Drugs acting on cns anticonvulsants

DRUGS ACTING ON CNS-
ANTICONVULSANTS
ANTICONVULSANTS
PREPARED BY:
MS. JYOTI RANI
ASSISTANT PROFESSOR
BUEST,SPES

What is Epilepsy ?
Recognised from the dawn of history as ‘disease of lightening’, it was correctly
described by JH Jackson little over a century ago.
 Epilepsy is a chronic disorder that causes unprovoked, recurrent seizures.
 A seizure is a sudden rush of electrical activity in the brain i.e. related to ‘depolarization
shift’ which consists of a synchronous and unusually large depolarization over which
shift’ which consists of a synchronous and unusually large depolarization over which
action potentials are superimposed.
 A mild seizure may be difficult to recognize. It can last a few seconds during which you
lack awareness.
 Stronger seizures can cause spasms and uncontrollable muscle twitches, and can last a
few seconds to several minutes. During a stronger seizure, some people become confused
or lose consciousness. Afterward you may have no memory of it happening.

Types of Epilepsy
Generalized Seizures (affect the whole brain)
1. Absence seizures, which used to be called “petit mal
seizures,” cause a blank stare. This type of seizure may
also cause repetitive movements like lip smacking or
blinking. There’s also usually a short loss of awareness.
2. Tonic seizures cause muscle stiffness.
3. Atonic seizures lead to loss of muscle control and can
make you fall down suddenly.
Focal/Partial Seizures (affect just one part of the
brain)
1. A simple partial seizure doesn’t involve loss of
consciousness. Symptoms include:
• alterations to sense of taste, smell, sight, hearing, or
touch
• dizziness
• tingling and twitching of limbs
make you fall down suddenly.
4. Clonic seizures are characterized by repeated, jerky
muscle movements of the face, neck, and arms.
5. Myoclonic seizures cause spontaneous quick twitching
of the arms and legs.
6. Tonic-clonic seizures used to be called “grand mal
seizures.” Symptoms include:
• stiffening of the body
• shaking
• loss of bladder or bowel control
• biting of the tongue
• loss of consciousness
• tingling and twitching of limbs
2. Complex partial seizures involve loss of
awareness or consciousness. Other symptoms
include:
• staring blankly
• unresponsiveness
• performing repetitive movements

CLASSIFICATION OF ANTI-CONVULSANTS
 Barbiturates: Phenobarbitone, Metharbital.
 Hydantoins: Phenytoin*, Mephenytoin, Ethotoin
 Oxazolidine diones:Trimethadione, Paramethadione
 Oxazolidine diones:Trimethadione, Paramethadione
 Succinimides: Phensuximide, Methsuximide, Ethosuximide*
 Urea and monoacyl ureas: Phenacemide,
 Benzodiazepines: Carbamazepine *, Clonazepam
 Miscellaneous: Primidone, Valproic acid , Gabapentin, Felbamate

Mechanism of Action of anticonvulsants
 Anticonvulsants have a stabilizing
influence on neuronal membrane—prevents
repetitive detonation of normal brain cells
during ‘depolarization shift’ where
intracellular accumulation of Na+ that
occurs during repetitive firing is prevented.
 This is achieved by prolonging the
inactivated state of voltage sensitive
inactivated state of voltage sensitive
neuronal Na+ channel that governs the
refractory period of the neurone.
 As a result high frequency discharges are
inhibited also allows Na+ channels to
recover even when their inactivation is
prolonged.
 While other effects are like
 reduction in Ca2+ influx,
 facilitation of GABA responses.

SAR of Anticonvulsants
 Many of the standard Anticonvulsants
that contain the ureide structure, as
shown in Figure,
 These have been used clinically for more
 These have been used clinically for more
than 30 years without much change in
their ureide structures.
 Small changes in the X substituent of the
ureide structure can cause significant
changes in the type of seizures
controlled.

