In the Name of GOD

Antiepileptics lecture note

Prepared and summarized by

M.R. Panjehshahin, Ph.D
Professor of Pharmacology
Shiraz Medical School

At the end of this lecture the students should be able to:

1- Describe the epilepsy symptom,its ethiology, epidemiology and importance in health
management.
2- Define seizure and describe the classification of seizure type.
3- Describe the mechanism of action, clinical use and side effects of different antiseizure
drugs based on current classification of the symptom.
Introduction
Approximately 1% of the world’s population has epilepsy, the third most common neurologic
disorder after dementia and stroke. Epilepsy is a heterogeneous symptom complex—a chronic
disorder characterized by recurrent seizures. Seizures are finite episodes of brain dysfunction
resulting from abnormal discharge of cerebral neurons. The causes of seizures are many and
include the full range of neurologic diseases—from infection to neoplasm and head injury.
The term ―epilepsy‖ is not usually applied to such patients unless chronic seizures develop later.
Seizures are occasionally caused by an acute underlying toxic or metabolic disorder, in which
case appropriate therapy should be directed toward the specific abnormality, eg, hypocalcemia.
In most cases of epilepsy, however, the choice of medication depends on the empiric seizure
classification.

Drug Development for Epilepsy

Classification of seizure types are shown in Table 24–1. There is some specificity according to
seizure type, which is most clearly seen with generalized seizures of the absence type. These
seizures respond to ethosuximide and valproate but can be exacerbated by phenytoin and
carbamazepine. Drugs acting selectively on absence seizures can be identified by animal screens,
using threshold pentylenetetrazol clonic seizures in mice or rats. In contrast, the maximal
electroshock (MES) test, identifies drugs such as phenytoin, carbamazepine, and lamotrigine,
which are active against generalized tonic-clonic seizures and complex partial seizures. The
maximal electroshock test as the major initial screen for new drugs led predominantly to the
early identification of drugs with a mechanism of action involving prolonged inactivation of the
voltage-gated Na+ channel. New antiseizure drugs are being sought not only by the screening
tests noted above but also by more focused approaches. Compounds are sought that act by one of
three mechanisms: (1) enhancement of GABAergic (inhibitory) transmission, (2) diminution of
excitatory (usually glutamatergic) transmission, or (3) modification of ionic conductances.
BASIC PHARMACOLOGY
OF ANTISEIZURE DRUGS
Pharmacokinetics
The antiseizure drugs exhibit many similar pharmacokinetic Properties, because most have been
selected for oral activity and all must enter the central nervous system. Although many
of these compounds are only slightly soluble, absorption is usually good, with 80–100% of the
dose reaching the circulation. Most antiseizure drugs (other than phenytoin, tiagabine, and
valproic acid) are not highly bound to plasma proteins. Antiseizure drugs are cleared chiefly by
hepatic mechanisms,.Many are converted to active metabolites that are also cleared by the liver.
These drugs are predominantly distributed into total body water. Plasma clearance is relatively
slow. Some have halflives longer than 12 hours. Many of the older antiseizure drugs are
potent inducers of hepatic microsomal enzyme activity.

DRUGS USED IN PARTIAL SEIZURES

& GENERALIZED TONI C-CLONI C
SEIZURES
The classic major drugs for partial and generalized tonic-clonic seizures are phenytoin (and
congeners), carbamazepine, valproate, and the barbiturates. However, the availability of newer
drugs— eslicarbazepine, lamotrigine, levetiracetam, gabapentin, oxcarbazepine, pregabalin,
retigabine, topiramate, vigabatrin, lacosamide, and zonisamide—is altering clinical practice in
countries where these compounds are available.

