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Therapeutics > Exam 3 lecture 4 (PD) > Flashcards

Exam 3 lecture 4 (PD) Flashcards

1
Q

PD definition

A

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

males more susceptible than females

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2
Q

PD symptoms

A

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

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3
Q

PD is characterized by a loss of

A

Dopaminergic neurons in SUBSTANTIA NIGRA

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4
Q

What is SNPC

A

substantia nigra pars compacta

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5
Q

What is the nigrostriatial system and what is its relevance

A

PD involves a loss of neurotransmission through the nigrostriatal system

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6
Q

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

A

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

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7
Q

Where do dopaminergic neurons project to

A

Striatum in basal ganglia

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8
Q

What else is PD characterized by that is worth noting

A

Lewy bodies in various regions in brain

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9
Q

What are lewy bodies?

A

Dense spherical protein deposits on surviving neurons in brain

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10
Q

Where are Lewy bodies found

A

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

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11
Q

Lewy bodies are enriched with a protein called

A

α-synuclein

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12
Q

What is the Braak stages of PD (!)

A

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

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13
Q

Where is substantia nigra located

A

In midbrain (part of basal ganglia)

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14
Q

SN pars compacta function and pathology

A

supplies dopamine to striatum.
It undergoes neurodegeneration in PD

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15
Q

Basal ganglia structures

A

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

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16
Q

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

A

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

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17
Q

What are the two pathways dopamine neurons signal through

A

D1 and D2

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18
Q

What is the difference between D1 and D2 signaling

A

D1 is DIRECT
D2 is indirect

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19
Q

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

A

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

20
Q

describe the role of antimuscarinic drugs in PD (!)

A

antimuscarinics are used as adjunct therapies for tremor in PD

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

21
Q

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

A

Dopamine is inhibitory while acetylcholine is excitatory
in indirect pathway

22
Q

What is the gold standard tx for PD

A

L-DOPA

23
Q

Know L-DOPA structure for exam

A
24
Q

Know carbidopa structure for exam (!)

A
25
Q

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

A

L-DOPA is an immediate precursor to dopamine

L-DOPA is orally active

26
Q

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

A

dopamine does not cross BBB

27
Q

Why does L DOPA cross BBB but dopamine does not

A

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

28
Q

side effects of L dopa

A

Nausea, HTN, psychosis

29
Q

What is sinemet

A

carbidopa
L-DOPA

30
Q

why is L-DOPA mixed with carbidopa

A

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

31
Q

Challenges associated with L DOPA(!)

A

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

32
Q

How can we alleviate challenges shown in L DOPA usage

A

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

33
Q

How is L DOPA converted dopamine

A

by dopamine decarboxylase

34
Q

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

A

apomorphine

35
Q

What kind of drug is apomorphine

A

mixed D1/D2 agonist

36
Q

Selegiline structure remember

A
37
Q

What are some major problems with long term therapy with levodopa

A

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)

38
Q

Name DA receptor agonists (non-ergolines)

A

Ropinrole
Pramipexole
Rotigotine (patch)

have fewer side effects than ergolines

39
Q

How do you take non-ergoline drugs

A

-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

40
Q

PD drugs that interfere with dopamine metabolism

A

MAO-B inhibitor
COMT inhibitor

41
Q

MAO-B inhibitor drugs

A

Selegiline and rasagiline

Safinamide

42
Q

COMT inhibitor drugs

A

Entacapone
Tolcapone
Opicapone

43
Q

Know selegiline structure for exam

A
44
Q

Which is irreversible MAO or COMT

A

MAO-I

45
Q

Distinct features of selegiline and rasagiline? What is their use

A

Triple bonds, indications of irreversible inhibitor.
both propargylamines

Both drugs can be used initially as monotherapies to delay the 1st use of L-Dopa

46
Q

MOA of COMT-I drugs for PD

A

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

47
Q
A

Therapeutics (38 decks)

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