Transcript Antiseizure drugs

Overview
• Seizures are sudden episodes of
neurological dysfunction caused by
abnormal electrical activity of the brain
• Seizures are common
• 1% of the population will have a seizure
Epilepsy
A group of chronic CNS disorders characterized by
recurrent seizures.
• Seizures are sudden, transitory, and uncontrolled
episodes of brain dysfunction resulting from abnormal
discharge of neuronal cells with associated motor,
sensory or behavioral changes.
Causes for Acute Seizures
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Brain Trauma
Encephalitis
Drugs
PKU
Photo epilepsy
Birth trauma
Withdrawal from
depressants
• Tumor
• Hypoxia
• Idiopathic
•High fever(Febrile
convulsion)
•Hypoglycemia
•Extreme acidosis
•Extreme alkalosis
•Hyponatremia
•Hypocalcemia
•Infection e.g. meningitis,
brain abscess, viral
encephalitis
Classification of Epileptic Seizures
I. Partial (focal) Seizures
A. Simple Partial Seizures
B. Complex Partial Seizures
II. Generalized Seizures
A. Generalized Tonic-Clonic Seizures
B. Absence Seizures
C. Tonic Seizures
D. Atonic Seizures
E. Clonic and Myoclonic Seizures
F. Infantile Spasms
AED Response – Established AEDs
• Earlier studies suggested that many patients
respond to monotherapy but fewer and fewer
patients respond to combination therapy.
70%
controlled*
Monotherapy
30% controlled* on 2
drugs
30% poorly
managed
Combinations of two or
more drugs provide little
more benefit
* Controlled was defined as adequately managed but not
necessarily seizure-free
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I. Partial (Focal) Seizures
A. Simple Partial Seizures
B. Complex Partial Seizures
Scheme of Seizure Spread
Simple (Focal) Partial
Seizures
Contralateral spread
A.
Simple Partial Seizures (Jacksonian)
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Involves one side of the brain at onset.
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Focal w/motor, sensory or speech disturbances.
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Confined to a single limb or muscle group.
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Seizure-symptoms don’t change during seizure.
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No alteration of consciousness.
EEG: Excessive synchronized discharge by a small group of
neurons. Contralateral discharge.
Scheme of Seizure Spread
Complex Partial Seizures
Complex Secondarily Generalized Partial Seizures
I. Partial (focal) Seizures
B.
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Complex Partial Seizures (Temporal Lobe
epilepsy or Psychomotor Seizures)
Produces confusion and inappropriate or dazed
behavior.
Motor activity appears as non-reflex actions.
Automatisms (repetitive coordinated movements).
Wide variety of clinical manifestations.
Consciousness is impaired or lost.
EEG: Bizarre generalized EEG activity with evidence of
anterior temporal lobe focal abnormalities. Bilateral.
II. Generalized Seizures
In Generalized seizures, both
hemispheres are
widely involved from
the outset.
Manifestations of the
seizure are determined
by the cortical site at
which the seizure
arises.
Present in 40% of all
epileptic Syndromes.
II. Generalized Seizures (con’t)
A.
Generalized Tonic-Clonic Seizures
Recruitment of neurons throughout the cerebrum
Major convulsions, usually with two phases:
1) Tonic phase
2) Clonic phase
Convulsions: motor manifestations, may or may not be present
during seizures, excessive neuronal discharge. Convulsions
appear in Simple Partial and Complex Partial Seizures if the
focal neuronal discharge includes motor centers; they occur
in all Generalized Tonic-Clonic Seizures regardless of the site
of origin. Atonic, Akinetic, Absence Seizures are nonconvulsive
II. Generalized Seizures (con’t)
A. Generalized Tonic-Clonic Seizures
Tonic phase:
- Sustained powerful muscle contraction
(involving all body musculature) which arrests
ventilation.
EEG: Rythmic high frequency, high voltage
discharges with cortical neurons undergoing
sustained depolarization, with protracted trains of
action potentials.
