Drugs of used in epilepsy

1. The central nervous system (CNS) constitutes
• the cerebral cortex,
• the limbic system,
• the midbrain,
• the brainstem,
• the cerebellum, and
•the spinal cord
Epilepsy is one of the most common disorders of the brain, affecting about 50
million individuals worldwide.
Epilepsy is a chronic and often progressive disorder characterized by
the periodic and unpredictable occurrence of epileptic seizures that are
caused by abnormal discharge of cerebral neurons.
Epilepsy is not a disease, but a syndrome of different cerebral
disorders of the CNS.
• This syndrome is characterized by paroxysmal, excessive, and
hypersynchronous discharges of large numbers of neurons.
These seizures may be identified on the basis of their clinical characteristics.
These clinical attributes, along with their electroencephalographic
(EEG) pattern, can be used to categorize seizures

2. • Seizures are basically divided into two major groups:
Partial and
Generalized.
• Partial (focal, local) seizures are those in which clinical or EEG evidence exists
to indicate that the disorder originates from a localized origin, usually in a portion
of one hemisphere in the brain.
• Partial seizures may be further subdivided into
Simple partial,
Complex partial, and
Partial seizures evolving into secondarily generalized seizures.
• In generalized seizures, the evidence for a local origin is lacking.
• Generalized seizures may be further subdivided into
Absence (nonconvulsive),
Myoclonic,
Clonic,
Tonic,
Tonic-clonic,
and atonic seizures.

3. • Patients are classified into appropriate types of epilepsy and epileptic
syndromes characterized by different seizure types, etiologies, ages of
onset, and EEG features.
• More than 40 distinct epileptic syndromes have been identified, making
epilepsy an extremely diverse collection of disorders.
• The first major division of epilepsy is localization- related (i.e., focal, local,
partial) epilepsies, which account for about 60% of all epilepsies.
• The remainder, about 40%, is composed of generalized epilepsies.
• An epilepsy, or epileptic syndrome, is either idiopathic, virtually synonymous
with genetic epilepsy; or
• symptomatic, which is attributed to a structural lesion or major identifiable
metabolic derangements.
• Both types of seizure patterns and epilepsy determine the choice and
prognosis of therapy.
• The most common, and most difficult to treat, seizures in adult patients are
complex partial seizures,
• whereas primary generalized tonic-clonic (formerly, "grand mal" epilepsy)
seizures respond in most patients to treatment with anticonvulsants.

4. • Many seizure types and epilepsy syndromes, there is little information about the
pathophysiological basis.
• Insight into how partial seizures, generalized tonic-clonic seizures, and generalized
absence seizures arise is substantial, given that these seizure types constitute about 90%
of seizures.
• In the absence of a specific etiologic understanding in any of the epilepsies or epileptic
syndromes, approaches to drug therapy of epilepsy must of necessity be directed at the
control of symptoms, that is, the suppression of seizures.
• In 1981, the International League Against Epilepsy (ILAE) proposed a classification
scheme for individual seizures that remains in common use.
• This classification is based on observation (clinical and EEG) rather than the underlying
pathophysiology or anatomy and is outlined later on in this article.
• In 1989, the ILAE proposed a classification scheme for epilepsies and epileptic
syndromes.[
• This can be broadly described as a two-axis scheme having the cause on one axis and the
extent of localization within the brain on the other.
• Since 1997, the ILAE have been working on a new scheme that has five axes:
• 1. ictal phenomenon, (pertaining to an epileptic seizure)
• 2. seizure type,
• 3. syndrome,
• 4. etiology,
• 5. impairment.

5. • Currently, all available drugs are anticonvulsant (i.e., antiseizure) rather than
antiepileptic.
• The latter term should be used only for drugs that prevent or treat epilepsy
and not solely its symptoms.
• The goal of therapy with an anticonvulsant agent is to have the patient seizure
free without interfering with normal brain function.
• Thus, the selection of an anticonvulsant agent is based primarily on its
efficacy for specific types of seizures.
• Although seizure control is generally good in most patients, a significant
proportion of patients with epilepsy suffer from intractable or drug-resistant
epilepsy, despite early treatment and an optimum daily dosage of an adequate
anticonvulsant agent.
• There is thus a need for new drugs with a greater benefit as related to side
effects and tolerability, even at the expense of efficacy, when compared to the
existing antiepileptic agent sizures and epilepsy.

