resting tremor, muscular rigidity, akinesia/bradykinesia, impairment of postural balance
What are the 4 cardinal features of Parkinson's?
loss of pigmented, dopaminergic neurons of substantia nigra
What is the cause of Parkinson's?
Lewy bodies
What is a common finding in patients with PD?
DA from substantia nigra increases direct pathway activity and decreases indirect pathway activity; causing cortex excitation/movement
How does the Basal Ganglia act normally?
lack of DA decreases direct pathway activity and increases indirect pathway activity; causing cortex inhibition/akinesia
How does the Basal Ganglia act in PD?
Levodopa
-exogenous L-Dopa, metabolic precursor of DA
bradykinesia, tremor, rigidity
Which symptoms are Levodopa best at treating? (3)
early into treatment/disease
During the disease course, when is Levodopa best?
low amount reaches brain, tolerance, increasing adverse effects, on-off phenomenon
What are the problems of L-DOPA? (4)
peripheral decarboxylation to DA; peripheral COMPT degradation
Why does a low amount of L-DOPA reach the brain? (2)
prevents peripheral degradation/conversion of L-DOPA into DA; dopa decarboxylase inhibitor
Carbidopa MOA?
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)
increase dose/frequency, use ER, add other therapies
How can we fix the end-of-dose " wearing off" phenomenon? (3)
anorexia, N/V, arrhythmias, dyskinesia (long term use)
What are the physical AE's of Levodopa? (4)
depression, confusion, nightmares, changes in mood/personality, impulsivity control
What are the behavioral AE's of Levodopa? (5)
MAO-A inhibitors (hypertensive crisis); Pyridoxine/Vit B6 (enhanced metabolism)
Which drugs do we AVOID with Levodopa? (2)
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)
akinesia; dyskinesia
Off-periods have marked ________; On periods have improved motility but ________.
enhances release of DA from neurons and delays reuptake; blocks NMDA glutamate receptors
Amantadine MOA?
for managing L-dopa induced dyskinesia
What is the utility of Amantadine?
confusion, livedo reticularis
AE's of Amantadine?
Livedo Reticularis
-diffuse mottling of skin (upper or lower extremities) often accompanied by
lower-extremity edema
HF, seizures
Which patients do we use Amantadine with caution? (2)
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?
-giline suffix, safinamide
What are the MAO-B inhibitors? (2)
reduce peripheral metabolism of L-DOPA; increases the amount of levodopa that reaches the brain
COMT inhibitors MOA?
-pone suffix
What are the COMT inhibitors?
patients with on/off phenomenon
Which patients have the most use with Dopamine Receptor Agonists?
arrhythmias
Which AE of Dopamine Receptor Agonists(DRAs) causes the
discontinuation of therapy?
Ropinirole, Pramipexole, Rotigotine, Apomorphine
What are the Dopamine Receptor Agonists (DRAs)? (4)
a
Which is more likely to cause mental side effects?
a) Dopamine Receptor Agonist
b) Levodopa
b
Which is better for treating symptoms?
a) Dopamine Receptor Agonist
b) Levodopa
directly; postsynaptic
DRAs act ________ on the ________ DA receptors.
Adenosine A2A Receptor antagonist
What class of drug is Istradefylline?
blocks A2A receptors; causing inhibition of the indirect pathway leading to prolongation of dopaminergic action
Istradefylline MOA?
add-on treatment to levodopa/carbidopa in patients w/ off episodes
What is Istradefylline for?
D2; ACh
_____ receptors in cholinergic striatal neurons regulate ______ release.
benztropine, trihexyphenidyl, diphenydramine
What are the Muscarinic Receptor Antagonists(M1)? (3)
treating tremors
What is the main use of M1 antagonists?
antiapoptotic; slow
MAO-B inhibitors possess __________ properties and might ________ disease progression.
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)
treat neurogenic orthostatic hypotension
What is the purpose of Droxidopa?
oral prodrug that is converted by AAAD into NE; increases blood pressure by inducing peripheral arterial/venous vasoconstriction
Droxidopa MOA?
primary autonomic failure; impaired compensatory autonomic reflexes
Neurogenic Orthostatic Hypotension is caused by ________ & ________.
carbidopa
Which medication may have drug interactions with Droxidopa?