PHENYTOIN
Phenytoin is the oldest nonsedative antiseizure drug, introduced in 1938.
Mechanism of Action
The mechanism of phenytoin’s action probably involves a combination of actions at several
levels. At therapeutic concentrations, the major action of phenytoin is to block Na+ channels and
inhibit the generation of rapidly repetitive action potentials. Presynaptic actions on glutamate and
GABA release probably arise from actions other than those on voltagegated Na+ channels.
Clinical Uses
Phenytoin is effective against partial seizures and generalized tonic-clonic seizures. In the latter,
it appears to be effective against attacks that are either primary or secondary to another seizure
type.
Pharmacokinetics
Absorption of phenytoin is highly dependent on the formulation of the dosage form.
Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in
most patients, although the time to peak may range from 3 to 12 hours. Phenytoin is highly
bound to plasma proteins. Drug concentration in cerebrospinal fluid is proportionate to the free
plasma level. Phenytoin accumulates in brain, liver, muscle, and fat. Phenytoin is metabolized to
inactive metabolites that are excreted in the urine. The elimination of phenytoin is dose-
dependent. At very low blood levels, phenytoin metabolism follows first-order kinetics.
However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to
metabolize phenytoin is approached. Further increases in dosage, though relatively small, may
produce very large changes in phenytoin concentrations. The half-life of phenytoin varies from
12 to 36 hours, with an average of 24 hours for most patients in the low to mid therapeutic
range. At low blood levels, it takes 5–7 days to reach steady-state blood levels.
Drug Interactions & Interference
with Laboratory Tests
Drug interactions involving phenytoin are primarily related to protein binding or to metabolism.
Since phenytoin is 90% bound to plasma proteins, other highly bound drugs, such as
phenylbutazone and sulfonamides, can displace phenytoin from its binding site. The drug has an
affinity for thyroid-binding globulin, which confuses some tests of thyroid function.
Phenytoin has been shown to induce microsomal enzymes responsible for the metabolism of a
number of drugs.
Toxicity
Dose-related adverse effects caused by phenytoin are often similar to those caused by other
antiseizure drugs in this group. Nystagmus occurs early. Diplopia and ataxia are the most
common dose-related adverse effects requiring dosage adjustment; sedation usually occurs only
at considerably higher levels. Gingival hyperplasia and hirsutism occur to some degree in most
patients. Long-term use may also result in abnormalities of vitamin D metabolism, leading to
osteomalacia. Idiosyncratic reactions to phenytoin are relatively rare. Hematologic complications
are exceedingly rare, although agranulocytosis has been reported in combination with fever and
rash.
MEPHENYTOIN , ETHOTOIN , & PHENACEMIDE
Many congeners of phenytoin have been synthesized, but only three have been marketed in the
USA, and one of these (phenacemide) has been withdrawn. The other two congeners,
mephenytoin and ethotoin, like phenytoin, appear to be most effective against generalized tonic-
clonic seizures and partial seizures.

CARBAMAZEPINE
It was initially marketed for the treatment of trigeminal neuralgia but has proved useful for
epilepsy as well.
Mechanism of Action
Carbamazepine, like phenytoin, blocks Na+ channels at therapeutic concentrations and inhibits
high-frequency repetitive firing in neurons in culture. Potentiation of a voltage-gated K+ current
has also been described. These effects probably account for the anticonvulsant action of
carbamazepine.
Clinical Uses
Carbamazepine has long been considered a drug of choice for both partial seizures and
generalized tonic-clonic seizures. Carbamazepine is not sedative in its usual therapeutic range.
The drug is also very effective in some patients with trigeminal Neuralgia. Carbamazepine is
also useful for controlling mania in some patients with bipolar disorder.
Pharmacokinetics
The rate of absorption of carbamazepine varies widely among patients, although almost complete
absorption apparently occurs in all. Peak levels are usually achieved 6–8 hours after
administration. Distribution is slow, and the volume of distribution is roughly 1 L/kg. The drug is
approximately 70% bound to plasma proteins; no displacement of other drugs from protein
binding sites has been observed. Carbamazepine has a very low systemic clearance at the start of
therapy but increased after one month. Typically, the half-life of 36 hours at the start, decreases
to as little as 8–12 hours in subjects receiving continuous therapy. Considerable dosage
adjustments are thus to be expected during the first weeks of therapy.
Drug Interactions
The increased metabolic capacity of the hepatic enzymes may cause a reduction in steady-state
carbamazepine concentrations and an increased rate of metabolism of other drugs, eg, primidone,
phenytoin, ethosuximide and clonazepam. Other drugs such as valproic acid may inhibit
carbamazepine clearance and increase steady-state carbamazepine blood levels.
Toxicity
The most common dose-related adverse effects of carbamazepine are diplopia and ataxia.
Rearrangement of the divided daily dose can often remedy this complaint. Other dose-related
complaints include mild gastrointestinal upsets, unsteadiness, and, at much higher doses,
drowsiness. Idiosyncratic blood dyscrasias with carbamazepine, including fatal cases of aplastic
anemia and agranulocytosis have been in elderly patients with trigeminal neuralgia, and most
have occurred within the first 4 months of treatment. The most common idiosyncratic reaction is
an erythematous skin rash.

