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ISSN: 2410-8790 Asif / Current Science Perspectives 2(2) (2016) 19-38 iscientic.org.

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Article type:

Review article

Article history:

Received September 2015

Accepted November 2015

April 2016 Issue

Keywords:

Antiepileptic drugs

Benzodiazepines

Phenytoin

Valproic acid

The main objective of antiepileptic drug (AED) therapy is to permit patients to

maintain a normal lifestyle by totally control of seizures with minimal adverse effects.

Phenobarbital (PBT), the first extensively used AED, consequently surge in AEDs

such as valproic acid (VLPA), bezodiazepines (BZDs) and phenytoin (PHT) was a

direct importance of the progress of animal seizure models. Thus many AEDs are

developed and associated with dose limiting adverse effects, adverse reactions and

toxicity by drug-drug interactions. The awareness that these early compounds could be

further optimized for acceptability and properties has rational drug design efforts for

progress of subsequent AEDs. Normally AEDs modulate voltage-gated ion channels,

facilitate inhibitory neurotransmissions, reduce excitatory neurotransmissions and/or

adjust synaptic release. This information, coupled with genetic links with epilepsy, has

assisted a more recent target-based approach to novel AEDs

© 2016 International Scientific Organization: All rights reserved.

Capsule Summary: Study on clinically used antiepileptic drugs and its effects on epileptic patients including their different adverse

effects are discussed. The new generation AEDs with novel mechanism of actions will enhance the probability for success in treating a

varied patient population together with those patients suffering from drug resistant forms of epilepsy.

Cite This Article As: Mohammad Asif. 2016. A review on antiepileptic drug and their uses, mechanism of actions, adverse effects

and drug interaction. Current Science Perspectives 2(2) 19-38

INTRODUCTION

Epilepsy or convulsions affects approximately 20-40 million

people globally. It is more commonly affected children than

adults, with frequency of nearly eight per 1000 children below

the age of seven years. Epilepsy is the second most general

neurological disorder, after stroke. It is a disorder of the CNS and

illustrated by extreme electrical discharge. A typical seizure may

comprise brief and periodic episodes of change in the usual state

of consciousness, loss of muscle tone, sensory and behavioral

changes. Seizures might be non epileptic if evoked in the normal

brain by treatments, like electric shock or chemical convulsions,

or epileptic when happening without evident provocation.

Seizures are originated by “occasional, sudden, extreme, rapid,

and local discharge of gray matter” and generalized convulsion

outcomes when normal brain tissue is attacked by the seizure

activity started in the abnormal focus. In few cases of epilepsy, a

seizure may be linked with occurrence of an infection, stroke,

tumor, or birth injury. Though, in other cases, it may be related

with a biochemical and (or) physiological defects in the brain

most probably due to an imbalance of excitatory and inhibitory

neurotransmitters (NTMs). This imbalance of NTMs may be a

result of genetic factors or structural pathology stress (Wagh et

al., 2011; Porter, and Meldrum. 2001; Macdonald and

Greenfield. 1997; Gerlach and Krajewski. 2010). A typical

therapeutic approach is to optimize the use of a single

antiepileptic drug (AED), given that about 60% of patients have

become seizure free by this approach. As a second line approach,

concomitant therapy with more than one ADE is used. Unluckily,

only 5% of patients who fail to react effectively to monotherapy

incident long term liberty from seizures using poly therapy. The

remaining patients are therapy-resistant in that seizures are not

Current Science Perspectives 2(2) (2016) 19-38

A review on antiepileptic drug and their uses, mechanism of actions, adverse effects and

drug interaction

Mohammad Asif

Department of Pharmacy, GRD(PG) Institute of Management & Technology, Dehradun, 248009, (Uttarakhand), India

*Corresponding author’s E-mail: [email protected]

A R T I C L E I N F O A B S T R A C T

mailto:[email protected]



effectively controlled (Coulter, 1998, French, et al., 2004; Fisher,

et al., 2005; Birbeck et al., 2007).

Seizure Classification

More than 40 distinctive epileptic signs have been recognized

and generally classified into partial and generalized seizures. The

partial seizures report for about 60 percent of all epilepsies and

usually are due to a lesion in some part of the cortex, tumors,

trauma, developmental malformations, stroke, and infections.

Partial seizures are related with electrical discharge that begins

locally and often remains localized. Partial seizure may generate

relatively simple signs without loss of consciousness, such as

involuntary muscle contractions, autonomic discharge or

abnormal sensory experiences or, they may cause more complex

effects on consciousness, mood and behavior, often termed

psychomotor epilepsy. In psychomotor epilepsy, which is often

related with a focus in the temporal lobe, the attack may consist

of stereotyped movements such as rubbing or tapping

movements, or much more complex behavior like walking,

dressing, or hair-combing. The seizure generally lasts for a few

minutes, after which the patient get wells with no memory of the

event. The manners during the seizure can be bizarre and

convoyed by a strong emotional response. The generalized

epilepsy report for approximately 40 percent of all epilepsies and

etiology is normally genetic. Generalized seizures involve the

entire brain, as well as the reticular system, thus generating

abnormal electrical activity throughout both hemispheres. Instant

loss of consciousness is feature of generalized seizures.

The major categories are tonic-clonic seizures (grand mal)

and absences (petit mal). A tonic-clonic seizure consists of an

initial powerful contraction of the entire musculature, genereting

a rigid extensor spasm. Respiration prevents and micturition,

defecation, and salivation are often occurs. The tonic phase lasts

for about one minute and is followed by a series of violent

synchronous jerks that slowly finishs in about 2-4 minutes. The

patient continues unconscious for a few more minutes and then

slowly recovers, feeling ill and confused. Injury may happen

during the convulsive episodes. Absence seizures occur in

children; they are much less dramatic but may occur more

regularly than tonic-clonic seizures. The patient suddenly ceases

whatever he/she was doing, occasionally stopping speaking in

mid-sentence, and stares blankly for a few seconds, with slight or

no motor disturbance. With optimal drug treatment, epilepsy is

prevented completely in about 75 percent of patients, and about

10 percent continue to have seizures at gaps of one month or less,

which severely interrupt their life and work. Therefore need to

improve the efficacy of therapy. The certain generalized seizures

are well correlated with experimental seizures produced in

animals by pentylenetetrazol (scPTZ), and partial seizures

correlated with seizures generated by maximal electroshock

(MES) method (Dunn et al., 1990; Mattson, et al., 1992; Rho, et

al., 1994; Bazil, and Pedley. 1998; Kwan, and Brodie. 2000;

Kwan, and Sander. 2004; Bialer et al., 2004; Bialer. 2006).

Common mechanism of action of antiepileptic drugs

Three major mechanisms of action are recognised: modulation of

voltage-gated ion channels; enhancement of γ-aminobutyric acid

(GABA)-mediated inhibitory neurotransmission; and

attenuation of glutamate-mediated excitatory neurotransmission

(Lowenstein, and Alldredge. 1998; Luszczki. 2009; Macdonald,

and Kelly. 1993; McAllister 1992; Rand, et al., 1995; Rogawski,

and Loscher. 2004; Scheffer, and Berkovic. 2003).

1. Voltage-gated ion channels:

Ion channels regulate the flow of positively and negatively

charged ions across neuronal cell membranes and ultimately

control the intrinsic excitability of the CNS. Voltage-gated Na+

channels are responsible for depolarization of the nerve cell

membrane and conduction of action potentials across the surface

of neuronal cells. At nerve terminals, voltage-gated Ca+ channels

are recruited by Na+ channel dependent depolarization, leading to

Ca+

entry, NTM release and chemical signaling across the

synapse. Ca+ channels are distributed, on a cellular and

anatomical basis. The AEDs (e.g., PHT, CBZ, valproate (VPA),

lamotrigine (LTG) involves the prolongation and and closing of

inactivation gate of Na+ ion channels, therefore reducing the

capability of neurons to fire at elevated frequencies. This

mechanism supplies protections against MES in animals and

focal seizures in humans. A low threshold Ca2+

ion current (T-

type) manages oscillatory comebacks in thalamic neurons. The

reduction of current by the use of AEDs such as [(ethosuximide

(ESM)], dimethadione, VPA).