6. Current Drugs
The anticonvulsant agents may be conveniently grouped into three general
categories
1. "First-generation" or older agents as exemplified by
phenytoin ,
carbamazepine,
valproate ,
the benzodiazepines ,
ethosuximide,
phenobarbital,
primidone and
trimethadione
all of which were introduced between 1910 and 1970.

7. 2. "Second-generation" or newer agents consisting of
vigabatrin,
gabapentin
felbamate,
lamotrigine
carbazepine
zonisamide,
tiagabine (14),
topiramate and
levetiracetam (16)
3. "Third-generation" agents are those agents that are in preclinical or clinical
development.

8. Chemical Classification
1 Hydantoin
Phenytoin (5,5-diphenylhydantoin; 5,5-diphenyl-2,4-imidazolidinedione)
Mephenytoin,
Ethotoin,
Fosphenytoin
2. Iminostilbene
Carbamazepine,
3. Aliphatic acid
Valproic acid,

9. 4.Benzodiazepine
Clorazepate
Clonazepam,
Diazepam,
5. Succinimide
Ethosuximide,
Methsuximide,
Phensuximide,
6. Barbiturate,
Phenobarbital,

10. 7. Dihydrobarbiturate
Primidone,
8. Oxazolidinedione
Trimethadione,
9. GABA analog
Vigabatrin,
10. Cyclohexaneacetic acid
Gabapentin,
11. Propanediol carbamate
Felbamate,

11. 12. Triazine
Lamotrigine
13. Iminostilbene

12. • PHYSIOLOGY AND PHARMACOLOGY
• Seizures in humans and laboratory animals result in rapid voltage changes in their
EEG patterns.
• These changes are accompanied by an extracellular depolarizing shift caused by a
large excitatory postsynaptic potential.
• The exact biochemical mechanisms leading to these discharges and the resultant
epileptic attack are still unknown. Several events, however, are known to occur.
• The EEG changes relate to the opening of specific ion channels in the neuronal
membrane.
• At the onset of the hypersynchronous discharge, the extracellular Ca2+
concentration falls and the extracellular K+ concentration rises.
• Further, the excessive neuronal discharge may release large amounts of excitatory
neurotransmitters at synapses that may result in an avalanche of stimulation.
• The current proposed cellular mechanisms by which the anticonvulsants exert their
effect are indicated for the "first-generation“ and "second-generation" agents.

13. Open
activated
Closed
inactivated
Resting
closed but
can be
activated
Depolarised
Polarised
Relationship between open, closed, and resting state of Na+ channels.

14. • These states are:
(1) the resting (closed) or non conducting state;
(2) the activation state resulting from changes in the resting potential of the
channel, which increases the ability of the channel to inwardly conduct Na+
across the cell membrane until an action potential is elicited; and
(3) this open channel state exists for a short period and closes rapidly to the
inactivated state, which terminates inward flow of Na+ and the
resulting voltage change.
• The reactivation to the resting state is membrane potential dependent, given that
repeated depolarizations delay the transformation back to the resting state.
• Drugs that interact with sodium channels to block ion flux cause the channels to inactivate
to a greater degree and with smaller depolarizations than normal.
• The relatively slow off-rate caused by- anticonvulsants that act as sodium channel
blocking agents provides an accumulated block after repeated depolarization (termed
use-dependency).
• Thus, in seizures, the sodium channel-blocking agents are effective only if the
depolarization lasts for at least 5 s.
• These agents normally do not interfere with the normal action potential or excitatory
synaptic potentials that typically last less than 200 ms.

15. • several first generation and second-generation agents act by blockade of voltage-
dependent Na+ channels; however, there are problems in explaining the clinical and
experimental facts concerning these agents.
• As an example, carbamazepine and phenytoin are listed as Na+ channel-blocking
agents; however, in the clinic, an epileptic patient found to be resistant to one of these
agents may respond favorably to alternative treatment with the other of the two drugs,
pointing out that these agents may act by more than one mechanism.
• GABAergic Mechanisms
• GABA, or 4-aminobutyric acid, formed by the decarboxylation reaction is present
within a large proportion of the central nervous system, where it is the major inhibitory
neurotransmitter controlling synaptic transmission and neuronal excitability.
• There are at present three known classes of GABA receptors, GABAA, GABA,, and
GAB&, with distinctive binding properties and different functional responses to GABA,
although each is involved with inhibition of the CNS. All GABA receptors are found as
pre- and postsynaptic receptors, and as autoreceptors.