OXCARBAZEPINE
Oxcarbazepine is closely related to carbamazepine and is useful in the same seizure types.
Oxcarbazepine has a half-life of only 1–2 hours. Its activity, therefore, resides almost exclusively
in its metabolite, eslicarbazepine, to which it is rapidly converted and which has a half-life
similar to that of carbamazepine, ie, 8–12 hours. The drug is mostly excreted as the glucuronide
of the metabolite. Some studies report fewer hypersensitivity reactions to oxcarbazepine, and
crossreactivity with carbamazepine does not always occur. Furthermore, the drug appears to
induce hepatic enzymes to a lesser extent than carbamazepine, minimizing drug interactions.
Most adverse effects that occur with oxcarbazepine are similar in character to reactions reported
with carbamazepine.

ESLICARBAZINE
Eslicarbazepine acetate (ESL) is a prodrug. ESL is more rapidly converted to S(+)- licarbazine
(eslicarbazine) than is oxcarbazepine; clearly both prodrugshave the same metabolite as active
product. The mechanism of action of carbamazepine, oxcarbazepine, and ESL appears to be the
same, ie, blocking of voltage-gated Na+ channels. Clinically, the drug is similar to
carbamazepine and oxcarbazepine in its spectrum of action. A possible advantage of ESL is its
once-daily dosing regimen. Minimal drug level effects are observed with co-administration
of carbamazepine, levetiracetam, lamotrigine, topiramate, and valproate. Oral contraceptives
may be less effective with concomitant ESL administration.

PHENOBARBITAL
Aside from the bromides, phenobarbital is the oldest of the currently
available antiseizure drugs.
Because of the sedative effects, many consider
the barbiturates the drugs of choice for seizures only in infants.
Mechanism of Action
The exact mechanism of action of phenobarbital is unknown, but enhancement of inhibitory
processes and diminution of excitatory transmission probably contribute significantly.
Phenobarbital binds to an allosteric regulatory site on the GABAA receptor, and it enhances the
GABA receptor-mediated current by prolonging the openings of the Cl– channels. Phenobarbital
can also decrease excitatory responses. Both the enhancement of GABA-mediated inhibition
and the reduction of glutamate-mediated excitation are seen with therapeutically relevant
concentrations of phenobarbital.
Clinical Uses
Phenobarbital is useful in the treatment of partial seizures and generalized tonic-clonic seizures,
although the drug is often tried for virtually every seizure type, especially when attacks are
difficult to control.

