Anticonvulsants

Anticonvulsants are the drugs used in the treatment of

experimentally produced seizures in laboratory animals and
antiepileptic are drugs used medically to control the epilepsies not
all of which are convulsive in humans.

Epilepsy is a disease due to central nervous system disorder which

is characterized by seizures and convulsion or other abnormal
body movements with loss of disorder of consciousness.

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 Classification
Barbiturates:- eg: Phenobarbitone, Mephobarbitone,
Methabarbital(Metharbital)

Hydantoins:- eg: Phenytoin*, Mephenytoin, Ethotoin

Oxazolidinediones:- eg: Trimethadione, Paramethadione

Succinimides:- eg: Phensuximide, Methsuximide, Ethosuximide*

Urea and monoacyl ureas:- eg: Carbamazepine*

Benzodiazepines:- eg: Clonazepam, Diazepam, Chlorazepate

Miscellaneous:- eg: Primidone, Valproic acid, Gabapentin, Tiagabine,

Felbamate, Phenacemide
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 Barbiturates
Most of the barbiturates are sedative and hypnotics, only few of
them show anticonvulsant characters.

General structure:

Name R1 R2 R3
Phenobarbitone C2H5 C6H5 H
Mephobarbitone C2H5 C6H5 CH3
Metharbital CH3 CH3 CH3

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 SAR of Barbiturates

Optimum activity is obtained when one substituent at C5 is

phenyl. The 5,5- diphenyl derivative has less activity than
phenobarbitone.

N1 and N3 substitution in some case also resulted in increased

activity.

5,5- dibenzyl barbituric acid causes convulsion.

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 Hydantoin
The hydantoins are close structural relatives of barbituric acid,
differing in lacking of 6-oxo groups.
The lack of this carbonyl group decreases the acidity, so it is
weaker acid than that of barbiturates.

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 SAR of Hydantoin
• 5-phenyl or other aromatic substitution is
essential for activity.

• Alkyl substituent at position 5 may contribute to

sedation, a property absent in phenytoin.

• Among other hypnotics 1,3-disubstituted

hydantoins, exhibit activity against chemically
induced convulsion.

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 PHENYTOIN

Synthesis

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 Mechanism of action
It is a sodium channel blocker.
Both the Na+ and Cl- ions are invariably present at much higher
concentration outside the cell, whereas K+ charged proteins and
organic cations are more abundantly available inside the cell.

Epileptic seizures causes Na+ ion accumulation within the central

neuron, which initiates enhanced synaptic nerve transmissions
following presynaptic stimulation.

Phenytoin decreases Na+ intracellular ion by activating biochemical

process that normally extrudes Na+ ion from neurons.

Reduces the calcium infl ux and inhibits the glutamate activity.

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USES
Phenytoin is used in the treatment of:
Generalized tonic-clonic seizures.
Partial seizures.
Trigeminal and other neuralgias.
Status epilepticus: Phenytoin is administered intravenously in
normal saline.

DOSE
100-200 mg twice daily oral, 25 mg/min slow i.v injection.

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ADVERSE EFFECTS

1. Hypertrophy and Hyperplasia of gums.

2. Hypersensitivity reactions include skin rashes,neutropaenia
3. Megaloblastic anaemia
4. Osteomalacia
5. It can inhibit insulin release and cause hyperglycaemia.
6. Foetal hydantoin syndrome- cleft lip,cleft palate etc.. due to use of
phenytoin during pregnancy

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DRUG INTERACTIONS

1. Carbamazepine and phenytoin induce each other’s metabolism.

2. Valproate displaces protein bound phenytoin and decreases its
metabolism; plasma level of unbound phenytoin increases.
3. Chloramphenicol, isoniazid, cimetidine and warfarin inhibit
phenytoin metabolism- can precipitate toxicity
4. Phenytoin competitively inhibits warfarin metabolism
5. Phenytoin induces microsomal enzymes and increases degradation
of steroids, doxycycline,theophylline.

