Parkinson's Disease and other Motor Disorders

Question 1

What was PD fist called ?

Answer 1

Shaking palsy.

Question 2

What are the main/classical symptoms of PD ?

Answer 2

• Loss of motor function
• Rigidity
• Akinesia
• Tremor at rest

Question 3

What is the main NT associated w/ PD ?

Answer 3

Dopamine.

Question 4

List all the signs ans symptoms of PD you know.

Answer 4

•  Shuffling gait
•  Stooped posture
•  Freezing
• Soft monotonic speech
• Swallowing problems
• Masked face
•  Executive dysfunctions - attention, impulse control, time, 
cues
•  Depression
•  Anxiety
•  Sleep
•  x 6 excess dementia

Question 5

What are the possible triggers of PD ?

Answer 5

Life events
Head trauma
Viral
Environmental eg MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a prodrug to the neurotoxin MPP+, which causes permanent symptoms of PD by destroying dopaminergic neurons in the substantia nigra of the brain)

Question 6

What is the current model for our understanding of PD ?

Answer 6

A decline in the number of DA neurons is seen naturally.\
Because humans now live much longer, the efefcts become observable as people age.
Early onset PD is simply when this decline in the number of DA neurons is more significant.

Question 7

How well can the brain compensate for the loss of DA neurons ?

Answer 7

Up to 80% of DA neurons in the SN can be lost befor PD symptoms appear.

Question 8

Describe the direct pathway in the basal ganglia.

Answer 8

1. Frontal cortex excites striatum
2. Striatum Inhibits GPi + SNR
3. GPi inhibits thalamus
4. Thalamus excites frontal cortex
5. Frontal cortex excites spinal cord etc.
   Net result : movement

Question 9

Describe the indirect pathway in the basal ganglia.

Answer 9

1. Frontal cortex excites striatum
2. Striatum inhibits GPe
3. GPe inhibits STN
4. STN excites GPi + SNR
5. GPi Inhibits thalamus
6. Thalamus excites frontal cortex
7. Frontal cortex excites spinal cord etc.
   Net result : no movement

Question 10

What is the role of DA in the basal ganglia ?

Answer 10

DA neurons (in the SNC) stimulate the direct pathway through excitatory D1Rs in the striatum and inhibit the indirect pathway through inhibitory D2R is the striatum as well.

Question 11

What are the 2 main strategies used to counter the loss of DA in PD ?

Answer 11

1. Replenish the remaining neurons w/ DA

2. Activate DARs w/ drufs

Question 12

What is the problem with administering DA directly ?

Answer 12

DA converted to NA and AD, can cause a massive sympathetic response.

Question 13

What are the 5 main DA pathways ?

Answer 13

• 1. Nigro-striatal; A9 - caudate/putamen => motor fct
• 2. Mesolimbic; A10 - nucleus accumbens => reward
• 3. Mesocortical; A10 - frontal cortex => psychosis
• 4. Median eminence; pituitary => prolactin secretion
• 5. Chemoreceptor trigger zone (CTZ) => nausea vomiting

Question 14

How is DA broken down ?

Answer 14

DA --> DOPAC (via MAO)
DOPAC --> HVA (Homovanillic Acid) (via COMT)
or 
DA --> 3-MT (via COMT)
3-MT --> HVA (via MAO)

Question 15

What drugs inhibits the enzyme L-DOPA decarboxylase ?
What effect does this have ?
What is another name for the enzyme inhibited ?

Answer 15

Carbidopa and benserazide inhibit DOPA decarbozylase, thus prevent the conversion of L-DOPA to dopamine.
DOPA decarboxylase is also called L-Aromatic Amino Acid Decarboxylase.

Question 16

Why are carbidopa and benserazide useful drugs ?

Answer 16

Because the inhibit L-DOPA decarbozylase in the periphery (unable to cross BBB) and thus allow treatment of PD without. Thus, carbidopa or benserazide can decrease peripheral DDC conversion of levodopa/L-DOPA to DA before it crosses the blood–brain barrier.

Question 17

What is selegiline ?

What is it used for ?

Answer 17

Selegeline is a MAO-B inhibitor

Question 18

What is the difference between MAO-A and MAO-B ?

Answer 18

MAO-A is involved in the metabolism of 5-HT, NA and DA whereas MAO-B metabolises DA.

Question 19

Name a COMT (Catechol-O-Methyl Transferase) inhibitor you know.
How is it used ?

Answer 19

Entacepone (cannot cross BBB) –> administered with carbidopa and L-DOPA, it allows higher plasma L-DOPA levels.

Question 20

What are the effects of high doses of L-DOPA on the CNS ?

Answer 20

• High doses
• Dyskinesia
• On-off effects
• Psychosis
• Nausea
• Reduced prolaction

Question 21

How long can L-DOPA alleviate symptoms of PD ?

Answer 21

2-10 years

Question 22

What are the effects of high doses of L-DOPA on the PNS ?

Answer 22

• Hypotension - NA displaced?

* Nausea - CTZ has no blood brain barrier

Question 23

Which receptor antagonist is usually given as an L-DOPA adjunct in the treatment of PD ?

Answer 23

Domperidone –> D2 R antagonist in the periphery (can’t cross BBB)

Question 24

What is usually the drug of choice for the treatment of drug-induced Parkinson’s ?

Answer 24

Benzhexol = a muscarinic antagonist (block actions of ACh in striatum)

Question 25

Which receptor agonists can be used to treat PD ?

Answer 25

Ropinirole - D2 agonist - monotherapy in younger
Bromocriptine/pergolide - D2 receptor agonists
Apomorphine - D1 and D2 agonist - refractory

Question 26

Which adjunct is also given with D2 agonists in PD ?

Answer 26

Domperidone (blocks D2 in the periphery)

Question 27

What other side effects can result from therapies seeking to increase DA levels in the brain ?

Answer 27

Mesolimbic; A10 - nucleus accumbens

Ventral tegmental area –> reinforcement, reward (compulsive gambling etc.)

Question 28

What is amantadine ?

Answer 28

Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.

Question 29

What other motor disorders do you know ?

What drugs can be used for these ?

Answer 29

• Huntingdons Chorea - tetrabenazine - depletes DA
• Restless legs - ropinirole
• Tourettes syndrome - haloperidol (DA antagonist), pimozide etc (+5HT?)