II. Generalized Seizures (con’t)
A. Generalized Tonic-Clonic Seizures
Clonic phase:
- Alternating contraction and relaxation,
causing a reciprocating movement which
could be bilaterally symmetrical or “running”
movements.
EEG: Characterized by groups of spikes on the EEG
and periodic neuronal depolarizations with clusters
of action potentials.
Scheme of Seizure Spread
Generalized Tonic-Clonic Seizures
Both hemispheres are
involved from outset
Neuronal Correlates of Paroxysmal
Discharges
Generalized Seizures
Neuronal Correlates of Paroxysmal Discharges
II. Generalized Seizures
B.
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Absence Seizures (Petite Mal)
Brief and abrupt loss of consciousness.
Sometimes with no motor manifestations.
Usually symmetrical clonic motor activity
varying from occasional eyelid flutter to
jerking of the entire body.
Typical 2.5 – 3.5 Hz spike-and-wave
discharge.
Usually of short duration (5-10 sec), but may
occur dozens of times a day.
II. Generalized Seizures
B.
Absence Seizures (Petite Mal) (con’t)
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Often begin during childhood (daydreaming attitude,
no participation, lack of concentration).
A low threshold Ca2+ current has been found to
govern oscillatory responses in thalamic neurons
(pacemaker) and it is probably involve in the
generation of these types of seizures.
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EEG: Bilaterally synchronous, high voltage 3-per-second spike-andwave discharge pattern.
spike phase: neurons generate short duration depolarization and a
burst of action potentials. No sustained depolarization or
repetitive firing.
Scheme of Seizure Spread
Primary Generalized
Absence Seizures
Thalamocortial
relays are believed
to act on a
hyperexcitable
cortex
Neuronal Correlates of Paroxysmal
Discharges
Generalized Absence Seizures
Scheme of Seizure Spread
II. Generalized Seizures (con’t)
C.
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Tonic Seizures
Opisthotonus, loss of consciousness.
Marked autonomic manifestations
D.
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Atonic Seizures (atypical)
Loss of postural tone, with sagging of the
head or falling.
May loose consciousness.
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II. Generalized Seizures (con’t)
Clonic and Myoclonic Seizures
Clonic Seizures: Rhythmic clonic contractions of all
muscles, loss of consciousness, and marked
autonomic manifestations.
Myoclonic Seizures: Isolated clonic jerks associated
with brief bursts of multiple spikes in the EEG.
F.
Infantile Spasms
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An epileptic syndrome.
Attacks, although fragmentary, are often bilateral.
Characterized by brief recurrent myoclonic jerks of
the body with sudden flexion or extension of the
body and limbs.
Types of
s
(focal)
Primary
Treatment of Seizures
Goals:
• Block repetitive neuronal firing.
• Block synchronization of neuronal discharges.
• Block propagation of seizure.
Minimize side effects with the simplest drug
regimen.
MONOTHERAPY IS RECOMMENDED IN MOST CASES
Treatment of Seizures
Strategies:
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Modification of ion conductances.
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Increase inhibitory (GABAergic) transmission.
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Decrease excitatory (glutamatergic) activity.
Actions of Phenytoin on Na+ Channels
Na+
A. Resting State
B. Arrival of Action
Potential causes
depolarization and
channel opens allowing
sodium to flow in.
Na+
Na+
C. Refractory State,
Inactivation
Sustain channel in
this conformation
GABAergic SYNAPSE
Drugs that Act at the
GABAergic Synapse
GABA-T
GAD
GAT
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GABA agonists
GABA antagonists
Barbiturates
Benzodiazepines
GABA synthesizing
enzymes
• GABA uptake inhibitors
• GABA metabolizing
enzymes
GLUTAMATERGIC SYNAPSE
Na+
Ca2+
AGONISTS
GLU
GLY
Mg++
K+
• Excitatory Synapse.