PRIMIDONE
Primidone, or 2-desoxyphenobarbital, was first marketed in the early 1950s. It was later reported
that primidone was metabolized to phenobarbital and phenylethylmalonamide (PEMA). All three
compounds are active anticonvulsants.
Mechanism of Action
Although primidone is converted to phenobarbital, the mechanism of action of primidone itself
may be more like that of phenytoin.
Clinical Uses
Primidone, like its metabolites, is effective against partial seizures and generalized tonic-clonic
seizures and may be more effective than phenobarbital. Primidone has been shown to be
effective in controlling seizures in infants and in older patients beginning treatment with
primidone; older patients show seizure control before phenobarbital concentrations reach the
therapeutic range. Primidone has an anticonvulsant action independent of its conversion to
phenobarbital.
Pharmacokinetics
Primidone is completely absorbed, usually reaching peak concentrations about 3 hours after oral
administration. Primidone is generally distributed in total body water. It is not highly bound to
plasma proteins; approximately 70% circulates as unbound drug. Primidone is metabolized by
oxidation to phenobarbital. Both primidone and phenobarbital also undergo subsequent
conjugation and excretion. Primidone has a larger clearance than most other antiseizure drugs.
Phenobarbital accumulates very slowly but eventually reaches therapeutic concentrations in most
patients. During chronic therapy, phenobarbital levels derived from primidone are usually two to
three times higher than primidone levels.
Toxicity
The dose-related adverse effects of primidone are similar to those of its metabolite,
phenobarbital, except that drowsiness occurs early in treatment and may be prominent if the
initial dose is too large.

FELBAMATE
Although Felbamate is effective in some patients with partial seizures, the drug causes aplastic
anemia and severe hepatitis at unexpectedly high rates and has been relegated to the status of a
third-line drug for refractory cases. In addition to its usefulness in partial seizures, felbamate has
proved effective against the seizures that occur in Lennox-Gastaut syndrome.

GABAPENTIN & PREGABALIN

Gabapentin, an analog of GABA, that is effective against partial seizures. Pregabalin is another
GABA analog, closely related to gabapentin, and has been approved for both antiseizure activity
and for its analgesic properties.
Mechanism of Action
In spite of their close structural resemblance to GABA, gabapentin and pregabalin do not act
directly on GABA receptors. They may, however, modify the synaptic or nonsynaptic release of
GABA. An increase in brain GABA concentration is observed in patients receiving gabapentin.
Its main mechanism of action is decreasing Ca2+ entry, with a predominant effect on presynaptic
channels. A decrease in the synaptic release of glutamate provides the antiepileptic effect.
Clinical Uses
Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic
seizures Gabapentin has also been promoted for the treatment of neuropathic pain and is now
indicated for postherpetic neuralgia in adults. The most common adverse effects are
somnolence, dizziness, ataxia, headache, and tremor. Pregabalin is approved for the adjunctive
treatment of partial Seizures. Pregabalin is also approved for use in neuropathic pain, including
painful diabetic peripheral neuropathy and postherpetic neuralgia.
Pharmacokinetics
Gabapentin is not metabolized and does not induce hepatic enzymes. The drug is not
bound to plasma proteins. Drug-drug interactions are negligible. Elimination is via renal
mechanisms; the drug is excreted unchanged. The half-life is relatively short, ranging from 5 to 8
hours Pregabalin, like gabapentin, is not metabolized and is almost entirely excreted unchanged
in the urine. The half-life of pregabalin ranges from about 4.5 hours to 7.0 hours, thus requiring
more than once-daily dosing in most patients.
LACOSAMIDE
Lacosamide is an amino acid-related compound that has been studied in both pain syndromes
and partial seizures. The drug was approved for the treatment of partial seizures.
Mechanism of Action
Lacosamide enhances slow inactivation of voltage-gated Na+ channels.
Clinical Uses
Lacosamide is approved as adjunctive therapy in the treatment of partial-onset seizures with or
without secondary generalization in patients with epilepsy who are age 16–17 years and older.
Adverse effects were dizziness, headache, nausea, and diplopia.
Pharmacokinetics
Oral lacosamide is rapidly and completely absorbed in adults, with no food effect. ioavailability
is nearly 100%. Elimination half-life is 13 hours.