16. • GABA, receptors are major receptors that are linked to chloride channels and are
activated by isoguvacine, modulated by barbiturates and the benzodiazepines, and
antagonized by bicuculline.
• This receptor is termed a heterooligomeric complex and is composed of at least
four types of multiple allosterically interacting binding sites (GABA, benzodiazepine,
barbiturate, and picrotoxin sites), together with an intrinsic chloride ion channel.
• Each of the allosteric binding sites is thought to be physically distinct, and can be
occupied simultaneously to induce their individual pharmacological effects through
allosteric interaction.
• It is established that the GABA, receptor complex plays a significant role in the
action of anticonvulsant agents.
• The older agents (i.e., phenobarbital, valproate, and the benzodiazepines) act
through this mechanism, whereas the newer agents (i.e., topiramate, felbamate,
vigabatrin, tiagabine, and gabapentin) are also GABAergic agonists, although by
different mechanisms.
• Topiramate, in addition to potentiating GABA, also prolongs inactivation of sodium
channels.
• Felbamate, also a GABA agonist, like topiramate, also blocks the (RS)-2-amino-3-
(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 25) as well
as the N-methyl-D-aspartate (NMDA, 26) receptors.

17. • Vigabatrin acts by blocking GABA-T, the enzyme responsible for the breakdown of
GABA ;
• Tiagabine acts by inhibiting the reuptake of the neurotransmitter.
GABA Receptors.
• In theory, drug that depresses GABA, receptor-mediated inhibition should also be
effective anticonvulsants. This has been demonstrated in some animal models, but
not yet in humans.
• Several phosphinic acid analogs of GABA have been synthesized and found to be
selective, orally active GABA, agonists in animals however, they have not been
advanced to the market.
• The GABAB agonist baclofen has been shown to prolong spike-and-wave
discharges in animal models, thus enhancing the amount of GABA available to the
receptor, and GABAB antagonists block them.
• Phosphinic acid analogs
• R = CzH5; n-C3H7; CH2C6H5; CH2C6Hll

18. Glutamate Receptors
• (S)-Glutamic acid the main excitatory neurotransmitter in the central nervous
system and other excitatory amino acids operate through four different classes of
receptors.
• In addition to the three heterogeneous classes of ionotropic excitatory amino acids
(iGluRs) [i.e., AMPA (25), NMDA (26), and kainic acid (28) receptors, a
heterogeneous class of G-protein-coupled excitatory amino acid receptors
(mGluRs) has been shown to have an important function in neuronal signaling
processes.
• It is now generally understood that both iGluRs and mGluRs play important roles in
health and disease processes including epilepsy.
• Inhibition of glutamatergic excitation, particularly mediated by the NMDA and non-
NMDA type of glutamate receptors, has been suggested to play a significant role.
• There is indeed evidence for an anti-glutamatergic action for the newer agents,
• There is also evidence that the older drugs act through this mechanism as well.
(26) NMDA

19. T-Type Ca2+ Channels
• Calcium channels have been classified into L-, N-, T-, P/Q-, and R-types on the basis of their
pharmacological and/or electrophysiological properties.
• The classification of voltage-dependent calcium channels divides these channels into three
groups:
1. high voltage-activated, which includes L-, N-, P-, and Q-types,
2. intermediate R-type; and
3. low voltage-activated, T-type.
• These channels are composed of a, P, and y-subunits whose sequences are known.
• The a,-subunit of voltage-sensitive Ca2+ channels has a secondary structure similar to that
of the a-subunit of Na+ channels as well as some sequence homology.
• Because of the homology between these two relevant sites, some Ca2+ channel-blockers,
such as verapamil, flunarizine, nifedipine and diltiazem, also act on Na+ channels.
• These agents, however, showed only low or absent anticonvulsant activity in controlled
trials.
• These were all L-type channel blockers.

