Transcript PHL 322 Antiepilepti..

Antiepileptic drugs
Seizures

Various forms (depending on the part of the brain
affected)

Result from episodic high-frequency discharge of
a group of neurons (excitotoxicity)

Starting locally

May then spread to other areas of the brain
Nature of Epilepsy
• The neurochemical basis of the abnormal
discharge is not well understood. It may be
associated with enhanced excitatory amino
acid transmission, impaired inhibitory
transmission, or abnormal electrical
properties of the affected cells. The
glutamate content in areas surrounding an
epileptic focus is often raised.
Nature of epilepsy
Abnormal electrical activity during seizure
can be detected by electroencephalograph
(EEG)
 Recording from electrodes distributed over
the surface of the scalp
 Can recognize various types of seizures.

Symptoms

Range from a brief lapse of attention to a
convulsion (several minutes)

Depends on the function of the region of the
brain that is affected
Affected brain regions

Motor cortex (convulsion)

Hypothalamus (peripheral autonomic
discharge)
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Reticular formation in the upper brainstem
(loss of consciousness)
Epilepsy
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Recurrent seizures

Treated mainly with drugs
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Brain surgery may be used for severe cases
Causes of epilepsy

No recognizable cause

May develop after brain damage
 Trauma,

infection or tumor growth
Or other kinds of neurological disease
Epileptogenesis

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Excitatory transmission is facilitated (e.g. glutamate)
Inhibitory transmission is reduced (e.g. GABA)
Abnormal electrical properties of the affected cells
EPILEPSY affects 5–10% of the general population.
It is due to sudden, excessive depolarization of
some or all cerebral neurons. This may be:
• localized (focal or partial seizure);
• spread to cause a secondary generalized seizure;
• may affect all cortical neurons simultaneously
(primary generalized seizure).
EEG
Cortex:
F – frontal
O – occipital
T – temporal
Rang et al.
Pharmacology
– 5th Ed. (2003)
Classification of seizures
Types of epilepsy
 Two
major seizure categories:
Partial
2. Generalized
1.
 Both
can be classified as:

Simple (if consciousness is not lost)
 Complex (if consciousness is lost)
The type of seizure determines the choice of drug!
Partial seizures
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Discharge begins locally
(often remain localized)

EEG discharge is
normally confined to one
hemisphere
Partial seizures
Symptoms include:
 Involuntary
muscle contraction
 Abnormal sensory experiences
 Autonomic discharge
 Or effects on mood and behavior
Complex partial seizures

Loss of consciousness

Discharge in the brainstem reticular
formation
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Are among the commonest types of
epilepsy
Jacksonian epilepsy
In motor cortex
 Repetitive jerking of particular muscle group
 May spread to involve much of the body
 Losses voluntary control of the affected parts
of the body
 Does not necessarily loss consciousness
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Psychomotor epilepsy
In temporal lobe
 The attack may consist of movements such as:

 Rubbing
movements
 Dressing or walking or hair-combing
Lasts for a few minutes
 Recover with no recollection of the event
 The behavior during the seizure can be bizarre
and accompanied by a strong emotional
response
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Generalized seizures
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Involve the whole brain,
including the reticular
system
characterized by immediate
loss of consciousness
Producing abnormal
electrical activity throughout
both hemispheres
Generalized seizures
Two important categories:
 Tonic-clonic
 Absence
seizures (grand mal)
seizures (petit mal)
Tonic-clonic seizures (grand mal)
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Tonic phase:
 An
initial strong
contraction of the whole
musculature, causing a
rigid extensor spasm
 Respiration stops,
defecation, micturition,
salivation often occur
 Lasts for about 1 minute
Tonic phase (stiffening of the body)
Tonic-clonic seizures (grand mal)
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Clonic phase:
A
series of violent,
synchronous jerks
after the tonic phase
 Gradually dies out in
2-4 minutes
Clonic phase (the body jerks)
Tonic-clonic seizures (grand mal)