LAMOTRIGINE
Mechanism of Action
Lamotrigine, like phenytoin, suppresses sustained rapid firing of neurons and produces a voltage-
and use-dependent blockade of Na+ channels. Lamotrigine also inhibits voltage-gated Ca2+
channels, which would account for its efficacy in primary generalized seizures in childhood,
including absence attacks. Lamotrigine also decreases the synaptic release of glutamate.
Clinical Uses
Although most controlled studies have evaluated lamotrigine as add-on therapy, it is generally
agreed that the drug is effective as monotherapy for partial seizures, and lamotrigine is now
widely prescribed for this indication. The drug is also active against absence and myoclonic
seizures in children and is approved for seizure control in the Lennox-Gastaut syndrome.
Lamotrigine is also effective for bipolar disorder. Adverse effects include dizziness,
headache, diplopia, nausea, somnolence, and skin rash.
Pharmacokinetics
Lamotrigine is almost completely absorbed. Protein binding is only about 55%. The drug is
metabolized primarily by glucuronidation, which is excreted in the urine. Lamotrigine has a half-
life of approximately 24 hours in normal volunteers; this decreases to 13–15 hours in patients
taking enzyme-inducing drugs. Valproate causes a twofold increase in the drug’s half-life; in
patients receiving valproate.

LEVETIRACETAM
Mechanism of Action
Levetiracetam modifies the synaptic release of glutamate and GABA through an action on
vesicular function. In addition, levetiracetam inhibits N-type calcium channels and inhibits
calcium release from intracellular stores.
Clinical Uses
Levetiracetam is marketed for the adjunctive treatment of partial seizures in adults and children
for primary generalized tonic-clonic seizures and for the myoclonic seizures of juvenile
myoclonic epilepsy. Adverse effects include somnolence, asthenia, ataxia, and dizziness. Less
common but more serious are mood and behavioral changes; psychotic reactions are rare.
Pharmacokinetics
Oral absorption of levetiracetam is nearly complete. Protein binding is less than 10%. The
plasma half-life is 6–8 hours, but may be longer in the elderly. Two thirds of the drug is excreted
unchanged in the urine; the drug has no known active metabolites.

PERAMPANEL
Perampanel is an orally active AMPA antagonist approved for the treatment of partial seizures.
Mechanism of Action
Perampanel acts selectively at postsynaptic AMPA receptors
Clinical Uses
Perampanel is approved for the adjunctive treatment of partial seizures with or without
secondary generalization in patients 12 years of age or older. Although the drug
was generally well tolerated, More common adverse effects were dizziness, somnolence, and
headache. Falls were more common at higher doses. A small number of patients experienced
serious or life-threating behavioral adverse reactions including aggression, hostility, irritability,
and anger, with or without a previous history of psychiatric disorders. Perampanel has a long
half-life, typically ranging from 70 to 110 Hours. Absorption is rapid and the drug is fully
bioavailable. Perampanel is 95% bound to plasma proteins. The drug is extensively
metabolized via initial oxidation and subsequent glucuronidation.
Drug Interactions
The most significant drug interactions with perampanel are with potent CYP3A inducer
antiseizure drugs such as carbamazepine, oxcarbazepine, and phenytoin. When perampanel was
administered with carbamazepine, the half-life decreased from 105 hours to 25 hours.

RETIGABINE (EZOGABINE)
Retigabine (ezogabine in the USA) is approved for the adjunctive treatment of partial-onset
seizures in adults. It is a potassiumchannel facilitator and unique in its mechanism of action.
Absorption is not affected by food; drug interactions are minimal. Most adverse effects are dose
related and include dizziness, somnolence, blurred vision, confusion, and dysarthria. In 2013,
reports began to appear of blue pigmentation, primarily on the skin and lips; the problem
is rather common, occurring in about one third of patients on long-term therapy. Decreased
visual acuity has been reported. Regulatory agencies have recommended use of retigabine only
in cases where other antiseizure drugs are not adequate or not tolerated.

