Antiseizure Drugs Mechanisms

Most ASDs exert their principal effects on the following molecular targets: GABA receptorsn
and voltagedependent sodium and calcium channels. Several ASDs are thougt to prosses multiple
relevant mecanisms of action (Rogawski and Loscher, 2014; White et al., 2017).
Until recently, the primary drugs for treating focal epilepsy were phenytoin and carbamaze-
pine, both of which block sodium channels in a voltage, frequency, and use dependent manner.
Repetitive neuronal firing is limited by both of these agents. Oxcarbamazepine, a structural analog
of carbamazepine, also block subtained repetitive firing and is especially effective againt focal sei-
zures. Lamotrigen olaso blocks sodium channels but has a broader spectrum of activity, with efficacy
againts both generalized and focal seizures. Lacosamide enchances slow activation of sodium chan-
nels (whereas older sodium channel-blocking ASDs enchance fast inactivation). Like most sodium
channel blockers, rufina,ide stabilizes fast sodium channel inactivation (Italiano & Perucca, 2013).
Binding of benzodiazepunes or barbiturates to their receptor recognition sites on postsynap-
tic GABA receptors results in enchanced inhibitory current. Vigabatrin is an irreversible inhibotor og
the major GABA degradative enzmen, GABA transaminase, and elevates synaptic GABA levels
(Italiano & Perucca, 2013).
Valproic acid is a broad-spectrum ASD that induce a wide variaty of biochemical and neuro-
physiologic changes in multiple neurotransmitter systems. Its precise mechanism of action remains
unclear, but recent study have indicated that valproid acid inhibits histone deacetylases. Valproid
acid also elevated brain GABA levels and diminishes repetitive firing, implaying and action on volt-
age-gates sodium channels (Italiano & Perucca, 2013).
Phenytoin is useful for the treatment of partial seizures and generalized tonic–clonic seizures
but not primary generalized seizures such as absence seizures or myoclonic seizures. In animal
models, phenytoin is protective against tonic seizures in the maximal electroshock test, but does not
protect against pentylenetetrazol-induced clonic seizures. Phenytoin is also active against seizures
in- duced by blockers of voltage-gated potassium channels (4-aminopyridine and dendrotoxin),
which enhance the release of glutamate and other neurotransmitters. Although phenytoin has many
pharmacological ac- tions, the action most relevant to its antiseizure activity is the inhibition of high-
frequency repetitive firing of voltage-gated sodium channels. Some of the other actions include
blockade of voltage-gated calcium channels and ionotropic glutamate receptors, which occur at su-
pratherapeutic concentrations (Roger et al., 2012).
Phenobarbital which was being tested as a hypnotic, was serendipitously observed to reduce
the frequency of seizures in patients with epilepsy. Phenobarbital has a diversity of pharma- cological
actions. Of particular importance is its ability to enhance GABA-mediated fast inhibitory synaptic
transmission. GABA is the major inhibitory neurotransmitter in the brain. GABA exerts fast synaptic
inhibition via GABAA receptors. In addition to localization at synapses, GABAA receptors are also
present perisynaptically and extrasynaptically; these receptors mediate nonsynaptic (tonic) inhibi-
tion. Barbiturates have a powerful action on nonsynaptic d-subunit-containing GABAA receptors.
The extent to which phenobarbital also enhances nonsynaptic GABAA receptor isoforms is not
known, but this action could potentially be significant. Structurally, each subunit of the GABAA re-
