This ppt covers the classification, structures and IUPAC names, Mechanism of action and uses of individual drugs...under anticonvulsants topic..Side effects/metabolism are also given for few

1. MEDICINAL CHEMISTRY I
B. PHARMACY II/IV (SECOND SEM.)
ANTI CONVULSANTS
Dr. K. Purna Nagasree
M.Pharm. (BITS, Pilani), Ph.D., PDF (DST, WOSA)
Associate Professor
VIGNAN INSTITUTE OF PHARMACEUTICAL TECHNOLOGY
(Approved by PCI, AICTE New Delhi and affiliated to JNTUK)
ANISO 9001:2015, ISO 14001:2015, OHSAS 18001:2007 Certified institution, beside VSEZ, Duvvada, Vishakapatnam-
530049, Andhra Pradesh, India
2021

2. SAR, MOA of anticonvulsants
Barbiturates: Phenobarbitone, Methabarbital
Hydantoins: Phenytoin*, Mephenytoin, Ethotonin
Oxazolidine diones: Trimethadione, Paramethadione
Succinimides: Phensuximide, Methsuximide,
Ethosuximide*
Urea and monoacylureas: Phenacemide, Carbamazepine
Benzodiazepines: Clonazepam
Miscellaneous: Primidone, Valproic acid, Gabapentin,
Felbamate

3. VII. Carbonic anhydrase inhibitors
VIII. GABA analogues
IX. Iminostilbenes
X. Miscellaneous
XI. Newer—anticonvulsants
ANTI CONVULSANTS/ANTI EPILEPTICS -
CLASSIFICATION

4. Anticonvulsants are drugs that are used to arrest
convulsions or seizures caused in epilepsy.
Epilepsy is a disease that occurs due to central nervous
system (CNS) disorder, which is characterized by seizures
and convulsions or abnormal body movements with the loss
of consciousness.
Approximately 1% of world’s population has epilepsy, the
second most common neurological disorder after stroke.
ANTI CONVULSANTS

5.  Involuntary muscle contractions that can take
place as a result of pathologic processes both
inside and outside the brain.
 They can occur in response to toxins, trauma,
hyperthermia, or medicinal overdose, or upon
discontinuation of medication.
 An imbalance between excitatory and inhibitory
neurotransmission
ANTI CONVULSANTS

6. ANTI CONVULSANTS - MOA
The anticonvulsant therapy mediated by these drugs
• By inhibiting sodium channels (phenytoin)
• By inhibiting gamma amino butyric acid (GABA)
transaminase enzyme (vigabatrin)
• By inhibition of T-type calcium currents (ethosuximide,
valproate)
• By GABA agonistic activity (benzodiazepine)

7.  They also change the intracellular ratio of
calcium and potassium ion concentrations,
and block the N -methyl-D-aspartate
(NMDA) receptor responsible for high-
frequency discharges that appear during
epilepsy

8. EPILEPSY - TYPES
Three principle types of epilepsy are found. They are as
follows:
Grandmal: In which the seizures last from 2 to 5 min, being
characterized by a sudden loss of consciousness, tonic and
clonic convulsions of all muscles associated with urinary
incontinence
Petitmal/Absence seizures: The seizures last from 5 to 30
sec, being characterized by brief attacks of
unconsciousness, usually occur in children at the age of 4
to 8 years
Psychomotor seizures: Characterized by attacks without

9. Types of epilepsies
 Status epilepticus

10. Epilepsy - types
1. Partial seizures are those in which excessive neuronal
discharges remain localized within a focal area of the brain.
 These are characterised by convulsions confined to a single limb,
muscle group, or specific localized sensory disturbances usually
without impairment of consciousness.
2. Generalized seizures impart unconsciousness. This includes
those seizures known as grand mal and petit mal.
Tonic-clonic ( grand mal ) seizures are characterised by major
convulsions. Usually, there is a sequential tonic spasm of all the
muscles in the body, followed by synchronous clonic jerking and a
prolonged depression of all central functions.
Petit mal (absence) seizures are characterised by a brief and
abrupt loss of consciousness, usually with some symmetrical clonic
motor activity ranging from eyelid blinking to jerking of the entire
body.

11. 3. Undetermined seizures
include neonatal seizures characterised by severe myoclonic
epilepsy, and epilepsy with continuous spike-waves during
slow-wave sleep.
4. Special syndromes or situation-related seizures occur only
when there is an acute metabolic or toxic event due to alcohol,
drugs, eclampsia, or non-ketonic hyperglycemia and febrile
convulsions.
Status epilepticus

13. BARBITURATES : METHABARBITAL
Used for the treatment of short term insomnia

14. Mode of action
 The mechanism is facilitated by GABA receptor
mediated synaptic inhibition, opens the chloride
channels, and inhibits the calcium dependent
release of neurotransmitters.
 In addition, at very high concentrations,
barbiturates depress sodium and potassium
channels and reduce the abnormal discharge of
electrical impulse.

15. SAR OF BARBITURATES
Optimum activity is observed when the
substitution at C-5 is phenyl.
2. The 5, 5’-diphenyl derivative have less activity than
phenobarbitone.
3. N1and N3 substituents in some cases resulted in an
increase in activity.

16. HYDANTOIN
S
The hydantoins are close structural relatives of
barbituric acid, differing due to the lack of C-6 oxo
group
The lack of this carbonyl group decreases the acidity.
So it is a weaker acid than that of barbiturates.

