Hosam Mohamed-
resting tremor, muscular rigidity, akinesia/bradykinesia, impairment of postural balance
What are the 4 cardinal features of Parkinson's?
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loss of pigmented, dopaminergic neurons of substantia nigra
What is the cause of Parkinson's?
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Lewy bodies
What is a common finding in patients with PD?
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DA from substantia nigra increases direct pathway activity and decreases indirect pathway activity; causing cortex excitation/movement
How does the Basal Ganglia act normally?
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lack of DA decreases direct pathway activity and increases indirect pathway activity; causing cortex inhibition/akinesia
How does the Basal Ganglia act in PD?
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Levodopa
-exogenous L-Dopa, metabolic precursor of DA
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bradykinesia, tremor, rigidity
Which symptoms are Levodopa best at treating? (3)
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early into treatment/disease
During the disease course, when is Levodopa best?
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low amount reaches brain, tolerance, increasing adverse effects, on-off phenomenon
What are the problems of L-DOPA? (4)
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peripheral decarboxylation to DA; peripheral COMPT degradation
Why does a low amount of L-DOPA reach the brain? (2)
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prevents peripheral degradation/conversion of L-DOPA into DA; dopa decarboxylase inhibitor
Carbidopa MOA?
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the increasing loss of neuronal storage capacity for DA & short half-life of L-DOPA
What are the causes of the end-of-dose "wearing off" phenomenon? (2)
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increase dose/frequency, use ER, add other therapies
How can we fix the end-of-dose " wearing off" phenomenon? (3)
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anorexia, N/V, arrhythmias, dyskinesia (long term use)
What are the physical AE's of Levodopa? (4)
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depression, confusion, nightmares, changes in mood/personality, impulsivity control
What are the behavioral AE's of Levodopa? (5)
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MAO-A inhibitors (hypertensive crisis); Pyridoxine/Vit B6 (enhanced metabolism)
Which drugs do we AVOID with Levodopa? (2)
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decreased nausea/GI symptoms, increased control of PD symptoms, decreased daily L-DOPA dose
What are the benefits of combining L-DOPA with Carbidopa? (3)
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akinesia; dyskinesia
Off-periods have marked ________; On periods have improved motility but ________.
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enhances release of DA from neurons and delays reuptake; blocks NMDA glutamate receptors
Amantadine MOA?
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for managing L-dopa induced dyskinesia
What is the utility of Amantadine?
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confusion, livedo reticularis
AE's of Amantadine?
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Livedo Reticularis
-diffuse mottling of skin (upper or lower extremities) often accompanied by
lower-extremity edema
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HF, seizures
Which patients do we use Amantadine with caution? (2)
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selective inhibition of the breakdown of DA by MAO-B in the striatum; increases the amount of DA in the brain
MAO-B inhibitor MOA?
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-giline suffix, safinamide
What are the MAO-B inhibitors? (2)
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reduce peripheral metabolism of L-DOPA; increases the amount of levodopa that reaches the brain
COMT inhibitors MOA?
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-pone suffix
What are the COMT inhibitors?
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patients with on/off phenomenon
Which patients have the most use with Dopamine Receptor Agonists?
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arrhythmias
Which AE of Dopamine Receptor Agonists(DRAs) causes the
discontinuation of therapy?
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Ropinirole, Pramipexole, Rotigotine, Apomorphine
What are the Dopamine Receptor Agonists (DRAs)? (4)
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a
Which is more likely to cause mental side effects?
a) Dopamine Receptor Agonist
b) Levodopa
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b
Which is better for treating symptoms?
a) Dopamine Receptor Agonist
b) Levodopa
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directly; postsynaptic
DRAs act ________ on the ________ DA receptors.
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Adenosine A2A Receptor antagonist
What class of drug is Istradefylline?
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blocks A2A receptors; causing inhibition of the indirect pathway leading to prolongation of dopaminergic action
Istradefylline MOA?
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add-on treatment to levodopa/carbidopa in patients w/ off episodes
What is Istradefylline for?
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D2; ACh
_____ receptors in cholinergic striatal neurons regulate ______ release.
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benztropine, trihexyphenidyl, diphenydramine
What are the Muscarinic Receptor Antagonists(M1)? (3)
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treating tremors
What is the main use of M1 antagonists?
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antiapoptotic; slow
MAO-B inhibitors possess __________ properties and might ________ disease progression.
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MAO-B inhibition diverts DA degradation to alternate route; no free radicals, synthesis of neurotrophic factors, synthesis of antioxidants, blocks apoptotic signaling
What may contribute to the antiapoptotic effect of MAO-B inhibitors? (4)
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treat neurogenic orthostatic hypotension
What is the purpose of Droxidopa?
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oral prodrug that is converted by AAAD into NE; increases blood pressure by inducing peripheral arterial/venous vasoconstriction
Droxidopa MOA?
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primary autonomic failure; impaired compensatory autonomic reflexes
Neurogenic Orthostatic Hypotension is caused by ________ & ________.
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carbidopa
Which medication may have drug interactions with Droxidopa?