ceptor con- sists of a large (200 amino acid) extracellular N-terminal domain that contains binding
sites for GABA and benzo- diazepines, an extracellular loop (M3–M4 loop), a large cytoplasmic loop
(M3–M4 loop), and four transmem- brane domains (M1–M4) of about 20 amino acids in length.
GABA binds at the interface of a and b subunits, whereas benzodiazepines bind at a homologous
site at the interface of a and g subunits. The extracellular N-terminus region contains three sites for
N-linked glycosylation and the two cysteine residues, which form a b-loop, and may function in bind-
ing GABA. The M2 domain, which is composed of several hydrophilic residues, is thought to line the
channel pore. The extremely variable (both in length and in composition) intracellular loop between
M3 and M4 of some subunits contains consensus sequences for phosphorylation by protein kinase
A and the tyrosine protein kinase. This domain is important for receptor trafficking and surface clus-
tering, through interactions with cytoplasmic proteins. The specific way in which binding of barbitu-
rates modulates the activity of GABAA receptors has not yet been fully defined. However, the second
and third transmembrane domains of the b-subunit appear to be critical for binding. Barbiturates
enhance activation of GABAA receptors by GABA and, at higher concentrations, they can directly
activate GABAA receptors, in the absence of GABA. GABA may act as a partial agonist at extrasyn-
aptic d-subunit-containing GABAA receptor isoforms that mediate tonic inhibition, which may render
them particularly sensitive to allosteric mod- ulation by barbiturates. Interestingly, chronic treatment
with barbiturates causes an increase in GABAA receptor d subunit mRNA; withdrawal results in
downregulation. Thus, the relative activity of barbiturates on synaptic and extrasynaptic GABAA re-
ceptors may vary with drug exposure. Besides its GABAergic actions, phenobarbital blocks voltage-
activated calcium channels current (and non-NMDA (AMPA/kainate) receptors. These actions may
contribute to the anticonvulsant action and also to side-effects (Roger et al., 2012).
Carbamazepine is effective in the treatment of partial seizures and generalized tonic–clonic
seizures. It also has a similar profile of activity in animal seizure models. Carbamazepine is metab-
olized to an active metabolite, carbamazepine epoxide, which is stable and which contributes to the
antiseizure activity. Carbamazepine blocks voltage-activated sodium channels in a similar fashion
to phenytoin. However, in contrast to phenytoin, carbamazepine produced less pronounced fre-
quency-dependent block. Thus, although phenytoin and carbamazepine have qualitatively similar
effects on sodium channels, their actions are quantitatively somewhat different. This could account
for differences in efficacy in different patients. Pharmacokinetic–pharmacodynamic correlation stud-
ies support the concept that the sodium channel effects of the drug account for its antiseizure effects.
Besides blocking sodium currents, carbamazepine has other pharmacological actions, but the rele-
vance of these actions to its therapeutic activity is uncertain. For example, carbamazepine blocks
calcium channels (particularly those of the L-type), but this is often observed only at concentrations
in excess of therapeutic levels. In one study, carbamazepine, at therapeutically relevant concentra-
tions (10–20 mM), was found to activate a voltage-dependent potassium current in rat neocortical
neurons in culture. Such an action on potassium currents is expected to oppose or diminish hyper-
excitability and could potentially be relevant to seizure protection (Roger et al., 2012).