2. Inhibitory neurotransmission:

The GABA is the predominant inhibitory NTM in the

mammalian CNS and is released at up to 40% of all synapses in

the brain. GABA is synthesized from glutamate by the action of

the enzyme glutamic acid decarboxylase. Following release from

GABA-ergic nerve terminals, it acts on the post-synaptic GABA-

A receptor, a ligand-gated ion channel comprising five

independent protein subunits arranged around a central chloride

ion (Cl-) pore. Nineteen GABA-A receptor subunits have been

identified to date (α1-6, β1-3, γ1-3, δ, ε, θ, π, ρ1-2), any five of

which could in theory form a functional channel, with subunit

composition conferring physiology and pharmacology. The

GABA-A receptor responds to GABA binding by increasing Cl-

conductance resulting in fast neuronal hyper-polarization or

inhibition. The drug may work directly on the GABA-receptor-

Cl- ion channel complex (e.g., barbiturates, BZDs), and inhibit

the metabolism of GABA (e.g., VPA, vigabatrin) or enhance the

release of GABA (e.g., gabapentin). This system affords

protection against generalized and focal seizures.

3. Excitatory neurotransmission:

Glutamate is the principal excitatory NTM in the mammalian

brain. Release from glutama- teergic nerve terminals, it exerts its

effects on three specific subtypes of ionotropic receptor in the

postsynaptic membrane, designated according to their agonist

specificities-AMPA, kainate and NMDA. These receptors

respond to glutamate binding by increasing cation conductance

resulting in neuronal depolarisation or excitation. The AMPA

and kainate receptor subtypes are permeable to Na+ and involved

in fast excitatory synaptic transmission. In contrast, the NMDA

receptor is permeable to both Na+ and Ca2+

, owing to a voltage-

dependent blockade by Mg2+

at resting membrane potential, is

only activated during periods of prolonged depolarization, as

might be expected during epileptiform discharges. Metabotropic

glutamate receptors perform a similar function to GABA-B



receptors; they are G-protein coupled and act predominantly as

auto receptors on glutamatergic terminals, limiting glutamate

release. Glutamate is removed from the synapse into nerve

terminals and glial cells by a family of specific Na+-dependent

transport proteins and is inactivated by the enzymes glutamine

synthetase (glial cells only) and glutamate dehydrogenase. Some

AEDs (e.g., PBT, topiramate) block the AMPA receptor and

some (Felbamate, remacemide) block NMDA receptors. This

vital mechanism has effected in the progress of new AEDs.

Antiepileptic drugs

Available AEDs manage seizures in about two thirds of the

epileptic patients. The potassium bromide (KBr) in year 1857

was used as an antiepileptic agent. The PBT was launched in

year 1912, and later, in year 1938, PHT was used as AED. For a

prolonged time period it was considered that a single AED would

be able to treat all types of epilepsy. The AEDs used in the

management of two major types of seizures namely partial and

generalized seizure, are relatively different in their profiles. The

phenobarbitone (PBT) was the first synthetic drug accepted as

AED. Its effectiveness was limited to generalized tonic-clonic

seizures, and to a lesser extent, simple and complex partial

seizures and had no effect on absence seizures. The PHT reduced

seizures without causing sedative effects. The MES test is

important, because drugs that are valuable against tonic hind

limb extension usually have proven to be useful against partial

and tonic-clonic seizures in humans. Another experiment,

seizures encouraged by the chemo-convulsant agent scPTZ, is

mainly valuable in recognizing drug molecules that are effective

against myoclonic or absence seizures in humans. The structures

of most of the AEDs introduced before 1965 were closely related

to PBT included hydantoins and succinimides. Between 1965

and 1990, chemically distinct structures of BZDs, iminostilbene

(CBZ), and branched-chain carboxylic acid (VLPA) were

introduced, followed in the 1990s by a phenyltriazine (LTG),

cyclic analog of GABA (gabapentin), sulfamate-substituted

monosaccharide (topiramate), nipecotic acid derivative

(tiagabine), and pyrrolidine derivative (levetiracetam) (Miller, et

al., 1999; Mohanraj, and Brodie. 2003; Morrell. 1998; Motte, et

al., 1997).

General classification of Antiepileptic drugs

The Various AEDs are classified in various classes (Dwivedi.

2001; Anderson. 1998; Chisholm. 2005), some AEDs were used

in earliest time and some drugs are currently used.

1. Aldehydes: Paraldehyde is one of the earliest anticonvulsants.

It is still used to treat status epilepticus, particularly where there

are no resuscitation facilities.

2. Aromatic allylic alcohols: Stiripentol, indicated for the

treatment of severe myoclonic epilepsy in infancy (SMEI).

3. Barbiturates: Barbiturates are drugs that act as CNS

depressants and they produce a wide spectrum of effects, from

mild sedation to anesthesia. The following are classified as

anticonvulsants: PBT, MethylPBT, Metharbital, Barbexaclone.

4. Benzodiazepins: Clobazam, clonazepam (CZP), Clorazepate,

Diazepam (DZP), Midazolam, Lorazepam, Nitrazepam, and

especially nimetazepam are powerful AEDs.

5. Bromides: Potassium bromide (in 1857), earliest effective

treatment for epilepsy.

6. Carbamates: Felbamate.

7. Carboxamides: Carbamazepine (CBZ).

8. Fatty acids: The following are fatty-acids: The VPAs

9. GABA analogs: Some AEDs are GABA analogue, example

Gabapentin, Pregabalin.

10. Hydantoins: AEDs with htdantion nucleus are Ethotoin,

PHT, MePHT

11. Oxazolidinediones: Paramethadione, Trimethadione,

Ethadione, Propionates.

12. Pyrimidinediones: Primidone.

13. Pyrrolidines: Brivaracetam, Levetiracetam, Seletracetam.

14. Succinimides: ESM, Phensuximide (PSM), Mesuximide.

15. Sulfonamides: Acetazolamide, Sultiame, Methazolamide,

Zonisamide.

16. Triazines: LTG.

17. Ureas: Pheneturide, Phenacemide.

18. Valproylamides (amide derivatives of VPA): Valpromide,

Valnoctamide

Drug development for epilepsy

For a long time it was assumed that a single drug could be

developed for the treatment of all forms of epilepsy, but the

causes of epilepsy are extremely diverse, encompassing genetic

and developmental defects, infective, traumatic, neoplastic, and

degenerative disease processes, drug therapy to date shows little

evidence of etiologic specificity. However some specificity is

according to seizure types. Drugs acting selectively on absence

seizures can be identified by animal screens, using either

threshold PTZ clonic seizures in mice or rats showing absence-

like episodes. In contrast, the MES test, with suppression of the

tonic extensor phase, identifies drugs such as PHT, CBZ, and

LTG that are active against generalized tonic-clonic seizures or

complex partial seizures. Use of the MES test as the major

primary screen for new drugs has probably led to the

identification of drugs with a common mechanism of action

involving prolonged inactivation of the voltage-sensitive Na+

channel. Limbic seizures induced in rats by the process of

electrical kindling (involving repeated episodes of focal electrical

stimulation) probably provides a better screen for predicting

efficacy in complex partial seizures (Dunn and Fielding. 1987;

Dunn and Corbett. 1992; Dwivedi, and Smar. 1994).

Basic pharmacology of antiepileptic drugs

The AEDs can be classified into five very similar chemical

groups: barbiturates, hydantoins, oxazolidinediones,

succinimides, and acetylureas. These groups have in common a

similar heterocyclic ring structure with a variety of substituents.

For drugs with basic structure, the substituents on the

heterocyclic ring determine the pharmacologic class, either anti-

MES or anti-PTZ. Very small changes in structure can alter the

mechanism of action and biological properties of the compound.

The remaining drugs-CBZ, VLPA, and the BZDs-are structurally

dissimilar, ie, felbamate, gabapentin, LTG, oxcarbazepine

(OXC), tiagabine, topiramate, vigabatrin, and levetiracetam.

Existing AEDs provide adequate seizure control in about two

thirds of patients. A fraction of the epileptic population is

resistant to all available drugs. New AEDs are being sought not

only by the screening tests but also by more rational approaches.

Compounds are sought that act by one of three mechanisms: (1)



enhancement of GABAergic (inhibitory) transmission, (2)

diminution of excitatory (usually glutamate ergic) transmission,

or (3) modification of ionic conductance (Farwell, et al., 1990;

Frank, et al., 1999; French, et al., 1999; He, et al., 2004;

Honmou, et al., 1995; Huguenard. 1999).

Drugs used in partial and generalized tonic-clonic seizures

The major drugs for partial and generalized tonic-clonic seizures

are PHT (or congeners), CBZ, VPA, and barbiturates. However,

availability of newer drugs- LTG, gabapentin, OXC, topiramate,

vigabatrin, and levetiracetam is altering clinical practice.

