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used interchangeably in the literature to
describe a diverse group of medications used clinically to provide seizure
control in patients with epilepsies.
anticonvulsant and antiepileptic drug (AED)
is the most prevalent neurological disorder
affecting more than 0.5% of the world’s population
characterized by recurrent seizures,
unprovoked by any identifiable causes
symptoms of disturbed electrical activity in the brain characterized by
episodes of abnormal, excessive, and synchronous discharge of a group of
neurons within the brain that cause involuntary movement, sensation, or
result from primary or acquired neurological disturbances of brain function as
a result of an imbalance between excitatory and inhibitory processes in the
commonly used AEDs
to prevent recurrence of seizure activity.
- valproic acid (VPA),
- carbamazepine (CBZ),
reason for this refractory to an AED may be a result of
coexistence of factors related to the epileptogenesis of the disease state or
to the development of pharmacodynamic or pharmacokinetic tolerances
Seizures are classified, based on their initial
signs and symptoms and the pattern seen on the electroencephalogram (EEG), ), into two broad categories
generalized seizures or as partial seizures.
Two major types of generalized seizures are
- generalized tonic–clonic seizures (grand mal) and
- the absence (petit mal) seizures.
preceded by a series of bilateral muscular
jerks followed by loss of consciousness
typical primarily generalized tonic–clonic seizure
consists of a sudden brief loss of consciousness (10 seconds), some- times with no
motor activity, although often some minor clonic motor activity exists.
typical absence seizure (classic petit mal)
recommended initial monotherapy for patients with generalized seizures are:
- Carbamazapine (CBZ),
- oxcarbazepine (OXC),
- phenytoin, and
- topiramate (TPM),
children with absence seizures are best treated
- VPA, or
Major types of partial seizure are
- simple partial seizures (focal) and
- complex partial seizures (temporal lobe or psychomotor)
most common seizure types experienced by
approximately 60% to 70% of the adult patients.
A prototypic simple partial seizure
Jacksonian motor epilepsy
first-line treatment for patients with newly
diagnosed or untreated simple partial seizures are
- CBZ or phenytoin for adults
- lamotrigine or gabapentin for elderly adults,
- and OXC for children.
is represented by the psychomotor or temporal
lobe seizure. There is an aura, then a confused or bizarre but seemingly purposeful behavior lasting 2 to 3 minutes, often with no memory of the event.
The complex partial seizure
is characterized by a neuronal hyper-
excitability in damaged areas of the nerves
; is quite similar to that of epilepsy
Mechanisms of Action of Anticonvulsants
(a)modulation of voltage-gated ion channels (Na, Ca2, and K)
(b)enhancement of y-aminobutyric acid (GABA)-mediated inhibitory neurotransmission
(c)attenuation of excitatory (particularly glutamate-mediated) neurotransmission in the brain
as Targets for Anticonvulsants
Voltage-Gated Ion Channels
in the presynaptic nerve terminal of the
excitatory glutamate receptors are the molecular target for phenytoin, CBZ, and
lamotrigine as well as some of the newer AEDs, such as OXC, felbamate (FBM),
Voltage-gated sodium channels (VGSCs)
These aromatic AEDs inhibit excessive neuronal
- binding to a site near the inactivation gate,
- thereby prolonging inactivation of VGSCs.
are essential in regulating Ca2 signaling,
which is associated with many important cellular events such as the release of
excitatory glutamate neurotransmitters, the plasticity changes of long-term potentiation in learning and memory, and the maintenance of homeostasis of
The voltage-gated calcium channels (VGCCs)
plays a critical role in the induction and
progression of epileptic seizures
excessive influx of Ca2
require strong depolarization for activation and
are the primary molecular targets of gabapentin and pregabalin, both of which
are effective in refractory partial seizures
- high-threshold L-type Ca2 channels in the presynaptic
- glutaminergic receptors
channels require only weak depolarization for activation and are the molecular targets
of AEDs such as ethosuximide and zonisamide.
low-threshold T-type Ca2 channels
is another attractive target for designing of
newer AEDs, because they are intimately associated with the membrane
Potentiation of the voltage-gated K channels
a novel AED recently marketed for the adjunctive therapy of refractory partial
seizures in adults, has been suggested to work by reducing the voltage-operated
A-type potassium currents as one of its mechanism of actions.
It is now well recognized that cellular
excitability leading to convulsive seizures can be attenuated by
GABAergic stimulation in the brain.
the major inhibitory neurotransmitter in the
is one of two ligand-gated ion channels responsible for mediating the effects of GABA
increased chloride conductance, thereby
preventing the spread of neuronal excitations.
Activation of the GABAA/benzodiazepine (BZD) receptors/chloride channel complex
The potential targets for AED’s action on the GABAergic inhibitory synapses
(a) drugs that enhance the biosynthesis of GABA (gabapentin, pregabalin, and VPA
(b) drugs that inhibit GABA degradation (vigabatrin)
(c) drugs that inhibit the reuptake of GABA (tiagabine)
(d) drugs that bind to an allosteric site on the postsynaptic GABAA receptor complex that increase chloride conduc- tance (barbiturates, BZDs,neurosteroids, FBM, TPM).