20. • In addition to T-type Ca2+ channel blockers on the market [i.e., ethosuximide,
zonisamide, and trimethadione, a new series of anticonvulsant:
aroyl(aminoacyl)pyrroles (lead compound RWJ 37868,33) have been
synthesized, which act by blocking Ca2+ influx into cerebellar cells.
Seizure
type
Anti
convulsant
agent
Blockade of
voltage
dependant Na+
channels
Potentiatio
n of
GABAergic
system
Blockade
of thalamic
T-type Ca+
channels
Blockade
of
Glutamater
gic
mechanism
Generalized
tonic-clonic
and partial
seizures
Vigabatrin,
Tiagabine
Gabapentin ±
++
++
+ ±
Broad
spectrum
Lamotrigine
Oxcarbazepi
ne
Topiramate
Felbamate
Zonisamide
++
++
+
+
++
+
+
+
±
+
++

21. Seizure type Anti
convulsant
agent
Blockade of
voltage
dependant
Na+ channels
Potentiation
of
GABAergic
system
Blockade of
thalamic T-
type Ca+
channels
Blockade of
Glutamatergi
c mechanism
Generalized
tonic-clonic
and partial
seizures
Phenytoin
Carbarnazepi
ne
Phenobarbital
++
++
+ + +
Broad
spectrum
Valproate
Benzodiazepi
nes
++ +
++
Absence
seizures
Ethosuximide +

22. Small changes in the X substituent of the Ureide can cause changes in the type of
seizures controlled.
NH
O
O
R
1 R
2
Ureide structure
Class of compounds X
Barbiturates O
C
NH
Hydantoins
NH
Oxazolidinediones
O
Succinimides
CH2

23. Hydantoins
• The hydantoins have a five membered ring structure containing two
nitrogen in an ureide configuration.
• These drugs suppress electrically induced convulsions in animals but
were ineffective against convulsions induced by Pentylenetetrazole,
Picrotoxin, or Bicuculline.

24. Phenytoin
• Is the protype & most commonly prescribed member of the hydantoin family of drugs.
• Bioequivalency is a problem with the hydantoins because of their very poor water solubility &
low therapeutic ratio.
• Pka is in the range of 8.06 to 8.33 & thus can form a water soluble sodium salt( pH˃11).
• Aqueous solutions of phenytoin sodium (pH11-12) gradually absorb CO2, neutralising the
alkalinity of the solution and causing partial hydrolysis & crystallisation of free phenytoin
resulting in turbid solutions.
• An IM injection may lead crystalissation of insoluble phenytoin at the site of injection
because of decrease of the Ph from 11.
• Phenytoin injection is incompatible in normal saline, or with parenteral solutions of many
drugs, especially basic drugs.

25. Mechanism of action
• It is indicated for initial monotherapy or adjunct treatment of complex partial or
tonic –clonic seizures, convulsive status epilepticus and prophylaxis.
• Often selected for monotherapy because of its high efficacy & relatively low
incidence of side effects.
• It is not used in the treatment of absence seizures because of it may increase
the frequency of occurrence.
• Phenytoin binds to & stabilizes the inactivated state of sodium channels thus
producing a use dependent blockade of repetitive firing & inhibition of the
spread of seizure activity to adjacent cortical areas.

26. Synthesis of Phenytoin

27. Adverse effects
• CNS effects are most frequent & include
1. nystagmus (means involuntary eye movement)
2. ataxia (gross lack of coordination of muscle movements)
3.dysarthria (condition that occurs when problems with the muscles that help you
talk make it difficult to pronounce words) &
4. sedation.
• Gingival hyperplasia , usually reversible, is common.
• Aromatic anticonvulsants, such as phenytoin cause a number of toxic effects,
including drug induced hypersensitivity syndrome that manifests with a triad of
reactions such as
1. rash
2. agranulocytosis ,
3. thrombocytopenia,
4. lymphadenopathy,
5. Steven’s Johnson syndrome(a life-threatening skin condition, in
which cell death causes the epidermis to separate from
the dermis), &
6. Hepatitis.
• Hypersensitivity though rare seems to be life threatening.

28. Fosphenytoin
• Is a soluble pro-drug disodium phosphate ester of Phenytoin.
• Develpoed as a replacement for parenteral phenytoin sodium to circumentvent
the pH & solubility associated with parenteral phenytoin sodium.
• Is freely soluble in aqueous solution & is rapidly absorbed by the IM route.
• This is rapidly metabolised (t1/2 8-15 min) to phenytoin by invivo phosphatases.
• Plasma Phenytoin concentrations are attained following IM or IV administration.
• It is administered IV following benzodiazepines for control of status epilepticus or
whenever there is a need to rapidly achieve therapeutic plasma concentrations.

