Transcript 2011 322EPILEPSY

EPILEPSY -I
Department of Pharmacology
College of Pharmacy
King Saud University
Definitions
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Epilepsy: is a chronic neurological disorder of brain function
characterized by a periodic recurrent, and unpredictable
occurrence of unprovoked seizures .
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Seizure: transient alteration of behavior due to disordered and
rhythmic firing of population of brain neurons.
These seizures are usually distressful and often incapacitating.
Seizures occur when there is abnormal, excessive,
synchronized firing of neurons. Can be local or generalized
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Convulsion: The major motor manifestations of a seizure
(rhythmic jerking of the limbs)
Etiology
is usually unknown (>70%). Seizures
are signs of underlying neurological
disturbances
Etiology or First Cause
• Birth and perinatal injuries
• Vascular insults
• Head trauma
• Congenital malformations
• Metabolic disturbances (serum Na+, glucose, Ca2+, urea)
• Drugs or alcohol (including withdrawal from barbiturate,
CNS depressants)
• Neoplasia (tumors)
• Infection or fever
• Genetic ( >25 single gene mutations identified)
Pathophysiology of Epilepsy
 High frequency discharge of impulses by interconnected
cerebral neurons
 Starts locally then spread
 Enhancement of excitatory transmission
 Reduction of inhibitory transmission
Symptoms of Epilepsy
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Convulsion (motor cortex involvement)
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Peripheral autonomic discharge (hypothalamus involvement )
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Loss of consciousness (reticular formation involvement)
 Others, staring, , jerking movements of the arms and legs and
amnesia
Diagnostic Tools
Electroencephalogram (EEG)
The most important tool for diagnosis epilepsy
Measures brain waves
Should be performed with 24 hours of seizure
Repeated EEGs are often required
Computerized Tomography (CT) Scans
Usually the first test ordered for first-time seizures
Magnetic Resonance Imaging (MRI)
Strongly recommended for children with first-time seizures
Also for seizures associated with significant mental or motor
problems
May help to determine if the disorder can be treated with surgery
EEG
Figure 1. Electroencephalograph (EEG) records in epilepsy
Distinguishing between seizure types is
important because different types of
seizure may have different causes,
prognoses and treatments.
Seizure types
Classified into two broad categories
organized according to the source of
the seizure within the brain:
Partial (localized to one region of the
brain)
Generalized (distributed throughout the
brain).
Types of Epilepsy
 Partial seizures
• Simple partial seizures: These seizures begin from a small
area in your brain and don't result in loss of consciousness
(20-60”)
• Complex partial seizures: These seizures also begin from a
small area of your brain. They alter consciousness and
usually cause memory loss (amnesia) and nonpurposeful
movements, such as repeated hand rubbing, lip smacking
(30”-2 min.)
• Secondary generalized seizures (partial seizures with
secondary generalization): These seizures occur when
simple or complex seizures spread to involve your entire
brain (1-2 min.)
Types of Epilepsy; cont.
 Generalized seizures
• Absence (petit mal seizures): These seizures are
characterized by sudden loss of consciousness, staring, &
stopping of body activities (<30”)
• Myoclonic seizures: These seizures usually appear as
sudden jerks of arms and legs
• Atonic seizures: Also known as drop attacks, these seizures
cause sudden collapse or fall down. After a few seconds,
consciousness is regained
• Generalized tonic-clonic (grand mal seizures): They're
characterized by a loss of consciousness, sustained
muscles contraction followed by periods of muscle
relaxation
Types of Epilepsy; cont.
 Status epilepticus:
Characterized by convulsions without cessation (lasting greater than
30 minutes)
• Mortality: 5 -15%
• Causes: hyponatremia, pyridoxine deficiency, abrupt
withdrawal of anticonvulsants or fever
Animal Models of Epilepsy
 Genetic strains that show epilepsy-like
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characteristics
Transgenic mouse strains
Local cortical damage
Convulsant drugs (pentylenetetrazol)
Kindling model
Kainate model
Kindling
Repeated low-level electrical stimulation to some brain sites in
animals can lead to permanent increases in seizure
susceptibility
In other words, a permanent decrease in seizure "threshold.”
Amygdala and parahippocampal regions are particularly
susceptible
Chemical stimulation may cause this too (repeated exposure to
pesticides can induce seizures in humans)
Changes in anatomy and cell morphology (loss of critical
components in the neural circuit)
Nature of epilepsy
Epilepsy affects about 0.5% of the population.
The characteristic event is the seizure, which is often
associated with convulsions but may occur in many other
forms.
The seizure is caused by an asynchronous high-frequency
discharge of a group of neurons, starting locally and spreading
to a varying extent to affect other parts of the brain. In absence
seizures, the discharge is regular and oscillatory.