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 FOSPHENYTOIN

Fosphenytoin is a water -soluble phenytoin prodrug that is administered

intravenously to deliver phenytoin, potentially more safely than
intravenous phenytoin.
USE:- It is most commonly used in the acute treatment convulsive status
epilepticus.

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 OXAZOLIDINEDIONES
Replacement of the NH group at position 1 of the hydantoin systems with
oxygen atoms yields the oxazolidine-2,4-dione system.

TRIMETHADIONE

3,5,5-trimethyl
oxazolidin-2,4-dione
USE:- It is used in the treatment of petit mal epilepsy. Dermatological and
hematological toxicities limit its clinical use.

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 SAR
• Replacement of the -NH group at position 1 of the
hydantoin system with an oxygen atom yields the
oxazolidine-2,4-dione system.
• 3,5,5-Trimethadione (tridione) was the first drug
introduced specifically for treating absence seizures.
It is also important as a prototype structure.
• The nature of the substituent on C-5 is important,
example, lower alkyl substituents towards antipetitmal
activity while acyl substituents towards antigrandmal
activity.
• The N-alkyl substituent does not alter or afford the
activity since all the clinically used agents from
this class undergo N-dealkylation in metabolism.
 SUCCINIMIDES

ETHOSUXIMIDE[zarontin]

3- Ethyl-3-methyl
pyrrolidin-2,5-dione

USE:- It is effective in the cure of petit mal epilepsy

MOA: Ca++ channel Blocker

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 SAR
The activity of antiepileptic agents, such as the oxazolidine
2,4-dione with substituted succinamides (CH2 replace O)
was logical choice for synthesis and evaluation.

• N-demethylation occurs to yield the putative active

metabolite. Both phensuximide and the N-demethyl
metabolite are inactivated by p-hydroxylation and
conjugation.
 Ethosuximide
Ethosuximide is a succinimide anticonvulsant

(3-ethyl-3-methyl-pyrrolidine-2,5-dione

Synthesis: methylethylketone and cyanoacetic ester, which undergo condensation.

Then hydrogen cyanide is added. After acidic hydrolysis and decarboxylation of the
synthesized dinitrile, 2-methyl-2-ethylsuccinic acid is formed. Reacting this product
with ammonia gives the diammonium salt, and heterocyclization into ethosuximide
takes place during subsequent heating.

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 Urea and monoacyl urea
CARBAMAZEPINE[Tegretol]

Dibenz-[b,f]-azepin-5-carboxamide

USE:- It is used to control grand mal and focal seizures. It is used in the
treatment of trigeminal neuralgia and treatment of manic depression.

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 Anticonvulsants - Carbamazepine
Carbamazepine (Tegretol, Equetro) is an anticonvulsant and mood-stabilizing drug
used primarily in the treatment of epilepsy and bipolar disorder.
MOA likely similar to barbiturates.

* NBS: N-BromoSuccinimide 7
 BENZODIAZEPINES
CLONAZEPAM

MOA: Benzodiazepines acts by enhancing pre and postsynaptic inhibition

through benzodiazepine receptor, which is an integral part of GABA-A
receptor Cl–channel.
It opens the Cl– channel through GABA facilitatory action. These drugs
also induce hyper-polarization and decrease firing rate of neurons.

USE:- It is effective in all type of epilepsy i.e. grand mal, psychomotor,

petit mal, myoclonic and status epilepsy.

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 MISCELLANEOUS
7) SODIUM VALPROATE

Sodium 2-propylpentanoic acid

2-propylpentanoic acid

VALPROIC ACID

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USE: Sodium valproate is moderately effective against chemically &
& electrically induced seizures in animals & possesses a satisfactory
margin of safety.
It is a drug of choice in patients with typical absence seizures.
It is also useful in the treatment of grandmal seizures.

MOA:-
◦ Its mechanism of action may be related to increased brain levels
of the inhibitory neurotransmitter, gamma amino butyric acid
(GABA).

◦ This increase in brain content of GABA is due to the inhibition of

enzyme that metabolize GABA by sodium valproate.

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synthesis

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