Oxcarbazepine, the 10-keto analog of carbamazepine, has a similar clinical utility and a sim-
ilar spectrum of activity in animal models to carbamazepine. It is actually a prodrug for its mono-
hydroxylated derivative (10,11-dihydro-10-hydroxy- carbamazepine; licarbazepine; MHD), to which
it is rapidly converted and which provides the bulk of the antiseizure activity. Unlike carbamazepine,
oxcarbazepine is not converted to a stable epoxide metabolite. Some have proposed that the epox-
ide could contribute to carbamazepine toxicity, but the evidence that oxcarbazepine is safer than
carbamazepine is scant. Oxcarbazepine, like phenytoin and carbamaze- pine, blocks the sustained
high-frequency repetitive firing of sodium-dependent action potentials. Oxcarbazepine can also in-
hibit calcium currents but, with the exception of ethosuximide, there is little evidence that effects on
calcium channels play a substantial role in the antiseizure activity of any clinical agents (Roger et
al., 2012).
Benzodiazepines have proven invaluable for the acute treatment of status epilepticus, but
their role in chronic antiseizure therapy is limited both by their sedative nature and by tolerance that
occurs in many patients. In addition, discontinuation of benzodiazepines may lead to with- drawal
symptoms. Approximately 35 benzodiazepines are available for the treatment of various central
nervous system disorders including epilepsy. Of these, six are typically prescribed for epilepsy: di-
azepam, clonazepam, clobazam, lorazepam, clorazepate, and midazolam. All of the pharmacologi-
cal actions of benzodiazepines result from their actions on GABAA receptors. Benzodiazepines have
a distinct binding site on the receptor and they modulate GABAA receptor function in an allosteric
manner. The g subunit of the GABAA receptor, when coexpressed with a1, a2, a3, or a5 receptor
subtypes, is essential for benzodiazepine activity. Once bound, benzodiazepines produce a confor-
mational change in the GABAA receptor such that the neurotransmitter GABA has a much higher
affinity for the GABAA receptor. This results in an increase in the frequency of channel opening,
which contrasts with the action of barbiturates that alter the burst duration (Rogers et al., 2012).
Lamotrigine is approved for the treatment of partial seizures and primary generalized tonic–
clonic seizures. In addition, the drug is effective in the treatment of certain generalized seizure types
such as absence seizures and seizures occurring in the Lennox–Gastaut syndrome. Lamotrigine
acts on voltagegated sodium channels in a similar fashion to phenytoin and carbamazepine. Since
lamotrigine is clinically useful in absence seizures and other types of primary generalized seizures,
it is unlikely that blockade of sodium channels is its sole antiseizure mechanism. In preclinical stud-
ies, lamotrigine confers protection against maximal electroshock seizures and is effective in various
kindling models. Lamotrigine may act by inhibiting glutamate release from nerve terminals. For ex-
ample, it inhibits veratridine-evoked release of glutamate and aspartate in rat cortical neurons. This
likely occurs by blocking the repetitive firing of action potentials through effects on voltagegated
sodium channels. Lamotrigine may preferentially inhibit glutamate release relative to GABA release,
as has been observed for other sodium channel agents. This observation may be critical to the un-
derstanding of how such drugs reduce brain excitability and seizures. Whether lamotrigine is a more
selective glutamate release inhibitor than other antiseizure agents is uncertain. In addition to its
inhibitory action on sodium channels, lamotrigine may also modify voltage-gated calcium currents.
In one study, lamotrigine blocked N-type calcium current in rat amygdala neurons (Rogers et al.,
2012).
Levetiracetam has proveen efficacy against partia; and generilezed seizures. Levetiracetam
binds to a specific synaptic vesicle protein, SV2A, which is involved in neurotransmitter release. The
exact mechanism by which SV2A biding leas to an antiepileptic action is unknown (Italiano &
Perucca, 2013).
Topiramate is a fructose derivative (2,3:4,5-Bis-0-(l- methylethylidene)-beta-D-fructopyranose sulfa-
mate), with multiple mechanisms of action: it blocks voltage-gated sodium channels, inhibits kainate- type
glutamate receptors, decreases L-type voltage-sensitive calcium currents, increases the opening of GABA-
mediated chloride channels, inhibits carbonic anhydrase and increases the potassium conductance. All these
actions lead to the reduction or the enhancement of the inhibition of neuronal excitation (Alberto et al., 2011).
Pregabalin, like gabapentin, bind to the alfa-2gama subunit of volatage-activated calcium
channels, reducing presynaptic glutamate release. Retigabine (ezogabine) selectively targets potas-
sium channels nad not only can reduce repetitive neuronal firing but also can block action potential
propagation at the critical axon hillock. Perampanel suppresses seizure activity by competitively
blocking AMPA-type glutamate receptors (Italiano & Perucca, 2013).