• Permeable to Na+, Ca2+
and K+.
• Magnesium ions block
channel in resting state.
• Glycine (GLY) binding
enhances the ability of
GLU or NMDA to open
the channel.
• Agonists: NMDA, AMPA,
Kianate.
Chemical Structure of Classical
Antiseizure Agents
X may vary as follows:
Barbiturates
-C–NHydantoins
-N–
Oxazolidinediones – O –
Succinimides
–C–
Acetylureas
- NH2 –*
*(N connected to C2)
Small changes can alter clinical activity and site of action.
e.g. At R1, a phenyl group (phenytoin) confers activity against partial seizures, but
an alkyl group (ethosuximide) confers activity against generalized absence seizures.
“Older” AEDs
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Phenobarbital
Phenytoin
Primidone
Ethosuximide
Carbamazepine
Valproate
1912
1938
1952
1960
1974
1978
Newer AEDS
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felbamate
gabapentin
lamotrigine
topiramate
tiagabine
levetiracetam
oxcarbazepine
Zonisamide
pregabalin
1993
1994
1995
1996
1998
1999
2000
2000
2005
Treatment of Seizures
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Hydantoins: phenytoin
Barbiturates: phenobarbital
Oxazolidinediones: trimethadione
Succinimides: ethosuximide
Acetylureas: phenacemide
Other: carbamazepine, lamotrigine, vigabatrin,
etc.
7) Diet
8) Surgery, Vagus Nerve Stimulation (VNS).
Treatment of Seizures
• Most classical antiepileptic drugs exhibit similar
pharmacokinetic properties.
• Good absorption (although most are sparingly
soluble).
• Low plasma protein binding (except for phenytoin,
BDZs, valproate, and tiagabine).
• Conversion to active metabolites (carbamazepine,
primidone, fosphenytoin).
• Cleared by the liver but with low extraction ratios.
• Distributed in total body water.
• Plasma clearance is slow.
• At high concentrations phenytoin exhibits zero order
kinetics.
Treatment of Seizures
Structurally dissimilar drugs:
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Carbamazepine
Valproic acid
BDZs.
New compounds:
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Felbamate
Gabapentin
Lamotrigine
Tiagabine
Topiramate
Vigabatrin
Pharmacokinetic Parameters
TREATMENT OF SEIZURES
Seizure disorder
Drugs
Tonic-clonic(Grand mal)
Drug of Choice
Carbamazepine or
Valproate or
Phenytoin or
Phenobarbital
Alternatives:
Topiramte
Lamotrigine (as adjunct or alone)
Gabapentin (as adjunct)
Partial (simple or complex)
Drug of choice
Carbamazepine or Topiramte or
Phenytoin or
Valproate
Alternatives:
Phenobarbital
Lamotringine (as adjunct or alone)
Gabapentin (as adjunct )
Treatament cont,d
Absence ( petit mal)
Drug of choice
Valproate or
Ethosuximide
Alternatives:
Clonazepam
Lamotrigine
Myoclonic, Atonic
Drug of choice
Valproate
Alternatives:
Clonazepam
Status Epilepticus
Drug of choice
Diazepam, i.v.
or Phenytoin, i.v. or Vaproate
Alternatives:
Phenobarbital, i.v
Febrile Seizures
Diazepam, rectal*
Diazepam ,i.v
Valproate
* Preferred
Treatment:
• Up to 80% of patients can expect partial or complete
control of seizures with appropriate treatment.
• Antiepileptic drugs suppress but do not cure
seizures
• Antiepileptics are indicated when there is two or
more seizures occurred in short interval (6m -1 y)
• An initial therapeutic aim is to use only one drug
(monotherapy)
Treatment ( Cont. )
• Advantage of monotherapy:
• fewer side effects, decreased drug-drug interactions, better
compliance, lower costs
• Addition of a second drug is likely to result in significant
improvement in only approx. 10 % of patients.
