الشريحة 1 - cden.tu.edu.iq
Transcript of الشريحة 1 - cden.tu.edu.iq
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مادة الادوية
المرحلة الثالثة
محمد غدير حاتم. م. م
2016-2017
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ANTIEPLEPTICS
Anticonvulsants
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Epilepsy
is a common neurological abnormality
affecting about 1% of the human population.
Epilepsy is a chronic, usually life-long disorder
characterized by recurrent seizures or
convulsions and usually, episodes of
unconsciousness and/or amnesia
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What is seizure
Seizures are finite episodes of brain dysfunction
resulting from abnormal discharge of cerebral
neurons .
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Types of
seizures
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Types of seizures
classified as:
general focal seizures;
seizures with or without loss of consciousness;
seizures with or without specific modes of
precipitation.
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The causes of seizures
Head trauma.
Meningitis.
Childhood fevers, Seizures often occur in hyperthermia (febrile seizures are very common in infants).
Brain tumors.
Degenerative diseases of the cerebral circulation.
Toxic manifestation of the action of central nervous system
(CNS) stimulants and certain other drugs( ? ). Eclampsia, uremia, hypoglycemia, or pyridoxine deficiency.
frequently as a part of the abstinence syndrome of individuals physically dependent on CNS depressants.
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Neuronal site of action of
Antiepileptics
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Antiepileptics
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Phenytoin
Phenytoin (DILANTIN) : is the oldest nonsedative
antiseizure drug(diphenylhydantoin).
introduced in 1938.
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Phenytoin Therapeutic uses
Generalized tonic–clonic seizures.
partial seizures with complex symptoms.
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Mechanism of action
Extracellular
Cell membrane
Intraceellular
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Mechanism of Action
enhance inactivation of voltage- gated sodium
and calcium channel and limit the spread of
electrical excitation by inhibiting sustained
high-frequency firing of neurons.
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Pharmacokinetic
phenytoin absorption is slow but usually
complete.
Phenytoin is highly bound (about 90%) to
plasma proteins.
It displays zero-order (or saturation) kinetics
in its metabolism
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Adverse effects of phenytoin
usually result from overdosage.
Nystagmus, ataxia, vertigo, and diplopia
(cerebellovestibular dysfunction).
Higher doses lead to altered levels of
consciousness and cognitive changes.
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Adverse effects of phenytoin
1. Skin rashes, morbilliform in character, are most common.
2. Exfoliative dermatitis or toxic epidermal necrolysis
Blood dyscrasias and hepatic necrosis.
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Gingival hyperplasia
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Gingival hyperplesia
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Gingival hyperplasia
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Gingival hyperplasia
occurs in up to 50% of patients.
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Adverse effects of phenytoin
Hirsutism also is an annoying side effect of
phenytoin, particularly in young females.
Thickening of subcutaneous tissue,
coarsening of facial features, and
enlargement of lips and nose (hydantoin
facies) are often seen in patients receiving
long-term phenytoin
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Adverse effects of phenytoin
phenytoin is teratogenic in humans, but the
mechanism is not clear.
it is known that phenytoin can produce a
folate deficiency, and folate deficiency is
associated with teratogenesis.
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Drug Interaction
Coadministration of the following drugs can result
in elevations of plasma phenytoin levels in most
patients:
cimetidine, chloramphenicol, disulfiram,
sulthiame, and isoniazid (in slow acetylators).
Phenytoin often causes adecline in plasma
carbamazepine levels if these two drugs are given
concomitantly.
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CARBAMAZEPINE
Is a tricyclic compound
Closely related to imipramine and other
antidepressants.
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Carbamazepine Mechanism of Action
Carbamazepine, like phenytoin, blocks sodium channels at
therapeutic concentrations and inhibits high-frequency
repetitive firing in neurons in culture.
It also acts presynaptically to decrease synaptic
transmission.
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Carbamazepine Clinical Uses:
1. Drug of choice for both partial seizures and generalized tonic-clonic seizures( not sedative).
2. It can be used with phenytoin in many patients who are difficult to control.
3. Very effective in Trigeminal neuralgia and other neuropathic pain.
4. useful in mania (bipolar disorder).
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Carbamazepine Adverse Effects
1. dose-related diplopia and ataxia.
2. mild gastrointestinal upsets.
