L9- Parkinson's Disease Treatment (background)

Question 1

PD:

• (1) is the direct cause of Sxs
• (2) main change in gross appearance
• (3) main microscopic feature

Answer 1

1- loss of DA neurons in SNc

2- pallor (loss of black pigmented neurons) and atrophy of SNc

3- Lewy Bodies: eosinophilic (pink) inclusion bodies containing α-synuclein

Question 2

when PD Sxs first appear, there is loss of (1)% of DA neurons in SNc and on autopsy about (2)% of neurons are missing

Answer 2

1- 70%

2- 90%

Question 3

list some of the factors that are thought to be involved in progression of PD

Answer 3

Genetic: mutation / overexpression of α-synuclein

Environmental: age, gender (M>F), concussions (boxing, football), MPTP (neurotoxin), pesticides, inhalation of heavy metals (Cu, Mn)

Question 4

Nigrostrital Tract:

• (1) composition / neurons
• (2) function
• loss of (1) will cause (3)

Answer 4

1- substantia nigra neurons with 80% of brains dopamine project to striatum (caudate, putamen) in basal ganglia

2- stimulation of movement (D1, direct pathway) OR inhibition of movement (D2, indirect pathway)

3- dec dopamine levels + movement abonormalities

Question 5

list the cardinal features of PD

Answer 5

• resting tremor
• muscle rigidity
• bradykinesia
• gait impairment

Question 6

Dopamine Synthesis:

• initially requires the influx of (1) across BBB / into neurons via (2)
• next is (3) reaction, the rate limiting step
• finally the (4) progression is seen in the catecholamine pathway

Answer 6

1- Tyr
2- System L (no Na+ required)

3- Tyr –> L-DOPA via Tyrosine Hydroxylase [+ BH4 –> BH2]

4- DOPA –> dopamine via DOPA decarboxylase

Question 7

In terms of dopamine synthesis, (1) levels are usually negligible because of (2). Therefore, treatment of PD with (1) is useful, because treatment with (3), the precursor to (1), is pointless since it already at a very high concentration.

Answer 7

1- L-DOPA
2- conversion to dopamine is rapid in comparison to rate limiting step (Tyr –> L-DOPA)
3- Tyr

Question 8

in general, basal ganglia:

• direct pathway has (1) effects on movements
• indirect pathway has (2) effects on movements

Answer 8

1- stimulatory (initiates)

2- inhibitory (prevents)

Question 9

(1) D1 receptor: main effect, type of receptor, cellular change
(2) D2 receptors: main effect, type of receptor, cellular change

Answer 9

1- D1 = Gs, excitatory, inc adenynyl cyclase (cAMP)

2- D2 = Gi, inhibitory, dec adenynyl cyclase (cAMP), inc K+ conductance, dec Ca2+ conductance

Question 10

In addition to the balance of D1 and D2 receptors in the Striatum affecting direct and indirect pathways, ______ are also important to this control of movement in the basal ganglia

Answer 10

cholinergic excitatory interneurons (stimulates GABA release from striatum)

Question 11

describe the goal of PD treatment

Answer 11

• restore dopamine in basal ganglia
• antagonize excitatory effects of cholinergic neurons

-**reestablishes correct dopamine/ACh balance

Question 12

list the drugs used in PD

Answer 12

• Dopamine precursors (levadopa)
• Dopamine receptor agonists
• inhibition of dopamine metabolism
• amantidine (an anti-viral)

-antimuscarinics

Question 13

• (1) is the therapy of choice
• (2) is/are the next most effective therapy
• (3) can be added in adjunct to reduce motor fluctuations in Pts in advanced disease
• (4) are useful adjuncts to help control tremor and drooling

Answer 13

1- Sinemet (= levodopa + carbidopa)
2- dopamine agonists (nonergots mostly)
3- dopamine metabolism inhibitors: MAOIs, COMT inhibitors
4- antimuscarinics