Parkinson's Disease

Question 1

Nigrostriatal pathway

Answer 1

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

Question 2

Mesolimbic pathway

Answer 2

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

Question 3

Mesocortical pathway

Answer 3

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

Question 4

Tuberoinfundibular pathway

Answer 4

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

Question 5

Rate limiting enzyme in DA synthesis

Answer 5

Tyrosine hydroxylase (slower enzyme)

Question 6

Dopamine release and trafficking

Answer 6

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.

Question 7

First step in dopamine inactivation

Answer 7

COMT degrades DA in periphery and in synapse

Question 8

Second step in dopamine inactivation (2)

Answer 8

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.

Question 9

Dopamine receptors (5)

Answer 9

D1-like: D1 and D5 –> stimulatory

D2-like: D2, D3, and D4 –> inhibitory

Question 10

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

Answer 10

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

Question 11

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

Answer 11

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

Question 12

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

Answer 12

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

Question 13

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

Answer 13

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

Question 14

Key features of PD

Answer 14

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

Question 15

What leads to PD?

Answer 15

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

Question 16

Role of DA in a HEALTHY brain

Answer 16

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

Question 17

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

Answer 17

more D2

Question 18

Is GABA inhibited or released in a healthy brain

Answer 18

Inhibited

Question 19

Role of DA in a PD brain?

Answer 19

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

Question 20

Is GABA increased or decreased in a PD brain?

Answer 20

Increased

Question 21

Where are dopaminergic neurons located?

Answer 21

Substantia Nigra

Question 22

Where are DA receptors located?

Answer 22

Dorsal Striatum

Question 23

What is the role of muscarinic receptors?

Answer 23

Excitatory. Lead to increased released of GABA

Question 24

What is L-DOPA

Answer 24

Precursor to DA

Question 25

If L-DOPA is given orally, what metabolizes it

Answer 25

AAD in GI

Question 26

What can you give with L-DOPA that inhibits AAD

Answer 26

Carbidopa

Question 27

How much L-DOPA normally reaches the brain

Answer 27

1%

Question 28

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

Answer 28

approx. 10%

Question 29

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

Answer 29

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

Question 30

Can L-DOPA be used long term

Answer 30

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

Question 31

Motor complications of long term L-DOPA use

Answer 31

"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

Question 32

Peak Dose Dyskinesia

Answer 32

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.

Question 33

Adverse side effects of L-DOPA

Answer 33

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

Question 34

Tolcapone

Answer 34

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

Question 35

Entacapone

Answer 35

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

Question 36

MOA of COMT Inhibitors

Answer 36

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

Question 37

Stalevo

Answer 37

Combo of L-DOPA, Carbidopa, and Entacapone

Question 38

MOA of MAO-B inhibitors

Answer 38

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.

Question 39

Selegiline

Answer 39

Deprenyl. MOA-B inhibitor

Question 40

Rasagiline

Answer 40

Azilect. MAO-B inhibitor

Question 41

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

Answer 41

Entacapone and Tolcapone

Question 42

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

Answer 42

Carbidopa

Question 43

Centrally - prevent breakdown of DA to 3MT via COMT

Answer 43

tolcapone (crosses BBB)

Question 44

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

Answer 44

Selegiline | Rasagiline

Question 45

MOA of D2-receptor Agonists

Answer 45

Mimic DA effects on D2 to decrease GABA

Question 46

Benefits of D2 agonists

Answer 46

fewer dyskinesias | Not as much peak-dose dyskenesia

Question 47

How do you dose PD drugs

Answer 47

based on sx and age

Question 48

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

Answer 48

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

Question 49

Bromocriptine

Answer 49

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

Question 50

Ropinirole

Answer 50

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

Question 51

Pramipexole

Answer 51

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

Question 52

Rotigotine

Answer 52

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

Question 53

D2 agonist side effects

Answer 53

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.

Question 54

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

Answer 54

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.

Question 55

Amantadine

Answer 55

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

Question 56

What effects do muscarinic antagonists have

Answer 56

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

Question 57

Trihexyphenidyl

Answer 57

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