Partial sizures affect localised brain regions, and the attack
may involve mainly motor, sensory or behavioural phenomena.
Unconsciousness occurs when the reticular formation is
involved. Generalised seizures affect the whole brain.
Two common forms of epilepsy are the tonic-clonic fit (grand
mal) and the absence seizure (petit mal). Status epilepticus is a
life-threatening condition in which seizure activity is
uninterrupted.
Many animal models have been devised, including
electrically and chemically induced generalised
seizures, production of local chemical damage and
kindling. These provide good prediction of
antiepileptic drug effects in humans.
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. Several
susceptibility genes, mainly encoding neuronal ion
channels, have been identified..
Repeated epileptic discharge can cause neuronal
death (excitotoxicity).
Current drug therapy is effective in 70-80% of
patients.
Excitotoxicity and oxidative stress
Excitatory amino acids (e.g. glutamate) can cause
neuronal death.
Excitotoxicity is associated mainly with activation of
NMDA receptors, but other types of excitatory amino
acid receptors also contribute.
Excitotoxicity results from a sustained rise in
intracellular Ca2+ concentration (Ca2+ overload).
Excitotoxicity can occur under pathological
conditions (e.g. cerebral ischaemia, epilepsy) in
which excessive glutamate release occurs. It can
also occur when chemicals such as kainic acid are
administered.
Raised intracellular Ca2+ causes cell
death by various mechanisms,
including
1.activation of proteases,
2.formation of free radicals,
3. and lipid peroxidation.
4.Formation of nitric oxide and
arachidonic acid are also involved.
Raised [Ca2+]i affects many processes, the
chief ones relevant to neurotoxicity being
1. increased glutamate release
2. activation of proteases (calpains) and lipases, causing
membrane damage
3. activation of nitric oxide synthase; while low
concentrations of nitric oxide are neuroprotective,
high concentrations in the presence of reactive oxygen
species generate peroxynitrite and hydroxyl free
radicals, which damage many important biomolecules,
including membrane lipids, proteins and DNA
4. increased arachidonic acid release, which increases
free radical production and also inhibits glutamate
uptake (site 6).
Various mechanisms act normally to
protect neurons against excitotoxicity,
the main ones being :
1.Ca2+ transport systems,
2.mitochondrial function and
3.the production of free radical
scavengers
Oxidative stress
Oxidative stress refers to conditions
(e.g. hypoxia) in which the protective
mechanisms are compromised,
reactive oxygen species accumulate,
and neurons become more susceptible
to excitotoxic damage.
Excitotoxicity due to environmental
chemicals may contribute to some
neurodegenerative disorders.
Measures designed to reduce
excitotoxicity include the use of
1.glutamate antagonists,
2. calcium channel-blocking drugs
3.free radical scavengers;
none are yet proven for clinical use.
Mechanism of action of antiepileptic
drugs
Current antiepileptic drugs are thought to act
mainly by three main mechanisms:
– reducing electrical excitability of cell membranes,
mainly through use-dependent block of sodium
channels
– enhancing GABA-mediated synaptic inhibition;
this may be achieved by an enhanced
postsynaptic action of GABA, by inhibiting GABA
transaminase, or by drugs with direct GABA
agonist properties
– inhibiting T-type calcium channels (important in
controlling absence seizures).
Newer drugs act by other mechanisms
yet to be elucidated.
Drugs that block glutamate receptors
are effective in animal models but are
unsuitable for clinical
Phenytoin
Mechanism of action:
– acts mainly by use-dependent block of sodium
channels thus it blocks sustained high
frequency repetitive firing of action potentials
- Membrane stabilization
– effective in many forms of epilepsy, but not
absence seizures
– metabolism shows saturation kinetics, therefore
plasma concentration can vary widely;
monitoring is therefore needed
–drug interactions are common
–main unwanted effects are
confusion, gum hyperplasia, skin
rashes, anemia, teratogenesis
–widely used in treatment of
epilepsy; also used as
antidysrhythmic agent
Phenytoin Indications
1. Generalized tonic-clonic (grand mal) and
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complex partial (psychomotor, temporal lobe)
seizure
Prevention and treatment of seizures occurring
during or following neurosurgery
Trigeminal neuralgia and migraine
Ventricular tachycardia, paroxysmal
supraventricular tachycardia and arrhythmias
associated with digitalis glycoside toxicity
Rheumatoid arthritis and discoid lupus
erythematosus
Phenytoin Side Effects
• CNS: nystagmus, ataxia uncoordinated muscle or
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eye movement mental confusion, dizziness,
insomnia , Cognitive impairment
Immunologic: rashes and systemic lupus
erythematosus
GI system: Nausea, vomiting, constipation, toxic
hepatitis and liver damage
Connective tissues: gingival hyperplasia,
coarsening of the facial features, and
hypertrichosis Hirsutism,, gingivial hyperplasia
Blood: thrombocytopenia, leukopenia,
granulocytopenia and megaloblastic anemia
Bone: osteomalacia
Precautions & Contraindications
Precautions:
Impaired liver function
Elderly patients
Hyperglycemia
Osteomalacia
Contraindications:
hypersensitivy to phenytoin or other hydantoins
Pharmacokinetics
• Absorption: oral & slow
• Metabolism: By the hepatic mixed function
oxidase system
• Excretion: Urine (5% as unchanged drug); as
glucuronides)
• Half-life elimination: Approximately 24 hours.