3. Unsteadiness.
At much higher doses,
1. drowsiness.
2. Hyponatremia and water intoxication have
occasionally occurred.
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Carbamazepine
The overall incidence of toxicity seems to be
fairly low at usual therapeutic doses.
idiosyncratic blood dyscrasias including fatal
cases of aplastic anemia and agranulocytosis
The mild and persistent leukopenia.
The most common idiosyncratic reaction is an
erythematous skin rash.
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Drug Interactions
1. IT induce the enzymes that metabolize other
anticonvulsant drugs, including phenytoin,
primidone, phenobarbital, valproic acid,
clonazepam, and ethosuximide.
2. A common drug–drug interaction is between
carbamazepine and the macrolide antibiotics
erythromycin
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. This property decreases the problems associated
with drug interactions when oxcarbazepine is
used in combination with other drugs. The
clinical uses and adverse effect profile of
oxcarbazepine appear to be similar to those of
carbamazepine.
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Oxcarbazepine It is chemically an
pharmacologically closely
related to carbamazepine,
but it has much less
capacity to induce drug-
metabolizing enzymes
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Phenobarbital
Is the oldest of the currently available antiseizure
drugs (sedative effects).
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Phenobarbital Chemistry
The four derivatives of barbituric acid clinically
useful as antiseizure drugs are:
1. phenobarbita.
2. mephobarbital,.
3. metharbital,.
4. primidone
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Mechanism of Action
The exact mechanism of action of phenobarbital is unknown.
Phenobarbital binds to an allosteric regulatory site on the GABA A receptor.
Phenobarbital also blocks excitatory responses induced by glutamate.
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Clinical Use
1. Treatment of partial seizures and generalized
tonic-clonic seizures, although the drug is often
tried for virtually every seizure type, especially
when attacks are difficult to control.
2. The drugs of choice for seizures only in infants
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Toxicity
Sedation
Ataxia
Nystagmus
Vertigo
Acute psychotic reaction
Nausea and vomiting
Morbilliform rash
Agitation and confusion
Rebound seizures on
discontinuance
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Valproic Acid
Sodium valproate, also used as the free acid,
valproic acid, was found to have antiseizure
properties
Chemistry
Valproic acid is one of a series of fatty
carboxylic acids that have antiseizure activity
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Mechanism of Action
reduces the propagation of abnormal electrical
discharge in the brain. It may enhance GABA
action at inhibitory synapses.
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Clinical Use
1. Treatment of myoclonic seizures.
2. The drug diminishes absence seizures but
is a second choice because of its
hepatotoxic potential.
3. Reduces the incidence and severity of
tonic-clonic seizures
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Toxicity It does not induce P-450 enzyme synthesis.
Nausea and vomiting.
Sedation, ataxia, and tremor.
Hepatic toxicity may cause a rise in hepatic enzymes in plasma, which should be monitored frequently.
Rash and alopecia may occur
Bleeding times may increase because of both thrombocytopenia and an inhibition of platelet aggregation.
Valproic acid inhibits phenobarbital metab- olism, thereby increasing circulating levels of that barbiturate.
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Ethosuximide
Mechanism of Action
Reduces propagation of abnormal electrical
activity in the brain.
Effect on Ca2+ currents, reducing the low-
threshold (T-type) current.
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Clinical uses
the first choice in absence seizures
Pharmacokinetics
well absorbed orally.
It is not bound to plasma proteins.
Ethosuximide does not induce P-450
enzyme synthesis.
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Toxicity
The drug is irritating to the stomach, and nausea and vomiting.
Drowsiness, lethargy, dizziness, restlessness, agitation, anxiety, and the inability to concentrate.
In sensitive individuals, a Stevens-Johnson syndrome or urticaria may occur, as well as leukopenia, aplastic anemia, and thrombocytopenia.
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Stephens Johnson
syndrome
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Benzodiazepines
Clonazepam suppresses seizure spread from
the epileptogenic focus, and is effective in
absence and myoclonic seizures but
tolerance develops.
Clorazepate is effective in partial seizures
when used in conjunction with other drugs.
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Benzodiazepines
Diazepam and Lorazepam, is the drug of choice in the acute treatment of status epilepticus.
Diazepam given intravenously or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic-clonic status epilepticus
Lorazepam has alonger duration of action.
