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Antiseizure Drugs
1
Introduction

Globally epilepsy is the third most
common
neurologic
disorder
after
cerebrovascular and Alzheimer's disease

Epilepsy affects 0.5-1% of the population
2
Introduction


Epilepsy is a heterogeneous symptom
complex—a chronic disorder characterized
by recurrent, periodic, and unpredictable
seizures
originating
from
several
mechanisms that have in common the
sudden, excessive, and synchronous
discharge of cerebral neurons
The term seizure refers to a transient
alteration of behaviour due to the
disordered, synchronous, and rhythmic
firing of populations of brain neurons
3
Introduction



Often, there is no recognisable cause, although it
may develop after brain damage, such as trauma,
stroke, infection or tumour growth, or other kinds
of neurological disease
In some subgroups, heredity Single gene defects,
usually of an autosomal dominant nature involving
genes coding voltage-gated ion channels or GABAA
receptors has proved to be a predominant factor.
This abnormal electrical activity may result in a
variety of events, including loss of consciousness,
abnormal movements, atypical or odd behaviour,
or distorted perceptions that are of limited
duration but recur if untreated
4
Introduction

Seizures are thought to arise from the cerebral cortex,
and not from other central nervous system (CNS)
structures such as the thalamus, brainstem, or
cerebellum

The behavioral manifestations of a seizure are
determined by the functions normally served by the
cortical site at which the seizure arises
5
Introduction

The clinical classification of epilepsy is done
on the basis of the characteristics of the
seizure rather than on the cause or underlying
pathology

The clinical classification of epilepsy defines
two major categories, namely partial and
generalised seizures

Either form is classified as simple (if
consciousness is not lost) or complex (if
consciousness is lost)
6
Partial seziures

Partial seizures are those in which the discharge
begins locally and often remains localised

The symptoms of each seizure type depend on the
site of neuronal discharge and on the extent to
which the electrical activity spreads to other
neurons in the brain

The symptoms depend on the brain region or
regions involved, and include involuntary muscle
contractions, abnormal sensory experiences or
autonomic discharge, or effects on mood and
behaviour
7
Partial seziures

Partial seizures with no loss of
consciousness are classified as simple PS

Partial seizures with an alteration of
consciousness are classified as complex PS

Partial seizures may progress, becoming
generalized tonic-clonic seizures
8
Partial seziures
1)
Simple partial

The electrical discharge does not spread, and
the patient is completely aware of the attack
and can describe it in detail

Diverse manifestations determined by the
region of cortex activated by the seizure
(e.g., if motor cortex representing left
thumb, clonic jerking of left thumb results; if
somatosensory cortex representing left
thumb, paresthesia of left thumb results)

Lasting approximating 20-60 seconds
9
Partial seziures
2)
Complex partial

It has a localized onset, but the discharge
becomes more widespread (usually bilateral)
and almost always involves the limbic system

Exhibit complex sensory hallucinations,
mental distortion, and impaired consciousness
lasting 30 seconds to 2 minutes with
purposeless movements such as lip smacking
or hand wringing (automatism)
10
Partial seziures
2)

Complex partial
After 30–120 seconds, the patient makes a gradual
recovery to normal consciousness but may feel tired or
ill for several hours after the attack
11
Generalized seziures

In contrast to partial seizures, which arise
from localized regions of the cerebral
cortex, generalized-onset seizures arise
from the reciprocal firing of the thalamus
and cerebral cortex

Primary generalized seizures may be
convulsive or nonconvulsive

The patient usually has an immediate
loss of consciousness
12
Generalized seziures
1)
Tonic-clonic:

Seizures result in loss of consciousness,
followed
by
tonic
(continuous
contraction) and clonic (rapid contraction
and relaxation) phases

The seizure may be followed by a period
of confusion and exhaustion due to the
depletion of glucose and energy stores
13
Generalized seziures
2)



