Parkinson’s Disease (PD)

Question 1

PD Overview

Answer 1

• Neurodegenerative disease.
- 1.2M cases in U.S.
• Dyskinesia
- Tremors, rigidity, bradykinesia, disturbed posture.
- Akinesia (extreme cases).
• Psychological symptoms
- Dementia, depression, memory impairment, psychosis.
• [GI symptoms too].

Question 2

PD and the brain

Answer 2

Lack of dopamine in substantia nigra of the midbrain.
- Lewy body formation as protein (alpha-synuclein) accumulates & cells die.

Question 3

Dopamine chemistry

Answer 3

• Dopamine is also a local chemical messenger in peripheral circulation. (unaffected by PD, but can be affected by PD treatments).
  • Catecholamine structure.
  • Does not cross blood-brain barrier.
  • Produced from L-DOPA.
• Natural precursor and primary drug for PD.
• levodopa = L-DOPA
• L-DOPA crosses blood-brain barrier.
• Enzyme: DOPA decarboxylase.

Question 4

Levodopa / carbidopa

Answer 4

• Raises dopamine levels in brain.
• Almost always administered in combination.
- [Combo trade name: Sinemet]
- Generic is available.
• On-off efficacy is very common.
- Varies from day to day.
- unrelated to serum levels of drug.
• Progressive loss of efficacy after 2-5 years due to continued loss of substantia nigra cells.
• Carbidopa does not cross blood-brain barrier, inhibits L-Dopa decarboxylase outside the brain.
- Allows more L-Dopa to reach the brain, minimizes side-effects.

Question 5

Peripheral side-effects of levodopa / carbidopa

Answer 5

• Orthostatic hypotension.
• Gl disturbances (nausea, vomiting) early in treatment.
• Tachycardia.
• Adverse interactions with anti-psychotic drugs.

Question 6

Selegiline

Answer 6

• Inhibitor of type B monoamine oxidase.
- MAO-B metabolizes/inactivates dopamine in brain.
• ***only in the brain!!!!!
- Inhibition produces higher dopamine levels.
• [Trade names: Eldepryl, Deprenyl]
• Commonly prescribed on its own and in combo with levodopa/carbidopa.
• [common side-effects: nausea, xerostomia]
• [other uses: treatment of restless legs syndrome; transdermal patch (trade name: Emsam) for treating depression]

Question 7

Dopamine agonists

Answer 7

• mimic action of dopamine.
- Cross blood-brain barrier.
- Used sometimes for PD, but much less than levodopa/carbidopa or selegiline.
- Also used/approved for restless legs syndrome.
• ropinirole
- [Trade name: Requip, available generic]
- [Similar but less common: Pramipexole/Mirapex]