17.  Grand mal seizures (phenytoin is the drug of
choice) and complex partial seizures

18. MODE OF ACTION: HYDANTOINS
Phenytoin and other hydantoins block the voltage-gated
sodium channels in the brain.
Hydantoin inhibits the influx of sodium ions, prevents
depolarization, and decreases electrical excitability
Voltage-gated sodium channels are responsible for the
generation of action potentials of nerve fibres through
selective transport of sodium ions across the cell
membrane, leading to the rapid depolarization of the cell
network and thereon to electrical excitability.
.

19. PHENYTOIN
Phenytoin is the first anticonvulsant - that anticonvulsant
activity could definitely be separated from sedative-
hypnotic activity
A common side effect is gingival hyperplasia, a reaction
that seldom occurs with mephenytoin
It is one of the most widely used antieplietic agents and it
is effective in most forms of epilepsy, except absence of
seizures. Some cases of trigeminal neuralgia respond well
to phenytoin.
Metabolism: Phenytoin is metabolized by CYPC9 into a
primary metabolite 5-(hydroxyl phenyl)-5-phenyl hydantoin

20. PHENYTOIN SYNTHESIS

21. MEPHENYOTIN
5-Ethyl-3-methyl-5-phenylimidazolidine-
2,4-dione
Metabolism: It is converted into N-demethyl
metabolite 5-phenyl-5-ethyl hydantoin.
.
It was introduced as a sedative- hypnotic and
anticonvulsant under the name Nirvanol, but it was
withdrawn because of toxicity.

22. ETHOTOIN
An antiepileptic, it is less toxic than phenytoin but also
less effective.

23. SAR OF HYDANTOINS
• 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,
while it remains ineffective against electric shock induced
convulsion.

24. OXAZOLIDINEDIONES

25. TRIMETHADION
E
It is used as an antipetitmal agent.
It is first drug introduced specifically for treating absence
seizures.
It causes nephrosis, aplastic anaemia and bone marrow
depression.
Metabolism: It is metabolized by N-demethylation to active
metabolite dimethadone and it is further excreted
unchanged.

26. PARAMETHADIONE
5-Ethyl-3, 5-dimethyl oxazolidine-2,4-dione
It is used as an anticonvulsant.

27. SAR OF
OXAZOLIDINEDION
ES
• Replacement of the -NH group at position 1 of the
hydantoin system with an oxygen atom yields the
oxazolidine-2,4-dione system.
• Trimethadione - 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 they all undergo N-dealkylation in metabolism.

28. MOA of oxazolidinediones
 Oxazolidinediones block T-type, voltage-
dependent calcium channels in thalamic neurons
and block the influx of calcium ions, thereby
preventing the depolarization of the membrane.
 This decreases the electrical excitability of the
neurons

29. SUCCINIMIDE
S

30. SUCCINIMIDES
Mode of action:
Succinimides selectively acts on T- type voltage
gated calcium channels in the thalamic neurons
region for the influx of calcium ions and inhibits them

31. Phensuximide
 It has low potency – second class
 Due to the phenyl substituent some activity against
generalized tonic-clonic and partial seizures.
 It is used in the treatment of petitmal epilepsy.
 N-demethylation occurs to yield active metabolite,
both phensuximide and N-demethyl metabolites are
inactived by para hydroxylation and conjugation.
1-Methyl-3-phenyl-2,5-pyrrolidinedione

32. METHSUXIMID
E
It is more active than phensuximide, and used in the
treatment of petitmal epilepsy
It is metabolized into N-demethylsuximide and the
metabolite is also an active compound.
1,3-Dimethyl-3-phenyl-2,5-
pyrrolidinedione

33. ETHOSUXIMI
DE
Drug of choice for petit mal
seizures
The drug is more active and less toxic than
Trimethadione.
.
Metabolism: It is metabolized into 3-(1-hydroxyethyl)
compound.

34. SAR of Succinimides
 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 active
metabolite. Both phensuximide and the N-demethyl
metabolite are inactivated by p-hydroxylation and
conjugation

35. Synthesis of ethosuximide

36. UREA AND
MONOACYLUREAS
Iminostilbenes -
Carbamazepine
Acetyl urea derivatives or phenyl acetyl ureas
Like phenytoin, carbamazepine inhibits voltage-
dependent sodium channels and is used to treat
partial seizures and grand mal seizures. It is also
useful in the treatment of pain associated with
trigeminal neuralgia

37. BENZODIAZEPINES

38. MISCELLANEOUS: PRIMIDONE,
VALPROIC ACID, GABAPENTIN, FELBAMATE
Gamma amino butyric acid (GABA)
analogues

39. PRIMIDONE
It is a 2-deoxy phenobarbital useful for the management
of grand mal , complex partial, and focal epileptic
seizures.
5-Ethyl-5-phenyldihydropyrimidine-4,6 -dione

40. VALPROIC ACID
Sodium salt of 2-propyl pentanoate
Valproate exerts its anticonvulsant activity by blocking voltage-
gated sodium ion channels and increases the GABA level in
brain.
The increase in GABA level is due to the inhibition of several
enzymes involved in GABA metabolism and increases the
activity of glutamic acid decarboxylate (GAD), the enzyme
responsible for GABA synthesis.
Uses : Valproate is employed for the management of
myoclonic and generalized tonic-clonic seizures

41. GABAPENTIN
It is a lipid-soluble GABA analogue
4- amino -3- cyclohexyl butyric acid

42. FELBAMATE
2-Phenyl-1,3-propanediol dicarbamate
Felbamate is the bis(carbamate ester) of 2-
phenylpropane-1,3-diol.
An anticonvulsant, it is used in the treatment of epilepsy.
It has a role as an anticonvulsant and a neuroprotective
agent.

44. DRUGS USED FOR TREATING
EPILEPTIC DISORDERS