Absence (petit mal):
These seizures involve a brief, abrupt,
and self-limiting loss of consciousness
The onset generally occurs in patients
at 3 to 5 years of age and lasts until
puberty or beyond
The patient stares and exhibits rapid
eye-blinking, which lasts for 3 to 5
seconds
14
Generalized seziures
Myoclonic:
 These seizures consist of short episodes of
muscle contractions that may reoccur for
several minutes without overt signs of
neurologic deficit
 They generally occur after wakening and
exhibit as brief jerks of the limbs
 Myoclonic seizures occur at any age but
usually begin around puberty or early
adulthood
3)
15
Generalized seziures
4)
Atonic seizures:

Are those in which the patient has
sudden loss of postural tone. If
standing, the patient falls suddenly to
the floor and may be injured. If
seated, the head and torso may
suddenly drop forward

Most often seen in children
16
Generalized seziures
5)
Febrile seizures:

Young children may develop seizures
with illness accompanied by high fever

The febrile seizures consist of
generalized tonic-clonic convulsions of
short duration and do not necessarily
lead to a diagnosis of epilepsy
17
Generalized seziures
6)



Status epilepticus:
Two or more seizures recur without
recovery of full consciousness between
them
These may be partial or primary
generalized,
convulsive
or
nonconvulsive
Status epilepticus is life-threatening
and requires emergency treatment
18
Pathophysiology

The are multiple mechanism that might contribute
to seizures:
1. Alteration in the number, type, and
distribution of ion channels in the neuronal
membranes
2. Biochemical modifications of receptors
3. Modulation of second messenger systems and
gene expression
4. Changes in extracellular ion concentrations
5. Alterations in the neurotransmitters uptake
and metabolism in the glial cells
6. Local neurotransmitter imbalance
19
Neural mechanisms of epliepsy

The underlying neuronal abnormality
in epilepsy is poorly understood

In general, excitation will naturally
tend to spread throughout a network
of interconnected neurons but is
normally prevented from doing so by
inhibitory mechanisms
20
Neural mechanisms of
epliepsy


The pivotal role of synapses in mediating
communication among neurons in the
mammalian
brain
suggested
that
defective synaptic function might lead to
a seizure:
a)
Reduction of inhibitory synaptic activity
b)
Enhancement of excitatory synaptic activity might be
expected to trigger a seizure
The neurotransmitters mediating the bulk
of
synaptic
transmission
in
the
mammalian brain are GABA (inhibitory) &
glutamate (stimulatory)
21
Neural mechanisms of
epliepsy


Neurons from which the epileptic
discharge originates display an unusual
type of electrical behaviour termed the
paroxysmal depolarising shift (PDS),
during which the membrane potential
suddenly decreases by about 30 mV and
remains depolarised for up to a few
seconds before returning to normal
This probably results from the abnormally
exaggerated and prolonged action of an
excitatory transmitter (activation of
NMDA receptors)
22
Neural mechanisms of
epliepsy

Electrophysiological analyses of individual neurons
during a partial seizure demonstrate that the neurons
undergo depolarization and fire action potentials at high
frequencies

Inhibition of the high-frequency firing is thought to be
mediated by reducing the ability of Na+ channels to
recover from inactivation
23
Neural mechanisms of
epliepsy

Activation of the GABAA receptor inhibits the
postsynaptic cell by increasing the inflow of Cl– ions into
the cell, which tends to hyperpolarize the neuron

Clinically
relevant
concentrations
of
both
benzodiazepines and barbiturates enhance GABAA
receptor–mediated inhibition through distinct actions on
the GABAA receptor
24
Neural mechanisms of
epliepsy

In contrast to partial seizures, which arise from
localized regions of the cerebral cortex, generalizedonset seizures arise from the reciprocal firing of the
thalamus and cerebral cortex

Thalamic neurons is pivotally involved in the generation
of the 3-Hz spike-and-wave discharges is a particular
type of Ca2+ current, the low threshold ("T-type")
current
25
Neural mechanisms of
epliepsy

T-type Ca2+ channels are activated at a much more
negative membrane potential "low threshold" than most
other voltage-gated Ca2+ channels expressed in the
brain

