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Antiseizure Drugs
1
Introduction
• Globally epilepsy is the third most common neurologic
disorder after cerebrovascular and Alzheimer's disease
• The term seizure refers to a transient alteration of
behaviour due to the disordered, synchronous, and
rhythmic firing of populations of brain neurons
• 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
2
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, including various inherited neurological
syndromes
• This abnormal electrical activity may result in a variety of
events, including loss of consciousness, abnormal
movements, atypical or odd behavior, or distorted
perceptions that are of limited duration but recur if
untreated
3
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
4
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)
5
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
6
Partial seziures
• Consciousness is usually preserved. Partial seizures
may progress, becoming generalized tonic-clonic
seizures
7
Partial seziures
1. Simple partial
• Caused by a group of hyperactive neurons exhibiting
abnormal electrical activity, which are confined to a
single locus in the brain
• The electrical discharge does not spread, and the
patient does not lose consciousness
• The patient often exhibits abnormal activity of a
single limb or muscle group that is controlled by the
region of the brain experiencing the disturbance
• lasting approximating 20-60 seconds
8
Partial seziures
2. Complex partial
• 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
• Motor dysfunction may involve chewing movements,
diarrhea, and/or urination
9
Generalized seziures
• Generalized seizures may begin locally, producing
abnormal electrical discharges throughout both
hemispheres of the brain
• Primary generalized seizures may be convulsive or
nonconvulsive
• The patient usually has an immediate loss of
consciousness
10
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
11
12
Generalized seziures
2) Absence:
• These seizures involve a brief, abrupt, and selflimiting 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
13
Generalized seziures
3) Myoclonic: These seizures consist of short episodes of
muscle contractions that may reoccur for several minutes.
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
4) 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
14
Generalized seziures
3) 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
15
Seizure type
Partial seizures
Simple partial
Features
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. Key feature is preservation of consciousness
Complex partial
Impaired consciousness lasting 30 seconds to 2 minutes, often associated with
purposeless movements such as lip smacking or hand wringing
Partial with
secondarily
generalized tonicclonic seizure
Simple or complex partial seizure evolves into a tonic-clonic seizure with loss of
consciousness and sustained contractions (tonic) of muscles throughout the body
followed by periods of muscle contraction alternating with periods of relaxation
(clonic), typically lasting 1-2 minutes
Generalized Seizures
Absence seizure
Abrupt onset of impaired consciousness associated with staring and cessation of
ongoing activities typically lasting less than 30 seconds
Myoclonic seizure
A brief (perhaps a second), shocklike contraction of muscles that may be restricted
to part of one extremity or may be generalized
Tonic-clonic seizure As described earlier in table for partial with secondarily generalized tonic-clonic
seizures except that it is not preceded by a partial seizure
16
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
17
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 or 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 γaminobutyric acid (GABA) and glutamate
18
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
19
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
20
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
21
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
22
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
23
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
24
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, but
frequently cause unwanted effects that range in
severity from minimal impairment of the CNS to
death from aplastic anemia or hepatic failure
25
Antiseziure Drugs
• An awareness of the antiepileptic drugs available,
including
their
mechanisms
of
action,
pharmacokinetics, potential for drug-drug 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
26
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
27
Antiseziure Drugs
• Drugs that are effective in seizure reduction
accomplish this by a variety of mechanisms:
1. Enhancement of inhibitory GABAergic impulses
2. Interference with excitatory glutamate transmission
3. Modification of ionic conductances:
– Inhibition of sodium channel function
– Inhibition of calcium channel function
28
Inhibition of sodium channel function
• Agents: phenytoin, carbamazepine, oxcarbazepine,
topiramate, valproic acid, zonisamide, and lamotrigine
• 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
29
30
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
31
Phenytoin
• Phenytoin is the oldest nonsedative antiseizure drug
• Phenytoin is the most important member of the
hydantoin group of compounds, which are structurally
related to the barbiturates
• Phenytoin is a valuable agent for the treatment of
generalized tonic–clonic seizures and for the treatment
of partial seizures with complex symptoms
32
Phenytoin
Mechanism of action
• Phenytoin blocks voltage-gated sodium channels by
selectively binding to the channel in the inactive state
and slowing its rate of recovery
• At concentrations 5- to 10-fold higher, multiple effects
of phenytoin are evident, including reduction of
spontaneous activity and enhancement of responses
to GABA
33
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
34
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
35
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
36
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
37
Phenytoin
Drug interactions
• Phenytoin 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
• Carbamazepine, which may enhance the metabolism of
phenytoin, causes a well-documented decrease in phenytoin
concentration
• Interaction between phenytoin and phenobarbital is variable
38
Phenytoin
Adverse effects
I.
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
39
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 months (Panel B); however, ataxia
persisted.
40
http://content.nejm.org/cgi/content/full/342/5/325
Phenytoin
Adverse effects
I.
Dose-depedent: Endocrine side effects:
–
–
–
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+
41
Phenytoin
Adverse effects
II. 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
42
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
43
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.
2.
3.