29. Ethotoin
• Differs from Phenytoin in that one phenyl substituent at position 5 has been
replaced by hydrogen bond, the NH- at position 3 is replaced by an ethyl group.
• Indicated in the treatment of tonic–clonic & complex partial seizures.
• Because it is considered as less toxic but also less effective & more sedating than
Phenytoin, ethotoin usually is reserved for use as an add on drug.
• Ethotoin does not share Phenytoin’s profile of anti-arrhythmic action.
• Its administration is contraindicated in patients with hepatic abnormalities &
hematological disorders.

30. Mephenytoin
• Is N-methylated at position 3 with an ethyl group replacing one of the phenyl
substituents at position 5.
• Indicated for focal & Jacksonian seizures.
• Mephenytoin produces more sedation than phenytoin & should be used only
when safer drugs have failed, because it is associated with an increased
incidense of serious toxicities, such as rash, agranulocytosis & hepatitis.
• Its N-desmethyl metabolite- 5-phenyl-5ethylhydantoin contributes to both
efficacy & toxicity for mephenytoin.

31. Structural requirement for anticonvulsant activity
• For a compound to act as anticonvulsants, the molecule should contain at least
one aryl/ lippohilic unit (A),
one or two hydrogen acceptor-donar atoms (HAD) &
an electron-donar atom (D)
in special arrangement to be recommended for anticonvulsant activity.
• A A A
Mephobarbital Phenytoin Carbamazepine
N
H
N
O
CH3
O
CH3
HAD
D
N
H
NH
O
O
D
HAD
N
N
O
H
H
D
HAD

32. A
A A
• Gabapentin
Lamotrigene Progabide
A
Zonisamide
N
C
H
H O
OH
HAD
D Cl
Cl
N
N
N
N
H H
N H
H
HAD
D
N
O
N H
H
OHF
Cl
D
HAD
S
O
N
O
O
N
H
H
D
HAD

33. A
D
HD
HA
3.09-9.09 A
1.89-2.70 A
2.23-5.73 A
2.64-7.40 A
3.62- 6.58 A
2.49-8.23 A

34. Iminostilbenes
Carbamazepine
• It is presently indicated as initial or adjunct therapy for complex partial, tonic-
clonic, and mixed type of seizures.
• Is one of the safest & most effective older AEDs for these seizure
types(phenytoin is the other) & is chosen for the monotherapy because of its
high effectiveness & relatively low incidence of side effects.
• Its tricyclic structure resembles that of the psychoactive drugs imipramine,
chlorpromazine & maprotiline & also shares some structural features with the
AEDs phenytoin, clonazepam & phenobarbital.
• In addition, CBZ has been found to be effective treatment of bipolar disorder &
trigeminal neuralgia.

35. Mechanism of action
• Similar to that of Phenytoin
• Effective in maximal electro shock(MES) test
• Ineffective against Pentylenetetrazole
• Not effective against absence or myoclonic seizures
• Acts on voltage dependent sodium channels to prevent the spread of seizures
• CBZ depresses synoptic transmission in the reticular activating system,
thalamus & limbic structure.
Adverse effects
• Gastric upset from CBZ may be diminished by taking the drug after meals.
• Common toxicities include blurred vision, drowziness, dizziness & ataxia.
• Tremor, depression, hyponatremia & cardiac disturbances are seen at high
serum concentrations.
• Idiosyncratic rashes are common; rarer severe idiosyncratic effects include
aplastic anaemia, agrnulocytosis, thrombocytopenia & jaundice.
• Therefore patients receiving CBZ should have periodic blood count
determinations & liver function tests.
• Both CBZ & oxcarbazepine can reduce plasma 25-hydroxy vitamin D levels.

