lecture 42

Question 1

what are TRAP symptoms of PD?

Answer 1

resting Tremor (primarily on one side of body)
Rigidity (muscle stiffness)
Akinesia/bradykinesia (slow movement)
Postural instability (impaired balance, coordination)

Question 2

what are other symptoms of PD (beside TRAP)?

Answer 2

mask-like appearance
speech difficulties, cognitive deficits, depression
olfactory deficits, sleep disturbances

Question 3

what system does the neurological deficit occur in in PD?

Answer 3

extrapyramidal system
noncorticol voluntary motor control

Question 4

what percentage of nigral dopamine neurons are lost before patient present with motor system?

Answer 4

50%

Question 5

what percentage of nerve terminals in the striatum are lost before a patient presents with motor symptoms?

Answer 5

70-80%

Question 6

how does the nigrostriatal system and PD correlate?

Answer 6

PD involves a loss of neurotransmission through the nigrostriatal system

Question 7

what are lewy bodies?

Answer 7

dense, spherical protein deposits that are remnants of surviving neurons in the brain

Question 8

what does stage 2 of the Braak pathological stages account for?

Answer 8

neuropathology in the raphe
potential link to REM sleep behavior disorder

Question 9

what does stage 3 of the braak pathological stages account for?

Answer 9

neuropathology in the substantia nigra
necessary for classic PD symptoms

Question 10

what does stage 6 of the braak pathological stages account for?

Answer 10

neuropathology of the entire neocortex
potential link to cognitive deficits

Question 11

what structures make up the basal ganglia?

Answer 11

striatum (caudata nucleus, putamen) and globus pallidus (external and internal segments)

Question 12

what is Gpi?

Answer 12

globus pallidus internal
smallest, most inner part of the GP

Question 13

what is the Gpe?

Answer 13

globus pallidus external
largest, most outer part of the GP

Question 14

what is the direct pathway of DA neuron signaling?

Answer 14

involves D1 receptors in the striatum
SNpc –> striatum –> Gpi/SNpr –> thalamus –> cortex

Question 15

what is the indirect pathway in DA neuron signaling?

Answer 15

involves D2 receptors in the striatum
SNpc –> striatum –> Gpe –> STN (Subthalamic nucleus) –> Gpi/SNpr –> thalamus –> cortex

Question 16

what part of DA signaling is disrupted in PD?

Answer 16

signaling from the SNpc to both D1 and D2 receptors in the striatum favors thalamocortical signaling

Question 17

in the indirect pathway, what neurotransmitters affect the control of motor movement?

Answer 17

acetylcholine is excitatory
dopamine is inhibitory

Question 18

what is the role of antimuscarinic agents in PD?

Answer 18

adjunct therapies for tremor in PD
used only in low doses due to their SE (like cognitive deficits)

Question 19

what are SE of L-DOPA at high doses?

Answer 19

nausea
HTN
psychosis

Question 20

how and by what means is L-DOPA converted into dopamine?

Answer 20

converted in the substantia nigra through DOPA decarboxylase (DDC)

Question 21

what is the role of carbidopa in making dopamine?

Answer 21

inhibits DDC in the periphery to prevent DDC from converting L-DOPA into dopamine

Question 22

why is there a difference in bioavailability between L-DOPA and DA?

Answer 22

DA has a net positive charge at pH7

Question 23

what is Sinemet?

Answer 23

combination of carbidopa and L-dopa designed to reduce the harsh SE

Question 24

what is on/off oscillations?

Answer 24

challenge associated with long term L-DOPA therapy
on state - exaggerated and aberrant motor effects known as dyskinesia
off state - fail to provide any effect

Question 25

what are the changes associated with moderate PD and L-DOPA response?

Answer 25

shorter duration motor response increased incidence of dyskinesia

Question 26

how can on/off oscilations be alleviated?

Answer 26

administering L-DOPA in a continuous (as opposed to pulsatile) manner

Question 27

how would you deal with the challenges associated with prodrug conversion and the patient eventually becoming unresponsive to L-DOPA?

Answer 27

use dopamine receptor agonist because the postsynaptic dopamine receptors are still present in the striatum

Question 28

what are examples of DA receptor agonists?

Answer 28

apomorphine, non-ergolines (ropinirole, pramipexole, rotigotine)

Question 29

what drugs are MAO-B inhibitors?

Answer 29

selegiline (deprenyl), rasagiline (azilect), and safinamide (xadago) inhibitors of dopamine metabolism

Question 30

what structure do selegiline and rasagiline have in common?

Answer 30

propargylamines (R2N-CH2-C=-CH) chemical properties lead to irreversible inhibition of MAO-B

Question 31

what is the MOA of safinamide?

Answer 31

MAO-B inhibitor with no propargylamine group used as an adjunct to L-DOPA/carbidopa during off episodes

Question 32

what drugs are COMT inhibitors?

Answer 32

entacapone, tolcapone, opicapone inhibit the methylation of the 3-OH group of DA or L-DOPA via catechol-O-methyl transferase (COMT)

Question 33

where do entacapone and opicapone work?

Answer 33

inhibition of COMT in the periphery, allowing more of it to reach the brain

Question 34

where does tolcapone work?

Answer 34

inhibition of COMT in the CNS, allowing levels of CNS DA to remain higher

Question 35

how do COMT inhibitiors and Sinemet react?

Answer 35

increase the duration of effect of Sinemet, nothing to do with potency tho

Question 36

what is Stalevo?

Answer 36

mixture of L-DOPA, carbidopa, and entacapone

Question 37

which of the following drugs would lead to increased levels of DA in the striatum? rotigotine benztropine selegiline pramipexole ropinirole

Answer 37

selegiline through inhibiting the metabolism of DA by MAO-B