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25 Cards in this Set
- Front
- Back
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Parkinson's Disease |
A slowly progressive degenerative neurological disorder 2nd most common degenerative disease of neurons Onset: middle age |
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Signs and Symptoms |
Tremors Rigidity Postural instability Slowed movement (bradykinesia- akinesia) Dementia, depression, impaired memory later |
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Pathophysiology of PD |
A loss of dopaminergic neurons in the substantia nigra A disorder of EPS- neuronal network that helps regulate movement Disruption of neurotransmitter function first ID in striatum Proper balance needs dopamine (inhibitory) and acetylcholine (excitatory) |
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Goals of PD Therapy |
Functional mobility Prolongs quality and quantity of life Drug selection and dosage- are based on extent to which interferes with work, ADLs (b/c effects are not as good over time) Drugs give symptomatic relief, no cure |
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Two types of drugs for treatment |
- Dopaminergic agents (activate dopamine receptors) - Anticholinergic agents (block Ach receptors) |
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Basic Mechanisms of PD drugs |
Dopamine agonists (bromocriptine) stimulates dopamine receptors directly Dopamine replacement (Levodopa) promotes dopamine synthesis MAO-B inhibitor (Selegiline) inhibits dopamine breakdown Anticholinergics- block muscarinic receptors in striatum |
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Main Therapy for PD |
Levodopa- converts dopamine in the brain and then further stimulates other receptors Carbidopa- blocks the destruction of Levodopa in periphery |
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Levodopa |
Cornerstone of therapy for PD Full therapeutic effect takes several months Beneficial effects diminish over time No immediate improvement seen After 5 years of Levodopa therapy, pt deteriorates to pre-treatment levels- disease gets worse |
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Levodopa MOA |
Enters brain via active transport system across BBB; taken up into few remaining dopamine terminals (in striatum); converted to dopamine (active form); utilizes decarboxylase (enzymes) and pyridoxine (Vit B6); active dopamine is released into synaptic space; binds to dopamine receptors on striatal GABAergic neurons; cause slower firing of GABA neurons |
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Levodopa Pharmacokinetics |
PO only Readily absorbed from small intestine Take on empty stomach Usual dosing: 0.5-1g/ day (dispensed in 100, 250, 500mg tabs) Given in 2 + divided doses |
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Levodopa Adverse Effects |
Nausea/ Vomiting- simulates CTZ (Medulla) Dyskinesias- once therapeutic levels are achieved CV effects- postural hypotension, dysrhythmias Psychosis- visual hallucinations, vivid dreams, paranoia Neurotoxicity- metabolites from conversion process toxic to cells mitochondria and other cell parts Darkens sweat and urine May activate malignant melanoma |
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Gradual Loss |
"Weaning Off" Develops near end of dosing intervals, plasma levels decrease to sub-therapeutic levels with disease progression |
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Abrupt Loss |
"On-off" Occurs at any time, even while drug levels are high "Off" times may last minutes to hours Episodes of "off" increase frequency and intensity |
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Diminishing Loss of Effect |
Shorten dosing intervals Give drug that prolongs Levodopa life Give direct acting dopamine agonist (Bromocriptine) Use Sinemet CR- a controlled release formulation Avoid high protein meals |
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Why not use dopamine itself? |
Dopamine doesn't readily cross BBB Dopamine has such a short half-life, not practical, would be of no benefit |
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Addressing Adverse Effects of Levodopa |
Low initial doses (decrease N/V, dyskinesias, psychosis) Increase salt/ H2O intake (decrease hypotension) Avoid protein rich meals- AAs compete Clozapine to decrease psychosis Avoid people with skin lesions |
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Benefit of Drug Holiday |
An interruption of Levodopa treatment Approx. 10 days in duration When: once adverse effects increase and therapeutic effectiveness decrease Restarted on low doses, effective therapy again Dangerous- perform in hospital, may immobilize pt, increase risk of DVTs, decubitus ulcers, aspiration, pneumonia |
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Food Interactions with Levodopa |
High protein meals decrease effects of Levodopa Amino acids from proteins compete with Levodopa for 2 things: absorption sites in small intestine and transport across BBB Could trigger an abrupt loss of effect ("off" episode) |
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Combination Therapy- Sinemet |
Levodopa + Carbidopa =Sinemet Most effective therapy for PD |
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Carbidopa |
Used to enhance the effects of Levodopa- no therapeutic effect of its own- cannot cross BBB |
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Sinemet MOA |
Inhibits decarboxylation (metabolism or degradation) of Levodopa in periphery, making Levodopa more available to CNS |
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Carbidopa + Levodopa |
If you give Levodopa by itself 2% gets to brain With Carbidopa, 10% gets to brain |
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Selegiline |
Reduces "weaning off" effect |
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Selegiline MOA |
Selective, irreversible inhibition of MAO-B, that typically inactivates dopamine in striatum. Preserves dopamine, prolongs the effects of Levodopa |
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Selegiline Adverse Effect |
Insomnia (metabolites- amphetamine derived) Give at breakfast/ noon |
