Exam 3 lecture 4 (PD)

Question 1

PD definition

Answer 1

PD is an age related irreversible neurodegenerative disease that affects 1,000,000 people in the US

males more susceptible than females

Question 2

PD symptoms

Answer 2

TRAP

Resting TREMOR (primarily on one side of body

RIGIDITY (muscle stiffness)

Akinesia/bradykinesia (slow movement)

POSTURAL instability (impaired balance/coordination)

Mask like appearance, speech difficulties, cognitive deficits, depression

Question 3

PD is characterized by a loss of

Answer 3

Dopaminergic neurons in SUBSTANTIA NIGRA

Question 4

What is SNPC

Answer 4

substantia nigra pars compacta

Question 5

What is the nigrostriatial system and what is its relevance

Answer 5

PD involves a loss of neurotransmission through the nigrostriatal system

Question 6

What percent of nigral dopamine neurons or nerve terminals are lost before patient presents with motor symptoms

Answer 6

50% of nigral dopamine neurons or 70-80% of nerve terminals in striatum

Question 7

Where do dopaminergic neurons project to

Answer 7

Striatum in basal ganglia

Question 8

What else is PD characterized by that is worth noting

Answer 8

Lewy bodies in various regions in brain

Question 9

What are lewy bodies?

Answer 9

Dense spherical protein deposits on surviving neurons in brain

Question 10

Where are Lewy bodies found

Answer 10

Not only found in SN but also other brain regions including cortex

Question 11

Lewy bodies are enriched with a protein called

Answer 11

α-synuclein

Question 12

What is the Braak stages of PD (!)

Answer 12

Stage 1- lower brainstem
Stage 2- raphe
Stage 3- substantia nigra (necessary for classic PD symptoms)
stage 4- mesocortex/thalamus
stage 5- neocortex/ prefrontal cortex
stage 6- entire neocortex

Question 13

Where is substantia nigra located

Answer 13

In midbrain (part of basal ganglia)

Question 14

SN pars compacta function and pathology

Answer 14

supplies dopamine to striatum.
It undergoes neurodegeneration in PD

Question 15

Basal ganglia structures

Answer 15

Striatum (caudate nucleus, putamen) and globus pallidus (external and internal)

Question 16

What are the two structures in striatum?
What are the two structures in Globus pallidus

Answer 16

Striatum- caudate nucleus and putamen
Globus pallidus- external and internal

Question 17

What are the two pathways dopamine neurons signal through

Answer 17

D1 and D2

Question 18

What is the difference between D1 and D2 signaling

Answer 18

D1 is DIRECT
D2 is indirect

Question 19

What happens to D1 and D2 signaling in PD (!)

Answer 19

signaling from SNPC to both D1 and D2 receptors in the striatum favors thalamocortical steroids, and this effect is disrupted in PD

Question 20

describe the role of antimuscarinic drugs in PD (!)

Answer 20

antimuscarinics are used as adjunct therapies for tremor in PD

antimuscarinics are only used at low doses due to their side effects (cognitive deficits)

Question 21

Role of dopamine and acetylcholine in control of muscle movements (!)

Answer 21

Dopamine is inhibitory while acetylcholine is excitatory
in indirect pathway

Question 22

What is the gold standard tx for PD

Answer 22

L-DOPA

Question 23

Know L-DOPA structure for exam

Question 24

Know carbidopa structure for exam (!)

Question 25

rationale for treating PD pt with L-DOPA? difference between L-DOPA and Dopamine (!)

Answer 25

L-DOPA is an immediate precursor to dopamine L-DOPA is orally active

Question 26

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

Answer 26

dopamine does not cross BBB

Question 27

Why does L DOPA cross BBB but dopamine does not

Answer 27

L DOPA crosses because it is a neutral molecule, Dopamine is positive at PH 7

Question 28

side effects of L dopa

Answer 28

Nausea, HTN, psychosis

Question 29

What is sinemet

Answer 29

carbidopa L-DOPA

Question 30

why is L-DOPA mixed with carbidopa

Answer 30

The dose of L-DOPA can be lowered by 4X by coadministering carbidopa

Question 31

Challenges associated with L DOPA(!)

Answer 31

-On/OFF oscilliations after several years of DOPA usage -Immediately after dosage, it can produce dyskinesia (motor effects) -Pro drug conversion

Question 32

How can we alleviate challenges shown in L DOPA usage

Answer 32

Oscilliations and dyskinesia Can be alleviated by administering DOPA in a continous manner instead of a pulsatile manner. Pro drug can be alleviated by using dopamine receptor agonists – this is reasonable because the postsynaptic dopamine receptors are still present in the striatum

Question 33

How is L DOPA converted dopamine

Answer 33

by dopamine decarboxylase

Question 34

What is a DA receptor agonist that can alleviate pro drug symptoms

Answer 34

apomorphine

Question 35

What kind of drug is apomorphine

Answer 35

mixed D1/D2 agonist

Question 36

Selegiline structure remember

Question 37

What are some major problems with long term therapy with levodopa

Answer 37

Dyskinesia and on/off states. This is after plasma levels decline. Pro drug conversion is also a problem. (eventually pts become unresponsive to L-DOPA, treat by dopamine receptor agonist like apomorphine)

Question 38

Name DA receptor agonists (non-ergolines)

Answer 38

Ropinrole Pramipexole Rotigotine (patch) have fewer side effects than ergolines

Question 39

How do you take non-ergoline drugs

Answer 39

-These drugs are typically given in ascending order -increase dose every 5-7 days to minimize side effects -generally used as a monotherapy for early stage PD

Question 40

PD drugs that interfere with dopamine metabolism

Answer 40

MAO-B inhibitor COMT inhibitor

Question 41

MAO-B inhibitor drugs

Answer 41

Selegiline and rasagiline Safinamide

Question 42

COMT inhibitor drugs

Answer 42

Entacapone Tolcapone Opicapone

Question 43

Know selegiline structure for exam

Question 44

Which is irreversible MAO or COMT

Answer 44

MAO-I

Question 45

Distinct features of selegiline and rasagiline? What is their use

Answer 45

Triple bonds, indications of irreversible inhibitor. both propargylamines Both drugs can be used initially as monotherapies to delay the 1st use of L-Dopa

Question 46

MOA of COMT-I drugs for PD

Answer 46

Inhibit methylation of 3-OH group of DA or L-DOPA by COMT