T-type currents amplify thalamic membrane potential
oscillations and bursts of action potentials in thalamic
neurons are mediated by activation of the T-type
currents
26
Antiseziure Drugs

Current antiseizure drugs are palliative
rather
than
curative;
therapy
is
symptomatic in that available drugs
inhibit seizures, but neither effective
prophylaxis nor cure is available

Choice of drug treatment is based on the
classification of the seizures being treated,
patient specific variables (for example, age,
comorbid medical conditions, lifestyle, and
other preferences), and characteristics of the
drug, including cost and interactions with
other medications
27
Antiseziure Drugs

The ideal anti-seizure drug would
suppress all seizures without causing any
unwanted effects

Unfortunately, the drugs used currently
not only fail to control seizure activity in
some patients (25-35% of patients), but
frequently cause unwanted effects that
range
in
severity
from
minimal
impairment of the CNS to death from
aplastic anemia or hepatic failure
28
Antiseziure Drugs

An awareness of the antiepileptic drugs
available, including their mechanisms of
action, pharmacokinetics, potential for drugdrug interactions, and adverse effects, is
essential for successful therapy

Measurement of drug concentrations in
plasma facilitates optimizing anti-seizure
medication, especially when therapy is
initiated, after dosage adjustments, in the
event of therapeutic failure, when toxic
effects appear, or when multiple-drug therapy
is instituted
29
Antiseziure Drugs

In newly diagnosed patients, monotherapy
is instituted with a single agent until
seizures are controlled or toxicity occurs

If seizures are not controlled with the
first drug, monotherapy with an alternate
antiepileptic drug(s)

However, multiple-drug therapy may be
required, especially when two or more
types of seizure occur in the same patient
30
Retigabine
Rufinamide
Lacosamide
Brivaracetam
Number of Licensed Antiepileptic Drugs
?
20
Pregabalin
Zonisamide
Levetiracetam
Oxcarbazepine
Tiagabine
15
Fosphenytoin
Topiramate
Lamotrigine
Gabapentin
10
Felbamate
Sodium Valproate
Carbamazepine
Ethosuximide
5
Phenytoin
Phenobarbital
Benzodiazepines
Primidone
Bromide
0
1840
1860
1880
1900
1920
1940
Calendar Year
1960
1980
2000
Number of Licensed Antiepileptic Drugs
20
Pregabalin
10
Zonisamide
Levetiracetam
Tiagabine Oxcarbazepine
Topiramate
5
Fosphenytoin
Lamotrigine
Gabapentin
Felbamate
0
1990
2000
Calendar Year
Antiseziure Drugs
Mechanism of action
1)
2)
3)
Enhancement of inhibitory
GABAergic impulses
Interference with excitatory
glutamate transmission
Modification of ionic conductances:
 Inhibition
of sodium channel
function
 Inhibition of calcium channel
function
33
Inhibition of sodium channel function

Agents:
phenytoin,
oxcarbazepine,
topiramate,
zonisamide, and lamotrigine
carbamazepine,
valproic
acid,

The sodium channel exists in three main
conformations: a resting (R) or activatable state,
an open (0) or conducting state, and an inactive
(I) or nonactivatable state

The anticonvulsant drugs bind preferentially to the
inactive form of the channel reducing the rate of
recovery of Na+ channels from inactivation would
limit the ability of a neuron to fire at high
frequencies
34
Voltage-gated sodium channel
Open
Inactivated
Na+
Na+
X
I
Na+
A = activation gate
I = inactivation gate
Goodman & Gilman’s. 12th ed. 2012
Carbamazepine
Phenytoin
I
Na+
Lamotrigine
Valproate
Inhibition of sodium channel
function

Inhibiting voltage-gated ion channels is a common
mechanism of action among anti-seizure drugs with
anti–partial-seizure activity
36
Phenytoin

Phenytoin is the oldest nonsedative
antiseizure drug

Phenytoin is a valuable agent for the
treatment of generalized tonic–clonic
seizures and for the treatment of
partial
seizures
with
complex
symptoms
37
Phenytoin
Pharmacokinetics