Barbiturates
Phenobarbitone
O
N
H
O
HN
O
CH2
CH3
1
2
3
5
4
6
MOA. Mechanism is likely related to the potentiation of GABA
inhibition in
the CNS. Barbiturates also antagonize glutamate excitation.
Clinical uses.
1. Phenobarbital is orally administered in the treatment of grand
5-ethyl-5-phenylpyrimidine-
2,4,6(1H,3H,5H)-trione
Phenobarbitone
1. Phenobarbital is orally administered in the treatment of grand
mal epilepsy.
2. It is less effective in the treatment of petit mal and
psychomotor epilepsies.
3. The injectable from of the drug is used to treat other types of
convulsions.
Adverse effects.
sedation, dizziness, drowsiness, ataxia (lack of muscular
coordination), and nystagmus (a rapid
involuntary movement of the eyeball).

O
N
O
HN
O
Metharbital
It is a barbiturate anticonvulsant. It has similar properties
to Phenobarbital.
Pharmacology. It belongs to a group of medicines called central
nervous system (CNS) depressants that induce drowsiness and
relieve tension or nervousness. Little analgesia is conferred by
barbiturates; their use in the presence of pain may result in
excitation.
Metharbital
5,5-diethyl-1-
methylpyrimidine-
2,4,6(1H,3H,5H)-trione
excitation.
MOA. binds at the GABAA receptor, leading to Cl- ionopore
openening. The post-synaptic inhibitory effect of GABA in the
thalamus is, therefore, prolonged. Barbiturates also causes direct
inhibition of excitatory AMPA type glutamate receptors, resulting in
a profound suppression of glutamatergic neurotransmission.
Use. It is used for the treatment of short term insomnia and in the
treatment of epilepsy.

Hydantoins-SAR
1. Hydantoins are cyclic monoacylureas. They possess imidazoline-2, 4-dione
heterocyclic system. Hydantoins are structurally related to barbiturates,
differing in lacking the 6-oxo moiety.
2. Hydantoins are weakly acidic than barbiturates. Thus aqueous solution of
sodium salts provide strongly alkaline solutions.
3. A clinically useful hydantoin possess an aryl substituent at the 5-position.
N
H
O
NH
O
Hydantoin
1
3
2
4
5
4. Hydantoin derivatives possessing of lower alkyl substituents have antiabsence
activity.

Phenytoin
N
H
O
NH
O
Phenytoin
5,5-diphenylimidazolidine
-2,4-dione
Phenytoin is a first line antiepileptic drug, but less commonly used
now because side effects are frequent and marginal overdose causes
steep rise in plasma concentration, producing neurotoxicity.
MOA. Phenytoin probably works by maintaining the deactivation of
voltage-sensitive sodium channels, thereby blocking the repetitive
firing of neurons.
Synthesis. Phenytoin may be synthesized by heating α-bromo-
diphenylacetylurea with alcoholic ammonia.
Clinical uses
1. Phenytoin is used alone or in
combination with phenobarbital
in the treatment of grand mal and
psychomotor epilepsy.
2. It is also used in the treatment of
other types of convulsions.

N
H
O
N
O
1
3
2
4
5
CH3
H2C
H3C
Mephenytoin
5-ethyl-3-methyl-5-
phenylimidazolidine-2,4-dione
Mephenytoin
It is a hydantoin, used as an anticonvulsant. It was introduced
approximately 10 years after phenytoin, in the late 1940s.
Clinical uses
1. Mephenytoin is used to control seizures in combination with
phenytoin.
2. It is used as a reserve drug (only when phenytoin has failed),
because the metabolic product (5-ethyl-5-phenylhydantoin) of
because the metabolic product (5-ethyl-5-phenylhydantoin) of
mephenytoin is highly toxic.
Ethotoin
is an anticonvulsant drug used in the treatment of epilepsy. It is
a hydantoin, similar to phenytoin.
Clinical uses.
Ethotoin is indicated for tonic-clonic and partial complex seizures.

