Pharmacology and Treatment of Basal Ganglia Disorders

Question 1

Explain what is meant by “TRAPD” with regard to Parkinson’s disease.

Answer 1

• T - tremor at rest
• R - rigidity
• A - akinesia (hypokinesia)
• P -
• D -

Question 2

Explain why Parkinson’s patients suffer from hypokinesia (suppression of voluntary movements).

Answer 2

• Loss of DAergic inhibition of GABAergic cells
• Increased activity of GABAergic neurons in globus pallidus
• Reduced activation of cortical areas

Question 3

Explain why Parkinson’s patients suffer from tremors.

Answer 3

• Cholinergic neurons in striatum strongly inhibited by DA
• Hyperactivity of cholinergic neurons linked to tremor
• Reduced inhibition of cholinergic neurons in PD

Question 4

Describe 4 causes of Parkinson’s Disease.

Answer 4

1. Higher incidence in rural areas
2. Genetic factors
3. Oxidative stress, neuroinflammation
4. Antipsychotics

Question 5

Name a drug that inhibits presynaptic reuptake of dopamine.

Answer 5

Cocaine

Question 6

Name 4 drug classes with the potential to treat Parkinson’s Disease.

Answer 6

• Dopamine reuptake inhibitors
• MAO_B inhibitors
• COMT inhibitors
• D₂ receptor agonists

Question 7

How could you devise a drug that would increase L-DOPA levels in the brain?

Answer 7

• Use an inhibitor of dopa decarboxylase that cannot cross the blood brain barrier
• L-DOPA will only be metabolised to DA in the brain

Question 8

Why is giving L-DOPA i.v. an ineffective treatment for Parkinson’s?

Answer 8

• L-DOPA is metabolised to DA by dopa decarboxylase outside of the CNS
• DA acts peripherally but very little reaches the brain

Question 9

Development of addictive tendencies in Parkinson’s patients is linked to which dopaminergic pathway?

Answer 9

Mesolimbic

Question 10

Name a MAOB inihbitor and explain how it is used to treat Parkinson’s.

Answer 10

• Selegiline
• Decreases metabolism of L-DOPA in brain and potentiates effect
• Protects against MPTP toxicity - but no evidence of neuroprotective role in patients

Question 11

Name a COMT inhibitor and explain how it is used to treat Parkinson’s.

Answer 11

• Entacapone
• Slows elimination of L-DOPA, increases half-life and augments action

Question 12

Name a dopamine agonist used to treat Parkinson’s, typically after 5 years of L-DOPA treatment.

Answer 12

Bromocriptine

Question 13

What is COMT?

Answer 13

Catechol-O-methyl transferase - an enzyme that breaks down DA and L-DOPA

Question 14

What is amantadine? What are the advantages and disadvantages of using it compared to L-DOPA?

Answer 14

• Antiviral drug found to increase DA release
• Less effective than L-DOPA
• Effectiveness reduces over time
• Side effects less severe

Question 15

Describe 3 surgical approaches to Parkinson’s treatment.

Answer 15

1. Lesions of internal globus pallidus cause decreased thalamic-cortical inhibition
2. Deep brain stimulation - implantation of electrodes into subthalamic nuclei
3. Implantation of foetal nigral tissue into striatum - synaptic connections formed but limited clinical benefit so far - severe dyskinesia is a side effect