The patient stays
unconscious for a
few more minutes
and then gradually
recovers, feeling ill
and confused
Post-convulsive phase (exhaustion)
Absence seizures (petit mal)
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Occur in children
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Much less dramatic
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May occur more frequently (many seizures each
day) than tonic-clonic seizures
Absence seizures (petit mal)
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The patient ceases whatever he was doing
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Sometimes stopping speaking in mid-sentence
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Stares vacantly for a few seconds, with little or no
motor disturbance.
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The patient is unaware of his surrounding
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Recovers with no after-effects
Absence seizures (petit mal)
Absence Seizures
Absence seizures (petit mal)
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Thalamic neurons activity depends on the
calcium channels that they express

Treated by blocking calcium channels
Lennox-Gastaut Syndrome
(LGS: Lennox Syndrome)
Severe kind of epilepsy
 Occurs in children
 Causes excitotoxic neurodegeneration
 Associated with progressive mental
retardation

Antiepileptic drugs

Effective in controlling seizures in about 70%
of patients

Their use is often limited by side-effects
Treatment
• Monotherapy with anticonvulsant
– Increase dose gradually until seizures are controlled
or adverse effects become unacceptable.
– Multiple-drug therapy may be required.
• Achieve steady-state kinetics
• Monitor plasma drug levels
• Avoid sudden withdrawal
AED Treatment Options
Partial seizures
Simple
Complex
Secondary
Generalized
Primary generalized seizures
TonicClonic
Tonic
Myoclonic Atonic
phenytoin, carbamazepine, phenobarbital,
gabapentin, oxcarbazepine, pregabalin
valproic acid, lamotrigine, topiramate,
(levetiracetam, zonisamide)
Absence
Ethosuximide
ANTISEIZURE DRUGS
1. Carboxamides (enzyme inductors – CYP450):
Carbamazepine (+ neuropathic pain – n. trigeminus,
postherpetic pain, etc.), Oxcarbazepine
2. Hydantoins: Phenytoin (enzyme inductor),
3. Barbiturates (Phenobarbital – enzyme inductors) and their
analogues (Primidone – prodrug)
4. Succinimides: Ethosuximide (petit mal)
5. Valproates (enzyme inhibitors): Sodium valproate (Depakin®)
6. Benzodiazepines: Clonazepam, Clorazepate, Diazepam
Lorazepam, Nitrazepam
7. GABA analogues: Gabapentin, Tiagabine
8. Hetereogenic anticonvulsants: Lamotrigine, Levetiracetam,
Pregabalin (partial seizures, peripheral neuropathic pain),
Topiramate, Vigabatrin
MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptics inhibit the neuronal discharge or its spread in one or
more of the following ways:
(1) Enhancing GABA synaptic transmission: barbiturates, benzodiazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topiramate, valproate; the result is increased permeability to chloride ion,
which reduces neuronal excitability. Valproate and topiramate block
GABA transaminase and tiagabine blocks reuptake of GABA.
(2) Reducing cell membrane permeability to voltage-dependent
sodium channels: carbamazepine, lamotrigine, oxcarbazepine,
phenytoin, topiramate, valproate.
(3) Reducing cell membrane permeability to calcium T-channels:
valproate, ethosuximide; the result is diminishing of the generation
of action potential.
(4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.
Treatment of Seizures
Strategies:
•
Modification of ion conductances.
•
Increase inhibitory (GABAergic) transmission.
•
Decrease excitatory (glutamatergic) activity.
Antiepileptic drugs