Treatment ( Cont. )
• when a total daily dose is increased, sufficient time
(about 5 t 1l2) should be allowed for the serum
drug level to reach a new steady-state level.
• The drugs are usually administered orally
• The monitoring of plasma drug levels is very
useful
• Precipitating or aggravating factors can affect
seizure control by drugs
Treatment ( Cont. )
• The sudden withdrawal of drugs should be avoided
withdrawal may be considered after seizure- free
period of 2-3 or more years
• Relapse rate when antiepileptics are withdrawn is 20 40 %
When to Withdraw Antiepileptic Drugs?
Normal neurological examination
Normal IQ
Normal EEG prior to withdrawal
Seizure- free for 2-5 yrs or longer
NO juvenile myoclonic epilepsy
Patients not meeting this ideal profile in all points, withdrawal may be
encouraged after careful assessement of the individual patient.
The Cytochrome P-450
Enzyme System
Inducers
Inhibitors
phenobarbital
valproate
primidone
topiramate (CYP2C19)
phenytoin
oxcarbazepine (CYP2C19)
carbamazepine
felbamate (CYP2C19)
felbamate (CYP3A) (increase phenytoin, topiramate
(CYP3A)
phenobarbital)
oxcarbazepine (CYP3A)
Phenytoin
Pharmacokinetics
• Well absorbed when given orally, however, it is also
available as iv. (for emergency)
• 80-90% protein bound
• Induces liver enzymes (Very Important)
• Metabolized by the liver to inactive metabolite
• Metabolism shows saturation kinetics and hence t ½
increases as the dose increased
• Excreted in urine as glucuronide conjugate
• Plasma t ½ approx. 20 hours
• Therapeutic plasma concentration 10-20 µg/ml (narrow)
• Dose 300-400 mg/day
Phenytoin ( Cont. )
Mechanism of Action:
Membrane stabilization by blocking Na & Ca influx
into the neuronal axon.
or inhibits the release of excitatory amino acids via
inhibition of Ca influx
Clinical Uses:
Used for partial Seizures & generalized tonic-clonic
seizures. But not effective for absence Seizures .
Also can be used for Rx of ventricular fibrillation.
Side effects:
Dose Related:
• G.I.T upset
• Neurological like headache, vertigo,
ataxia, diplopia, nystagmus
• Sedation
Side effects of Phenytoin ( Cont. )
Non-dose related:
• Gingival hyperplasia
• Hirsutism
• Megaloblastic anaemia
• Hypersensitivity reactions (mainly skin rashes and
lesions, mouth ulcer)
• Hepatitis –rare
• Fetal malformations- esp. cleft plate
• Bleeding disorders (infants)
• Osteomalacia due to abnormalities in vit D
metabolism
• Side effects of phenytoin ( Cont.)
• Pharmacokinetic Interactions
– Inhibitors of liver enzymes elevate its plasma levels
e.g. Chloramphenicol, INH,cimetidine.
– Inducers of liver enzymes reduce its plasma levels
e.g. Carbamazipine; Rifampicin, phenobarbital.
Fosphenytoin
• A Prodrug. Given i.v. or i.m. and rapidly
converted to phenytoin in the body.
• Avoids local complications associated with
phenytoin: vein irritation, tissue damage, pain
and burning at site, muscle necrosis with i.m.
injection, need for large fluid volumes.
• Otherwise similar toxicities to phenytoin.
CARBAMAZEPINE
Its mechanism of action and clinical uses are similar to that
of phenytoin. However, it is also commonly used for Rx of
mania and trigeminal neuralgia.
Pharmacokinetics
available as an oral form only
Well absorbed
80 % protein bound
Strong inducing agent including its own (can lead to failure of
other drugs e.g. oral contraceptives, warfarin, etc.