Oxazolidine diones
Oxazolidinediones were introduced as anticonvulsants in 1948.
They possess the following heterocyclic system :
Oxazolidine-2, 4-dione is analogous to hydantoin differs in having of
oxygen atom at position-1 instead of NH.
Trimethadione (Troxidone)
1
2
3
4
5
N
O
O
O
Trimethadione
3,5,5-
trimethyloxazolidine-
2,4-dione
It is an oxazolidinedione anticonvulsant. It is most
commonly used to treat epileptic conditions that are resistant
to other treatments.
Clinical uses. Troxidone is used in the treatment of absence
seizures

Paramethadione
It differs from trimethadione only in the substitution of one methyl
group with an ethyl group .
Paramethadione (brand name Paradione) is an anticonvulsant in
the oxazolidinedione class developed by the Illinois-based
pharmaceutical company Abbott Laboratories (known
as AbbVie since January 1, 2013 ).
MOA. Paramethadione acts to reduce T-type calcium currents in
thalamic neurons which has been proposed to underlie the 3-Hz
spike-and-wave discharge seen on electroencephalogram (EEG)
during absence seizures.
Uses.
It was approved by the Food and Drug Administration in 1949 for
the treatment of absence seizures, also called partial seizures.

Succinimides
Oxazolidinediones are toxic hence to replace them with less toxic drugs
succinimides were introduced in 1951 as antiepileptics.
The precise mechanism of action of succinimides is unknown. It has been
postulated that succinimides enhances inhibitory processes in the brain,
by some effect on specific inhibitory neurotransmitter systems.
Succinimides refers to compounds that contain the succinimide group.
Succinimides refers to compounds that contain the succinimide group.
These compounds have some notable uses.
Several succinimides are used as anticonvulsant drugs, including
 ethosuximide,
 phensuximide, and
 methsuximide.

Ethosuximide
Ethosuximide is considered the first choice drug for treating
absence seizures in part because it lacks the idiosyncratic
hepatotoxicity of the alternative anti-absence drug, valproic acid.
MOA. Ethosuximide binds with T-type voltage sensitive calcium
channels. The latter involves in mediating the entry of calcium
ions into excitable cells and are also involves in variety of
calcium-dependent processes, including muscle contraction,
calcium-dependent processes, including muscle contraction,
hormone release, neurotransmitter release, gene expression, cell
division and cell death.
T-type voltage sensitive calcium channel are also involved in the
modulation of firing patterns or neurons which is necessary for
the information processing and also in cell growth processes.
Use.
Ethosuximide is used for:
The control and prevention of absence or petit mal seizure

Synthesis.
i. Methylethylketone and cyanoacetic ester are condensed in Knoevanagel reaction conditions.
ii. Hydrogen cyanide is added to the resulting product.
iii. Dinitrile so formed undergoes acidic hydrolysis and decarboxylation to form 2-methyl-2-
ethylsucinic acid.
iv. Reaction of the above formed compound with ammonia gives a diazonium salt which on
heterocyclization produces ethosuximide.

Phensuximide
Phensuximide
O
N
O
Phensuximide is a member of the succinimide class with
anticonvulsant properties.
MOA. It suppresses the paroxysmal three cycle per second spike
and wave EEG pattern associated with lapses of consciousness in
petit mal seizures.
It's effects may be related to its ability to inhibit depolarization-
1-methyl-3-
phenylpyrrolidine-2,5-
dione
It's effects may be related to its ability to inhibit depolarization-
induced accumulation of cyclic AMP and cyclic GMP in brain
tissue.
Thus the frequency of attacks is reduced by depression of nerve
transmission in the motor cortex.
Clinical uses. Phensuximide belongs succinimide class of
antiepileptic agent used to treat convulsions but it is reported to
be less effective

Methsuximide
Mesuximide (or methsuximide, methosuximide) is
a succinimide anticonvulsant medication.
MOA. It is thought to owe its activity to its major metabolite
N-desmethylmethsuccimide.
Clinical use.
methsuximide
O
N
O
Clinical use.
1. Methsuximide is a succinimide antiepileptic agent used
to treat complex partial seizures.
2. is indicated for the control of absence seizures that are
refractory to other drugs.
1,3-dimethyl-3-
phenylpyrrolidine-2,5-dione

Urea and monoacyl ureas
Phenacemide
 also known as phenylacetylurea, is an anticonvulsant of
the ureide (acetylurea) class.
 It is a congener and ring open analog of
phenytoin (a hydantoin) and
phenytoin (a hydantoin) and
 It is structurally related to the barbiturates and to
other hydantoins.
 Phenacemide was introduced in 1949 for the treatment
of epilepsy, but was eventually withdrawn due to toxicity.