Phenytoin absorption is slow but usually complete,
and it occurs primarily in the duodenum

Absorption of phenytoin is highly dependent on
the formulation of the dosage form. Particle size
and pharmaceutical additives affect both the rate
and the extent of absorption

Phenytoin sodium should never be given IM
because it can cause tissue damage and necrosis

Fosphenytoin is a prodrug and is rapidly converted
to phenytoin in the blood that can be
administered IM
38
Phenytoin
Pharmacokinetics

The pharmacokinetic characteristics of
phenytoin are influenced markedly by its
binding to serum proteins, by the nonlinearity
of its elimination kinetics, and by its
metabolism by CYPs

Phenytoin is extensively bound (about 90%) to
serum proteins, mainly albumin

The majority (95%) of phenytoin is
metabolized principally in the hepatic
endoplasmic reticulum by CYP2C9/10 and to a
lesser extent CYP2C19
39
Phenytoin
Pharmacokinetics

The elimination of phenytoin is dose-dependent:

At very low blood levels, phenytoin metabolism follows
first-order kinetics

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 the drug increases markedly, & steady state
is not achieved
40
Ave. Serum Conc. (mg/L)
A) Nonlinear Pharmacokinetics:
A) Nonlinear
B) Linear
C) Nonlinear
(Michaelis-Menten type)
Clearance decreases as dose
increases
PHT
C) Nonlinear
pharmacokinetics:
Clearance increases with dose
CBZ
Daily Dose (mg/kg/day)
Cloyd and Birnbaum, 1995
Phenytoin Concentration (mg/L)
60
Elderly (aged 65-79 years)1
Vmax=5.5 mg/kg/day
Km=5.8 mg/L
50
40
Nonelderly (aged 19-64 years)2
Vmax=8.45 mg/kg/day
Km=6.25 mg/L
30
20
10
0
0
2
4
6
8
Daily Dose (mg/kg) as PHT Acid
1. Bauer LA, Blouin RA. Clin Pharmacol Ther. 1982;31:301-304. 2. Cloyd J, et al. Presented at:
10th Epilepsy International Symposium; 1978; Vancouver, British Columbia.
Phenytoin
Drug interactions

Drug interactions involving phenytoin are
primarily related to protein binding or to
metabolism

Highly bound drugs, such as salicylates,
valproate, phenylbutazone and sulfonamides,
can competitively displace phenytoin from its
binding site

The protein binding of phenytoin is decreased
in the presence of renal disease, neonate, in
patients with hypoalbuminemia
43
Phenytoin
Drug interactions



PTN
induces
microsomal
enzymes
responsible for metabolism of a number
of drugs (e.g. oral anticoagulants)
Treatment with phenytoin can enhance
the metabolism of oral contraceptives
and lead to unplanned pregnancy
The metabolism of phenytoin itself can be
either
enhanced
or
competitively
inhibited by various drug metabolized by
CYP2C9 or CYP2C10
44
Phenytoin
Drug interactions

Carbamazepine, which may enhance the
metabolism of phenytoin, causes a welldocumented decrease in phenytoin
concentration

Interaction between phenytoin
phenobarbital is variable
and
45
Phenytoin
Adverse effects

Dose-depedent: usually result from
overdosage

Characterized by nystagmus, ataxia, vertigo, and diplopia
(cerebellovestibular dysfunction)

Higher doses lead to altered levels of consciousness and
cognitive

Gingival hyperplasia occurs in about 20% of all patients
during chronic therapy and is probably the most common
manifestation of phenytoin toxicity in children and young
adolescents
46
Figure 1. A 17-year-old boy had generalized tonic–clonic seizures for four years. When the seizures began, a computed
tomographic scan of his brain and an electroencephalogram were normal. Treatment with 300 mg of phenytoin per day
was subsequently begun and continued unsupervised for a period of two years. Examination revealed coarsening of facial
features and severe gingival hyperplasia (Panel A), brisk deep-tendon reflexes, and cerebellar ataxia. Withdrawal of
phenytoin was followed by marked regression of the gingival hyperplasia within three months47(Panel B); however, ataxia
persisted.
http://content.nejm.org/cgi/content/full/342/5/325
Phenytoin
Adverse effects