Metabolized by the liver to CBZ 10.11-epioxide(active) and
CBZ -10-11-dihydroxide (inactive)
Pharmacokinetics of CBZ( Cont. )
• Excreted in urine as glucuronide conjugate
• Plasma t1/2 approx. 30 hours
• Therapeutic plasma concentration 6-12 µg/ml
(narrow).
• Dose 200-800 mg/day (given BID as sustained
release form)
• Side Effects of Carbamazepine:
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G.I upset
Drowziness, ataxia and headache; diplopia
Hepatotoxicity- rare
Congenital malformation (craniofacial anomalies &
neural tube defects).
• Hyponatraemia & water intoxication.
• Late hypersensitivity reaction (erythematous skin rashes,
mouth ulceration and lymphadenopathy.
• Blood dyscrasias as fetal aplastic anemia (stop
medication); mild leukopenia (decrease the dose)
Pharmacokinetic interactions of CBZ
• Inducers of liver enzymes reduce
its
plasma level
e.g. Phenytoin; Phenobarbital; Rifampicin
• inhibitors of liver enzymes elevate its
plasma levels
e.g. erythromycin,INH ,verapamil;
Cimetidine
Phenobarbital
Mechanism of Action:
• Increases the inhibitory neurotransmitters
(e.g: GABA ) and decreasing the excitatory
transmission.
• Also, it also prolongs the opening of Clchannels.
• Absorption: rapid
• Half-life: 53-118 hours (long)
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Phenobarbital
• Partial seizures, effective in neonates
• Second-line drug in adults due to more severe CNS
sedation
• Adverse effects: CNS sedation but may produce
excitement in some patients. Skin rashes if allergic.
Tolerance and physical dependence possible.
• Interactions: severe CNS depression when combined
with alcohol or benzodiazapines. Stimulates
cytochrome P-450
Primidone
• Partial seizures
• Mechanims—see phenobarbital
• Absorption: Individual variability in rates. Not highly
bound to plasma proteins.
• Metabolism: Converted to phenobarbital and phenylethyl
malonamide, 40% excreted unchanged.
• Half-life: variable, 5-15 hours.
• Adverse effects: CNS sedative
• Drug interactions: enhances CNS depressants, drug
metabolism, phenytoin increases conversion to PB
Vigabatrin (restricted)
Pharmacological effects:Drug of choice for
infantile spasms, Use for partial seizures and
West’s syndrome.
• Not bound to proteins ,Not metabolized and
excreted unchanged in urine
• Plasma t1/2 4-7 hrs
Side effects:
Visual field defects, psychosis and depression
(limits its use).
VIGABATRIN (-vinyl-GABA)
• Contraindicated if preexisting mental
illness is present.
Toxicity:
•Drowsiness
•Dizziness
•Weight gain
•Agitation
•Confusion
•Psychosis
• Irreversible inhibitor of GABAaminotransferase (enzyme
responsible for metabolism of GABA)
=> Increases inhibitory effects of
GABA.
Lamotrigine
Pharmacological effects
Resembles phenytoin in its pharmacological effects
Well absorbed from GIT
Metabolised primarily by glucuronidation
Does not induce or inhibit C. P-450 isozymes ( its metabolism is
inhibitted by valproate )
Plasma t 1/2 approx. 24 hrs.
• Mechanism of Action:
Inhibits excitatory amino acid release (glutamate & aspartate )
by blockade of Na channels.
• Side effects:
• Skin rash, somnolence, blurred vision, diplopia, ataxia,
headache, aggression, influenza – like syndrome
LAMOTRIGINE (Lamictal)
Toxicity:
•Dizziness
•Headache
•Diplopia
•Nausea
•Somnolence
•Life
threatening
rash
“StevensJohnson”
• Add-on therapy with valproic acid
(w/v.a. conc. have be reduced =>
reduced clearance).
• Low plasma protein binding
• Effective in myoclonic and generalized
seizures in childhood and absence
attacks.
• Involves blockade of repetitive firing
involving Na channels, like phenytoin.