36. • CBZ increases levels of phenytoin & decreases levels of felbamate, lamotrigine, oral
concentraceptives, theophylline, valproate & zonisamide.
• CBZ levels are increased by propoxyphene, erythromycin, chloramphenical,
isoniazid, verapamil & cimetidine.
• CBZ levels are decreased by phenobarbital, phenytoin, felbamate & primidone.
• Macrolide antibiotics inhibit CBZ metabolism, thus increasing CBZ plasma levels &
decreasing clearance with the potential for toxicity effects.
• CBZ should be used with caution in patients with a history of CHF or cardiac
arrhythmia because it may aggravate them.
quinone & stilbene part of the carbamazepine metabolites are responsible for
hypersensitivity reactions.
N
NH2
O
N
NH2
O
OH
Carbamazepine 2-hydroxy carbamazepine
N
H
OH
2-hydroxyiminostilbene
N
O
CBZ-Iminoquinone

37. Synthesis of Carbamazepine
NO2 O2N
NH2 NH2
N
H
NO2
CH2Cl
NaOH
2-(O-aminostyryl)-aniline
H2
NH2 NH2
-NH3
N-Bromosuccinimide
N
Br
CH3CO
N-Acetylation
Dehydrochlorogenation
Reduction
Sodiumin amylalcohol
heating in collidine
N
H
Phosgene followed by heating
with carbonyl chloride
COCl2
NH3
N
C
CH3
O
Carbamazepine

38. Oxcarbazepine
• Plasma concentration are nine fold more than Carbamazepine.
• MOA is similar to that of Carbamazepine.
• An additional action on calcium & potassium channels may contribute to
the therapeutic effect.
Adverse effects
• Patients with hypersensitivity reactions to Carbamazepine can be
expected to show cross sensitivity.
• Improved toxicity profile for oxcarbazepine when compared to CBZ may
result from absence of the epoxide or iminoquinone metabolite.
• Most common side effects are headache, dizziness, nystagmus, blurred
vision, somnolence, nausea, ataxia & fatigue.

39. Barbiturates
• Are substituted pyrimidine derivatives with an ureide configuration.
• Are lipophilic weak acids (pKa 7-8) that are well distributed into the brain.
• Although many barbiturates display sedative-hypnotic activity, only a few have
antiseizure properties.
• Paradoxically, many barbiturates cause convulsions at larger doses.
• The barbiturates clinically useful as AEDs are phenobarbital, mephobarbital &
primidone.

40. Mechanism of action
• The mechanism of anti-seizure action for the barbiturates is unknown but is thought to
involve blockade of sodium channels & enhancement of GABA-mediated inhibitory
transmission.
Phenobarbital
• Commonly used for convulsive disorders & is the drug of choice for seizuresin
infants up to 2 months of age.
• Indicated in the treatment of partial & generalized tonic-clonic seizures in all age
groups, although it is less effective than phenytoin or CBZ in adults.
• Although ocassionally used as monotherapy, it usually is combined with another
AED.
• Because of its slow onset of action, it is administered after benzodiazepines for
the treatment of status epileptics.

41. • For emergency control of acute convulsive disorders associated with eclampsia
( although magnesium sulfate is the standard treatment), meningitis, tetanus &
toxic reactions to strychnine or local anaesthetics.
• Is a weak acid (pKa 7.4.log p=1.53 at Ph 7.4) i.e approximately 50% ionized at
physiological pH & is well distributed into the CNS.
• Oral bioavailability is of 80-100 %.
• Oral absorbtion is slow but nearly complete.
• 40-60% protein bound & exhibits a long plasma t1/2 of 2 to 6 days.
• 25 to 50 % of dose is excreted unchanged in the urine.
• Remainder is metabolised to its inactive metabolite- 5-p-hydroxyphenyl-5-ethyl-
barbituric acid, which is then conjugated as its glucuronide or sulfate & is
excreted in the urine.
• Alkalinizing the urine or increasing the urine outflow substantially increases the
rate of excretion of unchanged phenobarbital & its metabolites.

42. • Because of its inducing effect on hepatic enzymes, phenobarbital has many drug
interactions, decreasing plasma levels of CBZ, valproate, lamotrigine, tiagabine,
zonisamide, warfarin, theophylline, cimitidine & those of other CYP3A4 substrates.
• Serum concentrations of phenobarbital are increased by valproate.
Adverse effects
• Serious toxicity is rare, but drowziness is the most common side effects reported for
phenobarbital.
• Of the barbiturates, only phenobarbital, mephobarbital & primidone are antiseizure
at subhypnotic doses.
• The sedative effect of phenobarbital limits its use in older children & adults.
• When compared to phenyoptin or CBZ, phenobarbital shows more sedation,
irritability, paradoxical hyperactivity & impaired intelluctal function.
• Rare are the idiosyncratic hypersensitivity reactions to phenobarbital that i9nclude
rash, agranulocytosis, aplastic anaemia & hepatitis.