• High protein binding
• Enzyme inducer.
Drug interactions
• Alcohol intake, amiodarone, chloramphenicol,
diazepam, H2-antagonists, isoniazid → increase
phenytoin level
• Phenylbutazone, salicylates, succinimides,
sulfonamides → increase phenytoin level
• Carbamazepine and sucralfate → decrease
phenytoin level
• Corticosteroids, warfarin, digitoxin, doxycycline,
estrogens, furosemide, oral contraceptives,
quinidine, rifampin, theophylline, vitamin D →
phenytoin decreases their level
Valproate
Mechanism of action:
Enhancement of GABA action
2. Weak inhibition of GABA transaminase,
3.Blocks voltage-dependent sodium channels
4.T-type Ca2+ channel blockade
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Indications:
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Treatment of absence, myoclonic partial, and tonicclonic seizure
Migraine prophylaxis
Bipolar disorder
Adverse Effects
relatively few unwanted effects
• GI side effects: nausea, vomiting and anorexia
• CNS: ataxia, tremors, sedation,
• Rashes and alopecia
• Elevates liver enzymes; hepatitis (rarely)
• Acute pancreatitis
• Hyperammonia
baldness, teratogenicity, liver damage (rare, but
serious). The most serious side effect is
hepatotoxicity
Precautions & Contraindications
Precautions:
• Hepatic Dysfunction
• Pancreatitis
• Blood disorders
• Thrombocytopenia
Contraindications:
• Active liver disease
• Hypersensitivity to valproate
• Family history of severe hepatic dysfunction
Pharmacokinetics
• Metabolism: hepatic via glucuronide conjugation
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and mitochondrial beta-oxidation
Half-life elimination:adults(9-16 hrs)
Children(4-14hrs)
Excretion: urine
Protein binding: 80%to90%
Valproate is hepatic enzyme inhibitor
Drug interactions
• Valproate inhibits metabolism of phenobarbital,
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lamotrigine, lorazepam & phenytoin
Valproate is displaced by aspirin from plasma
protein
Plasma conc. Of valproate reduced by
carbamazepine
The concomitant use of valproic acid and
clonazepam may induce absence status in patients
with a history of absence type seizures
Cholestyramine reduces absorption of valproate
Carbamazepine:
derivative of tricyclic antidepressants
Na+ channel inactivation
similar profile to that of phenytoin but with fewer
unwanted effects
effective in most forms of epilepsy (except absence
seizures); particularly effective in psychomotor
epilepsy; also useful in trigeminal neuralgia
strong inducing agent, therefore many drug
interactions
low incidence of unwanted effects, principally
sedation, ataxia, mental disturbances, water
retention.
Carbamazepine is a powerful inducer of
hepatic microsomal enzymes, and thus
accelerates the metabolism of many other
drugs, such as phenytoin , oral
contraceptives, warfarin and corticosteroids.
In general, it is inadvisable to combine it with
other antiepileptic drugs. Ozcarbazepine,
introduced recently, is a prodrug that is
metabolised to a compound closely
resembling carbamazepine , with similar
actions but less tendency to induce drugmetabolising enzymes.
Ethosuximide:
the main drug used to treat absence
seizures; may exacerbate other forms
acts by blocking T-type calcium
channels
relatively few unwanted effects, mainly
nausea and anorexia.
Secondary drugs include:
phenobarbital: highly sedative
various benzodiazepines (e.g. clonazepam );
diazepam used in treating status
epilepticus.
Diazepam , given intravenously or rectally, is used to
treat status epilepticus, a life-threatening condition
in which epileptic seizures occur almost without a
break. Its advantage in this situation is that it acts
very rapidly compared with other antiepileptic drugs.
With most benzodiazepines, the sedative effect is
too pronounced for them to be used for maintenance
therapy.
Clonazepam and the related compound clobazam
are claimed to be relatively selective as antiepileptic
drugs. Sedation is the main side effect of these
compounds, and an added problem may be the
withdrawal syndrome, which results in an
exacerbation of seizures if the drug is stopped
abruptly
Newer agents that are becoming widely used
because of their improved side effect profile
include vigabatrin, lamotrigine , felbamate ,
gabapentin , pregabalin , tiagabine,
topiramate and zonisamide