DOC for partial seizures, also used for generalized tonicclonic seizures
Peripheral neuropathy, e.g. trigeminal neuralgia
In some patients with mania (bipolar disorder)
45
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 a pharmacologically
active metabolite with significant anticonvulsant effects of
its own
46
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
47
Carbamazepine
Side effects
a) Dose-dependent
• Diplopia and ataxia: most common
• Mild gastrointestinal upsets, unsteadiness, and,
at much higher doses, drowsiness
• Hyponatremia and water intoxication
48
Carbamazepine
Side effects
b) 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
49
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
50
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
51
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
52
Lamotrigine
• Clinical Uses
1) Partial seizures, absence and myoclonic seizures in
children, and for seizure control in the Lennox-Gastaut
syndrome
2) Lamotrigine is also effective for bipolar disorder
53
Lamotrigine
• Lamotrigine is almost completely absorbed and has a
• 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
54
Lamotrigine
• The most common adverse effects are dizziness, ataxia,
blurred or double vision, nausea, vomiting, and rash when
lamotrigine was added to another anti-seizure 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
55
Topirmate
• Topiramate main mechanism of action nis likely to involve
blocking of voltage-gated Na+ channels
• It also acts on high-voltage activated (L-type) 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
56
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
57
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
58
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 include
drowsiness, cognitive impairment, and potentially serious
skin rashes
• Zonisamide does not interact with other antiseizure drugs
59
Valproic Acid & Sodium Valproate
• Mechanism of action
1) Like phenytoin and carbamazepine, it prolongs the
recovery of voltage-activated Na+ channels from
inactivatioI
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
60
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
61
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
62
Valproic Acid & Sodium Valproate
I. Dose-dependent
• GIT: nausea, vomiting, abdominal pain, and
heartburn
• Sedation if valproate is added to phenobarbital
• Weight gain
• Increased appetite
• Hair loss
63
Valproic Acid & Sodium Valproate
I.
1)
2)
3)
4)
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
64
Valproic Acid & Sodium Valproate
I. Idiosyncratic
5. 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 is recommended
when starting the drug
• Hepatotoxicity is reversible in some cases if the drug
is withdrawn
65
Valproic Acid & Sodium Valproate
Teratogenicity
• Valproic acid use during pregnancy can produce
teratogenic effects :
1) Neural tube defects: spina bifida
2) Cardiovascular,
orofacial,
and
digital
abnormalities
66
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
67
Enhancement of inhibitory GABAergic impulses
• Several antiepileptic drugs (e.g. phenobarbital and
benzodiazepines) enhance the activation of GABAA
receptors, thus facilitating the GABA-mediated
opening of chloride channels
• Enhancement of the action of GABA as an inhibitory
transmitter:
– Vigabatrin acts by inhibiting the enzyme GABA
transaminase, which is responsible for inactivating
GABA
– Tiagabine inhibits GABA uptake
68
Phenobarbital
• It has relatively low toxicity, is inexpensive, and is
still one of the more effective and widely used
drugs
• Phenobarbital, exert maximal anti-seizure action
at doses below those required for hypnosis,
which determines their clinical utility as antiseizure agents
69
Phenobarbital
• Mechanism of Action
• Phenobarbital increased the GABAA receptor–
mediated current by increasing the duration of bursts
of GABAA receptor–mediated currents
• At higher concentrations: blocks some Ca2+ currents
(L-type & N-type), suppresses high-frequency
repetitive firing in neurons through an action on Na+
conductance, and decrease glutamate release
70
Phenobarbital
Pharmacokinetics
• Oral absorption of phenobarbital is complete but
somewhat slow
• Up to 25% of a dose is eliminated by pHdependent renal excretion of the unchanged
drug; the remainder is inactivated by hepatic
microsomal enzymes, principally CYP2C9
71
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, although the
drug
72
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
73
Phenobarbital
D/D interactions
• Phenobarbital
induces
uridine
diphosphateglucuronosyltransferase (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
74
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
75
Vigabatrin
• Vigabatrin is an irreversible inhibitor of GABA
aminotransferase (GABA-T), the enzyme responsible
for the degradation of GABA
• Vigabatrin may also inhibit the vesicular GABA
transporter
• Vigabatrin is useful in the treatment of partial
seizures and infantile spasms refractory to other
treatments
• ADEs: drowsiness, dizziness, weight gain, & visual
field defects in 30–50% of patients
76
Tiagabine
• Tiagabine is an inhibitor of GABA transporter, GAT-1,
and thereby reduces GABA uptake into neurons and
glia
• Tiagabine is indicated for the adjunctive treatment of
partial seizures
• ADRs: dose-dependent nervousness, dizziness,
tremor, difficulty in concentrating, and depression,
and idiosyncratic rash
77
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 highfrequency firing of neurons, similar to the effects of
phenytoin, carbamazepine, and valproate
78
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
79
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
80
Other antiepileptic drugs
Ethosumximide
• It reduces low threshold Ca2+ currents (T-type
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
82
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)
83
Felbamate
- It produces a use-dependent block of the NMDA
receptor, with selectivity for the NR1-2B 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
84
Gabapentin & Pregabalin
• Analogs of GABA
• Gabapentin and pregabalin bind avidly to the α2δ
subunit of N-type Ca2+ channels, which decrease
Ca2+ entry
• Are absorbed after oral administration and are not
metabolized in humans, and are excreted
unchanged, mainly in the urine
• They do not induce hepatic enzymes and drug-drug
interactions are negligible
85
Gabapentin & Pregabalin
• Gabapentin and pregabalin are effective for partial
seizures, with and without secondary generalization,
when used in addition to other anti-seizure drugs
• Most common adverse effects of somnolence,
dizziness, ataxia, and fatigue
86
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
87
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
88
Acetazolamide
• Carbonic anhydrase inhibitor
• Mechanism of action:
1) Mild acidosis in the brain may be the mechanism
2) Diminishing the depolarizing action of bicarbonate ions
moving out of neurons via GABA receptor ion channels
• Its usefulness is 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
89