43. • Long term use of phenobarbital may precipitate folate, vitamin k or vtamin D
deficiency.
• Should be used with caution in patients with renal impairment.
• Barbiturates are known to cause fetal abnormalities & a neonatal coagulation
defect responsive to vitamin K.
Mephobarbital
• Pka of 7.7
• Approximately 50% of an oral dose is absorbed from the GIT.
• The principal route of mephobarbital metabolism is N-demethylation by liver to
form phenobarbital, which may be excreted in the urine unchanged and as its
p-hydroxy metabolite & glucuronide or sulfate conjugates.
• Less commonly used in the treatment of generalised & partial seizures.
• Like phenobarbital, it is classified as a long acting barbiturate.

44. Primidone
• Is the 2-deoxy derivative of phenobarbital
• For initial or adjunctive treatment of simple partial, complex partial & tonic-clonic
seizures.
• Less effective against these type of seizures than is phenytoin or CBZ & it shares
the antiseizure & sedative actions similar to that of phenobarbital.
• Often is used to treat benign familial tremor.
• Metabolised by liver enzymes to phenobarbital & phenylethylmalonamide.
• All three molecules have anti-seizure activity.
• Phenylethylmalonamide appears to be weaker & to be more toxic metabolite.

45. Benzodiazepines
• The benzodiazepines diazepam, lorazepam, clonazepam, clorazepate &
midazolam are effective for seizure control.
• Duration of action for Diazepam- 2 hrs
midazolam- 3-4 hrs
clonazepam-24 hrs
lorazepam- 72 hrs
• Diazepam & lorazepam can be administered either IV or IM for control status
epilepticus
• Midazolam has a faster onset of action than diazepam & lorazepam because of
its rapid absorbtion from the injection site & seizure arrest is attained within 5 to
10 minutes.

46. • Diazepam Clonazepam Lorazepam
Clorazepate Midazolam

47. Mechanism of action
• Benzodiazepines are thought to produce their anti-seizure effect primarily by
enhancing the effect of the inhibitory neurotransmitter GABA on the GABAA
chloride channel.
• Additional evidence suggests that the benzodiazepines may diminish voltage-
dependent sodium, potassium & calcium currents in a manner independent of the
GABAA / benzodiazepine receptor complex.
Diazepam
• Given orally for adjunctive control of convulsive disorders
• As rectal gel for refractory patients with epilepsy
• Parenterally as part of the regimen for the treatment of status epilepticus or other
severe, recurrent seizures.
• Rectal diazepam gel is an effective & well tolerated therapy for acute repetitive
seizures.

48. Kinetics
• Orally administered diazepam is less effective as an AED, because tolerance
to the anti-seizure effects of diazepam develops within a short period.
• Diazepam gel is rapidly absorbed rectally, having greater than 90%
bioavailability.
• Useful to control prolonged febrile seizures in children.
• IV for rapid control of status epilepticus
• Because of its high lipid solubility, IV diazepam enters the CNS rapidly.
• However, the initial high brain concentrations is reduced quickly because of its
redistribution, thus status epilepticus may return.
• To prevent the return of status epilepticus, the initial dose of diazepam is
followed by parentral phenytoin & phenobarbital as needed for the control of
tonic-clonic status epilepticus.
• For absence status epilepticus, diazepam usually is followed by ethosuximide.

49. Adverse effects
• Dizziness, ataxia, headache, nervousness, euphoria & rash occour less
frequently.
• Excessive use of rectal diazepam may produce rebound seizures.
• Intravenous administration may produce infrequent respiratory depression &
hypotension.
• Other sedative drugs such as barbiturates, valproates, narcotics,
phenothiazines, monoamine oxidase inhibitors & antidepressants can potentiate
the effects of diazepam.
• Because diazepam clearence is decreased in the elderly & in patients with
hepatic insufficiency, a dosage reduction may be warranted.