Dose-depedent:
effects:
Endocrine
side

Inhibition of release of anti-diuretic hormone (ADH) in
patients with inappropriate ADH secretion

Hyperglycemia and glycosuria due to inhibition of insulin
secretion

Osteomalacia, with hypocalcemia and elevated alkaline
phosphatase activity, due to both altered metabolism of
vitamin D and the attendant inhibition of intestinal
absorption of Ca2+
48
Phenytoin
Adverse effects


Idiosyncratic
reactions
(Hypersensitivity
reactions):
seen
shortly after therapy has begun: rash
in 2-5% of patients and occasionally
more serious skin reactions, including
Stevens-Johnson syndrome and toxic
epidermal necrolysis
Systemic lupus erythematosus and
potentially fatal hepatic necrosis have
been reported rarely
49
Phenytoin
Teratogenicity

Phenytoin has been implicated in
a specific syndrome called fetal
hydantoin syndrome

The symptoms of this disorder
may include abnormalities of the
skull and facial features, growth
deficiencies,
underdeveloped
nails of the fingers and toes,
and/or
mild
developmental
delays
50
Carbamazepine

It is one of the most widely used antiepileptic drugs, is chemically
derived from the tricyclic antidepressant drugs

The mechanism of action of carbamazepine appears to be similar to
that of phenytoin

Clinical Uses
1)
DOC for partial seizures, also used for generalized tonic-clonic seizures
2)
Peripheral neuropathy, e.g. trigeminal neuralgia
3)
In some patients with mania (bipolar disorder)
51
Carbamazepine
Pharmacokinetics

Carbamazepine is absorbed slowly and erratically
after oral administration

The drug has a notable ability to induce
microsomal enzymes. Typically, the half-life of 36
hours observed in subjects after an initial single
dose 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

Carbamazepine-10,11-epoxide
is
pharmacologically
active
metabolite
significant anticonvulsant effects of its own
a
with
52
Carbamazepine
Drug interactions

Phenobarbital, phenytoin, and valproate may
increase the metabolism of carbamazepine by
inducing CYP3A4

Carbamazepine may enhance the metabolism
of phenytoin

Concurrent administration of carbamazepine
may lower concentrations of valproate,
lamotrigine, tiagabine, and topiramate

The metabolism of carbamazepine may be
inhibited by propoxyphene, erythromycin,
cimetidine, fluoxetine, and isoniazid
53
Carbamazepine
Side effects
1)
Dose-dependent

Diplopia and ataxia: most common

Mild gastrointestinal upsets, unsteadiness, and, at much
higher doses, drowsiness

Hyponatremia and water intoxication
54
Carbamazepine
Side effects
2)
Dose-independent

The most common idiosyncratic reaction is an
erythematous skin rash

Transient, mild leukopenia occurs in ~10% of
patients during initiation of therapy and
usually resolves within the first 4 months of
continued treatment

Idiosyncratic blood dyscrasias, including fatal
cases of aplastic anemia and agranulocytosis

Transient elevation of hepatic transaminases
in plasma in 5-10% of patients
55
Oxcarbazepine

It is a keto analog of carbamazepine

Oxcarbazepine is a prodrug that is almost
immediately converted to its main active
metabolite, a 10-monohydroxy derivative

Its mechanism of action is similar to that of
carbamazepine

Oxcarbazepine
is
less
potent
than
carbamazepine:
clinical
doses
of
oxcarbazepine may need to be 50% higher
than those of carbamazepine to obtain
equivalent seizure control
56
Oxcarbazepine




Oxcarbazepine is a less potent enzyme
inducer than carbamazepine
Oxcarbazepine does not induce the
hepatic enzymes involved in its own
degradation
Most adverse effects that occur with
oxcarbazepine are similar in character to
reactions reported with carbamazepine
Hyponatremia may occur more commonly
with
oxcarbazepine
than
with
carbamazepine
57
Lamotrigine