RUFINAMIDE
Mechanism of Action
Rufinamide decreases sustained high-frequency firing of neurons in vitro and is thought to
prolong the inactive state of the Na+ channel.
Clinical Uses
Rufinamide is approved in the USA for adjunctive treatment of seizures associated with the
Lennox-Gastaut syndrome in patients age 4 years and older. The drug is effective against all
seizure types in this syndrome, especially against tonic-atonic seizures. Recent data also
suggest it may be effective against partial seizures. The most common adverse events are
somnolence, vomiting, pyrexia, and diarrhea.
Pharmacokinetics
Rufinamide is well absorbed, but plasma concentrations peak between 4 and 6 hours. The half-
life is 6–10 hours, and minimal plasma protein binding is observed. The drug is extensively
metabolized to inactive products. Most of the drug is excreted in the urine; an acid metabolite
accounts for about two thirds of the dose.

STIRIPENTOL
Stiripentol is used with clobazam and valproate in the adjunctive therapy of refractory
generalized tonic-clonic seizures in patients with severe myoclonic epilepsy of infancy (SMEI,
Dravet’s syndrome) whose seizures are not adequately controlled with clobazam and valproate.
The mechanism of action of stiripentol is not well understood but it has been shown to enhance
GABAergic transmission in the brain It can increase the effect of other AEDs by slowing their
inactivation by cytochrome P450. Stiripentol is a potent inhibitor of CYP3A4, CYP1A2, and
CYP2C19. Adverse effects of stiripentol itself are few, but the drug can dramatically increase the
levels of valproate, clobazam, and the active metabolite of the latter, norclobazam. These drugs
must be used cautiously together to avoid adverse effects.

TIAGABINE
Mechanism of Action
Tiagabine is an inhibitor of GABA uptake in both neurons and glia It prolongs the inhibitory
action of synaptically released GABA, but its most significant effect may be potentiation
of tonic inhibition.
Clinical Uses
Tiagabine is indicated for the adjunctive treatment of partial seizures. Minor adverse events are
dose related and include nervousness, dizziness, tremor, difficulty in concentrating, and
depression Excessive confusion, somnolence, or ataxia may require discontinuation. Rash is an
uncommon idiosyncratic adverse effect.
Pharmacokinetics
Tiagabine is 90–100% bioavailable, has linear kinetics, and is highly protein bound. The half-life
is 5–8 hours and decreases in the presence of enzyme-inducing drugs. The drug is oxidized in the
liver by CYP3A. Elimination is primarily in the feces (60–65%) and urine (25%).
TOPIRAMATE
Mechanism of Action
Topiramate mechanism of action, is likely to involve blocking of voltage-gated Na+ channels.
It also acts on high-voltage activated (L-type) Ca2+ channels. Topiramate potentiates the
inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites.
Topiramate also depresses the excitatory action of kainate on glutamate receptors.
Clinical Uses
Clinical trials of topiramate as monotherapy demonstrated efficacy against partial and eneralized
tonic-clonic seizures. The drug is also approved for the Lennox-Gastaut syndrome, and may be
effective in infantile spasms and even absence seizures. Topiramate is also approved for the
treatment of migraine headaches. Dose-related adverse effects occur most frequently in the first 4
weeks and include somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness,
and confusion. Acute myopia and glaucoma may require prompt drug withdrawal. The drug is
teratogenic in animal models.
Pharmacokinetics
Topiramate is rapidly absorbed (about 2 hours) and is 80% bioavailable. The drug is primarily
excreted unchanged in the urine. The half-life is 20–30 hours. Drug interactions do occur and can
be complex, but the major effect is on topiramate levels rather than on the levels of other
antiseizure drugs.

