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PBT 3 Exam 2 > Parkinson's Disease > Flashcards

Parkinson's Disease Flashcards

1
Q

Nigrostriatal pathway

A 
Substantia Nigra (DA producing cells) --> Dorsal Striatum (DA released here)
Voluntary motor control
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2
Q

Mesolimbic pathway

A

VTA –> ventral striatum
psychosis: positive symptoms of schizophrenia
pleasure and reward

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3
Q

Mesocortical pathway

A

VTA –> frontal cortex (pre-frontal)
Higher order processing
attention, decision making
psychosis: negative symptoms

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4
Q

Tuberoinfundibular pathway

A

Arcuate nucleus of the Hypothalamus –> median eminence of the Hypothalamus
DA goes to pituitary gland –> control of pituitary hormones (such as prolactin)

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5
Q

Rate limiting enzyme in DA synthesis

A

Tyrosine hydroxylase (slower enzyme)

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6
Q

Dopamine release and trafficking

A
  1. DA released upon depolarization of presynaptic terminal
  2. DA binds to pre- & post-synaptic DA receptor and activates them.
  3. DA is transported back into the pre-synaptic terminal by the dopamine transporter.
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7
Q

First step in dopamine inactivation

A

COMT degrades DA in periphery and in synapse

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8
Q

Second step in dopamine inactivation (2)

A
  1. physical removal –> removed via DA transporter (DAT) back into presynaptic terminal. Once there, DA is either repackaged for future use or degraded by MOA-B
  2. Terminal inactivation by MOA-B in presynaptic terminal. Metabolizes DA into DOPAC.
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9
Q

Dopamine receptors (5)

A

D1-like: D1 and D5 –> stimulatory

D2-like: D2, D3, and D4 –> inhibitory

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10
Q

What does the alpha unit do in a D1-like receptor?

A

activation of the alpha receptor leads to activation of adenylate cyclase, which converts ATP–>cAMP. cAMP activates protein kinase C, which opens Na+ and Ca2+ channels to allow those ions to flow into the cell. More positive = depolarization = more potential for an AP

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11
Q

What does the beta-gamma unit do in a D1-like receptor?

A

Opens K+ channels, which leads to an efflux of K+ out of the cell. Overall net ion exchange (more Na+ and Ca2+ into cell) leads to depolarization

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12
Q

What does the alpha unit do in a D2-like receptor?

A

activation of the alpha receptor INHIBITS adenylate cyclase. No AC prevents the conversion of ATP–> cAMP. Decrease in protein kinase C, which prevents the opening of Na+ and Ca2+ channels. No sodium or calcium ions flow into cell

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13
Q

What does the beta-gamma unit do in a D2-like receptor?

A

Opens K+ channels, which leads to an efflux of K+ out of the cell. Overall net ion exchange (LESS Na+ and Ca2+ into cell) leads to hyperpolarization = less likely to generate an AP

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14
Q

Key features of PD

A
  1. Bradykinesia: Hallmark feature. Slowed ability to start/stop movements - cannot walk in a straight line. Voluntary movements take energy and focus -> initiation of movement is difficult.
  2. Muscular Rigidity: Muscles tense, not sore, hard to move
  3. Resting tremor: hand shakes at rest but stops when holding something/action completed (think picking up coffee cup). See in early to mild stages. Pt shakes all the time as disease progresses.
  4. Impairment of postural balance: cardinal feature –> cannot keep balance if pushed over.

Advanced stages: depression due to disease limitations on life; dementia due to old age

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15
Q

What leads to PD?

A

Degeneration of dopaminergic neurons in the substantia nigra. 60-80% degeneration is needed for sx. NOT curable

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16
Q

Role of DA in a HEALTHY brain

A

DA released from SUBSTANTIA NIGRA –> binds D1 and D2 located on GABAergic neurons in DORSAL STRIATUM.
D1: stimulates GABA release
D2: inhibits GABA release
More D2 than D1, so effect of DA is to DECREASE GABA.
Muscarinic –> DA does not bind. Ach binds, leading to increased GABA release.
Net effect is to inhibit GABA

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17
Q

Are there more D1 or D2 receptors in a healthy brain?

A

more D2

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18
Q

Is GABA inhibited or released in a healthy brain

A

Inhibited

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19
Q

Role of DA in a PD brain?

A

DA cells in SUBSTANTIA NIGRA die –> less DA released in DORSAL STRIATUM.
D2 receptors not activated as much, so less inhibition of GABA
Muscarinic receptors not affected –> excitatory, lead to GABA release.
Lots of GABA release leads to poor motor control

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20
Q

Is GABA increased or decreased in a PD brain?

A

Increased

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21
Q

Where are dopaminergic neurons located?

A

Substantia Nigra

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22
Q

Where are DA receptors located?

A

Dorsal Striatum

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23
Q

What is the role of muscarinic receptors?