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, particularly the N- and
P/Q-type channels, which would account
for its efficacy in primary generalized
seizures in childhood, including absence
attacks
Lamotrigine also decreases the synaptic
release of glutamate
58
Lamotrigine

Clinical Uses
a)
Partial
seizures,
absence
and
myoclonic seizures in children, and
for seizure control in the LennoxGastaut syndrome
b)
Lamotrigine is also effective for
bipolar disorder
59
Lamotrigine





Lamotrigine is almost completely absorbed
The drug has linear kinetics and is
metabolized primarily by glucuronidation to
the 2-N-glucuronide, which is excreted in the
urine
Lamotrigine has a half-life of approximately
24 hours
Administration of phenytoin, carbamazepine,
or phenobarbital reduces the t1/2 and plasma
concentrations of lamotrigine
Valproate causes a twofold increase in the
drug's half-life
60
Lamotrigine



The most common adverse effects are
dizziness, ataxia, blurred or double
vision, nausea, vomiting, and rash when
lamotrigine was added to another antiseizure drug
A few cases of Stevens-Johnson syndrome
and
disseminated
intravascular
coagulation have been reported
The incidence of serious rash in pediatric
patients is higher than in the adult
population
61
Topirmate
Topiramate main mechanism of action nis
likely to involve blocking of voltage-gated
Na+ channels
 It also acts on high-voltage activated (Ltype) Ca2+ channels
 It 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

62
Topirmate

Clinical uses:
1)
Partial and generalized tonic-clonic seizures
2)
Lennox-Gastaut syndrome
3)
Infantile spasms
4)
Absence seizures
5)
Treatment of migraine headaches
63
Topirmate

Topiramate is well tolerated

The most common adverse effects are
somnolence, fatigue, weight loss, and
nervousness

It can precipitate renal calculi, which is most
likely due to inhibition of carbonic anhydrase

Topiramate has been associated with
cognitive impairment and patients may
complain about a change in the taste of
carbonated beverages
64
Zonisamide

Zonisamide primary site of action appears to be
the Na+ channel

it also acts on T-type voltage-gated Ca2+ channels

It is effective against partial and generalized
tonic-clonic seizures and may also be useful
against infantile spasms and certain myoclonias

Adverse
effects:
drowsiness,
cognitive
impairment, and potentially serious skin rashes

Zonisamide does
antiseizure drugs
not
interact
with
other
65
Anti-seizure drug-induced
reduction of current through Ttype Ca2+ channels

Agents: valporate and ethusximide

They reduce the flow of Ca2+ through T-type Ca2+
channels thus reducing the pacemaker current that
underlies the thalamic rhythm in spikes and waves seen
in generalized absence seizures
66
Ca+2
Valproate
Ca+2
X
I
Ca+2
Goodman & Gilman’s. 12th ed. 2012
Ethusuximide
Ethosumximide
It reduces low threshold Ca2+ currents (Ttype currents) in thalamic neurons
 Ethosuximide has a very narrow spectrum
of clinical activity & is particularly
effective against absence seizures
 Administration
of ethosuximide with
valproic acid results in a decrease in
ethosuximide clearance and higher
steady-state concentrations owing to
inhibition of metabolism

68
Ethosumximide

The most common dose-related side
effects are GIT complaints (nausea,
vomiting, and anorexia) and CNS
effects
(drowsiness,
lethargy,
euphoria, dizziness, headache, and
hiccough)
69
Valproic Acid & Sodium
Valproate

Mechanism of action
1) Like phenytoin and carbamazepine, it prolongs the
recovery of voltage-activated Na+ channels from
inactivation
2) It increases the levels of GABA in the brain: it
stimulates the activity of the GABA synthetic enzyme,
glutamic acid decarboxylase, and inhibit GABA
degradative enzymes, GABA transaminase and succinic
semialdehyde dehydrogenase
3) Blockade of NMDA receptor-mediated excitation
4) Reductions of T-type Ca2+ currents in the thalamus
70
Valproic Acid & Sodium
Valproate

