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22 Cards in this Set
- Front
- Back
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Parkinsons disease
-cause |
Loss of dopamine neurons in substantia nigra (projections to basal ganglia)
-Lewy bodies—protein aggregates in DA cells |
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Why is PD usually so slow in developing?
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Lots of “spare” DA neurons (reserve). Must lose ~80% before symptoms occur.
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Hallmark symptoms of PD (4)
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Bradykinesia
Muscle rigidity Resting tremor Postural instability (TRAP) |
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Dopaminergic circuitry are found in two places
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1. Ventral tegmental area (VTA) – which has a lot of projections to the nucleus accumbens that deals with reward
2. Substantia nigra (SN) (what we will be talking about today) -Has projection to thalamus then project to the motor cortex SN putamen thalamus motor cortex cause movement Putamen + caudate =stratum |
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Normal DA vs. Parkinsons DA activity in brain
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Normal:
1. DA activity in striatum 2. Decreased GABAergic output to thalamus 3. Movement! PD: 1. Dec. DA activity in striatum 2. Increased GABAergic output to thalamus 3. No movement |
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MPTP
-what is it |
MPTP is a neurotoxin
Inhibition of mitochondria leading to destruction of DA neurons Early 1980s…illicit drug making disaster |
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Why are the DA neurons dying? (4 main causes)
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1. Genetic
-Usually the earlier onset and more aggressive -Protein aggregates (Lewy bodies) that cause cell death 2. Oxidative damage 3. Environmental -Pesticides, cycad plant (as food source), heavy metals 4. Drug induced -MPTP -Antipsychotics (D2R antagonists) (mimics PD) |
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Treatment Strategies for PD
(3) |
1. Increase dopamine
-Increase DA synthesis -Decrease DA degradation -Agonism of DA receptors (D2R) 2. Amantadine 3. Decrease Ach -Specifically muscarinic |
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Levodopa (L-Dopa)
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DA doesn’t cross blood-brain barrier
L-dopa does cross BBB Very little l-dopa makes it to the brain Carbidopa inhibits peripheral conversion to DA |
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COMT inhibitors (2)
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1. Entacapone
-Peripheral only 2. Tolcapone -Hepatic toxicity -Central and peripheral effects |
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Levodopa (+ carbidopa + entacapone)
- side effects (7) |
Hypotension
Arrythmias Nausea (chemoreceptor trigger zone) End-of-dose deterioration of function On/off oscillations Dyskinesia at peak of dose Hallucinations (due to dopamine agonist) |
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MAOB Inhibitors
-drugs (2) -indications (6) |
Selegiline, rasagilene
-Prolongs effect of L-Dopa -Irreversible & selective (at low doses) -Mild antidepressant effects -May provide neuroprotection from PD -Symptomatic effect is small -Major food/medicine interaction issues |
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Selegiline, rasagilene
Adverse effects (5) |
MAOB Inhibitors
-Confusion -Hallucinations -Insomnia (from amphetamine/methamphetamine compounds) -Hypotension -Dyskinesias |
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Dopamine Agonists
-(3 classes) -benefits |
1. Ergot alkaloids (non-specific)
-Bromocriptine -Pergolide -Cabergoline 2. Non-ergot DA agonists -Pramipexole (D3R agonist) -Ropinirole (D2R agonist) 3. Apomorphine Benefits: Don’t need conversion No free radical metabolites (less oxidative damage risk) Not active in a “normal” manner Specificity for DA receptors subtypes |
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Bromocriptine and Pergolide
Adverse Effects (7) |
(Ergot dopamine Agonists)
Cerebral vascular accident Seizure Acute myocardial infarction Dizziness Hypotension Abdominal cramps Nausea |
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Ropinirole and Pramipexole Adverse Effects (7)
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(Non-ergotDopamine Agonists)
Dyskinesia, Orthostatic hypotension Extrapyramidal movements Somnolence Dizziness Hallucinations Compulsive behavior |
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Amantadine
-indication -MOA |
Antiviral agent with antiparkinsonian activity
Exact mechanism of action is uncertain (NMDA antagonist) -Increases dopamine release, inhibits dopamine reuptake, stimulates dopamine receptors, and it may possibly exert central anticholinergic effects. |
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Amantadine Adverse Effects (4)
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Confusion
Hallucinations Nightmare Dry mouth |
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Anti-muscarinics (3)
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1. Benztropine
2. Trihexyphenidyl 3. Diphenhydramine (benadryl: antimuscarinic effects) antislude side effects |
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Anticholinergic Adverse Effects (5)
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1. Memory impairment
2. Confusion 3. Hallucinations 4. Caution is advised in patients with known closed-angle glaucoma 5. Anti Slud side effects (dry mouth, constipation, urinary retention, etc) |
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Non-pharmacological treatment (PD) - (1)
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Deep brain stimulation
-Thalamus -Subthalamic nucleus |
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Treatment strategy summary for PD
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Decrease the dopaminergic projection either through direct or indirect pathway.
Treatment strategy so far -Increase dopaminergic by giving L-Dopa -Give dopamine agonist on D2R (most effective) -Or decrease degradation of dopamine w/ MAObI -Inhibiting muscarinic projects (Ach) |