1. Phenytoin

Phenytoin is the oldest non sedative AED, introduced in 1938

that altered electrically induced seizures in lab animals. It has

much lower sedative properties than compounds with alkyl

substituents at the 5 position. A more soluble prodrug of PHT,

fosPHT, is parenteral use. This phosphate ester compound is

rapidly changed to PHT in the plasma. PHT has major effects on

several physiologic systems. It alters Na+, K

+, and Ca

2+

conductance, membrane potentials, and concentrations of amino

acids, NTMs norepinephrine, acetylcholine, and GABA. PHT

blocks sustained high-frequency repetitive firing of action

potentials. This effect is seen at therapeutically relevant

concentrations. It is a use-dependent effect on Na+ conductance,

arising from preferential binding to and prolongation of the

inactivated state of the Na+ channel. This effect is also seen with

therapeutically relevant concentrations of CBZ and VPA and

probably contributes to their antiseizure action in the MES model

and in partial seizures. PHT, CBZ, and sodium VPA all markedly

reduced the number of action potentials elicited by the current

pulses. At high concentrations, PHT also inhibits the release of

serotonin and norepinephrine, promotes the uptake of dopamine,

and inhibits monoamine oxidase (MAO) activity. In addition,

PHT paradoxically causes excitation in some cerebral neurons. A

reduction of Ca+

permeability, with inhibition of Ca+ influx

across the cell membrane, may explain the ability of PHT to

inhibit a variety of Ca+ induced secretory processes, including

release of hormones and NTMs. The mechanism of PHT's action

probably involves a combination of actions at several levels. At

therapeutic concentrations, the major action of PHT is to block

Na+

channels and inhibit the generation of repetitive action

potentials. PHT is one of the most effective drugs against partial

seizures and generalized tonic-clonic seizures. Other drugs,

notably PBT and CBZ, cause decreases in PHT steady-state

concentrations through induction of hepatic microsomal

enzymes. The INH inhibits the metabolism of PHT, resulting in

increased steady-state concentrations when the two drugs are

given together.

2. Mephenytoin, ethotoin, and phenacemide

Many congeners of PHT have been synthesized, but only three

have been marketed in the USA, and one of these (phenacemide)

has been withdrawn from the market. The first two congeners,

mePHT and ethotoin, like PHT, appear to be most effective

against generalized tonic-clonic seizures and partial seizures. The

occurrence of severe responses like agranulocytosis, dermatitis,

or hepatitis is higher for mephenytoin than for PHT. Ethotoin

may be proposed for patients hypersensitive to PHT, but larger

doses are essential. The unfavorable effects and toxicities are

usually less severe than those related with PHT, but the drug

appears to be less efficient. Both ethotoin and mephenytoin

(MPHT) share with PHT the property of saturable metabolism

within the therapeutic dosage variety. Mephenytoin is

metabolized to 5,5-ethylphenylhydantoin by demethylation. This

metabolite, nirvanol, gives most of the antiepileptic activity of

mephenytoin. Both mephenytoin and nirvanol are hydroxylated

and undergo successive conjugation and excretion. The third

congener of PHT, phenacemide, is a analog of PHT.

3. Carbamazepine

Carbamazepine (CBZ) is closely related to imipramine and other

tricyclic antidepressants, it is a tricyclic compound useful in

management of bipolar depression. It was initially used for the

therapy of trigeminal neuralgia but has established as useful

antiepileptic agent as well. The ureide moiety (-N-CO-NH2)

present in the heterocyclic ring of the majority AEDs is also exist

in CBZ. The mechanism of action of CBZ showed to be like as

of PHT. Like PHT, CBZ exhibited activity against MES seizures.

The CBZ blocks Na+ channels at therapeutic concentration and

inhibits high-frequency recurring firing in neurons. It also

operates presynaptically to reduce synaptic transmissions. These

effects possibly account for the anti-epileptic action of CBZ. It

interacts with adenosine receptors and also inhibits uptake and

release of norepinephrine from brain synaptosomes but does not

control GABA uptake in brain. The indication suggested that the

postsynaptic action of GABA can be potentiated by CBZ. It is

the drug of choice for partial seizures, and may be use for

treatment of generalized tonic-clonic seizures. It is also valuable

in some patients with mania (bipolar disorder).

4. Oxycarbazepine

Oxycarbazepine is directly related to CBZ and helpful in the

same seizure types, but it may have a superior toxicity profile. Its

activity, consequently, resides nearly entirely in the 10-hydroxy

metabolite, to which it is rapidly converted and which has a half-

life similar to that of CBZ (8–12) hrs. The drug is mostly

excreted as the glucuronide of the 10-hydroxy metabolite. It is

less potent than CBZ, doses of OXC may need to be 50% higher

than those of CBZ to obtain equivalent seizure control. Fewer

hypersensitivity reactions to OXC were reported. It induce

hepatic enzymes to a lesser extent than CBZ. Adverse effects

such as hyponatremia that do occur with OXC are similar in

character with CBZ.

5. Phenobarbital

Aside from the bromides, PBT is the oldest currently available

AEDs. Although it has long been considered one of the safest of

the AED, the use of other medications with lesser sedative

effects has been urged. The barbiturates are considers as the

drugs of choice for treatment of seizures only in infants. The four

barbituric acid derivatives are clinically useful as AEDs are

phenobarbitone (PBT), mephobarbital, metharbital, and

primidone. The first three are subsequently similar and

considered collectively. The metharbital is methylated barbital

and mephobarbital is methylated PBT; both are demethylated.

The PBT may selectively repress abnormal neurons, inhibiting

the extending and suppressing firing from the foci. Like PHT,



PBT suppresses high-frequency recurring firing in neurons in

culture by an action on Na+ ion conductance, but only at elevated

concentrations. Also at elevated concentrations, barbiturates

block some Ca2+

ion currents (L-type and N-type). The PBT

binds to an allosteric regulatory site on the GABA-BZD receptor,

and it improved the GABA receptor-mediated current by

extending the openings of the Cl-channels. The PBT also blocks

excitatory responses stimulated by glutamate, mainly those

mediated by activation of the AMPA receptor. Both the

enrichment of GABA-mediated inhibition and the decline of

glutamate mediated excitation are seen with therapeutically

applicable concentrations of PBT. The PBT is valuable in the

therapy of partial seizures and generalized tonic-clonic seizures,

even though the drug is often tried for all seizure type,

particularly when attacks are complicated to manage.

6. Primidone

Primidone (2-desoxyPBT) was metabolized in to PBT and

phenylethylmalonamide (PEMA). All these three compounds are

active against convulsions. Although primidone is changed to

PBT, the mechanism of action of primidone itself may be further

like that of PHT. Primidone, similar to its metabolites, is useful

against partial seizures and generalized tonic-clonic seizures and

may be more effective than PBT. It was considered to be drug of

choice for partial seizures, but the partial seizures in adults

strongly suggest that CBZ and PHT are superior to primidone.

Finally, MES seizures in animals suggest that primidone has an

antiepileptic action independent of its conversion to PBT and

PEMA (relatively weak).

7. Vigabatrin

Drugs to enhance the effects of GABA include efforts to find

GABA agonists and prodrugs, GABA transaminase inhibitors,

and GABA uptake inhibitors. Vigabatrin (-vinyl-GABA) is an

irreversible inhibitor of GABA aminotransferase (GABA-T),

enzyme responsible for degradation of GABA. It apparently acts

by increasing the amount of GABA released at synaptic sites,

thereby enhancing inhibitory effects. Vigabatrin may also

potentiate GABA by inhibiting the GABA transporter. It is

effective in a wide range of seizure models. The S(+) enantiomer

is active and R(–) enantiomer appears to be inactive. It is used in

the management of partial seizures and West's syndrome. Typical

toxicities consist of dizziness, drowsiness and weight gain. Less

frequent but more worrying adverse effectss are confusion,

agitation and psychosis.

8. Lamotrigine

Lamotrigine was developed when some scientist considered that

the antifolate action of certain AEDs (eg, PHT) may contribute to

their efficiency. Some phenyl-triazine compounds were

developed for their antifolate properties and were active against

seizure. The LTG, like PHT, reduces continued rapid firing of

neurons and produces a voltage and use-dependent inactivation

of Na + channels. This effect most likely explained the LTG is

effectiveness in focal epilepsy. It shows likely that LTG has a

different mechanism of action to report for its efficacy in

generalized seizures, together with absence attacks; this

mechanism may occupy actions on voltage-activated Ca2+

channels. The LTG is effective as monotherapy for partial

seizures. It is also effective against absence and myoclonic

seizures in children. Adverse effects comprise nausea, dizziness,

headache, diplopia, somnolence, and skin rash.