A

Excitatory. Lead to increased released of GABA

24
Q

What is L-DOPA

A

Precursor to DA

25
Q

If L-DOPA is given orally, what metabolizes it

A

AAD in GI

26
Q

What can you give with L-DOPA that inhibits AAD

A

Carbidopa

27
Q

How much L-DOPA normally reaches the brain

A

1%

28
Q

How much L-DOPA reaches the brain if given with carbidopa

A

approx. 10%

29
Q

Why does combo tx with L-DOPA and carbidopa reduce side effects?

A

Lower L-DOPA dose can be given because more will reach the brain, thus reducing the SE of L-DOPA

30
Q

Can L-DOPA be used long term

A

No. It becomes less effective as neurons die. It also leads to dyskinesias.

31
Q

Motor complications of long term L-DOPA use

A

“wearing off” effect: due to loss of DA neurons, same dose doesn’t last as long. Sx appear before the next dose. Need to supplement with other drugs (such as MAO-I or COMT inhibitor) at this point or increase dose frequency of L-DOPA

32
Q

Peak Dose Dyskinesia

A

Thought to be due to excessive stimulation of striatal DA receptors. L-DOPA dose is moving target - too much drug, patient gets dyskinesia, not enough drug patient displays PD sx. Pt will be okay with reduced dose for a while but dyskinesias will return.

33
Q

Adverse side effects of L-DOPA

A

GI side effects: N/V, anorexia - most common with L-DOPA alone b/c you need a higher dose
Dyskinesias: occurs in 80% of patients
Arrhythmias, tachycardias, etc: due to increased catecholamine release (L-DOPA converted to DA, NE, and Epi in periphery). PVC is classic issue

34
Q

Tolcapone

A

Tamsar. COMT inhibitor. CNS and PNS action -Crosses BBB

35
Q

Entacapone

A

Comtan. COMT inhibitor. Peripherally acting only. Blocks conversion of L-DOPA to 3-O-M DOPA

36
Q

MOA of COMT Inhibitors

A

Used ONLY in COMBO Tx.
Work to increase t1/2 of L-DOPA so more gets to the brain.
Centrally acting –> increases amount of DA in brain by preventing breakdown

37
Q

Stalevo

A

Combo of L-DOPA, Carbidopa, and Entacapone

38
Q

MOA of MAO-B inhibitors

A

MAO-B inhibitors prevent the breakdown of DA in pre-synaptic terminals. Thus allowing more DA to be repackaged into vesicles.
A - better at breaking down DA; B - better at breaking down NE. End up blocking both with needed doses. Same issues with MAO-I apply, less risk for Tyramine toxicity.

39
Q

Selegiline

A

Deprenyl. MOA-B inhibitor

40
Q

Rasagiline

A

Azilect. MAO-B inhibitor

41
Q

Peripherally - Prevent breakdown of L-DOPA to 3-O-MD via COMT

A

Entacapone and Tolcapone

42
Q

Peripherally - Prevent breakdown of L-DOPA to DA via AAD

A

Carbidopa

43
Q

Centrally - prevent breakdown of DA to 3MT via COMT

A

tolcapone (crosses BBB)

44
Q

Centrally - prevent breakdown of DA to DOPAC via MAO-B

A

Selegiline

Rasagiline

45
Q

MOA of D2-receptor Agonists

A

Mimic DA effects on D2 to decrease GABA

46
Q

Benefits of D2 agonists

A

fewer dyskinesias

Not as much peak-dose dyskenesia

47
Q

How do you dose PD drugs

A

based on sx and age

48
Q

should you start with L-DOPA or D2-agonist in pt with mild sx only?

A

No. Drugs lose efficacy over time. Start with MAO-I as monotx in mild sx

49
Q

Bromocriptine

A

Parlodel. D2 agonist/D1 partial agonist. Not used much

50
Q

Ropinirole

A

Requip. Selective D2 agonist. Mild to moderate sx, can be used as monotx

51
Q

Pramipexole

A

Mirpex. Selective D2 and D3 agonist. Mild to moderate, can be used as monotx

52
Q

Rotigotine

A

Neupro. D2 agonist, skin patch. Mild and early stage PD monotx

53
Q

D2 agonist side effects

A

GI: N/V, anorexia
Cardiovascular: Hypotension, especially at beginning of tx. Arrhythmia
Mental disturbances: Due to D2 activation –> mimics positive sx of schizophrenia b/c D2 is everywhere.

54
Q

Should you start a pt on L-DOPA or D2 agonist first?

A

Either. Some controversial data says D2 is slightly less effective than L-DOPA, however, you can start with either knowing you will have to switch drugs at some point.

55
Q

Amantadine

A

Symmetrel. Anti-viral agen
Believed to increase DA and have anti-cholinergic properties
Used for tx of tremors
Muscarinic and NMDA antagonist = REDUCE GABA
NOT a monotx
Becomes less effective over time as DA neurons die

56
Q

What effects do muscarinic antagonists have

A

can reduce tremors. NOT effective in tx of bradykinesia. NOT a monotx

57
Q

Trihexyphenidyl

A

Artane. Modest effects, binds to muscarinic receptor. Anticholinergic SE

PBT 3 Exam 2 (8 decks)

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