Parkinson's Disease and Dopamine

Question 1

What are the motor signs and symptoms of Parkinson’s disease?

Answer 1

• Tremor
• Rigidity of limbs
• Bradykinesia (difficulty in initiating movement)
• Impairment of postural reflexes
• Facial
  
  • ​impassive, no blinking
• Speech
  
  • ​monotonous, hypophonic
• Movement
  
  • ​decreased manual dexterity

Question 2

What are the non-motor signs and symptoms of Parkinson’s Disease?

Answer 2

• Cognitive deficiencies
• Depression
• Raised anxiety levels
• Olfactory deficiencies
  
  • ​first function lost in the disease
• Sleep disturbances
• Fatigue
• Pain
• Bowel and bladder problems
• Sexual dysfunction

Question 3

What is Parkinson’s Disease?

Answer 3

Parkinson’s disease is a neurodegenerative diseased that is caused by a loss of dopaminergic neurons from the substantia nigra.

It is best characterised as a prominent hypokinetic movement disorder; but also affects cognitive processes, emotion and autonomic function due to being a disorder influencing many circuits of the brain.

Patients have reduced dopamine levels and Lewy bodies present at post-mortem.

Symptoms don’t manafest until 80% of dopaminergic neurons are lost - by which time it is often too late/severe to remidy.

Question 4

List the general principles of the management of Parkinson’s disease?

Answer 4

1. Restore dopamine deficiency

• Increased DA synthesis
• Increase DA release
• DA receptor agonists
• Reduce DA metabolism

2. Restore dopaminergic / cholinergic balance in striatum

• In healthy people, DA has an inhibitory effect on ACh neurons
• ACh neurons are overactive in Parkinson’s Disease
• Use cholinergic antagonists

Drugs provide symptomatic relief only -> palliative rather than curative

Question 5

Illustrate dopaminergic transmission within the CNS

Answer 5

Question 6

Describe the properties of L-DOPA as a treatment for Parkinson’s

Answer 6

**Levodoper/L-DOPA **is an amino acid isomer that is a natural precursor to dopamine.

Over **90% of L-DOPA is metabolised in the periphery **

• Large doses required to get CNS efficacy
• Peripheral conversion to dopamine and noradrenaline results in significant side effects
  
  • nausea, vomitting, orthostatic hypertension and cardiac dysrhythmia

Is formulated with a peripheral DOPA decarboxylase (DDC) inhibitor to counteract the peripheral effects

• carbidopa or benserazide normally

Treatment requires some functional dopaminergic neurons to convert it to dopamine. There is debate on when it should be used because of this.

• No point of giving L-DOPA to the CNS when there is no dopaminergic neurons to convert it = give early in disease progression.
• Administering L-DOPA can cause increased death of dopaminergic neurons = delay administration until benefit > risk

Fluctuations in motor control

• Extreme differences present between on-treatment and off-treatment
• Dopamine levels fluctuate throught day/night

Rapid absorption on empty stomach

Short half-life (1-2 hours)

Effectiveness declines with time

• Continued degeneration of dopaminergic neurons mean less L-DOPA can be synthesised
• Need to continually increase dose or incorporate other drugs

Question 7

What are the adverse effects of levodopa?

Answer 7

Question 8

What dopamine agonists are used in the therapy of Parkinson’s Disease?

Answer 8

Bromocriptine & Cabergoline

• can be used as monotherapy
  
  • improves rigidity and bradykinesia
• preferred in younger patients
  
  • gradual increasing dosage

Pergolide

• only as an adjuct to L-DOPA

Side effects of all dopamine agonists:

• Similar to L-DOPA
• Hallucinations, confusion, delirium nausea and hypotension more common
• Dyskinesias less prominent
• Arrythmias and MI

Question 9

What classes of drugs are used to reduce the metabolism of dopamine within the CNS?

Answer 9

MAO_B Inhibitors

• reduce metabolism of dopamine via neuronal uptake pathway
• no hypertensive crises ( like MAO_A inhibitors)
• early use may delay disease progression

COMT Inhibitors

• reduce metabolism of L-DOPA
• used as an adjunct to L-DOPA

Dopamine release enhancers (Amantadine)

• less efficacious than L-DOPA and more rapid tolerance
• adverse effects
  
  • restlessness, agitation, hallucinations
  • orthostatic hypotension
• has anticholinergic activity to rebalance the dopaminergic/cholinergic system

Question 10

What treatments are used to address the imbalance between dopaminergic and cholinergic systems?

Answer 10

Muscarinic receptor antagonists are used as adjucts to L-DOPA only.

They have only a modest effect on tremor, rigidity and bradykinesia.

Adverse effects include the classic ‘SLUD’ anti-muscarinic side effects; reduced:

• Salivation
• Lacrimation (tears)
• Urination
• Defaction

Question 11

Illustrate the extra-pyramidal motor system that is affected by Parkinson’s disease

Answer 11

Question 12

Outline some potential future treatments of Parkinson’s disease

Answer 12

Adenosine A2a receptor antagonists

• interact with D2 dopamine receptors in the basal ganglia -> makes them more sensitive to L-DOPA

mGluR5 antagonists

• reduces glutamate levels and allows L-DOPA to be used at a higher dose

Deep Brain Stimulation

Optogenetics

• stimulating cells in the brain “on” with light to produce dopamine

Cell replacement therapy

• iPSC’s used to reprogramme cell types into dopaminergic neurons before transplanting them into the substantia nigra