9. Felbamate

Felbamate has been is successful in some patients with partial

seizures, the drug causes aplastic anemia and hepatitis at

surprisingly high rates. The mechanism of action is not

identified. The strong indication suggested that it is a NMDA

receptor blockade via the glycine binding site. Felbamate has a

half-life of 20 hrs and is metabolized by hydroxylation and

conjugation; considerable amount of the drug is excreted

unaffected in urine. When added to therapy with other AEDs,

felbamate enhanced plasma PHT and VLPA levels but reduces

levels of CBZ. It is used in partial seizures and also active

against the seizures that happen in Lennox-Gastaut syndrome.

10. Gabapentin

Gabapentin is a derivative of GABA and effective against partial

seizures. It is found to be more effective as an AED and appears

not to act on GABA receptors. It may change GABA

metabolism, its non synaptic release, or its reuptake by GABA

transporters. An enhancement in brain GABA concentration is

seen. Gabapentin is carrying into the brain by the L-amino acid

transporter. It anticonvulsant action is against MES-induced

seizure model. The drug also connected to the subunit of voltage-

sensitive Ca2+ channels. Gabapentin is active as an adjunct

against partial and generalized tonic-clonic seizures. It is also

effective in neuropathic pain and for post therapeutic neuralgia in

adults. The most frequent adverse effects are somnolence, ataxia,

dizziness, headache, and tremor.

11. Topiramate

Topiramate is a substituted monosaccharide and structurally

different from other AEDs. Topiramate blocks recurring firing of

cultured spinal cord neurons, like PHT and CBZ. Its mechanism

of action is blocking of voltage dependent Na+ channels and also

appears to potentiate the inhibitory effect of GABA, acting at a

site unlike from the BZD or barbiturate sites. Topiramate also

reduced the excitatory action of kainate on AMPA receptors. It is

possible that all three actions given to topiramate as antiepileptic

agent. It is effective against both partial and generalized tonic

clonic seizures. It has a broader range, with effective against

Lennox-Gestaut syndrome, West's syndrome and absence

seizures. Although no idiosyncratic reactions have been well-

known, side effects are somnolence, fatigue, cognitive slowing,

dizziness, paresthesias, nervousness and confusion. Acute

myopia and glaucoma may require quick drug withdrawal. The

drug is teratogenic in animal models but no human fetal

deformities.

12. Tiagabine

Tiagabine is a nipecotic acid derivative and act as an inhibitor of

GABA uptake in both neurons and glia. It preferentially inhibited

the transporter isoform-1 (GAT-1) rather than GAT-2 or GAT-3

and raises extracellular GABA levels in the forebrain and

hippocampus parts of brain. It extended the inhibitory activity of

synaptically released GABA. In rodents it is effective against

kindled seizures but weak against the MES model. Tiagabine is



point out for the adjunctive therapy of partial seizures. Adverse

effects are nervousness, dizziness, tremor, difficulty in

concentrating, and depression. Confusion, somnolence, or and

ataxia may need discontinuation. Psychosis and rash is an rare

adverse effects.

13. Zonisamide

Zonisamide is a sulfonamide analogue and it mainly site of

action appears to be on the Na+ channel; it may also operates on

voltage-dependent Ca 2+ channels. The drug is efficient against

partial and generalized tonic-clonic seizures and may also be

helpful against infantile spasms and certain myoclonias. Adverse

effects contain drowsiness, cognitive impairment, and potentially

severe skin rashes and it does not interact with other AEDs.

14. Levetiracetam

Levetiracetam is a piracetam derivative that is unsuccessful

against seizures induced by MES or PTZ but has well-known

activity in the kindling model. Its mechanism of action is

indefinite. It has a brain-specific binding site and affects

allosteric modulations of GABA receptors, high-voltage

activated Ca2+ channels and several K + channels. The drug is

used for therapy of partial seizures. Levetiracetam is not

metabolized by cytochrome P450. Adverse effects consist of

somnolence, asthenia, and dizziness. Idiosyncratic reactions are

uncommon.

Drugs used in generalized seizures

1. Ethosuccimide

Ethosuccimide (ESM) is a succinimide and has little effect

against MES but considerable efficacy against PTZ-induced

seizures and was originated as a "pure petit mal" drug. Its

responsibility as the first choice anti-absence drug as

idiosyncratic hepatotoxicity of the optional drug VLPA. The

ESM is the last AED which having cyclic ureide structure. The

three anti-seizure succinimide drugs are ESM, PSM, and

methsuximide. The ESM has an essential effect on Ca2+

currents,

reducing the low-threshold (T-type) current. The T-type Ca2+

currents are thought to provide a pacemaker current in thalamic

neurons responsible for generating the rhythmic cortical

discharge of an absence attack. Inhibition of this current could

account for the specific therapeutic action of ESM. It also

inhibits Na+/K

+ATPase, depresses cerebral metabolic rate, and

inhibits GABA aminotransferase. PSM and methsuximide are

phenylsuccinimides that were developed before ESM and used

mainly as anti-absence drugs. Methsuximide has been used for

partial seizures, it is more toxic, PSM less effective than ESM.

Unlike ESM, these two compounds have some activity against

MES seizures. The desmethyl metabolite of methsuximide has

exerts the major anti-seizure effect.

2. Vaproic acid and sodium valproate

Sodium valproate (VPA) is also used as the free acid, VLPA has

antiseizure activity. It was marketed in France in 1969, VLPA is

fully ionized at body pH for that reason the active form of the

drug may be assumed to be the VPA ion. VLPA is a series of

fatty carboxylic acids that have antiseizure effect; this activity

appears to be greatest for carbon chain lengths of five to eight

atoms. Branching and unsaturation do not significantly alter the

activity but may increase its lipophilicity, thereby increasing its

duration of action. The amides and esters of VLPA are also

active AEDs. VPA is active against both PTZ and MES seizures

like PHT and CBZ. VPA blocks sustained high-frequency

repetitive firing of neurons at therapeutic concentrations. Its

action against partial seizures may be a consequence of this

effect on Na+ currents. Blockade of NMDA receptor-mediated

excitation may also be important. The increased levels of GABA

in the brain after administration of VPA, although the mechanism

remains unclear. An effect of VPA to facilitate glutamic acid

decarboxylase (GAD), enzyme responsible for GABA synthesis

has been described. An inhibitory effect on the GABA

transporter GAT-1 may contribute. At very high concentrations,

VPA inhibits GABA-T in the brain, thus blocking degradation of

GABA. However, at the relatively low doses of VPA needed to

abolish PTZ seizures, brain GABA levels may remain

unchanged. VPA produces a reduction in the aspartate content of

rodent brain. At high concentrations, VPA has been shown to

increase membrane K+ conductance. The low concentrations of

VPA tend to hyperpolarize membrane potentials and may exert

an action through a direct effect on the K+

channels of the

membrane. VPA probably owes its broad spectrum of action to

more than one molecular mechanism. It is very effective against

absence seizures. Although ESM is the drug of choice when

absence seizures occur alone, VPA is preferred if the patient has

concomitant generalized tonic-clonic attacks. The reason for

preferring ESM for uncomplicated absence seizures is VPA's

idiosyncratic hepatotoxicity. VPA has unique ability to control

certain types of myoclonic seizures. Other uses of VPA include

management of bipolar disorder and migraine prophylaxis. It

inhibits the metabolism of several drugs, including PBT, PHT,

and CBZ. The side effects and toxicity of PHT are enhanced. The

inhibition of PBT metabolism may cause levels of the barbiturate

to rise precipitously, causing stupor or coma.

3. Oxazolidinediones

Trimethadione, the first oxazolidinedione, was introduced 1945

and drug of choice for absence seizures until the introduction of

succinimides in 1950s. The use of the oxazolidine -diones

(trimethadione, paramethadione, and dimethadione) is now very

limited. They contain an oxazolidine ring and have similar in

structure to other AEDs introduced before 1960. These drugs are

active against PTZ-induced seizures. Trimethadione raises the

threshold for seizure discharges following repetitive thalamic

stimulation. Its active metabolite dimethadione has the same

effect on thalamic Ca2+

currents as ESM (reducing the T-type

Ca2+

current). Thus, suppression of absence seizures is likely to

depend on inhibiting the pacemaker action of thalamic neurons.

The most common adverse effect is sedation and unusual adverse

effect is hemeralopia, a glare effect in which visual adaptation is

impaired. Accumulation of dimethadione causes a very mild

metabolic acidosis and should not be used during pregnancy.

Other drugs used in management of epilepsy

Some drugs not classifiable by application to seizure type are

discussed in this section.