FELBAMATE
Toxicity:
•Aplastic anemia
•Severe hepatitis
• Effective against partial seizures
but has severe side effects.
• Because of its severe side effects,
it has been relegated to a thirdline drug used only for refractory
cases.
Gabapentin
• Structural analogue of GABA .May increase the
activity of GABA or inhibits its re-uptake.
Pharmacokinetics:
Not bound to proteins
Not metabolized and excreted unchanged in urine
• Does not induce or inhibit hepatic enzymes (similar
to lamotrigine)
• Plasma t ½ 5-7 hours
GABAPENTIN
Toxicity:
•Somnolence.
•Dizziness.
•Ataxia.
•Headache.
•Tremor.
• Used as an adjunct in partial and
generalized tonic-clonic seizures.
• drug-drug interactions are negligible.
• Low potency.
• An a.a.. Analog of GABA that does not
act on GABA receptors, it may
however alter its metabolism, nonsynaptic release and transport.
Topimerate
• Add-on for refractory partial or generalized seizures.
Effective as monotherapy for partial or generalized
seizures, Lennox-Gastaut syndrome.
• Use-dependent blockade of Na+ channels, increases
frequency of GABAA channel openings, may interfere with
glutamate binding to AMPA/KA receptor
• Half-life: 20-30 hours (long)
• Adverse effects: CNS sedative
• Drug interactions: Stimulates CYP3A and inhibits CYP2C19,
can lessen effectiveness of birth control pills
Topiramate ( Cont. )
Clinical Uses:
Recently, this drug become one of the safest antiepileptics
which can be used alone for partial and generalized tonicclonic, and absence seizures.
TIAGABINE (Gabatril)
Toxicity:
•Abdominal pain and
nausea (must be taken
w/food)
•Dizziness
•Nervousness
•Tremor
•Difficulty concentrating
•Depression
•Asthenia
•Emotional liability
•Psychosis
•Skin rash
• Adjunctive therapy in partial and
generalized tonic-clonic seizures
• Bioavailability > 90 %
• Highly protein bound ( 96% )
• Metabolized in the liver
• Plasma t ½ 4 -7 hrs
• Mode of action:
• inhibits GABA uptake and
increases its level
Zonisamide
Pharmacokinetics:
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Well absorbed from GIT (100 %)
Protein binding 40%
Extensively metabolized in the liver
No effect on liver enzymes
Plasma t ½ 50 -68 hrs
Clinical Uses:
Add-on therapy for partial seizures
Side Effects:
Drowsiness, ataxia , headache, loss of appetite,nausea&
vomiting, Somnolence .
Levetiracetam
• Add-on therapy for partial seizures
• Binds to synaptic vesicle protein SV2A, may
regulate neurotransmitter release
• Half-life: 6-8 hours (short)
• Adverse effects: CNS depresssion
• Drug interactions: minimal
Ethosuximide
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Absence seizures
Blocks T-type Ca++ currents in thalamus
Half-life: long—40 hours
Adverse effects: gastric distress—pain, nausea,
vomiting. Less CNS effects that other AEDs,
transient fatigue, dizziness, headache
• Drug interactions: administration with
valproate results in inhibition of its
metabolism
VALPROATE (Depakene)
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Toxicity:
•Elevated liver enzymes
including own.
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•Nausea and vomiting.
•Abdominal pain and
heartburn.
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•Tremor, hair loss,
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•Weight gain.
•Idiosyncratic
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hepatotoxicity.
•Negative interactions with
other antiepileptics.
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•Teratogen: spina bifida
Fully ionized at body pH, thus active
form is valproate ion.
Mechanism of action, similar to
phenytoin.
 levels of GABA in brain.
Facilitates
Glutamic
acid
decarboxylase (GAD).
Inhibits the GABA-transporter in
neurons and glia (GAT).
 [aspartate]Brain?
• May increase membrane potassium
conductance.
• Inhibits metabolism of several drugs such as
Carbamazepine; phenytoin, Topiramate and
phenobarbital.
