Term
|
Definition
Major molecular targets:
– components of the GABA system
•GABAA receptors,
•GAT-1 GABA transporter
•GABA transaminase
– voltage-gated Na+ channels
– voltage-gated Ca2+ channels |
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Term
Generalized Seizures
(convulsive or non-convulsive) |
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Definition
•Tonic-clonic seizures
•Absence (petit mal)
•Atonic seizures
•Myoclonic seizures |
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Term
|
Definition
SIMPLE
•Manifestations without loss of consciousness.
•Motor, sensory, vegetative or psychic.
•Seizure-symptoms don’t change during seizure.
COMPLEX (temporal lobe seizures…psychomotor)
•Bizarre attacks of confused behavior
•Usually preceded by a warning sensation (“aura”)
•Usually an impairment of consciousness
Patient will remember little of attack |
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Term
Anticonvulsants
General Adverse Effects: |
|
Definition
•CNS depression (most common)
•Dizziness, sedation, impaired learning and cognitive abilities
•GI
•Anorexia, nausea, vomiting
•Skin
•Mild rash to Stevens-Johnson syndrome (rare) |
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Term
Anticonvulsants
Classic First Generation Drugs |
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Definition
•Carbamazepine
•Valproate
•Phenytoin |
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Term
Anticonvulsants
New Second Generation Drugs |
|
Definition
•Lamotrigine
•Topiramate
•Levetiracetam
•Pregabalin |
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Term
|
Definition
Mechanism of action:
–limits repetitive firing of action potentials
•blocks voltage-activated Na+ channels |
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Term
|
Definition
Absorption, distribution and metabolism:
–water insoluble; oral only
–T½ 36hrs (initial); 8-12hrs (continuous)
–extensively bound to plasma proteins (75-85%)
–induces its own metabolism in liver via CYP450
–carbamazepine-10,11-epoxide is active metabolite |
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Term
Carbamazepine
Unique Adverse Effects: |
|
Definition
–hematological disorders
•aplastic anemia and agranulocytosis
•usually occurs within 4 months of initiation or increase in dose
–drug interactions due to CYP450 induction
–dry mouth, glossitis and stomatitis
–in children, need to emphasize oral hygiene
•63% sugar in chewable tablet |
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Term
Valproate
Mechanism of action: |
|
Definition
–may enhance GABA function
•via synthesis, transport and metabolism
–may limit repetitive firing of action potentials
blocks voltage-activated Na+ channels |
|
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Term
Valproate
Absorption, distribution and metabolism |
|
Definition
–water soluble; well absorbed
–T½ 9-18hrs
–extensively bound to plasma proteins (85-95%)
metabolized in liver via oxidation/glucuronidation |
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Term
Valproate
Unique Adverse Effects |
|
Definition
–hepatotoxicity
•risk is greatest in patients under 2-years of age
•polytherapy
–hypersalivation
–inhibits 2nd phase of platelet aggregation
–drug interactions
•related to plasma protein binding sites
•potent inhibitor of oxidation and glucuronidation |
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Term
Phenytoin
Mechanism of action: |
|
Definition
–limits repetitive firing of action potentials by producing a sustained depolarization
•blocks voltage-activated Na+ channels |
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Term
Phenytoin
Absorption, distribution and metabolism |
|
Definition
–exhibits zero-order kinetics
–T½ 12-36hrs (avg. of 24hrs)
–extensively bound to plasma proteins (70-95%)
–no active metabolites |
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Term
Phenytoin
Unique Adverse Effects: |
|
Definition
–gingival hyperplasia
–hirsutism
–teratogenicity
•“Fetal Hydantoin Syndrome”
–growth deficiency with microcephaly, hypoplasia of the nails and distal phalanges.
–cardiac defects and abnormal genitalia
–drug interactions
•displaces other drugs due to plasma protein binding
can alter the metabolism of other drugs |
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Term
Lamotrigine
Mechanism of action |
|
Definition
–limits repetitive firing of action potentials by producing a sustained depolarization
•blocks voltage-activated Na+ and Ca2+ channels
•inhibition of glutamate release |
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Term
Lamotrigine
Absorption distribution, metabolism
|
|
Definition
•low plasma protein binding
•T½ 24hrs (valproate doubles) |
|
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Term
Topiramate
Mechanism of action: |
|
Definition
–limits repetitive firing of action potentials
•blocks voltage-activated Na+ and Ca2+ channels
•inhibition of glutamate release
•enhances GABA |
|
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Term
Topiramate
Absorption, distribution and metabolism |
|
Definition
| Rapidly absorbed; bioavailability is almost 100%; no active metabolites; excreted in urine |
|
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Term
Topiramate
Unique Adverse Effects |
|
Definition
–kidney stones (inhibition of carbonic anhydrase) |
|
|
Term
Levetiracetam
Mechanism of action: |
|
Definition
–blockade of a brain-specific, stereo-selective binding site known as the synaptic vesicular protein (SV2A)
•important for the availability of Ca2+-dependent neurotransmitter vesicles (glutamate and/or GABA)
•inhibition of Ca2+ release from IP3-sensitive stores |
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Term
Levetiracetam
Absorption, distribution and metabolism: |
|
Definition
| Rapidly absorbed; bioavailability is almost 100%; no active metabolites; excreted in urine |
|
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Term
Pregabalin
(and Gabapentin)
Mechanism of action: |
|
Definition
–do not act on GABA receptors, but may alter its metabolism, release and transport
binds to the α2δ subunit of the voltage-gated Ca2+ channel (but are not channel blockers…reduces neurotransmitter release) |
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|
Term
Pregabalin
(and Gabapentin)
Absorption, distribution and metabolism: |
|
Definition
–Rapidly absorbed; bioavailability is greater than 90%; no active metabolites; excreted in urine. |
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|
Term
Benzodiazepines
approved by FDA for treatment of epilepsy: |
|
Definition
–Clonazepam
–Clorazepate
–Diazepam – tablets and injectable DOC->>>status epilepticus
–Lorazepam – injectable
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|
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Term
Ethosuximide
Mechanism of action: |
|
Definition
–reduces low-threshold Ca2+ currents (T-type) in thalamic neurons
possible effect on K+channels |
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Term
Ethosuximide
Absorption, distribution and metabolism |
|
Definition
| Rapidly and completely absorbed; no active metabolites; excreted in urine. |
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Term
Treatment of Seizures
Partial Seizures
DOC |
|
Definition
SIMPLE and COMPLEX,
•Carbamazepine
•Phenytoin
•Valproate
Alternatives:
Lamotrigine,
Pregabalin,
Topiramate,
Levetiracetam.
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|
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Term
Treatment of Seizures
Generalized Seizures
DOC |
|
Definition
TONIC-CLONIC SEIZURES (Grand Mal)
•Carbamazepine
•Phenytoin
•Valproate*
Alternatives:
Lamotrigine,
Pregabalin,
Topiramate,
Levetiracetam.
*Not approved except if absence seizure is involved |
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Term
Treatment of Seizures
Status Epilepticus |
|
Definition
Initial:
•Diazepam (intra-rectal gel)
–effects only last 5-15 minutes
•Lorazepam
–effects last 2-8 hours
Follow-up:
•Phenytoin
–takes 15-30 minutes to work |
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