1. Benzodiazepines



N

NO

O

H3C

Cl

N

NO

H3C

Cl

H2NNH

O

O

HN

NH

O

O

Clobazepam DZP Phenacemide Pimidoner

O

N NH2

OCH3

N

NO

CH3 O

NH2H3C

NH2

N

O

CH3

NH2

O

Dezinamide Nafimidone Pregabelin Levetiracetam

HNNH

O

O

N

O NH2

O

N

O NH2

HO

N

O NH2

PHT OXC 10-Hydroxycarbazepine CBZ

NH

NH

H3C O

O NH

NH

H3C O

OO

NH2

NH2

H3C O

O

OH

NH2

O

Primidone Phenobarbitone Phenylethylmalonamide (PEMA) Vigabatrin

N

NN

Cl

Cl

H2N NH2

O

O

NH2

O

NH2

O

O

OH

H2N

O

O

O O

OH3C

H3C CH3

CH3

OS NH2

O O

Lomatrigine Felbamate Gabapentin Topiramate

Fig. 1: Structures of various antiepileptic drugs



Six BZDs play prominent roles in the therapy of epilepsy. Many

BZDs are quite similar chemically, slight structural alterations

result in differences in activity. They have two different

mechanisms of anti-seizure action, which are shown to different

degrees by the six compounds. The DZP is relatively more potent

against MES and CZP against PTZ (latter effect correlate with an

action at the GABA-BZD allosteric receptor site). DZP is highly

effective against continuous seizure activity, especially

generalized tonic-clonic status epilepticus. Lorazepam is to be

more effective and longer-acting than DZP in the treatment of

status epilepticus. CZP is a long-acting drug with efficacy against

absence seizures. It is one of the most potent AED. It is also

effective in some cases of myoclonic seizures and infantile

spasms. Nitrazepam used especially for infantile spasms and

myoclonic seizures but less potent than CZP. Clorazepate

dipotassium is used for treatment of complex partial seizures.

Drowsiness and lethargy are common adverse effects. Clobazam

is widely used in variety of seizures. It is a 1,5-BZD (all other

BZD drugs are 1,4-BZDs) has less sedative. It does interact with

some other AEDs and causes adverse effects. Two prominent

aspects of BZDs limit their usefulness. The first is their

pronounced sedative effect. Children may manifest a paradoxical

hyperactivity. The second problem is tolerance, in which seizures

may respond initially but recur within few months.

2. Acetazolamide

Acetazolamide is a diuretic its main action is the inhibition of

carbonic anhydrase. Mild acidosis in the brain may be the

mechanism by which the drug exerts its antiseizure activity. The

Figure 1: Continuous……

N

S

S

CH3

O OH

CH3 ON

SO

OH2N

NHH3C

H3CO

O H3C CH3

OHO

ONH3C

H3C O

O

H3C

Tiagabine Zonisamide ESM VLPA Trimethadione

NN

O

Cl

H3C

HNN

OOH

O

Cl

HNN

O

O2N

Cl

HNN

O

Cl

Cl

OH

DZPe Clorazepate CZP Lorazepam

NH

O

NH2

O

OH

NN

N NH2

O

H3C

Phenacemide Denzimol Dezimamide

O

N

N

HN

O

N

SO

H3C Cl

H3C

O

O

OH

CH3

CH3CH3

Nafimidone Rolitoline Stripientol



depolarizing action of bicarbonate ions moving out of neurons

via GABA receptor ion channels will be diminished by carbonic

anhydrase inhibition. It has been used for all types of seizures but

it rapid development of tolerance, with return of seizures usually

within a few weeks.

3. Ziprasidone

Ziprasidone led the exploration of oxindole. It is a novel

effective atypical antipsychotic agent having an oxindole

scaffold and approved for the treatment of schizophrenia.

Ziprasidone was, however, known to be a potent serotonin and

dopamine antagonist.

Therapeutic strategy

For most AEDs, relationships between blood levels and

therapeutic effects have been characterized to a high degree. The

therapeutic index for most AEDs is low. Thus, effective

treatment of seizures requires an awareness of the therapeutic

levels and pharmacokinetic properties as well as the

characteristic toxicities of each agent. Measurements of AED

plasma levels are extremely useful (VanLandingham, et al.,

1998; Wallace, et al., 1998; Xie, et al., 1995; Lambert et al.,

1994; Sachdeo, et al., 1999; Sachdeo, et al., 1997; Sivenius, et

al., 1991).

Management of epilepsy

1. Partial Seizures & Generalized Tonic-Clonic Seizures

The choice of drugs was usually limited to PHT, CBZ, or

barbiturates. There has been a strong tendency in the past few

years to limit the use of sedative AEDs such as barbiturates and

BZDs to patients who cannot tolerate other medications. In the

1980s, the trend was to increase the use of CBZ. Although the

choice now appears to be divided between CBZ and PHT, all of

the newer drugs have shown effectiveness against these seizures.

2. Generalized Seizures

The drugs used for generalized tonic-clonic seizures are the same

as for partial seizures. In addition, VPA is clearly useful. Three

drugs are effective against absence seizures. Two are non-

sedating and therefore preferred, ESM and VPA. CZP is also

highly effective but has disadvantages of dose related adverse

effects and development of tolerance. The drug of choice is

ESM, although VPA is effective in some ESM-resistant patients.

LTG and topiramate may also be useful. Specific myoclonic

syndromes are usually treated with VPA. Other patients respond

to CZP, nitrazepam, or other BZDs, although high doses may be

necessary, with accompanying sedation and drowsiness.

Zonisamide and levetiracetam may be useful. Another specific

myoclonic syndrome, juvenile myoclonic epilepsy, can be

aggravated by PHT or CBZ; VPA is the drug of choice followed

by LTG and topiramate. Atonic seizures are often refractory to

all available medications, although some reports suggest that

VPA may be beneficial, as may LTG. BZDs have been improve

seizure control in some patients but may worsen the attacks in

others. Felbamate has been effective in some patients, although

the drug's idiosyncratic toxicity limits its use. If the loss of tone

appears to be part of another seizure types (absence or complex

partial).

3. Drugs Used in infantile spasms

The treatment of infantile spasms is unfortunately limited to

improvement of control of the seizures rather than other features

of the disorder, such as retardation. Most patients receive

corticotropin, therapy must often be discontinued because of

adverse effects. If seizures recur, repeat courses of corticotropin

or corticosteroids can be given, or other drugs may be tried.

Other drugs used are BZDs such as CZP or nitrazepam, their

efficacy in this heterogeneous syndrome may be nearly as good

as that of corticosteroids. Vigabatrin may also be effective.

4. Status Epilepticus

There are many forms of status epilepticus. The most common,

generalized tonic-clonic status epilepticus is a life-threatening

emergency, requiring immediate cardiovascular, respiratory,

metabolic management as well as pharmacologic therapy. The

latter virtually always requires i.v. administration of AEDs. DZP

is the most effective drug in most patients and is given by i.v. to

a maximum total dose of 20–30 mg in adults. DZP may depress

respiration. The effect of DZP is not lasting, but the 30- to 40-

minute seizure-free interval allows more definitive therapy to be

initiated. For patients who are not actually in the throes of a

seizure, DZP therapy can be omitted and the patient treated at

once with a long-acting drug such as PHT. Some physicians

prefer lorazepam, which is equivalent to DZP in effect and

perhaps somewhat longer-acting. Until the introduction of

fosphenytoin, the mainstay of continuing therapy for status

epilepticus was i.v. PHT, which is effective and non sedating. It

should be given as a loading dose of 13-18 mg/kg in adults; the

usual error is to give too little. Administration should be at a

maximum rate of 50 mg/min. It is safest to give the drug directly

by i.v. push, but it can also be diluted in saline; it precipitates

rapidly in the presence of glucose. Careful monitoring of cardiac

rhythm and B.P is necessary, especially in elderly people. At

least part of the cardiotoxicity is from the propylene glycol in

which the PHT is dissolved. FosPHT, which is freely soluble in

i.v. solutions without the need for propylene glycol or other

solubilizing agents, is a better parenteral agent. This prodrug is

two thirds to three quarters as potent as PHT on mg basis. In

previously treated epileptic patients, the administration of a large

loading dose of PHT may cause some dose-related toxicity such

as ataxia. For patients who do not respond to PHT, PBT can be

given in large doses: 100–200 mg i.v. to a total of 400–800 mg.

Respiratory depression is a common complication, especially if

BZDs have already been given, and there should be no hesitation

in instituting intubation and ventilation. Although other drugs

such as lidocaine have been recommended for the treatment of

generalized tonic-clonic status epilepticus, general anesthesia is

necessary in highly resistant cases. For patients in absence status,

BZDs are still drugs of first choice. Rarely, i.v. VPA may be

required. The generalized tonic-clonic status epilepticus is a life

threatening emergency requiring immediate cardiovascular,

respiratory, metabolic management along with AEDs. The i.v.

injection of 20-30 mg of DZP or lorazapam is followed by a long

acting drug such as PHT (15-20 mg/kg), i.v. PHT (15-20 mg/kg)

alone successfully treats 41-90 percent of patients, i.v. PBT (20

mg/kg in adults) is also effective in treatment of status

epilepticus.