• Clinical Use:
– Very effective against absence, myoclonic
seizures.
– Also, effective in gen. tonic-clonic siezures
(primarly Gen)
– Less effective as compared to carbamazepine
for partial seizures
– Like Carbamazepine also can be used for Rx of
mania
• Side Effects of Sod. valproate:
• Nausea, vomiting and GIT disturbances (Start
with low doses)
• Increased appetite & weight gain
• Transient hair loss.
• Hepatotoxicity
• Thrombocytopenia
• Neural Tube defect (e.g. Spina bifida) in the
offspring of women. (contraindicated in
pregnancy)
Status Epilepticus
Status epilepticus exists when seizures recur within
a short period of time , such that baseline
consciousness is not regained between the
seizures. They last for at least 30 minutes. Can
lead to systemic hypoxia, acidemia,
hyperpyrexia, cardiovascular collapse, and renal
shutdown.
• The most common, generalized tonic-clonic status
epilepticus is life-threatening and must be treated
immediately with concomitant cardiovascular,
respiratory and metabolic management.
Treatment of Status Epilepticus in Adults
Initial
• Diazepam, i.v. 5-10 mg (1-2 mg/min)
repeat dose (5-10 mg) every 20-30 min.
• Lorazepam, i.v. 2-6 mg (1 mg/min)
repeat dose (2-6 mg) every 20-30 min.
Follow-up
• Phenytoin, i.v. 15-20 mg/Kg (30-50 mg/min).
repeat dose (100-150 mg) every 30 min.
• Phenobarbital, i.v. 10-20 mg/Kg (25-30mg/min).
repeat dose (120-240 mg) every 20 min.
DIAZEPAM AND LORAZEPAM
Toxicity
•Sedation
•Children may
manifest a
paradoxical
hyperactivity.
•Tolerance
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Given I.V.
Lorazepam may be longer acting.
Have muscle relaxant activity.
Allosteric modulators of GABA
receptors.
• Potentiate GABA function by
increasing the frequency of
channel opening.
Treatment of Seizures
PARTIAL SEIZURES ( Simple and Complex,
including
secondarily generalized)
Drugs of choice: Carbamazepine
Phenytoin
Valproate
Alternatives: Lamotrigine, phenobarbital,
primidone, oxcarbamazepine.
Add-on therapy: Gabapentin, topiramate,
tiagabine, levetiracetam, zonisamide.
Treatment of Seizures
PRIMARY GENERALIZED TONIC-CLONIC SEIZURES
(Grand Mal)
Drugs of choice:
Carbamazepine
Phenytoin
Valproate*
Alternatives: Lamotrigine, phenobarbital,
topiramate, oxcartbazepine, primidone,
levetiracetam.
*Not approved except if absence seizure is involved
Treatment of Seizures
GENERALIZED ABSENCE SEIZURES
Drugs of choice: Ethosuximide
Valproate*
Alternatives:
Lamotrigine, clonazepam,
zonisamide, topiramate (?).
* First choice if primary generalized tonic-clonic seizure is also
present.
Treatment of Seizures
ATYPICAL ABSENCE, MYOCLONIC, ATONIC*
SEIZURES
Drugs of choice:
Valproate
Clonazepam
Lamotrigine**
Alternatives: Topiramate, clonazepam,
zonisamide, felbamate.
* Often refractory to medications.
**Not FDA approved for this indication. May worsen myoclonus.
Treatment of Seizures
INFANTILE SPASMS
Drugs of choice: Corticotropin (IM) or
Corticosteroids (Prednisone)
Zonisamide
Alternatives: Clonazepam, nitrazepam,
vigabatrin, phenobarbital.
Treatment of Seizures in Pregnancy
Phenytoin
Carbamazepine
Phenobarbital
Primidone
They may all cause hemorrhage in the infant due to
vitamin K deficiency, requiring treatment of mother
and newborn.