Benzodiazepines
Carbamazepine *
is an anticonvulsant medication used primarily in the
treatment of epilepsy and neuropathic pain. It is used
in schizophrenia along with other medications and as a
second-line agent in bipolar disorder.
Synthesis. Reaction of 5H-dibenz[b,f]azepine with potassium
Carbamazepine
N
O NH2
5H-dibenzo[b,f]azepine-5-
carboxamide
Synthesis. Reaction of 5H-dibenz[b,f]azepine with potassium
cyanate to get carbamazepine.
carboxamide
Uses.
1. It is used to control grandmal
and focal seizures.
2. It is also used in the treatment
of trigeminal neuralgia and
3. the treatment of manic
4. depression.

Clonazepam
It is a medication used to prevent and treat seizures, panic disorder,
and the movement disorder known as akathisia.
It is a tranquilizer of the benzodiazepine class. It is taken orally.
Effects begin within one hour and last between six and twelve hours.
Clinical uses.
1. Clonazepam is used in the treatment of grand mal epilepsy.
2. It is the alternate drug for the treatment of petit mal in patients
who fail to respond to ethosuximide therapy.
3. It suppresses various types of status epilepticus seizures but
because of its cardiorespiratory depressant effect, it is second to
diazepam.

Miscellaneous
Valproic acid
• Valproic acid is not chemically related to other anticonvulsants.
• Valproic acid is a branched short-chain fatty acid (SCFA) made
from valeric acid.
MOA. Valproate's precise mechanism of action is unclear.
O OH
Valproic acid
2-propylpentanoic acid
MOA. Valproate's precise mechanism of action is unclear.
Proposed mechanisms include affecting GABA levels,
blocking voltage-gated sodium channels, and inhibiting histone
deacetylases.
Use.
1. It is used primarily to treat epilepsy and bipolar disorder.
2. It is also used to prevent migraine headaches.

Primidone
Primidone is an antiepileptic agent related to barbiturates.
Primidone is a diketone derived from hexahydropyrimidine.
Use.
It is used to treat partial and generalized seizures, as well
as essential tremors. It is taken by mouth.
O
N
H
HN
O
5-ethyl-5-
phenyldihydropyrimidin
e-4,6(1H,5H)-dione
Primidone
e-4,6(1H,5H)-dione
O
NH2
O
O
H2N
O
2-phenylpropane-1,3-diyl
dicarbamate
Felbamate Felbamate
is an anticonvulsant. used in the treatment of epilepsy.
It is used to treat partial seizures (with and without
generalization) in adults and partial and generalized
seizures associated with Lennox–Gastaut syndrome (LGS)
is a complex, rare, and severe childhood-onset epilepsy in
children.

Gabapentin
Gabapentin containing primary amino and carboxyl groups,
is better represented as an internal salt resulting from
proton transfer from the acidic carboxyl group to the basic
amino group.
MOA.The name and structure again suggests GABA
mediated pharmacology but surprisinglythe mechanism of
action remains unknown.
Gabapentin
O
HO
NH2
2-(1-(aminomethyl)cyclo
hexyl)acetic acid
action remains unknown.
Uses.
1. It is an anticonvulsant medication primarily used to
treat partial seizures and neuropathic pain.
2. It is a first-line medication for the treatment of
neuropathic pain caused by diabetic
neuropathy, postherpetic neuralgia, and central pain.
hexyl)acetic acid

Drugs acting on cns anticonvulsants

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