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Toxicity
Sedative properties, drowsiness, somnolence,
and fatigue.
Higher dosage ataxia, dizziness and behavior
changes.
Respiratory depression and cardiac depression
may occur when given intravenously in acute
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Felbamate
it is effective in some patients with partial
seizures.
has been relegated to the status of a third-
line drug for refractory cases.
effective against the seizures that occur in
Lennox-Gastaut syndrome.
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Felbamate
The mechanism of action of felbamate is not
established.
The strongest evidence suggests NMDA
receptor blockade via the glycine binding site.
Toxicity
drug causes aplastic anemia and severe
hepatitis at unexpectedly high rates
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Gabapentin
Gabapentin is an amino acid, an analog of GABA, that is
effective against partial seizures.
Its mechanism is not known
The drug also binds to the 2 subunit of voltage-
sensitive Ca2+ channels.
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Clinical Use
Gabapentin is effective as an adjunct against
partial seizures and generalized tonic-clonic
seizures. treatment of neuropathic pain and is
now indicated for postherpetic neuralgia in
adults above.
Adverse effects
somnolence, dizziness, ataxia, headache, and
tremor.
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Lamotrigine
Lamotrigine has a broad spectrum of action and
is effective
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Mechanism of Action
Lamotrigine, like phenytoin, suppresses
sustained rapid firing of neurons and produces a
voltageanduse-dependent inactivation of sodium
channels.
This mechanism may involve actions on voltage-
activated Ca2+ channels.
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Clinical Use
the drug is effective as monotherapy for partial
seizures.
the drug is also active against absence and
myoclonic seizures in children.
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Adverse effects
dizziness,
headache, diplopia, nausea, somnolence, and skin rash.
The rash is considered a typical hypersensitivity reaction.
pediatric patients are at high risk; some studies suggest that a potentially life-threateningdermatitis will develop in 1–2% of pediatric patients.
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Tiagabine
Tiagabine is an inhibitor of GABA uptake in
both neurons and glia.
Clinical Use
Tiagabine is indicated for the adjunctive
treatment of partial seizures. required. Some
patients appear to do well with tiagabine
monotherapy, which is generally well tolerated.
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Adverse events:
(dose-related)
1. nervousness, dizziness, tremor,
2. difficulty in concentrating, and depression.
Excessive confusion, somnolence, or ataxia
may require discontinuation.
3. Psychosis occurs rarely.
Rash is an uncommon idiosyncratic adverse
effect.
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Zonisamide
is a sulfonamide derivative.
Mechanism of action:
on the sodium channel; it may also act on
voltage-dependent calcium channels.
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Clinical uses
The drug is effective against partial and
generalized tonic-clonic seizures and may also be
useful against infantile spasms and certain
myoclonias.
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Adverse effects
Drowsiness, cognitive impairment.
Potentially serious skin rashes.
Zonisamide does not interact with other
antiseizure drugs.
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Levetiracetam
Its mechanism of action is unknown.
It has a brain-specific binding site and affects
allosteric modulations of GABA receptors, high-
voltage activated Ca2+ channels and some K+
channels.
The drug is marketed for the treatment of partial
seizures.
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Levetiracetam
Oral absorption is nearly complete; it is rapid
and unaffected by food.
Kinetics are linear. Protein binding is less than
10%.
The plasma half-life is 6–8 hours, and may be
longer in the elderly.
Two thirds of the drug is excreted unchanged in
the urine.
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Levetiracetam
Drug interactions are minimal.
levetiracetam is not metabolized by cytochrome
P450.
Adverse effects include somnolence, asthenia,
and dizziness. Idiosyncratic reactions are rare.
Drugs Used
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Acetazolamide
Acetazolamide is a diuretic whose main action is
the inhibition of carbonic anhydrase
Mild acidosis in the brain may be the mechanism
by which the drug exerts its antiseizure activity;
alternatively, the depolarizing action of
bicarbonate ions moving out of neurons via
GABA receptor ion channels will be diminished
by carbonic anhydrase inhibition.
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Acetazolamide
Acetazolamide has been used for all types of
seizures but is severely limited by the rapid
development of tolerance, with return of
seizures usually within a few weeks.
The drug may have aspecial role in epileptic
women who experience seizure exacerbations at
the time of menses; seizure control may be
improved and tolerance may not develop
because the drug is not administered