5. Neuropathic pain and anxiety



All AEDs must applied for their actions by adjusting the activity

of the basic mediators of neuronal excitability: voltage and

NTM–gated ion channels. The Ca2+

channel subunit is

accountable for chronic pain states and axiety. Gabapentin is

exclusive among Ca2+

channel ligands. Since the subunit appears

to be ordinary to all voltage-dependent Ca2+

channel, it is

believable that gabapentin modulates the activity of more than

one type of neuronal Ca2+ channel. It is likely that gabapentin

exerts functional effects only with particular combinations of

subunits. The modulations of voltage-dependent neuronal Ca2+

channels are essential in the antiepileptic action of ligands.

Pregabalin was used for the therapy of both neuropathic pain and

anxiety.

Special aspects of the toxicology of antiepileptic drugs

1. Teratogenicity

The teratogenicity of AEDs shows that a distinctive pattern of

physical abnormalities in infants of mothers with epilepsy is

associated with the use of AEDs during pregnancy, rather than

with epilepsy itself. AEDs taken by pregnant women to prevent

seizures are among the most common causes of potential harm to

the fetus. AEDs are used frequently to prevent seizures, PBT,

PHT, and CBZ were found to cause major malformations,

microcephaly, growth retardation, and distinctive minor

abnormalities of the face and fingers in infants exposed to them

during pregnancy. Moreover, epilepsy is very often associated

with CNS psychiatric disorders. The potential teratogenicity of

AEDs is controversial and important. It is important because

teratogenicity resulting from long-term drug treatment and may

have a profound effect even if the effect occurs in only a small

percentage of cases. Furthermore, patients with severe epilepsy,

in whom genetic factors rather than drug factors may be of

greater importance in the occurrence of fetal malformations, are

often receiving multiple AEDs in high doses. The children born

to mothers taking AEDs have an increased risk, perhaps two fold

congenital malformations. PHT has been implicated in a specific

syndrome called fetal hydantoin syndrome (skeletal, CNS, limb,

and orofacial defects) and a similar syndrome has been attributed

both to PBT and to CBZ. VPA has also been implicated in a

specific malformation, spina bifida. It is estimated that a

pregnant woman taking VPA has a 1–2% risk of having a child

with spina bifida. In problem of a pregnant woman with epilepsy,

most epileptologists agree that while it is important to minimize

exposure to AEDs, both in numbers and dosages, it is also

important not to allow maternal seizures to go unchecked.

Topiramate has shown teratogenic effects in animals. The risk of

the pregnant mother having a full blown seizure and having brain

injury (hypoxia) are much higher than having a fetus with

congenital defects. Thus, the risk to benefit ratio should be

seriously considered.

2. Withdrawal conditions

Abrupt withdrawal of AEDs may increase seizure frequency and

severity in patients with epilepsy. Some drugs are more easily

withdrawn than others. Withdrawal of AEDs whether by accident

or by design can cause increased seizure frequency and severity.

There are two factors to consider: the effects of the withdrawal

itself and the need for continued drug suppression of seizures in

the individual patient. In many patients, both factors must be

considered. The abrupt discontinuance of AEDs ordinarily does

not causes seizures in non epileptic patients provided the drug

NH

C2H5

O

O

O CH3

HAD

D

A

NH

NH

O

O

D

HADA

N O

H

H

HAD

D

A

HN

CH3

Cl

O

H S

NCH3

O

HAD

D

A

Mephobarbitone PHT CBZ Ralitoloine

N

H

HO

OH

HAD

D

A

NN

NCl

Cl

NH H

NH

H

HAD

D

A

N

F

Cl

O

N

H

H

OH

D

HAD

A

NO

S

O

N

O

H

H

D

HAD

A

Gabapentin LTG Progabide Zonisamide

Fig. 2: Structural elements required for Anticonvulsant activity.



levels are not above the usual therapeutic range when the drug is

stopped. Barbiturates and BZDs are the most difficult to

discontinue; weeks or months may be required, with very gradual

dosage decrements, to accomplish their complete removal,

especially if the patient is not hospitalized. Because of the

heterogeneity of epilepsy, complete discontinuance of AEDs is

an especially difficult problem. If a patient is seizure-free for 3 or

4 years, gradual discontinuance is usually warranted.

3. Overdose

The AEDs are CNS depressants but are rarely lethal. Very high

blood levels are usually necessary before overdoses can be

considered life-threatening. The most dangerous effect of AEDs

after large overdoses is respiratory depression, which may be

potentiated by other agents, such as alcohol. Treatment of AED

overdose is supportive; stimulants should not be used. Efforts to

hasten removal of AEDs, such as alkalinization of the urine

(PHT is a weak acid), are usually ineffective.

4. General side effects of antiepileptic drugs

Table 3: Classification of epileptic seizures

Seizure type

Partial Seizures

Features Antiepileptic drugs

Conventional Recently

developed

Simple partial Diverse manifestations determined by the region of cortex

activated by seizure (e.g., if motor cortex representing left thumb,

clonic jerking of left thumb results; if somatosensory cortex

representing left thumb, paresthesias of left thumb results),

lasting approximately 20-60 seconds. Key feature is preservation

of consciousness. May progress from hand- arm-shoulder-girdle-

trunk to entire body

CBZ,

PHT, PBT,

primidone,

VPA

Gabapentin,

LTG

Complex partial Impaired consciousness lasting 30 seconds to two minutes, often

associated with purposeless movements such as lip smacking or

hand wringing. Confusion, amnesia, full coordi-nation (e.g.

dressing, undressing) and aura.

CBZ, PBT,

PHT,

primidone,

VPA

Gabapentin,

LTG

Partial with

secondarily

generalized tonic-

clonic seizure

Simple or complex partial seizure evolves into a tonic-clonic

seizure with loss of Consciousness and sustained contractions

(tonic) of muscles throughout the body followed by periods of

muscle contraction alternating with periods of relaxation (clonic),

typically lasting 1 to 2 minutes. Increased heart rate, increased

blood pressure, loss of bladder and bowel control.

CBZ, PBT,

PHT,

primidone,

VPA

Gabapentin,

LTG

Generalized Seizures

Absence seizure

(Petit mal)

Abrupt onset of impaired consciousness withstaring and cessation

of ongoing activities typically lasting less than 30 seconds.

Common in children, disappears after adolescence.

CZP, ESM,

VPA

LTG

Myoclonic seizure A brief (perhaps a second), shock like contraction of muscles

which may be restricted to part of one extremity or be

generalized.

VPA

Tonic-clonic

seizure (Grand

mal)

As described above for partial with secondarily generalized

tonic-clonic seizures except that it is not preceded by a partial

seizure.

CBZ, PBT,

PHT,

primidone,

VPA.



Diarrhea, vomiting, upper respiratory tract infection,

constipation, dyspepsia, ataxia, nervousness, allergic skin

reaction, nausea, headache, dizziness, aplastic anemia, hepatic

failure is the common site effects of currently used AEDs. The

cognitive side effects of CBZ, PHT and VPA Sod are

comparable and associated with modest psychomotor slowing

accompanied by decreased attention and memory.

Neuropsychological side effects emerge according to a dose

dependent relationship; however, both quality of life and

memory may be affected, even when serum blood concentrations

are within standard therapeutic ranges. In children, drug effects

are seen in decreased performance or memory. Some children are

at heightened risk for developing disproportionate cognitive side

effects with CBZ.

Interactions of drugs associated with antiepileptic agents

Epilepsy is a chronic disease that may require long-term AED

therapy. The efficacy of single AED therapy for the management

of epilepsy is well recognized. For epileptic patients who do not

respond to mono-drug therapy, treatment with multiple AEDs is

essential. About 28% of epileptic patients were prescribed

multiple drug therapy. The multiple drug therapy or polytherapy

is commonly needed for the treatment of co- morbidities in

epileptic patients. The AEDs are known to interact with

cardiovascular agents including anticoagulants, β-blockers,

diuretics, angiotensin converting enzyme (ACE) inhibitors,

angiotensin-II receptor blockers, Ca2+

channel blockers, and 3-

hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase

inhibitors (statins). Moreover, AEDs are prescribed to treat a

variety of non epileptic conditions including migraine headache,

chronic neuropathic pain, mood disorders, and schizophrenia.

