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Neurotransmitters->
20, others likely
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Parkinson’s
Disease
- 1 million Americans
- •Neurodegenerative disorder
- –Loss
- of dopaminergic neurons in Basal Ganglion
- –Movement
- requires balance between dopamine and ACh
- •Rigidity,
- tremor, instability, bradykinesia…akinesia
•Therapeutic goal
- –Improve
- activities of daily living (ADL)
- –Drug
- selection and dosages are determined by ADL performance
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Why not just give dopamine?
•Catecholamine
–Must be given IV
–Very short half-life
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–Can’t cross blood brain barrier
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Why not Levodopa/Dopar
–Only 2% gets into brain
•Need active transport
–Metabolized to dopamine in the brain
–Initially highly effective, then diminish over time
–Wearing off-near dose time-(CR)
–On/off-at any time maybe r/t protein
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Levodopa/Dopar (Adverse reactions and contraindication)
•Adverse reactions
•N/V, dyskinesias, dysrhythmias, hypotension
•20% develop psychosis-clozapine is best choice
•Contraindicated
•malignant melanoma-can activate neoplasm
•MAO inhibitors-hypertensive crisis
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Drug Holiday
Taking up to 10 days off treatment can increase drug effectiveness.
But it’s no picnic.
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Sinemet =
Levodopa + Carbidopa
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•Carbidopa
- –Blocksthe metabolizing of levodopa to dopamine in the gut
- –Increaseslevodopa in the brain
- –Decreasesdopamine metabolism in periphery, so decreases cardiovascular effects
- –Abnormalmovements and psychoses may occur sooner
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Dopamine Agonists
•Increase activation of dopamine receptors
•Less effective than dopamine
–Best for mild symptoms
–Not affected by proteins
•Adverse effects: hallucinations, sedation, postural hypotension
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Dopamine Agonists
- Promote activation of dopamine receptors
- •Selegiline/Carbex
•Prevention of dopamine degradation
- •Promotion of dopamine release, inhibits reuptake
- •Amantadine/Symmetrel–Anti-viral
- •Direct activation of dopamine receptors
- •Ropinorole/Requip
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Anticholinergic agents? Examples
Prevent activation of cholinergic receptors
•Benztropine (Cogentin)
•Blockade of cholinergic receptors
•Decrease tremors and rigidity, not bradykinesias
•Side effects:
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Hippocampus-
- limbic system
- memory, emotion, motivation
- spatial navigation
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Alzheimer’s Disease
5.1 million Americans
5.1 million Americans
•Degeneration of cholinergic neurons
–neuritic plaques, neurofibrillary tangles
•Progressive memory loss
•Neuropsychiatric symptoms
•Neuromotor decline
•Prognosis-4-8 years
•10,000 die annually
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Cholinesterase Inhibitors
–Mild to moderate symptoms
–Prevent breakdown of Ach
•Improve availability
•Only 20-30% of patients respond
–Donepezil (Aricept)-less side effects
–Cholinergic side effects
•??
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NMDA receptor antagonist
memantin/namenda
–N-methly-D-aspartate
•For moderate to severe
•Better tolerated than C I
•Decreases and can reverse symptoms
•Modulates action of glutamate
Blocks extracellular influx of calcium in memory cells
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Alzheimer’s Disease Prevention
-2010
Possible benefit:
•Mediterranean Diet
•Folic Acid
•Statins
Minimal protection
•Physical Activity
•Cognitive training
•Vitamins
•Omega-3
•Estrogens
•NSAIDS
•ASA
•Antihypertensive
•Homocysteine
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