Monitoring Antiseizure Drug Therapy

Clinical Monitoring of Efficacy
Clinical assessment of patient is of paramount impostence in the assessment of the effec-
tiveness of therapy. The ideal response would be the total elimination of seizure without any adverse
effects of the therapy. A satisfactory clinical response for patient, however, might be subtantial re-
duction of seizures with elimination of or decrease in adverse effects. One of the common clinical
errors is the premature interpretation of the clini cal response. Assessment of the seizure control
requires and accurate record of the seizure frequency and the severity before and during therapy.
Seizure may be eliminated, reduced, or increased in frequency, or become more or less severe
during therapy. Patient with epilepsy have varying seizure frequent rate before therapy. The leght of
time requered to assess clinical response varies withe the frequency of seizure observed before
begining therapy. Patient in with infrequent seizure need longer period of observation on therapy to
permit assessment of clinical response. Achievement of steady state with a new drug regiment is
necessary to determine whatever a medicatin has been given an adequate trial at any specific dose.
The time to achieve a teady state varies considerably from drug to drug, depending on the drug’s
half-life (Glauser et al., 2013).
 Intrepretation of clinical necessary is especially difficult. Clinical improvement or deterioration
after the addition of second antiseizure drug could be attribute to numerous factors. Such factor
include the additive or synergistic effect of the two medications, the effect of the second drug alone,
and the effect of the second drug on the metabolism and/or displeasemnt of the initial drug. It is
important to make clinical conclusions only after a steady state is reached with the new drug regi-
ment. If improvement is obtained after the additional of the second medication, the clinical should
attempt to taper and discontunoe the first medication, to determine whether the clinical improvement
is in effect of synergic therapy or that of the second medication itself (Kenneth et al., 2017).

Clinical Monitoring of Adverse Effect

The clinical state of the patient is more important than laboratory testing for the assessment
of adverse effects. It is possible to monitor clinical states continously, whereas laboratory test gen-
erally are obtained at arbitrary tiems; therefore, impending organ dysfunction often maybe detected
earlier by clinical changes, rether than by laboratory tests. The most frequent adverse effects are
dose releated and often involve the nervous sytem. Common manifestations of the adverse effects
are cognitive changes and drowsiness, impaired attantion, incoordination, ataxia, and diplopia. In
addition to central nervous system adverse reactions, the liver also may produce signs of oxicity.
Early sign of liver failure include anorexia, nausea, vomiting, lethargy, adn abdominal pain (Italiano
& Perucca, 2013).

Adverese Drug Reactions To Antiseizure Drugs

The most frequent adverse druh reactions to antiseizure drugs are dose related, mild, and re-
versible. Less frequently observed but potentially more serious are the idiosyncratic adverse reac-
tions, which generally are not related to dosage but may be attributable to individual peculiarities of
drug metabolism, that is, lack of pathways to process toxic metabolites (Anderson & Lynn, 2009).
Central Nervous System Adverse Reactions
The general nervous system adverse reaction profile for children is similar for adults. Most
of the older any seizure drugs and their active metabolites have similiar side effect profiles, compris-
ing of the cognitive impairment, sedation, dizziness, dipoplia, ataxia, headache, and affects on som-
nolence.the effects of antiseizure drugs on cognitive function generally are concentration and dose
dependent. Drug therapy is known to contribute to cognitive deficits, especially treatment with mul-
tiple drugs. Side effect frequenly occur in children who are given phenobarbital. Phenobarbital has
been associated with a significant depression of cognitive function when is used for treatment of
febrile seizure in children. Children had lower mean intelligence quotient (IQ) scores both during and
6 months after stopping therapy with phenobarbital. The adverse effect are reminiscent of complaints
present in attention-deficit disorders and include overactivity, aggressiveness, inattention, and irrita-
bility (Kenneth et al., 2017).
Gastrointestinal Effects
Weight Gain
A survey in children and adolescents taking valproic acid found the most common side effect
to be weight gain. The incidence of unwanted weight gain was 26% in adults and 15% in children
and aldolescents. An increase in weight was observed more than twice as frequently in female
(Aderson & Saneto, 2012).
Weight Loss
Sustained weight loss was reported in children on maintenance topiramate therapy. Seventy-
five percent of children and adults during clinical reseacrh trials reported a loss of appetite and de-
crease in body weight while taking felbamate. Zonisamide aslo is associated with weight loss in
children (Kenneth et al., 2017).
Gastric Irritation
Sign of gastric irritation, with heartburn, nausea /vomiting, and indigestion, are seen with use
of some antisezure drugs. Gastric irritation during valproic acid therapy can be reduced with admin-
istration of lower doses or by taking medication with food. Aggresseive medical intervention with
antacids and H2 receptor antagonists has been helpful (Kenneth et al., 2017).
Gingival Hyperplasia
Gingiva hyperplasia occurs in 10% to 20% of persons treated with phenytoin and is mopre
frequent in young persons. It is observed more frequently in persons taking higher dosages, often
appears 2 to 3 months after begining therapy, and reages its maximum severity in 12 to 18 months.
Gingival hyperplasia generally resolves within 2 to 5 months after discontinoution or a reduction in
medication (Kenneth et al., 2017).
Osteomalacia
Osteomalacia (rikets) may occur in patients taking antiseizure drugs. Many antiseizure drugs
presumably enhance hepatic convertion of 25-hydroxivitamin D to biologically inactive metabolites.
Clinical overt rickets was observed in 10% of institutionalized children on phenobarbital and/ or phen-
ytoin. In these patient, sunlight was more important for the maintenance of serum 25-hydroxyvita-
min Dthan were suplements of vitamin D (Kenneth et al., 2017).
Tremor and Movement Disorders
The beign essential type of tremor seen with valproic acid therapy begins whitin 1 month of
initiating therapy and is dose dependent, occuring in some patients with blood valproid acid levels
greater 40 mg/mL. Reduction of tremor may occur with reduction of dose. Tremor also has been
seen with use of lamotrigine and gabapentin (Kenneth et al., 2017).

