Transcript seizures - UW Canvas

Drugs for Epilepsy
Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.
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Epilepsy: new definition as of 2014
Diagnosis of epilepsy: a person is considered to have
epilepsy if he or she meets any of the following conditions:
• At least two unprovoked (or reflex) seizures occurring greater
than 24 hours apart.
• One unprovoked (or reflex) seizure and a probability of further
seizures similar to the general recurrence risk (at least 60%)
after two unprovoked seizures, occurring over the next 10 years.
Diagnosis of an epilepsy syndrome
– Epilepsy is considered to be resolved for individuals who had
an age-dependent epilepsy syndrome but are now past the
applicable age, or those who have remained seizure-free for
the last 10 years, with no seizure medicines for the last 5
years.
• Fisher RS et al. A practical clinical definition of epilepsy, Epilepsia
2014; 55:475-482. This definition was also adopted as a position
of the International League Against Epilepsy (ILAE).
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Epilepsy: overview
• ‘Umbrella term’ for a group of heterogeneous
disorders characterized by excessive excitability of
neurons in the CNS
• All seizures are caused by abnormal electrical
disturbances in the brain.
• Different kinds of seizures
– May present with a range of symptoms from as
subtle as a blank stare… to as marked as
unconsciousness or convulsions
• In U.S.  2.3 million people have epilepsy
• Incidence is highest during the 1st year of life and in the
elderly
• Between 60-70% of patients can be seizure-free
with drug therapy.
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Seizures: what is the focus?
• Definition . . . .
The seizure focus is the site in the brain from
which the seizure originated.
• Seizures arise from many possible conditions,
such as:
• Congenital defects
• Hypoxia at birth
• Head trauma
• Cancer
• And more
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Seizures: what is the focus?
The symptoms of any particular seizure depend
on the location in the brain of the seizure
focus
Where are the hyperexcitable neurons located?
− More limited part of the brain 
partial or local seizure
− Larger portion of the brain 
generalized seizure
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Seizures: Types
• Partial (focal) seizures
– Simple partial
– Complex partial
– Secondarily generalized
• Generalized seizures
– Tonic-clonic (grand mal)
– Absence (petit mal)
– Atonic
– Myoclonic
– Status epilepticus (SE)
– Febrile
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Antiepileptic Drugs
(aka AEDs, or “antiseizure medications”)
• Effects:
– Suppress discharge of neurons within a
seizure focus
– Suppress propagation of seizure activity
from the focus to other areas of the brain
• Mechanisms of action involving:
– Sodium
– Calcium
– Glutamate
– GABA
– (potassium?)
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Therapeutic Goals
• Treatment goal:  seizures to an extent that
allows patient to live a normal life
* Balance seizure control vs. acceptability of
undesired side effects
• Non-drug treatment options:
– Neurosurgery (best success rate)
– Vagal nerve stimulation
– Ketogenic diet
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Therapeutic Goals, cont’d
• Diagnosis and drug selection
– Most AEDs selective for specific seizure
disorders
– Must accurately diagnose seizure & then then
treat with AED that treats that type of seizure
* May have to try several AEDs before an
effective regimen can be established
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Therapeutic Goals, cont’d
• Drug evaluation
– Trial period
– Need to determine effectiveness
– Frequent dosage adjustment may be needed
• Patient teaching
• Monitoring plasma drug levels
– Traditional AEDs vs. newer AEDs
– Helpful in major convulsive disorders
– Less helpful for absence seizures
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Therapeutic Considerations
• Promoting patient adherence
*Seizure control dependent on patient compliance
• Withdrawing antiepileptic drugs
– Spontaneous remission
– Withdraw slowly over a period of 6 weeks to
several months
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Classifications of Antiepileptic Drugs
Two major categories:
Both equally effective – neither group superior
• Traditional antiepileptic drugs (AEDs)
– phenytoin
– carbamazepine
– valproic acid
– and others
• Newer AEDs
– oxcarbazepine
– Lamotrigine
– Levetiracetam
– and others
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Phenytoin [Dilantin]
• Especially effective against partial and tonic-clonic
seizures
• Mechanism of action:
selective inhibition of sodium channels
• Varied oral absorption
• Half-life: 8 to 60 hours
• Dosage is highly individualized
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Figure 24-1A Relationship between dose and plasma level for phenytoin compared with
most other drugs.
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Figure 24-1B Relationship between dose and plasma level for phenytoin compared with
most other drugs. Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.
