Anticonvulsants are drugs that are used to arrest convulsions or seizures caused in epilepsy. Seizure: associated with abnormal episodic high frequency discharge of impulses by a group of neurons in brain which starts local abnormal discharge & then spray to the other area of brain. Convulsion: body muscles are contract and release rapidly & repeatedly, resulting in uncontrol shaking of body. Epilepsy: these are a group of disorder of the CNS characterized by paroxysmal cerebral dysrhythmia, brief episodes (seizure) or disturbance of consciousness with or without characteristic body movements (convulsions).

1. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 1 | P a g e
Anticonvulsants
Anticonvulsants are drugs that are used to arrest convulsions or seizures caused in epilepsy.
Seizure: associated with abnormal episodic high frequency discharge of impulses by a group of neurons in
brain which starts local abnormal discharge & then spray to the other area of brain.
Convulsion: body muscles are contract and release rapidly & repeatedly, resulting in uncontrol shaking of
body.
Epilepsy: these are a group of disorder of the CNS characterized by paroxysmal cerebral dysrhythmia, brief
episodes (seizure) or disturbance of consciousness with or without characteristic body movements
(convulsions).
Types of seizure/epilepsy
Focal (Partial seizure) Generalized seizure
• Simple partial seizure
• Complex partial seizure
Pathophysiology of Epilepsy
1. Hyperexcitability:
Mutation of gene that code for sodium channel protein
Sodium channel opens for long time
This making neuron hyper-excitative
• Tonic-clonic
• Absence
• Myoclonic
• Clonic
• Tonic
• Atonic

2. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 2 | P a g e
Glutamate and excitatory Neurotransmitter (NTS) release
Large amount of glutamate binds with glutamatergic neuron
Trigger excessive Ca2+
release at post synaptic cell
Excessive Ca2+
can be neurotoxic to the affected cell
Hippocampus having large volume of glutamatergic neurons
Results in Epileptic seizure
2. Hyper synchronization
Due to, all neuron in group & generate impulses at one part
This is due to imbalance b/t Inhibitory and excitatory neurotransmitters
Major inhibitory NTS- GABA and Excitatory NTS- glutamate, aspartate
Increases in level of excitatory NTS leads to
Convulsion & epilepsy
Note: most of the antiepileptic drugs are acts on GABAA receptor.
Classification of anticonvulsants drugs
Barbiturates Hydantoins Oxazolidinedione derivatives Succinimides
• Phenobarbitone
• Methabarbitone
• Methabarbital
• Phenytoin
• Mephenytoin
• Ethotoin
• Phenyl ethyl
hydantoin
• Trimethadione
• Paramethadione
• Malidione
• Dimedone
• Phensuximide
• Methsuximide
• Ethosuximide
Urea and monoacylureas
• Phenacemide
• Carbamazepine
Benzodiazepines
• Clonazepam
• Nitrazepam
Miscellaneous
1.GABA analogue
• Gabapentin
• Vigabatrin
2. Carbonic anhydrase inhibitors
• Acetazolamide
• Ethoxazolamide

3. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 3 | P a g e
Three Principal 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: 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 convulsions and lasts from 2 to 3
min.
SAR OF ANTICONVULSANTS
1. Barbiturate
The acidity value within certain limits, gives proper ratio of ionized forms that leads to cross the Blood
Brain Barrier (BBB).
Substitution at C-5 (R2, R3) position should be alkyl chain length is 6-10 carbon to attain optimal activity.
Substitution at R2, R3 position with branched chain shows greater lipid solubility and hypnotic activity but
has shorter duration of action.
The greater branching shows more potent will be the drug. eg.: - pentobarbitone
Alicyclic or aromatic substituted analogue are more potent than aliphatic substituted analogue with the
same number of carbon atom.
Substitution at C-5 position shows the higher potency.
Replacement of Oxygen atom by Sulphur atom at C-4 and C-6 position, reduce the hypnotic activity.
Replacement of Oxygen atom by Sulphur atom at C-2 position leads to rapid onset of action and shorter
duration of action.
2. Hydantoins

4. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 4 | P a g e
5-phenyl or other aromatic substitution at R2 and R3 position is essential for activity.
Alkyl substituent at R2 and R3 position show sedative activity.
Among other hypnotics 1,3-disubstituted hydantoins, exhibit activity against chemically induced
convulsion.
3. Oxazolidinediones
Replacement of the -NH group at position 1 of the hydantoin system with an oxygen atom yields the
oxazolidinedione system.
Alkyl Substitution (lower alkyl substituents) at R2 and R3 position leads toward absence seizure drugs.
The N-alkyl substituent does not alter the activity since all the clinically used agents from this class
undergo N-dealkylation in metabolism.
4. Succinimides
Replacement of the O atom at position 1 of the Oxazolidinedione system with CH2 yields the Succinimide
system.
N-Methylation (R1 position) decreases activity against electroshock seizures and impart more activity
against chemically induced convulsion.
Alkyl and phenyl substitution at R2 and R3 leads to potent activity.

5. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 5 | P a g e
Mechanism of action of anticonvulsant drugs
The anticonvulsant therapy mediated by these drugs is through different aspects of neurotransmission
inhibition in the brain:
➢ 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).
1. Barbiturates
MOA:
Barbiturates
Bind to other modulatory site (barbiturate site) on GABAA
Potentiate the inhibitory effect of GABA
Increases the frequency of Cl-
channel opening
Increases in chloride conductance

6. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 6 | P a g e
Membrane hyperpolarization
Antiepileptic affect
Uses: Tonic-clonic and simple partial seizures, particularly in children.
Side effect: major drawback is sedative. Megaloblastic anaemia
2. Hydantoins
MOA:
Phenytoin
Stabilizing the neuronal membrane
Prevent the spread of seizure discharge
Phenytoin binds to
Voltage dependent Na+ channel (inactivated state)
Prevent further entry of Na+ ions into the neuron
Results in reduces the intraneuronal Na+ ion concentration
Inhibits the generation of action potential
Reduces the spreading of seizure discharge

7. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 7 | P a g e
Uses: effective in most forms of epilepsy, except absence of seizures.
Side effects: hypertrophy of gums, gingival hyperplasia
Synthesis of phenytoin
3. Oxazolidinediones and succinimides
MOA: Blocks T-type Ca2+ channels in thalamic neurons to counteract the slow, spike and wave, firing pattern
thought to be important in absence epilepsy.

8. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 8 | P a g e
Synthesis of Ethosuximide
Uses: Drug of choice for absence seizures (not effective against partial or tonic-Clonic seizures).
Side effects: Anorexia, GIT upset, pancytopaenia. Rash, drowsiness, fatigue.
Note: Overdose can cause coma and respiratory depression.
4. Urea and monoacylureas
MOA
Same as phenytoin action on Na+
channel prolongation of inactivated state
Uses: Partial and generalised seizures (tonic-clonic), but not absence seizures. Also neuropathic pain and
bipolar disorder.
Side effect: Drowsiness, headache, mental disorientation, motor disturbances. Rare, but serious: liver damage.

9. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 9 | P a g e
Synthesis of carbamazepine:
5. BZD (Clonazepam)
Same as Benzodiazepines
6. Valproic Acid
MOA:
➢ Phenytoin like prolongation of NA+
channel inactivation
➢ Also inhibit the enzyme GABA transaminase that is responsible for breakdown of inhibitory NTS and
thus increasing GABA level.

10. Unit-IV_ ANTICONVALSANTS MEDICINAL CHEMISTRY-I
Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 10 | P a g e
Uses: Most forms of epilepsy (esp. useful in myoclonic seizures). Manic phase of bipolar disorder. Migraine
Side effect: Nausea & vomiting, Weight gain. Reproductive dysfunction. Hepatic (especially in infants) and
pancreatic toxicity.
7. Gabapentin
MOA: Action on voltage-activated Ca2+ channels to block Ca2+ entry and exocytosis of transmitter
(glutamate) from nerve endings. (Enhanced release of GABA has also been suggested.)
Uses: Adjunctive treatment for partial seizures. Widely used to treat neuropathic pain.
Side effect: Sedation, dizziness and unsteadiness.
Overall drugs MOA