They all have risks of congenital anomalies (oral cleft,
cardiac and neural tube defects).
Teratogens:
Valproic acid causes spina bifida.
Topiramate causes limb agenesis in rodents and
hypospadias in male infants.
Zonisamide is teratogenic in animals.
INTERACTIONS BETWEEN ANTISEIZURE
DRUGS
With other antiepileptic Drugs:
- Carbamazepine with
phenytoin
Increased metabolism of carbamazepine
phenobarbital
Increased metabolism of epoxide.
- Phenytoin with
primidone
- Valproic acid with
clonazepam
phenobarbital
phenytoin
Increased conversion to phenobarbital.
May precipitate nonconvulsive status
epilepticus
Decrease metabolism, increase toxicity.
Displacement from binding, increase
toxicity.
ANTISEIZURE DRUG INTERACTIONS
With other drugs:
 phenytoin, phenobarb, carb.
phenytoin and phenobarb
met.
cimetidine
displaces pheny, and BDZs
isoniazid
 toxicity of phenytoin
oral contraceptives
antiepileptics  metabolism.
salicylates
displaces phenytoin and v.a.
theophyline
carb and phenytoin may
effect.
antibiotics
anticoagulants
Table 2. Proposed Mechanisms of Antiepileptic Drug Action
↓Na+
↓Ca+
↓K+
↑ Inh.
↓Excitatory
channels
channels
channels transmission transmission
________________________________________________________________________________
Established AED’s
PHT
+++
CBZ
+++
ESM
+++
PB
+
+++
+
BZD’s
+++
VPA
+
+
++
+
New AED’s
LTG
+++
+
OXC
+++
+
+
ZNS
++
++
VGB
+++
TGB
+++
GBP
+
+
++
FBM
++
++
++
++
TPM
++
++
++
++
LEV
+
+
+
________________________________________________________________________________
+++ primary action, ++ possible action, + probable action.
From P. Kwan et al. (2001) Pharmacology and therapeutics 90:21-34. [Data from Upton (1994), Schachter (1995),
McDonald and Kelly (1995), Meldrum (1996), Coulter (1997), and White (1999).]
Weight Issues
• Risk of weight gain
– Valproate
– Gabapentin and
pregabalin
• “Risk” of weight loss
– Topiramate
– Zonisamide
– Felbamate
Drugs that decrease efficacy of oral
contraceptives
•
•
•
•
•
•
Phenytoin
Carbamazepine
Phenobarbital
Primidone
Topiramate at higher doses
Oxcarbazepine
Lifestyle changes to minimize
seizures
•
•
•
•
Avoid sleep deprivation
Avoid alcohol
Treat fevers quickly
Occasional patients should avoid specific
factors such as strobe lights, etc
• Pill boxes/reminders
Herbal meds reported to
worsen seizures
•
•
•
•
•
•
•
•
•
•
•
•
•
Bearberry
Black cohosh
Borage
Damiana
Echinacea
Ephedra*
Ergot
Evening Primrose Oil
Gingko (prob safe)
Ginseng
Goldenseal
Green Tea
Guarana
•
•
•
•
•
•
•
•
•
•
•
•
•
Histalet Forte
Kava Kava
Ma Huang*
Metabolife
Monkshood
Phen-Fen*
Sage
St. John’s Wort
Uva-Ursi
Water-hemlock
European water hemlock
Wormwood
Yohimbe
Herbal meds with significant
interactions with seizure meds
•
•
•
•
•
•
•
•
•
•
•
Chamomila
Choke cherry
Comfrey
Dillapiol
Echinacea
Eucalyptus Oil
Grapefruit juice
Licorice
Mentat
Nicotinamide
Paeoniae radix
•
•
•
•
•
•
•
•
•
Piperine
Psyllium
Pyrrolizidine
Sage
St. John’s Wort
Septilin
Shankapushpi
Sho-seiryu-to
Wild cherry