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Phenytoin (cont’d)
• Adverse effects
– Nystagmus
– Sedation
– Ataxia
– Diplopia
– Cognitive impairment
– Gingival hyperplasia
– Skin rash
** Teratogenic in animals & humans
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Phenytoin (cont’d)
Gingival hyperplasia
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Phenytoin (cont’d)
• Drug interactions
– Decreases the effects of oral contraceptives,
warfarin, and glucocorticoids
– Increases levels of diazepam, isoniazid,
cimetidine, alcohol, valproic acid
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Carbamazepine [Tegretol]
• Uses:
– Epilepsy
– Bipolar disorder
– Trigeminal and glossopharyngeal neuralgias
• Mechanism of action
• Adverse effects
– Neurologic effects: nystagmus, ataxia
– Hematologic effects: leukopenia, anemia,
thrombocytopenia
– Dermatologic effects: rash, photosensitivity
reactions
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Valproic Acid
[Depakene, Depakote, Depacon]
• Uses
– Seizure disorders
– Bipolar disorder
– Migraine
• MOA
• Adverse effects
– GI effects
– Hepatotoxicity: liver failure
– Pancreatitis
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Phenobarbital
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One of our oldest AEDs
Effective, inexpensive, can be admin once daily
MOA – potentiates GABA
Uses
– Epilepsy (partial and generalized tonic-clonic
seizures)
– Promotes sleep and sedation
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Newer AEDs
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First line treatment
Are equally effective
Are better tolerated
Less drug interactions
– Oxcarbazepine (Trileptal)
– Gabapentin (Neurontin)
– Levetiracetam (Keppra)
– Pregabalin (Lyrica)
• Initially approved as adjunctive therapy but now
some agents approved for monotherapy
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Lamotrigine (Lamictal)
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Phenyltriazine class of drugs
MOA: Unknown; suspect effects on sodium channels
Dose: 25 mg – 200 mg
PK: Rapidly absorbed orally
Peak plasma level 1.4 - 4.8 hours
Overdose: No antidote, supportive care
Drug Interactions: OC’s and other AED’s
Adverse Effects: mood changes, anxiety, dizziness,
drowsiness, blurred vision
• Life threatening: Steven’s Johnson syndrome
esp in children and at high doses
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Alzheimer’s
Disease
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Alzheimer’s Disease Pathophysiology
• Degeneration of neurons
– Role of hippocampus
→ Important role in memory
– Role of cerebral cortex
→ Speech, perception, reasoning, higher
functioning
• Reduced cholinergic transmission
– In advanced disease, levels of ACh are 90%
below normal
• Beta-amyloid and neuritic plaques
– Form outside of neurons esp. hippocampus
and cortex causing neuronal injury
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Alzheimer’s Disease Pathophysiology
• Neurofibrillary Tangles and Tau
– Tangles inside the neurons form along with
plaques outside the neuron
• Apolipoprotein E4 (apoE4)
– Genetically inherited, 1 or 2 copies ↑risk
• Endoplasmic reticulum-associated binding protein
• Homocysteine
– Elevated levels ↑ risk
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Figure 22-1A Healthy Neuron
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Figure 22-1B Histologic changes in
Alzheimer's disease.
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Alzheimer’s Disease Symptoms
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Memory loss
Confusion
Disoriented
Impaired judgment
Personality changes
Difficulty with self-care
Behavior problems
– wandering, pacing, agitation, screaming
• Inability to recognize family members
• Inability to communicate
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Alzheimer’s Disease: First Approved Drugs
• Cholinesterase Inhibitors
− Prevent breakdown of ACh by AChE with resulting
enhanced transmission
• Do not cure AD and do not stop progression but they
may slow progression
• For use in pts with mild to moderate symptoms
• May improve quality of life (QOL) & cognitive function
for some patients but no evidence of marked
improvement or delay of disease progression
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Alzheimer’s Disease: Cholinesterase Inhibitors
• Donepezil (Aricept)
–Daily dosing: Oral
–Metabolized P450 pathway
• Rivastigmine (Exelon)
–BID dosing-oral also patch
–Metabolized by cholinesterase
• Galantamine (Razadyne)
–Daily ER or BID
–Metabolized P450 pathway
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Alzheimer’s Disease: NMDA Antagonist
• NMDA receptor antagonists (N-methyl-D-aspartate)
• MOA: Modulates glutamate at NMDA receptors
promoting calcium influx, thereby increasing signaling
• NMDA receptors believed to play a critical role in
learning and memory
• Memantine (Namenda)
– Indicated for moderate to severe AD
– Half life 60-80 hours
– Dizziness, Headache, Confusion
– Dose 5 - 21 mg depending on formulation
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Figure 22-2 Memantine mechanism of action.
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Questions?
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