VIGABATRIN
Mechanism of Action
Vigabatrin is an irreversible inhibitor of GABA aminotransferase It may also inhibit the
vesicular GABA transporter. A decrease in brain glutamine synthetase activity is probably
secondary to the increased GABA concentrations.
Clinical Uses
Vigabatrin is useful in the treatment of partial seizures and infantile spasms. The half-life is
approximately 6–8 hours, but considerable evidence suggests that the pharmacodynamic activity
of the drug is more prolonged and not well correlated with the plasma half-life.
Typical toxicities include drowsiness, dizziness, and weight gain. Less common but more
troublesome adverse reactions are agitation, confusion, and psychosis; preexisting mental illness
is a relative contraindication. In addition, long-term therapy with vigabatrin has been associated
with development of peripheral visual field defects in 30–50% of patients. Vigabatrin is usually
reserved for use in patients with infantile spasms or with complex partial seizures refractory to
other treatments.

ZONISAMIDE
Zonisamide is a sulfonamide derivative. Its primary site of action appears to be the Na+ channel;
it also acts on T-type voltage-gated Ca2+ channels. The drug is effective against partial and
generalized tonic-clonic seizures and may also be useful against infantile spasms and certain
myoclonias. It has good bioavailability, linear kinetics, low protein-binding, renal excretion, and
a half-life of 1–3 days. Adverse effects include drowsiness, cognitive impairment, and
potentially serious skin rashes. Zonisamide does not interact with other antiseizure drugs.

DRUGS USED IN GENERALIZED

SEIZURES
ETHOSUXIMIDE
Mechanism of Action
Ethosuximide has an important effect on Ca2+ currents, reducing the low-threshold (T-type)
current. This effect is seen at therapeutically relevant concentrations in thalamic neurons.
Inhibition of this current could therefore account for the specific therapeutic action of
ethosuximide. It was introduced as a ―pure petit mal‖ drug.
Clinical Uses
Ethosuximide is
particularly effective against absence seizures, but has a very narrow spectrum of clinical
activity. Data continue to show that ethosuximide and valproate are the drugs of choice for
absence seizures and are more effective than lamotrigine.
Pharmacokinetics
Absorption is complete following administration of the oral dosage forms. Peak levels are
observed 3–7 hours after oral administration of the capsules. Ethosuximide is not protein-bound.
The drug is completely metabolized, principally by hydroxylation, to inactive metabolites.
Ethosuximide has a very low total body clearance (0.25 L/kg/d). This corresponds to a half-life
of approximately 40 hours, although values from 18 to 72 hours have been reported.
Drug Interactions & Toxicity
Administration of ethosuximide with valproic acid results in a decrease in ethosuximide
clearance and higher steady-state concentrations owing to inhibition of metabolism.
The most common dose-related adverse effect of ethosuximide is gastric distress, including pain,
nausea, and vomiting. Other dose-related adverse effects are transient lethargy or fatigue and,
much less commonly, headache, dizziness, hiccup, and euphoria

VALPROI C ACID & SODIUM

VALPRO ATE
Valproic acid is one of a series of fatty carboxylic acids that have antiseizure activity. It is
fully ionized at body pH, and for that reason the active form of the drug may be assumed to be
the valproate ion regardless of whether valproic acid or a salt of the acid is administered.
Mechanism of Action
Valproate is active against both pentylenetetrazol and maximal electroshock seizures. Like
phenytoin and carbamazepine, valproate blocks sustained high-frequency repetitive firing of
neurons. 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. Several studies have
shown increased levels of GABA in the brain after administration of valproate, although the
mechanism for this increase remains unclear.
Clinical Uses
Valproate is very effective against absence seizures and is often preferred to ethosuximide when
the patient has concomitant generalized tonic-clonic attacks. Valproate is unique in its ability to
control certain types of myoclonic seizures; in some cases the effect is very dramatic. The drug is
effective in tonic-clonic seizures, especially those that are primarily generalized. Intravenous
formulations are occasionally used to treat status epilepticus.
Pharmacokinetics
Valproate is well absorbed after an oral dose, with bioavailability greater than 80%. Peak blood
levels are observed within 2 hours. Food may delay absorption, and decreased toxicity may result
if the drug is given after meals. Valproic acid is 90% bound to plasma proteins. Since valproate
is both highly ionized and highly protein-bound, its distribution is essentially confined to
extracellular water. Clearance for valproate is low and dose dependent; its half-life varies from 9
to 18 hours.
Drug Interactions
Valproate displaces phenytoin from plasma proteins. In addition to binding interactions,
valproate inhibits the metabolism of several drugs, including phenobarbital, phenytoin, and
carbamazepine, leading to higher steady-state concentrations of these agents. Valproate can
dramatically decrease the clearance of lamotrigine.
Toxicity
The most common dose-related adverse effects of valproate are nausea, vomiting, and other
gastrointestinal complaints such as abdominal pain and heartburn. Sedation is uncommon with
valproate alone. Other reversible adverse effects, seen in a small number of patients, include
weight gain, increased appetite, and hair loss. The idiosyncratic toxicity of valproate is largely
limited to hepatotoxicity. The risk is greatest for patients under 2 years of age and for those
taking multiple medications. The other observed idiosyncratic response with valproate is
thrombocytopenia. There is a substantial increase in the incidence of spina bifida in the offspring
of women who took valproate during pregnancy. In addition, an increased incidence of
cardiovascular, orofacial, and digital abnormalities has been reported. These observations must
be strongly considered in the choice of drugs during pregnancy