Three main mechanisms:
1. Enhancement
of GABA action
2. Inhibition of sodium channel function
3. Inhibition of calcium channel function
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Other mechanisms include:
 Inhibition
of glutamate release
 Block of glutamate receptors
GABA
Barbiturates
Benzodiazepines
Gabapentin
Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin
Na+
Carbamazepine
Lamotrigine
Oxcarbazepine
Phenytoin
Topiramate
Valproate
Ca2+
Ethosuximide
Levetiracetam
Pregabalin
Valproate
I. Na+ Channel Inhibitors
blocks voltage-gated sodium channels by selectively
binding to the channel in the inactive state and slowing its
rate of recovery
Antiseizure drugs, enhanced Na+ channel inactivation
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
Na+ Channel Inhibitors
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Phenytoin (Dilantin, Phenytek)
Fosphenytoin (Cerebyx)
Carbamzepine (Tegretol, Carbatrol)
Oxcarbazepine (Trileptal)
Valproic Acid (Valproate; Depakene, Depakote)
Lamotrigine (Lamictal)
Topiramate (Topamax)
Zonisamide (Zonegran)
Na+ Channel Inhibitors
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Phenytoin (Dilantin, Phenytek):
Oldest nonsedative antiepileptic drug.
Narrow therapeutic window (~ 40-100 μmol/l)
Well absorbed.
– Indications:
• First choice for partial and generalized tonic-clonic seizures
• Some efficacy in clonic, myoclonic, atonic,
• No effect on infantile spasms or absence seizures
– Drug Interactions:
• Decreases blood levels of many medications
• Increases blood levels of phenobarbital & warfarin
Na+ Channel Inhibitors
Phenytoin (Dilantin, Phenytek):
– Adverse Effects:
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Hirsutism & coarsening of facial features
Acne
Gingival hyperplasia (20-40%)
Megaloplastic anemia. (corrected by folic acid)
Decreased serum concentrations of folic acid,
thyroxine, and vitamin K with long-term use.
• “Fetal hydantoin syndrome”: teratogenic
• includes growth retardation, microencephaly, and craniofacial
abnormalities (e.g., cleft palate) and is possibly due to an epoxide
metabolite of phenytoin.
Phenytoin Induced Gingival Hyperplasia
17 year old boy treated with
300mg/day phenytoin for 2
years (unsupervised)
Partial recovery at 3 months
after discontinuation
• Fosphenytoin
is a prodrug
• rapidly converted to phenytoin in the blood, providing
high levels of phenytoin within minutes.
• Fosphenytoin may also be administered intramuscularly
(IM).
• Phenytoin sodium should never be given IM because it
can cause tissue damage and necrosis.
• Fosphenytoin is the drug of choice and standard of care
for IV and IM administration.
• Due to sound-alike and look-alike names, there is a risk
for medication error to occur.
– The trade name of fosphenytoin is Cerebyx®
– Celebrex®, the cyclooxygenase-2 inhibitor
– Celexa®, the antidepressant.
Na+ Channel Inhibitors
2. Carbamzepine (Tegretol, Carbatrol):
• Derived from Tricyclic, antidepressant (bipolar)
– Indications:
• First choice for complex partial and generalized
tonic-clonic seizures.
– Contraindications:
• May exacerbate absence or myoclonic seizures.
• Blood disorders
• Liver disorders
Na+ Channel Inhibitors
Carbamazepine (Tegretol, Carbatrol):
– Drug Interactions: A powerful inducer of hepatic microsomal
enzymes
• CBZ metabolism is affected by many drugs, and CBZ affects
the metabolism of many drugs. oral contraceptives, warfarin,
corticosteroids, etc.
– Determination of plasma levels and clearance may be
necessary for optimum therapy.
• Adverse Effects:
– Common: Diplopia and ataxia (most common), gastrointestinal
disturbances; sedation at high doses
– Occasional: Retention of water and hyponatremia; rash,
agitation in children