Clinical uses
1)
Valproate is a broad-spectrum anti-seizure drug
effective in the treatment of absence, myoclonic,
partial, and tonic-clonic seizures
2)
Intravenous formulations are occasionally used to
treat status epilepticus
3)
Management of bipolar disorder
4)
Migraine prophylaxis
71
Valproic Acid & Sodium
Valproate





Valproate is well absorbed after an oral dose,
with bioavailability greater than 80%
Food may delay absorption, and decreased
toxicity may result if the drug is given after
meals
Valproic acid is 90% bound to plasma
The vast majority of valproate (95%)
undergoes hepatic metabolism, with < 5%
excreted unchanged in urine
Its hepatic metabolism occurs mainly by UGT
enzymes (20%) and β-oxidation
72
Valproic Acid & Sodium
Valproate
1)
Dose-dependent

GIT: nausea, vomiting, abdominal pain, and
heartburn

Sedation if valproate is added to phenobarbital

Weight gain

Increased appetite

Hair loss
73
Valproic Acid & Sodium
Valproate
2)




Idiosyncratic
Thrombocytopenia
Acute pancreatitis
Hyperammonemia
Elevation of hepatic transaminases in
plasma is observed in up to 40% of
patients
and
often
occurs
asymptomatically during the first
several months of therapy
74
Valproic Acid & Sodium
Valproate
2)

Idiosyncratic
Hepatotoxicity:

Risk is greatest for patients under 2 years of
age and for those taking multiple medications

Most fatalities have occurred within 4 months
after initiation of therapy

Careful monitoring of liver function
recommended when starting the drug

Hepatotoxicity is reversible in some cases if
the drug is withdrawn
is
75
Valproic Acid & Sodium Valproate
Teratogenicity

Valproic acid use during pregnancy can produce
teratogenic effects :

Neural tube defects: spina bifida

Cardiovascular, orofacial, and digital abnormalities
76
77
Valproic Acid & Sodium Valproate
D/D interactions

Valproate displaces phenytoin from
plasma proteins

Valproate inhibits the metabolism of
several drugs that are substrates for
CYP2C9, including phenytoin and
phenobarbital, and UGT , including the
metabolism
of
lamotrigine
and
lorazepam
78
Enhancement of inhibitory
GABAergic impulses
1)
Several
antiepileptic
drugs
(e.g.
phenobarbital and benzodiazepines) enhance
the activation of GABAA receptors, thus
facilitating the GABA-mediated opening of
chloride channels
2)
Enhancement of the action of GABA as an
inhibitory transmitter by:
a)
Inhibiting the enzyme GABA transaminase,
which is responsible for inactivating GABA:
vigabatrin
b)
Inhibiting GABA uptake: tiagabine
79
Na+
Vigabatrin
GABA-T
GABA
Succinic Semialdehyde
SSD
Valproate
metabolites
Tiagabine
GAT-1
Benzodiazepine
Cl-
GABA recognition site
Barbiturates
Phenobarbital

It has relatively low toxicity, is
inexpensive, and is still one of the
more effective and widely used drugs

Phenobarbital, exert maximal antiseizure action at doses below those
required
for
hypnosis,
which
determines their clinical utility as
anti-seizure agents
81
Phenobarbital

Mechanism of Action
1)
Phenobarbital increased the GABAA receptor–
mediated current by increasing the duration
of bursts of GABAA receptor–mediated
currents
2)
At higher concentrations: blocks some Ca2+
currents (L-type & N-type), suppresses highfrequency repetitive firing in neurons
through an action on Na+ conductance, and
decrease glutamate release
82
Phenobarbital
Pharmacokinetics

Oral absorption of phenobarbital is
complete but somewhat slow

Up to 25% of a dose is eliminated by
pH-dependent renal excretion of the
unchanged drug; the remainder is
inactivated by hepatic microsomal
enzymes, principally CYP2C9
83
Phenobarbital
Anti-seizure properties

It is often tried for virtually every seizure type,
especially when attacks are difficult to control