Metabolic acidosis in a pediatric patient receiving topiramate

Topiramate is used for the management of several seizure types

in children >2 years of age. With the exception of cognitive

dysfunction, nephrolithiasis, weight loss, and paresthesia,

adverse effects in children are similar to other those noted with

other AEDs. Three year old child with complex partial seizures

and secondary generalization received topiramate 45 mg (6.2

mg/kg/d) orally twice daily for approximately 4 weeks. He

developed asymptomatic metabolic acidosis that was evidenced

by a decrease in HCO3-, which was unresponsive to treatment

with NAHCO3. The child was weaned off topiramate and the

metabolic acidosis resolved 48 hours after its discontinuation

(Steiner, et al., 1999; Kelly, et al., 1990; Lynch, et al., 2004;

Mattson, et al., 1985; Suzdak, and Jansen. 1995).

Discovery of lesser neurotoxic and effective anticonvulsant

agents

The compounds were screened for antiepileptic properties in the

MES, scPTZ, strychnine (scSTY) and picrotoxin (scPIC) seizure

threshold tests in mice. Neurotoxicity was determined using the

rotorod test in mice. The compounds were also studied for

behavioral despair and depression using actophotometer and

porsolt’s swim pool test respectively.

Anticonvulsant drugs and their structural features

The chemical variety and different mechanisms of action of

AEDs create it difficult to discover a general way of discover

new drug molecule. Novel AEDs are revealed through usual

screening and/or structure alteration of available drug. Rational

drug design procedure of new AEDs could be attained in several

ways. The first approach is the recognition of new targets

through improved accepting of molecular mechanisms of

epilepsy. Another way is to alter already accessible drugs and

regimen. The new AEDs showing different structures include

amino acids, amides , sulfonamides (hydroxyamides,

carboxyamides, benzylamides, dimethylanilides, alkanoamides,);

heterocyclic compounds (derivatives of imidazoles, indazoles,

indoles, piperazine and arylpiperazines, pyrrolidin-2,5-diones,

lactams, pyridazinone, semi-thiosemicarbazones, quinazolinones,

thiadiazoles, thiadiazoles, isatin, xanthones), enaminones,

imidooxy derivatives and VLPA derivatives. These innovative

structural classes of drug moleculess can confirm usefulness for

N

NO

O

H3C

Cl

N

NO

H3C

Cl

H2NNH

O

O

HN

NH

O

O

Clobazepam Diazepam Phenacemide Pimidoner

O

N NH2

OCH3

N

NO

CH3 O

NH2H3C

NH2

N

O

CH3

NH2

O

Dezinamide Nafimidone Pregabelin Levetiracetam

Fig. 3: Other anticonvulsant agents



Table 4: Antiepileptic drugs and their side effects

Drug Effective

level

Clinical uses Mechanism Side effects

PHT

10-20

μg/ml

Partial and

tonic-clonic.

Prolongs closing of inactivating

gate of sodium channels of

excitatory NT receptors in the CNS

Ataxia. Vertigo. Diplopia. Nystagmus. Tissue

overgrowth (gingival Hirsutism) Altered

vitamin D metabolism. Altered folate

metabolism. Weak inducer of drug

metabolizing, Fetal malformation.

CBZ

4-12

μg/ml

Partial and

tonic-clonic.

Prolongs closing of inactivating

gate of sodium channels of

excitatory NT receptors in the CNS

Sedation. Ataxia. Blurred vision. Serious

hematological toxiciry (aplastic anemia,

agranulocytosis Potent inducer of drug

metabolizing enzyme.

PBT

10-40

μg/ml

Partial and

tonic-clonic.

Facilitates the inhibitory action of

GABA, increases the duration of

chloride channel opening at

GABA-A receptors.

Sedation.

Abnormal vitamin D metabolism. Decreased

folate level. Irritability and hyperactivity in

children.

Respiratory depression possible. Induces ALA-

synthetase. Risk of dependence, withdrawal,

Interaction with alcohol. Interaction with MAO

inhibitors. Potent inducer of drug metabolizing

enzymes.

ESM

50-100

μg/ml

Absence

seizures.

Inhibits low-threshold T-type

calcium currents in thalamic

neurons.

Nausea, anorexia, mood changes, headaches.

VLPA

Divalpro

ex Na

50-100

μg/ml

Partial, tonic-

clonic, and

absence.

Prolongs inactivation of sodium

channels of excitatory NT

receptors in CNS. Inhibits low-

threshold T-type calcium currents

in thalamic neurons.

Increases the amount of GABA in

CNS.

Increases GAD activity.

Decreases GABA-T and succinic

semialdehyde dehydrogenase

activity.

Nausea. Alopecia. Hepatitis. Potent inhibitor of

drug metabolizing enzymes.

Interaction with aspirin, warfarin (bleeding).

Interaction with alcohol, other CNS

depressants.

CZP

0-1 μg/ml Absence and

myoclonic.

Facilitates the inhibitory actions of

GABA.

Sedation. Lethargy (50 percent).

Dependence and withdrawal symptoms.



the design of upcoming targets and development of new drug

molecules.

Structural feature and structural activity relationship of

antiepileptic drugs

For the compounds to act as AEDs, the molecules should have at

least one aryl or lipophilic units (A), one or two hydrogen

acceptor-donor atoms (HAD) and an electron donor atom (D) in

a unique spatial arrangement to be recommended for antiepileptic

activity. Some identified and structurally diverse molecule with

antiepileptic activity, for examples, mephobarbitone, ethotoin,

PHT, CBZ, gabapentin, LTG, progabide, ralitoloine and

zonisamide etc are characterized their structural elements. The

distance between these structural elements should be most

favorable in the ranges represented (Fig 1.20). The distances are

calculated using different computational tools for three

dimensional structures of the drugs.

Over the years, the field of epilepsy has received a great deal

of attention from research investigators in the hope of

discovering new drugs that are more effective and have minimal

adverse effects. Though several new AEDs have been

introduced, some types of epilepsies are still not adequately

controlled with the current therapy. Adverse reactions and lack of

efficacy for certain types of epilepsies are some of the limitations

of existing medications. The AEDs exert their action by different

mechanisms. They include an enhancement of the GABA-ergic

neurotransmission, effects on neuronal voltage-gated Na+ and/or

Ca2+

channels. Epilepsy is most common neurological disorder,

second to stroke. The number of drugs useful for the treatment of

epilepsy is remarkably small. New AEDs have been developed

that may constitute novel and effective therapies for epilepsies.

Their use has been proposed in the treatment of seizure disorders

such as epilepsy, in the therapy of stroke and other neurological

disorders such as Parkinson's disease. They act as excitatory

amino acid antagonists and inhibitors of L-glutamate

neurotransmission. These compounds afford protection in the

MES-model in both mice and rats, by either i.p or oral route. The

study represents them as glutamate antagonists. Neurotoxicity of

the compounds was also noticed at the same dose levels.

Vitamine B6 is the precursor in the formation of co-enzyme

pyridoxal-5-phosphate which is responsible for the

decarboxylation of glutamic acid to form GABA and since

hydrazine derivatives can inactivate the co-enzyme. Pyridoxal-5-

phosphate via hydrazone formation, these facts conform the

fundamental role of GABA in the arrest of convulsion (Privitera,

et al., 2003; Ptacek. 1997; Sachdeo, et al., 1992; Twyman, et al.,

1989; Biton, et al., 1999).

MePHT and Ethotonin are like PHT but require larger doses.

Oxacarbazepine, a drug like CBZ, is metabolized to 10-hrydoxy

derivative which has lesser induction of drug metabolizing

enzyme than CBZ. Primidone is metabolized to

phenylethylmalinomide and PBT and has similar profile to PBT.

At last, upcoming efforts to finding novel AEDs are

expected to focus on mechanism motivated discovery of novel

drug molecules, followed by knowledgeable animal testing in

appropriate drug-resistant animal models. Several latest

achievements (pregabalin, brivaracetam) have shown that

information of the mechanism of action gives the developer a

significant benefit in improving effectiveness through improved

target effectiveness and selectivity, thus reducing the potential

for dose associated adverse effects. However, till date even

current progresses have not appreciably reduced the size of DRE

population. It is the anticipate that new generation AEDs with

novel mechanisms will enhance the likelihood for success in

treating a heterogeneous patient population together with those

patients suffering from drug resistant types of epilepsy. New

Table 4: Continuous…..

DZP

600

μg/ml

Status

epilepticus

Increases the frequency of opening

of chloride channel of GABA-A

receptor.

Behavioral disturbances in children.

Interaction with alcohol. Interaction with

VLPA.