50. Carbamate
• Felbamate is a dicarbamate that is structurally similar to the antianxiety drug
meprabamate.
Mechanism of action
• Althuogh unknown, it antagonises the NMDA recceptor by binding to the glycine
recognition site, preventing the usual glycine-induced increase in calcium channel
operating frequency & lowering calcium currents.
OCONH 2
OCONH 2
H
Felbamate
OCONH 2
OCONH 2
F
2
-
fluoro felbamate

51. • Metabolism of felbamate
H
OCONH2
OCONH2
Felbamate
OH
H
OCONH 2
2phenyl
-
1,3
-
propanediol monocarbamate
OH
H
O
OCONH 2
3
-
carbamyl
-
2
-
phenyl proponic acid
H
OCONH 2
O
H
3
-
carbamyl
-
2
-
phenyl propionaldehyde
CH2
O
H
2
-
phenylpropenal
(Atropaldehyde)
GSH
O
H
S
Glutathione
Glutathione metabolite

52. • Adverse effects
• Rare occurence of aplastic anaemia & of severe hepatotoxicity, which may be
associated with the in vivo formation of reactive metabolites.
Lamotrigine
• Can be used as a monotherapy.
• Mechanism of action
• Ability to produce a blockade of sodium channel repititive firing. In addition,
lamotrigine appears to reduce glutaminergic exciatatory transmission, although
the mecanism of action remains unclear.
Adverse effects
• Increased incidence of severe rashes, particularly in children or patients taking
valproate. This increase can be attenuated by very slow dose escalation,
because rashes appear within the first 8 weeks of treatment.
• Other common side effects include dizziness, headache, blurred vision, nausea.
Cl
Cl
N
N
NNH2 NH2

53. Valproic acid & its derivatives
• Valproic acid is effective against both MES test & pentylenetertazole induced
seizures in animals & possesses a satisfactory margin of safety.
• Because the pKa of valproic acid is 4.7, the drug is completely ionized at
physiological pH; thus, the valproate ion is almost certainly the
pharmacologically active species.
CH3
CH3
C OH
O
CH3
CH3
C OH
O
CH2
CH3
C OH
O
Valproic acid
(dipropylacetic acid)
(E)-2
-
ene
-
valproic acid 4
-
ene
-
valproic acid

54. Mechanism of action
• Valproate appears to increase the inhibitory effect of GABA, possibly by
activation of glutamic acid decarboxylase or inhibition of GABA transaminase.
• Valproate recently has been shown to decrease the uptake of GAB into cultured
astrocytes, this action may contribute to the AED efficacy.
• Valproate is known to produce a blockade of high frequency repetitive firing by
slowing the rate of Na+ recovery from inactivation, a mechanism consistent with
the actions of phenytoin & CBZ.
• Valproate blocks the low-threshold T-type Ca2+ channel.
Uses
• Indicated in adjunct treatment of absence seizures or as an adjunct when
absence seizures occur in combination with either tonic-clonic seizures,
myoclonic seizures or both.
• For patients with unambiguous idiopathic generalised epilepsy, valproate often
is the drug of choice, because it controls absence, myoclonic & generalized
tonic-clonic seizures well.
• It is also approved by US FDA for use in complex partial seizures, occurring with
or without other seizure types in adults or children 10 years of age or older.
•

55. Synthesis of Sodium Valproate
CH3
CH3
OH
4
-
heptanol
CH3
CH3
Br
HBr
4
-
bromoheptane
CH3
CH3
CN
KCN
NaOH
Hydrolysis
CH3
CH3
COONa
SodiumValproate

56. Screening methods for anti-epileptic activity.
• Chemical method
• Electrical method (MES)
• Genetical method
Principle
• MES induced convulsions in animals represent grand mal type of epilepsy
• Chemo covulsions produce clonic type of convulsions resemble petit mal type
of convulsions in man.
• The MES convulsions are divided into five phases such as
a) tonic flexion
b) tonic extensor
c) clonic convulsion
d) stupar
e) recovery or death
This procedure may be used to produce convulsions both in rats & mice.

57. Procedure
• Hold the animal properly, place corneal electrodes on the cornea & apply the
prescribed current. Note the different stages of convulsions i.e a, b, c, d, e. Note
the time (sec) spent by the animal in each phase of the convulsions.
• Inject phenytoin intraperitoneally to a group of 4-5 rats. Wait for 30 min &
subject the animals to elctroconvulsions.
• Note the reduction in time or abolition of tonic extensor phase of MES
convulsion.