It is useful in the treatment of partial seizures and
generalized tonic-clonic seizures
84
Phenobarbital
D/D interactions

Interactions between phenobarbital and other drugs
usually involve induction of the hepatic CYPs by
phenobarbital

The interaction between phenytoin and phenobarbital is
variable

Concentrations of phenobarbital in plasma may be
elevated by as much as 40% during concurrent
administration of valproic acid
85
Phenobarbital
D/D interactions

Phenobarbital
induces
uridine
diphosphate-glucuronosyltransferase
(UGT) enzymes as well as the CYP2C
and CYP3A subfamilies

Drugs metabolized by these enzymes
can be more rapidly degraded when
co-administered with phenobarbital;
importantly, oral contraceptives are
metabolized by CYP3A4
86
Primidone



A prodrug converted to phenobarbital &
phenylethylmalonamide (PEMA): all three
compounds are active anticonvulsants
It is effective against partial seizures and
more generalized tonic-clonic seizures
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
87
Benzodiazepines

At
therapeutically
relevant
concentrations, benzodiazepines act at
subsets of GABAA receptors and increase
the frequency, but not duration, of
openings at GABA-activated Cl– channels

At higher concentrations, diazepam and
many other benzodiazepines can reduce
sustained
high-frequency
firing
of
neurons, similar to the effects of
phenytoin, carbamazepine, and valproate
88
Benzodiazepines

Diazepam given intravenously or
rectally is highly effective for stopping
continuous seizure activity, especially
generalized
tonic-clonic
status
epilepticus.
However,
its
short
duration of action is a disadvantage

Lorazepam is longer acting than
diazepam in the treatment of status
epilepticus and is sometime preferred
89
Benzodiazepines

Clonazepam is useful in the therapy of
absence seizures as well as myoclonic
seizures
in
children.
However,
tolerance to its anti-seizure effects
usually develops after 1-6 months of
administration
90
Other
antiepileptic
drugs
Levetiracetam

Levetiracetam modifies the synaptic
release of glutamate and GABA through an
action on synaptic vesicle protein (SV2A)

It neither induces nor is a high-affinity
substrate
for
CYP
isoforms
or
glucuronidation enzymes and thus is
devoid of known interactions with other
antiseizure drugs, oral contraceptives, or
anticoagulants
92
Levetiracetam

It is approved for adjunct therapy of
partial seizures in adults and children for
primary generalized tonic-clonic seizures
and for the myoclonic seizures of juvenile
myoclonic epilepsy

Side effects most often reported include
dizziness, sleep disturbances, headache,
and weakness
93
Gabapentin

Gabapentin is an an analog of GABA, that
is effective against partial seizures

It dose not act directly on GABA receptors

It modifies the synaptic or nonsynaptic
release of GABA: an increase in brain
GABA concentration is observed in

Gabapentin binds avidly to the α 2 δ
subunit of voltage-gated N-type Ca 2+
channels: decrease Ca 2+ entry, with
causes a predominant decreasethe
synaptic release of glutamate
94
Gabapentin

Gabapentin is not metabolized and does
not induce hepatic enzymes

Absorption is nonlinear and dosedependent at very high doses

The drug is not bound to plasma proteins

Drug-drug interactions are negligible

Elimination is via renal mechanisms

The half-life is relatively short (5-8 hrs)
95
Gabapentin


Clinical uses:
1)
effective as an adjunct against partial
seizures and generalized tonic-clonic
seizures
2)
Treatment of neuropathic
postherpetic neuralgia
pain
and
ADRs: somnolence, dizziness, ataxia,
headache, and tremor
96
Felbamate
It produces a use-dependent block of the
NMDA receptor, with selectivity for the NR12B subtype
 It
also
produces
a
barbiturate-like
potentiation of GABAA receptor responses
 it is effective in some patients with partial
seizures and it is effective in patients with
Lennox-Gastaut syndrome
 However, it causes aplastic anemia and severe
hepatitis at unexpectedly high rates and
therefore has been relegated to the status of
a third-line drug for refractory cases

97