PD

Question 1

What is parkinsons disease?

Answer 1

A neurodegenarative disorder- loss of neurones in the nigrostriatal pathway (motor function)

affects dopaminergic neurones from the substantia nigra, pars compacta

Question 2

What are the clinical features of PD? (TRAP)

Answer 2

T- involuntary tremor
R- rigidity
A- akinesia or bradykinesia
P- muscle weakness and loss of posture

Question 3

How are dopamine neurones affected in PD?

Answer 3

Impaired synthesis, storage, release

Decreased striatal concentration of dopamine

Question 4

What other neurones are affected besides dopamine? (3)

Answer 4

NA
cholinergic
serotonergic

Question 5

What are lewy bodies?

Answer 5

Abnormal protein inclusions that contain protein a-synuclein
Lewy bodies are resistant to protein degradation
They make neurones susceptible to oxidation stress

Question 6

What is the role of a synuclein? (3)

Answer 6

1. Shown to regulate enzyme activity
2. Regulate synaptic vesicle function and DA release into the synaptic cleft
3. Necessary for trafficking DAT to cell surface

Question 7

How does dopamine facilitate movement?

Answer 7

Inhibits the indirect (D2) and stimulates the direct (D1) pathway- creating a net bias that facilitates voluntary movement

In PD, decrease amount of dopamine unbalances the system. Direct pathway is no longer activated and indirect pathway and overactivated (glutamate and cholinergic inputs drives indirect pathway)

Question 8

What is levodopa given in combination with?

Answer 8

Carbidopa, benserazide (peripheral dopa decarboxylase inhibitors) - 4:1
This helps reduce GI S/E and increase concentration of levodopa available to cross the BBB

Question 9

What is the biggest consequence of long term use of levodopa?

Answer 9

Dyskinesia or motor fluctuations (involuntary chloreiform movements) are experienced within 5 years of initiation

Greater risk in younger people and at higher doses

Question 10

What are some adverse effects of levodopa?

How long do these last for?

Answer 10

1. Nausea
2. Psychological effects (confusion, hallucination, nightmares)
3. Postural hypotension

First few weeks of treatment only

Question 11

List the different ergoline and non ergoline dopamine receptor agonists?

Answer 11

Ergoline: bromocriptine, pergoline, cabergoline

Non ergoline: apomorphine, pramipexole, rotigotine (patcha available)

Question 12

What advantage does dopamine receptor agonist have over levodopa?

Answer 12

1. No competition for absorption and transport
2. Longer duration of action
3. Dont undergo oxidative metabolism

Question 13

Adverse effects of dopamine agonists?

Answer 13

More than levodopa

1. N+V
2. Daytime somnolence
3. Hypotension
4. Peripheral oedema
5. Hallucinations
6. Psychosis

Question 14

When is dopamine agonists used?

Answer 14

1. Patients not responsive to levodopa- added to levodopa therapy
2. In early treatment before levodopa is used, especially in younger patients <60

Question 15

When is apomorphine used?

Answer 15

Rescue situation
In patients with severe motor fluctuations (on/off period refractory to other treatment)

NEED TO PRE TREAT WITH DOMPERIDONE (10-20 tds 3 days before tx)

Question 16

How do MAO-B inhibitors work? what are 2 examples?

Answer 16

Inhibit MAO-B, an enzyme that catabolises dopamine in the brain
Can be used before levodopa, delayed the use for 9-12 months or as an adjunct therapy

Selegiline and Rasagiline

Question 17

What drug acts as a COMT inhibitor?

Answer 17

Entacapone - Stalevo

Question 18

How to COMT inhibitors work to help PD?

Answer 18

Inhibits activity of catechol-O-methyltransferase which metabolises levodopa, this produces more stable and sustained plasma levodopa concentrations and hence prolongs therapeutic effects

Question 19

When should selegiline be dosed and why?

Answer 19

In the morning or lunchtime

Can cause insomnia due to amphetamine metabolites

Question 20

What is the MOA of anticholinergics in PD?

Answer 20

To resolve cholinergic excess by blocking activity at the basal ganglia.
Dopamine usually inhibits the release of ach, therefore in PD the inhibition is lost. Hyperactivity of ach on muscarinic receptors contributes to rigidity and tremor.

Question 21

What is an example of an anticholinergic used? and what S/E are associated?

Answer 21

Benztropine

Confusion, constipation, dry mouth, dizziness, blurred vision

Question 22

What is the proposed mechanism of action of amantidine? (5)

Answer 22

1. May increase dopamine release
2. Block dopamine reuptake
3. Stimulate dopamine receptors
4. Anticholinergic effects
5. Antagonist at NMDA recptors

Treatment of dyskinesias

Question 23

What is dopamine dysregulation syndrome?

Answer 23

Behaviours such as punding, compulsive medication use and impulse control disorders

Caused by sensitisation of the mesolimbic dopamine reward circuitry

Question 24

What are 5 types of motor fluctuations?

Answer 24

1. Wearing off - levodopa dose no longer lasting
2. Dyskinesias
3. Unpredictable on off efct
4. Suboptimal peak (no on response)
5. Early morning dystonia

Question 25

What are some strategies to reduce off time? (7)

Answer 25

1. Increase dose of dopamine medication
2. Divide dose into small but more frequent
3. Add another dopamine medication
4. Add COMT or MOA B inhibitor
5. Levodopa SR for night dose
6. Separate dose from meals
7. Apomorphine