Lorazapam

Chlorazepate

Partial

myoclonic,

absence

Trimethadion

e

20

μg/ml

Absence Inhibits low-threshold T-type

calcium currents in thalamic

neurons

Sedation. Hemeralopia.

Hepatitis and nephrosis.

Mild neutropenia (20 percent).

Aplastic anemia.

Side effects are serious and limiting.

Bromide 10-20

μg/ml

Epilepsy in

porphyrias.

Not known. Skin rash.

Sedation. Behavioral changes



AEDs have expanded the therapeutic alternatives in treating

patients with refractory epilepsy and those who cannot bear

conventional therapy. Although these drugs are capable, further

clinical practice will be essential to validate the usefulness of

these agents. This will supportive for researcher to find out

newer AEDs with lesser adverse effects. A further study to

Table 5: New antiepileptic drugs and their side effects

Drug Clinical uses Mechanism Side effects

Felbamate Partial seizures. Lennox-

Gastaut syndrome.

Possible blockade of NMD A

receptor.

Severe hepatitis.

Aplastic anemia.

Gabapentin

LTG

Adjunct drug for partial and

generalized tonicclonic

seizures. Partial seizures

Increases the release of GAB

A. Prolongs closing of

inactivating gate of

Na+ channel.

Somnolence. Dizziness. Ataxia.

Headache. Dizziness. Headache.

Diplopia. Somnolence. Skin Rash.

Levetiracetan

Adjunct for partial seizures

with or without secondary

generalization

Not known Minimal drowsiness. Anxiety.

Amnesia

OXC

Partial seizures with or without

Generalization

Blockade of voltage sensitive

sodium channels

CNS side effects, hematological

abnormalities and effects on drug

metabolizing enzymes are less than

CBZ.

Tiagabine

Adjunct for partial seizures. Inhibition of GABA uptake. Nervousness. Dizziness. Tremor.

Depression.

Topiramate

Partial and generalized tonic-

clonic seizures.

Prolongs closing of

inactivating gate of Na+

channel, potentiates the

GABA effect and blocks

AMPA receptors

Somnolence. Fatigue. Dizziness.

Parestheia. Confusion.

Vigabatrin

not available in

USA)

Partial seizures. Irreversible inhibitor of

GABA

aminotrasferase (GABA-T).

Drowsiness. Dizziness.

Weight gain. Psychosis.

Zonisamide Partial and generalized tonic-

clonic seizures.

Inactivation of Na+ and Ca

2+

channels

Drowsiness. Cognitive impairment.

Table 6: Efficacy of antiepileptic drugs in other conditions

Drug Established efficacy Possible efficacy

CBZ Mania, mood, stabilization, trigeminal

neuralgia.

Behavioral disturbances of dementia, neuropathic

pain.

Gabapentin Neuropathic pain (e.g., diabetic neuropathy). Mania, movement disorders (e.g., Parkinson’s

disease).

LTG None. Mania, migraine, neuropathic pain.

PHT None. Neuropathic pain, trigeminal neuralgia.

VPA Mania, migraine. Behavioral disturbances of dementia, movement



acquire more information about biological activity is in

improvement.

Anticonvulsant drugs and their structural features

Epilepsy is a common neurological disorder, affecting 0.5 to 1%

of the population globally. Novel AEDs are exposed through

predictable screening and/or structure alteration. Rational drug

design procedure of a new anticonvulsant could be attained in a

number of ways. The first approach is the recognition of new

targets through improved understanding of molecular

mechanisms of epilepsy. An additional way is to modify already

presented drugs and formulations. The new AEDs representing a

variety of structures include amino acids, sulfonamides, amides

(hydroxyamides, alkanoamides, benzylamides, dimethylanilides,

carboxyamides); heterocyclic compounds (analogues of

imidazoles, indazoles, indoles, arylpiperazine and piperazines,

pyrrolidin-2,5-diones, pyridazinone, lactams, semi-

thiosemicarbazones, quinazolinones, thiadiazoles, isatin,

NH

C2H5

O

O

O CH3

HAD

D

A

NH

NH

O

O

D

HADA

N

O

H

H

HAD

D

A

N

F

Cl

O

N

H

H

OH

D

HAD

A

Mephobarbitone Phenytoin Carbamazepine Progabide

NN

NCl

Cl

NH H

NH

H

HAD

D

A

N

H

HO

OH

HAD

D

A

HN

CH3

Cl

O

H S

NCH3

O

HAD

D

A

NO

S

O

N

O

H

H

D

HAD

A

Lamotrigine Gabapentin Ralitoloine Zonisamide

Fig. 4a: Structural necessities for the AEDs and their SAR (A= Hydrobhobic agent; D= Electron donor group; HAD=

Hydrogen bond receptor/donor unit)

Note: The distance between these structural elements should be optimum in the ranges depicted in the Fig. 4b. The distances are

calculated using various computational tools for three dimensional structures of the drugs.

A

D

HD

HA

3. 0

9-

9. 0

9A

0

3.62 - 6.58 A0

2.49 - 8.23 A0

2.64- 7.74A 0

2.23 - 5.73 A 0

1.8

9-

2.7

0A

0

Fig. 4b: Distance ranges between the structural elements required for Anticonvulsant activity.



xanthones), imidooxy, enaminones compounds and valproic acid

analogues (Birbeck et al., 2007; Bialer. 2006; Chisholm. 2005;

Luszczki. 2009).

Structural necessities for the AEDs and their SAR

For the compounds to perform as AEDs, the molecules should

holding at least one aryl or lipophilic group or units (A), one or

two hydrogen acceptor-donor atoms (HAD) and an electron

donor atom (D) in a unique spatial arrangement to be suggested

for antiepileptic action. Some well known and structurally

dissimilar compounds with antiepileptic activity, for examples of

such drugs are ethophenytoin, mephobarbitone, PHT, CVZ,

gabapentin, lamotrigine, progabide, ralitoloine and zonisamide

etc are represent their structural elements.

DISCUSSION AND CONCLUSIONS

The field of epilepsy has received a great deal of attention from

research investigators in the hope of discovering new drugs that

are more effective and have minimal adverse effects. Though

several new AEDs have been introduced, some types of

epilepsies are still not adequately controlled with the current

therapy. Adverse reactions and lack of efficacy for certain types

of epilepsies are some of the limitations of existing medications.

Antiepileptic drugs exert their action by different mechanisms.

They include an enhancement of the GABA-ergic

neurotransmission, effects on neuronal voltage-gated sodium

and/or calcium channels (Najafi et al., 2011). Epilepsy is most

common neurological disorder, second to stroke. The number of

drugs useful for the treatment of epilepsy is remarkably small.

New AEDs have been developed that may constitute novel and

effective therapies for epilepsies. It was found that both

pyridazines and pyridazinones derivatives exhibited remarkable

anticonvulsant activity (Edith et al., 2002; Hallot, et al., 1986).

The pyridazinones along with hydrazines, semicarbazones and

thiosemicarbazones which are derived from pyridyl ketones have

been found to be non neurotoxic AEDs and are potent orally

active. They act as excitatory amino acid antagonists and

inhibitors of L-glutamate neurotransmission. These compounds

afford protection in the MES model in both mice and rats, by

either route, intraperitoneal and oral. The study represents them

as glutamate antagonists (Siddiqui et al., 2007; Samanta et al.,

2011). Vitamine B6 is the precursor in the formation of co-

enzyme pyridoxal-5-phosphate which is responsible for the

decarboxylation of glutamic acid to form GABA and since

hydrazine derivatives can inactivate the co-enzyme. pyridoxal-5-

phosphate via hydrazone formation, these facts conform the

fundamental role of GABA in the arrest of convulsion

(Chisholm. 2005; Luszczki. 2009; Bialer et al., 2004). Finally,

while early AEDs may be potent, many have dose-limiting

toxicity and/or unacceptable side-effects, which prevent attaining

sufficient brain levels to entirely control seizures. Several new

achievement (pregabalin, brivaracetam) have shown that facts of

the mechanism of action gives the significant advantage in

improving effectiveness through improved target potency and

selectivity, thus lowering the effects of dose-related side effects.

However, recent advances have not appreciably reduced the size

of drug resistance seizure patients (Kwan, and Brodie. 2000;

Mohanraj and Brodie. 2003). In this regard, the natural resources

might also be helpful (Ali et al., 2015; Ashraf et al., 2015; Asif,

2015a, b, c, d, e, f, g, h, i, 2016; Hussain et al., 2016; John et al.,

2015; Mensah and Golomeke, 2015) and the new generation

AEDs with novel mechanism of actions will enhance the

probability for success in treating a varied patient population

together with those patients suffering from drug resistant forms

of epilepsy.

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