OXAZOLIDINEDIONES
Trimethadione is active against pentylenetetrazol-induced seizures. Trimethadione raises the
threshold for seizure discharges after repetitive thalamic stimulation. Trimethadione is rapidly
absorbed, with peak levels reached within 1 hour after drug administration. Trimethadione is
completely metabolized in the liver. The most common and bothersome dose-related adverse
effect of the oxazolidinediones is sedation. These drugs should not be used during pregnancy.
Use of the oxazolidinediones—trimethadione, paramethadione, and dimethadione—is now very
limited; the latter two are not readily available.

OTHER DRUGS USED IN

MANAGEMENT OF EPILEPSY
Some drugs not classifiable by application to seizure type are discussed in this section.

BENZODIAZEPINES
Six benzodiazepines play prominent roles in the therapy of epilepsy. The mechanisms of
antiseizure action is the potentiation of GABA action on chloride channel.
Diazepam given intravenously or rectally is highly effective for stopping continuous seizure
activity, especially generalized tonic clonic status epilepticus.
Lorazepam appears in some studies to be more effective and longer acting than diazepam in the
treatment of status epilepticus and is preferred by some experts.
Clonazepam is a long-acting drug with documented efficacy against absence seizures. It is also
effective in some cases of myoclonic seizures and has been tried in infantile spasms. Sedation is
prominent, especially on initiation of therapy; starting doses should be small.
Nitrazepam is not marketed in the USA but is used in many other countries, especially for
infantile spasms and myoclonic seizures. It is less potent than clonazepam, and superiority
to that drug has not been documented.
Clorazepate dipotassium is approved in the USA as an adjunct to treatment of complex partial
seizures in adults. Drowsiness and lethargy are common adverse effects.
Clobazam is widely used in a variety of seizure types. The drug is approved in the USA for
treatment of Lennox-Gastaut syndrome.
Limitations
Two prominent aspects of benzodiazepines limit their usefulness. The first is their pronounced
sedative effect, which is unfortunate both in the treatment of status epilepticus and in chronic
therapy. Children may manifest a paradoxical hyperactivity, as with barbiturates. The second
problem is tolerance, in which seizures may respond initially but recur within a few months. The
remarkable antiseizure potency of these compounds often cannot be realized because of these
limiting factors.

ACETAZOLAMIDE
Acetazolamide is a diuretic whose 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.
Acetazolamide has been used for all types of seizures but is severely limited by the rapid
development of tolerance, with return of seizures usually within a few weeks. The drug may
have a special role in epileptic women who experience seizure exacerbations at the time of
menses.

Reference:

Basic & Clinical Pharmacology, Katzung- 13th Edition, 2015, Mc Graw Hill pp. 396-420