Managing Adverse Effects

The clinical and the patient are faced with adverse effects approximately 30% of the time
when antiseizure drugs are used, especially during initiation of therapy. In general, management of
adverse effects depend on the problem. Most adverse effect are consentration dependent, and are
less prominent at lower doses and blood consentrations. Seizure control may or may not be main-
tained at lower dose; if not, the clinician and the patient need to consider whether a compromise in
acceptable with regard to either increased seizures or incresed adverse effects, or if alternative
medication should be considered (Kenneth et al., 2017).
At time, toxicity is encountered only with high drug concentrations and is seen only at peak
times; for these patients, it may be possible to avoid toxicity by more fequent and lower doses or by
the use of extended release formulations. Gatric irritation generally is dose depedent and may be
managed in several ways. The amount of drug can be reduced; the effective dose to gastric mucosa
can be lowered by use of enteric-coated formulations, or the patient can be protected by use of H2
receptor antagonists (Kenneth et al., 2017).
Idiosyncratic reactions pose onather problem. mild, asymptomatic elevations of liver en-
zymes do not mandate discontinuation of therapy if not in excess of 2 to 3 times normal values.
Stevens-Johnson syndrome adn toxic epidermal necrolysis, clinically symptomatic hepatotoxicity,
pancreatitis, and most rashes are indications for immediate cessation of responsible medication. If
the rash was mild, however, and especially if the patient had an otherwise favorable clinical re-
sponse to the drug, a cautious rechallenge might be considered. Successful resumption of therapy
has been reported in a number of patients, especially with valproat acid after that drug was discon-
tinued, when a more gradual dose escalation was used (Kenneth et al., 2017).

Risk of Drug Discontinuation

The obvious risk of stopping antiseizure grug therapy is the recurrence of seizures. In most
cases, seizure control can be regained with resumption of the previous drug therapy. Response to
therapy after a relapse may be rapid and satisfactory. Approximately 90% of patients who experince
seizure after antiseizure drug discontinuation have a 2-year remission after therapy is resumed. Thus
control was usually but not always regained despite increasing doses of a previously successful drug
regimen. A gudeline has been published to assit physician and the family considerating discontinau-
tion of antiseizure drug therapy (Kenneth et al., 2017).
Families should discuss withdrawing antiseizure drugs with their neurologist once children
have become free of siezures for 1 year or longer while on antiseizure drug therapy. Children whose
EEGs have become normal have a somewhat better chance of successful withdrawal of therapy.
however, there are critical life transitions when the risk of discontinuing therapy outweighs continu-
ation. These are when children have been seizure free and are eligible to begins driving, and when
they are living home and transitioning to chollage or independent living. finally, for some patients,
withdrawal of antiseizure drugs is rarely successful-for example, those with abnormalitoes on neu-
rologic examination or wiyh certain seizure syndromes such as as juvenile myoclonic epilepsy, Len-
nox-Gastaut syndrome, or infantile spasms (Kenneth et al., 2017).