism of Action of Phenyltriazine:

• ___________________________, stabilizing presynaptic neuronal membranes, inhibiting glutamate release producing no excitatory response.

Glucuronidation

Metabolism of Phenyltriazine

Felbamate

drugs under Dicarbamate

Dicarbamate Structure

Dicarbamate

very potent and widely used agent but has very toxic severe side effects: aplastic anemia and hepatic failures

interacts with NMDA

Mechanism of Action of Dicarbamate:

• ________________________ decreasing glutamate transmission resulting to decreased neuronal excitation

ester hydrolysis and oxidation

Metabolism of Dicarbamate