– Rare: Idiosyncratic blood dyscrasias and severe rashes
Na+ Channel Inhibitors
3. Oxcarbazepine (Trileptal):
– FDA approved in 2000 for partial seizures
• Complex partial seizures
• Primary & secondarily generalized tonic-clonic
seizures
– Is a prodrug whose actions are similar to those of
carbamazepine; it has a short half-life of 1—2 hour.
– Its activity is due to a 10-hydroxy metabolite with a
half-life of 10 hours.
– Fewer adverse effects than CBZ, phenytoin
Na+ Channel Inhibitors
4. Valproic Acid (Valproate; Depakene, Depakote):
– Other Mechanisms of Action:
1) Some inhibition of T-type Ca2+ channels.
2) Increases GABA production and decreases GABA
metabolism. (Inhibition of GABA transaminase )
– Indications:
• Simple or complex partial, & primary generalized tonic-clonic
• Also used for absence, myoclonic, and atonic seizures.
• Highly effective for photosensitive epilepsy and juvenile
myoclonic epilepsy.
• Low toxicity and lack of sedative action
– Contraindications:
• Liver disease
Na+ Channel Inhibitors
4. Valproic Acid (Valproate; Depakene, Depakote):
– Drug Interactions:
• Affects metabolism of many drugs through liver
enzyme inhibition
Na+ Channel Inhibitors
4. Valproic Acid (Valproate; Depakene, Depakote):
– Adverse Effects:
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Weight gain (30-50%)
Dose-related tremor
Transient hair loss
Polycystic ovary syndrome (PCOS) and menstrual
disturbances
Bone loss
Ankle swelling
The most serious side-effect is hepatotoxicity
An increase in serum glutamic oxaloacetic
transaminase (sign of liver damage)
Na+ Channel Inhibitors
5. Lamotrigine (Lamictal):
– Other Mechanism of Action:
• May inhibit synaptic release of glutamate.
– Indications:
• Adjunct therapy (ages 2 & up):
– Simple & complex partial seizures
– Generalized seizures of Lennox-Gastaut Syndrome
• Monotherapy (adults):
– Simple & complex partial seizures
– Contraindications:
• May make myoclonic seizures worse.
Na+ Channel Inhibitors
5. Lamotrigine (Lamictal):
– Adverse Effects:
• Rash (10%)
– Rare progression to serious systemic illness
• Increased alertness
Na+ Channel Inhibitors
6. Topiramate (Topamax):
– Other Mechanism of Action:
• Enhances post-synaptic GABAA receptor currents.
• Kainate receptor antagonist (blocks a certain type of
glutamate channel)
– Indications:
• Adjunct therapy for partial and primary generalized
• seizures in adults and children over 2.
• Decreases tonic and atonic seizures in children with LennoxGastaut syndrome.
– Contraindications:
• History of kidney stones, teratogenic
Na+ Channel Inhibitors
6. Topiramate (Topamax):
– Drug Interactions:
• CBZ, phenytoin, phenobarbital, & primidone decrease blood
levels
– Adverse Effects:
• Nervousness & paresthesias
• Psychomotor slowing, word-finding difficulty, impaired
concentration, interference with memory
• Weight loss & anorexia
• Metabolic acidosis
Na+ Channel Inhibitors
7. Zonisamide (Zonegran):
• is a sulfonamide derivative that has a broad spectrum
of action
– Other Mechanism of Action:
• Inhibits T-type Ca2+ currents.
• Binds to GABA receptors.
• Facilitates dopaminergic and serotonergic
neurotransmission.
Na+ Channel Inhibitors
7. Zonisamide (Zonegran):
– Indications:
• Approved for adjunct treatment of partial seizures
in adults.
• Appears to have a broad spectrum:
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Myoclonic seizures
Infantile spasms
Generalized & atypical absence seizures
Lennox-Gastaut Syndrome
– Drug Interactions:
• Phenytoin and carbamazepine decrease its half-life by half.
Na+ Channel Inhibitors
7. Zonisamide (Zonegran):
– Adverse Effects:
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Weight loss
Abnormal thinking
Nervousness
Agitation/irritability
Usually well tolerated