HUF 2-73 Parkinson's disease and its treatments

Question 1

Parkinson;s disease

Answer 1

• Neuronal degeneration at SNc
• Progressive loss of DA neurons (genetic, viral, environmental, toxin, drug-induced)
• Presence of Lewy bodies (aggregation of α-synuclein) in degenerating neurons

Motor symptoms (asymmetric):

• Bradykinesia
• Rigidity
• Resting Tremor
• Postural instability (impaired balance and coordination)

Non-motor symptoms:

• Cognitive impairment / dementia
• Mood disorders
• Postural hypotension
• Speech and swallowing problems
• Parkinson’s disease vs. Parkinsonism (motor symptoms of PD)

Question 2

Nigrostriatal pathway

Answer 2

DA

• increases excitatory effect of direct pathway (initiating movements)
• reduces inhibitory effect of indirect pathway (preventing inhibition of movements)

Question 3

Drug Treatment for Parkinsonism

Answer 3

Control motor symptoms by enhancing remaining DA transmission of nigrostriatal pathway (Levodopa)

Question 4

Central DA transmission

Answer 4

1. Tyrosine
2. L-DOPA
3. DA
4. Vesicular transporter => Synaptic vesicles
5. Exocytosis upon Ca2+ influx
6. Bind to postsynaptic receptors
7. DA reuptake => MAO
8. COMT in postsynaptic receptors

Tyrosine
|   (Tyrosine hydroxylase)
DOPA
|   (DOPA decarboxylase)
DA

Question 5

Levodopa (L-DOPA)

Answer 5

• Oral
• ~80% patients show initial improvements
• Effectiveness decrease with time
• Side effects:
  1. Nausea and vomiting (activation of chemoreceptor trigger zone CTZ and vomiting centre)
  2. Sedation
  3. Peripheral conversion to DA (gut wall, liver, kidney)
  => CVS abnormalities e.g. hypotension, arrhythmia
  4. Excessive DA produced from high dose
  => Psychological disturbance
  e.g. psychosis, hallucination, confusion

Question 6

Problems associated with long term Levodopa treatment

Answer 6

1. Decline in efficacy over time (same dose)
2. “On-off” effect (motor fluctuations)
   - Oscillation between states of decreases mobility and controlled symptoms
   - Peak-dose dyskinesia: dyskinesia when [Levodopa] reaches peak
   - Wearing off: end-of-dose akinesia

• Early onset patients: better to delay start of levodopa treatment

Question 7

Dopamine receptor agonist

Answer 7

• For early onset patients => Levodopa treatment can be delayed
• Stimulate D2R
• Ergoline derivatives: Bromocriptine
• Non-ergoine derivatives: Ropinirole, Rotigotine

Potent DA receptor (non-ergoline) agonist: Apomorphine

• sc injection (rapid onset, short duration)
• rapid hepatic metabolism
• rescue treatment for profound “off state” from levodopa

Amantadine

• Stimulate DA release
• Activate DAR
• Block DA reuptake (at high doses)

Question 8

Antimuscarinic agents

Answer 8

• Benzatropine, Trihexyphenidyl
• Effectively for early stages of Parkinson’s disease
• Improve symptoms of resting tremors and rigidity; NOT good for managing bradykinesia
• Manage antipsychotics-induced Parkinsonism (movement dysfunctions)
• Side effects: dry mouth, constipation, impaired vision, urinary retention, confusion, dementia (memory impairment)
• NOT good for patients showing signs of dementia (degeneration of cortical cholinergic neurons)

Question 9

ACh-DA Balance Hypothesis

Answer 9

• Striatum
• DA neurons from substantia nigra inhibit GABAergic neurons in striatum
• ACh neurons in striatum excite GABAergic neurons in striatum

Question 10

Site of action for drugs used to treat Parkinsonism

Answer 10

• Levodopa enters into brain and is converted to DA by DOPA decarboxylase

Enhance Levodopa action:
- Central and peripheral conversion of Levodopa prevented by DOPA decarboxylase inhibitor and COMT inhibitors (cannot pass BBB)

Question 11

Peripheral DOPA decarboxylase inhibitors

Answer 11

• Carbidopa, Benserazide
• Do not cross BBB
• Inhibit peripheral conversion of Levodopa (gut wall, liver, kidney)
• Sinemet: Levodopa + Carbidopa
• Madopar: Levodopa + Benserazide

Question 12

Selective irreversible MAO-B inhibitors

Answer 12

• Selegiline (L-deprenyl): metabolised to methamphetamine
  => CVS side effects, psychosis in high conc.
• Rasagiline: NOT metabolised to methamphetamine derivatives
• Slow down metabolism of DA by MAO-B
  => ↑ neuronal [DA]
• Neuroprotective effects of Selegilin / Rasagiline
  ∵ Induction of anti-apoptotic proteins e.g. Bcl-2

Question 13

COMT inhibitors

Answer 13

COMT

• Expressed in brain (synaptic degradation)
• Expressed in tissues (peripheral conversion)

COMT inhibitor
- Slow down metabolism of DA by COMT
=> Reduce dose of Levodopa needed

1. Tolcapone
   - Side effects: hepatotoxicity (limited usage)
2. Entacapone
   - Does not cross BBB
   - Prevent peripheral metabolism of Levodopa before Levodopa reaches the brain