Parkinson's Disease

Question 1

What is Parkinson’s Disease?

Answer 1

• Loss of 70-80% of dopamine containing neurons in substantia nigra
• Bradykinesia
• Resting tremor
• Muscular rigidity
• treatment based on replacement of dopamine
• Increased synthesis
• Reduced breakdown
• Agonists acting at dopamine receptors

Question 2

What are amine neurotransmitters?

Answer 2

• Dopamine
• Noradrenaline
• Adrenaline
  expression of specific enzymes determines which transmitter the neurone can synthesise

Question 3

How is Parkinson’s Disease treated?

Answer 3

• Increased synthesis of L-Dopa = levodopa
• Entry to CNS mediated by aromatic amino acid transporter
• Converted to dopamine in dopaminergic neurons
• Give with carbidopa or beserazide, inhibits DOPA decarboxylase so reduces conversion to noradrenaline in PNS

Question 4

How is levodopa synthesised?

Answer 4

1.) Tyrosine - via tyrosine hydroxylase - DOPA
2.) - DOPA via DOPA decarboxylase - dopamine
3.) Uptake into vesicles via vesicular transporter
4.) Then dopamine - via dopamine B-hydrolase - noradrenaline

Question 5

What are the actions of L-dopa in PD?

Answer 5

• Improvement in tremor, rigidity and bradykinesia
• can fluctuate dramatically - wears off within hours
• Improved formulations - sustained release, both immediate and extended release beads
• Intestinal gel administered through gastronomy tube into jejunum

Question 6

What are the adverse effects of L-DOPA?

Answer 6

• Nausea and anorexia (treat with doperidone (DA agonist in periphery) or cyclizine (antihistamine))
• Hypotension
• Dyskinesiaas (involuntary movements)
• Hallucinations, psychosis and confusion
  Treat with non-dopaminergic antipsychotics (e.g. clozapine, quetiapine)
• Also impulse control disorders
• Increased risk of suicide

Question 7

What are MAO-B inhibitors ?

Answer 7

• Inhibit breakdown of dopamine
• effective in early PD
• Fewer adverse effects
• Monotherapy or in combination with L-DOPA and carbidopa
• Selegiline - after oral administration, metabolites are l-amphetamine derivatives - anxiety, insomnia
• Transdermal adminstration is better
• Rasagiline improves sleep and mood

Question 8

What are dopamine receptors?

Answer 8

-D2 = antagonsists = anti-psychotics
D2 = Agonist for Parkinson’s disease, hyperprolacrinemia
D3- Agonists for Parkinson’s
D4 : Agonists for ADHD

Question 9

What are Dopamine agonists ?

Answer 9

Dopamine agonists
Bromocriptine (older)
Pramipexole and ropinirole (newer) — better tolerated
ADRs
* drowsiness,
* hallucinations,
* compulsive behaviours e.g. gambling, binge eating, hypersexuality

Muscarinic antagonists

Procyclidine : used prior to intro of L-DOPA , hardly used now
- Typical antimuscarinic side effects - particulary confusion and constipation