GABA, is biosynthesized at the GABAergic neurons by
the decarboxylation of the amino acid, L-glutamic acid (itself an excitatory amino acid neurotransmitter in the brain).
The rate-limiting enzyme that catalyzes this
conversion (BIOSYNTHESIS OF GABA )
L-glutamic acid decarboxylase (GAD).
The essential cofactor for this enzymatic
reaction (biosynthesis of gaba) is
pyridoxal phosphate (vitamin B6
GABA, after its release from the synaptic nerve
terminal, is degraded by another pyridoxal-dependent enzyme,
the GABA transaminase (GABA-T),
transaminase (GABA-T), which transfers an amino group from GABA to ketoglutarate producing
- L-glutamic acid and succinic acid semialdehyde
a 3-substituted GABA, may have the ability to activate GAD, in addition to their major anticonvulsant action at the high-thresh- old L-type Ca2 channels in the presynaptic glutaminergic receptors
gabapentin and especially pregabalin
of these drugs are weak activators of GAD, was
able to elevate brain GABA levels (75%–100%) in patients with epilepsy within
hour after the first dosing.
gabapentin and pregabalin
Similar to gabapentin and pregabalin, also elevates brain levels of GABA in patients
DRUGS THAT INHIBIT GABA DEGRADATION
is an irreversible inhibitor of GABA-T,
rationally designed based on the biochemical mechanism of transamination
competes with GABA for binding to GABA-T and forms a Schiff base intermediate with the
cofactor, pyridoxal phosphate similar to GABA.
DRUGS THAT INHIBIT REUPTAKE OF GABA
structurally related to nipecotic acid, is a selective inhibitor of the neuronal and glial
GAT1 at the GABAergic neurons and an effective drug for the treatment of
patients with refractory epilepsy.
enhances GABA- mediated inhibitory
neurotransmission by increasing the frequency of chloride channel openings
that binding of BZD agonists such as clonazepam to its receptor
a broad-spectrum AED, also binds and increases the frequency of chloride channel
opening but at a different site than the BZDs.
modulate sodium and calcium influx and
are involved in mediating excitatory synaptic transmission including the initiation and spread of seizure activity.
- N-methyl-D-aspartic acid (NMDA)/
- a-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptors
Excitatory Glutamate-Mediated Receptors as
Target for Anticonvulsants; ligand-gated glutamate receptors
Activation of these receptors is responsible for important functions in the brain including long-term potentiation in memory acquisition, learning, and some neurodegenerative disorders. These receptors are potential therapeutic targets for epilepsy.
is an established AED with a simple chemical structure but an unusually broad spectrum of
Limited use due to significant toxic side effect.
Valproic Acid (VPA)
Very effective against all seizure types except absence.
BNs of Phenytoin
(Dilantin, Kapseals, Phenytek)
a prodrug of phenytoin, was developed and marketed to avoid complications such
as vein irritation, tissue damage, and muscle necrosis associated with parenteral phenytoin administration.
CBZ is useful in generalized tonic–clonic and partial seizures.
BNs of Carbamazepine and Oxcarbazepine
with multiple mechanisms of action.
- Pregabalin, (S)-3-isobutyl-GABA.
BNs of Gabapentin and Pregabalin
a broad spectrumof action, is a carbamate ester of 2-phenyl-1, 3-propanediol, structurally similar to the anxiolytic drug meprobamate.
-was found to be associated with rare but
severe side effects such as aplastic anemia, idiosyncratic reactions and hepatic failures.
AED of the phenyltriazine class, has been found effective against refractory
LAMOTRIGINE (what is the Brand Name)
MOA of Lamotrigine
- Blockage of sodium channels that is both voltage- and use dependent.
- Inhibits the high-threshold calcium channel, possibly through inhibition of presynaptic N-type calcium channels and also blocks glutamate release
A sulphamate-substituted monosaccharide, a derivative of the naturally occurring sugar D-fructose that exhibits broad and potent AED actions at both glutamate and GABA receptors.
TOPIRAMATE (Brand name?)
appears to block glutamate release,
antagonize glutamate kainic acid/AMPA receptors, and increase GABAergic transmission by binding to a site distinct from BZDs or barbiturates on the GABAA receptor complex
Sulfonamide-type anticonvulsant approved for adjunctive therapy in the treatment
of partial seizures in adults with epilepsy.
is an analog of the nootropic agent, piracetam.
-does not have any affinity for the AMPA receptor thereby has no nootropic activity for
the treatment of Alzheimer disease.
excitatory synaptic currents, thus decreasing membrane conductance.
Blocks GABA reuptake as a major mode of its anticonvulsant
considered the prototypical anticonvulsant needed for treating patients with absence seizures
BN of ETHOSUXIMIDE and METHSUXIMIDE
Zarontin and Celontin
4-vinyl analog of GABA, produces its pharmacological action by irreversibly blocking GABA catabolism catalyzed by GABA-T.
-Caused a reversible visual field defect associated with retinal function in the eyes
Useful in absence
seizures and in myoclonic
seizures.Tolerance to the anticonvulsant effect of the clonazepam often developed rather quickly, and it is a
common problem with the BZDs
BN of Clonazepam