Treatment of Parkinson's Disease

Question 1

L-DOPA

Answer 1

Mechanism: Precursor to DA that can cross the BBB
Use: Tx of Parkinson’s symptoms, but doesn’t slow progression
Toxicity: Vomiting – stimulates DA neurons in area postrema
- Dry mouth, abdominal pain, burning tongue
- Orthostatic hypotension & cardiac arrhythmias – DA in plasma activates vascular receptors
- Depression, anxiety, agitation, insomnia, hallucinations, confusion (meso-limbic & -cortical)
Metabolism:Extensive peripheral metabolism when given alone
- Crosses BBB
- Rapidly absorbed from GI, but short t1/2 requires controlled release formulations
Interaction:- Administered with carbidopa
- Only useful for 5-6 years, so delay use until needed

Complications develop with prolonged treatment:

• “Wearing off” – benefit from each dose becomes shorter
• “On-off” – fluctuations b/t mobility & immobility
• Dose-related clinical fluctuations & dyskinesias (chorea & dystonia)

Question 2

Carbidopa

Answer 2

Mechanism; Inhibits peripheral aromatic amino acid decarboxylase (AAAD), which converts l-DOPA to DA
Use: Prevent peripheral metabolism of l-DOPA
Metabolism: Does not cross the BBB, so brain AAAD is still functional
Interactions: Administered with l-DOPA

Question 3

Entacapone

Answer 3

Mechanism: Inhibits peripheral COMT (converts l-DOPA to 3-o-methyldopa, a competitive inhibitor of l-DOPA transport across the BBB)
Use: Prevent peripheral metabolism of l-DOPA
Interaction: Administered with l-DOPA & carbidopa, especially to combat “wearing off” and “on-off” effects

Question 4

Selegiline

Answer 4

Mechanism: Therapeutic dose inhibits MAO-B, which normally catabolizes DA; hence increases levels of DA

High dose inhibits MAO-A

Use:Tx of Parkinson’s when l-DOPA is insufficient or intolerable
Toxicity: - Nausea
- Orthostatic hypotension
- Tyramine reaction (hypertensive crisis) if given in high concentrations
Metabolism: Crosses BBB
Interaction: - Decreases free radical production
- Early use delays need for l-DOPA
- Late use decreases “off time” in combination with other meds
- Serotonin syndrome may result if given with fluoxetine or meperidine

Question 5

Bromocriptine

Answer 5

Mechanism:Ergot derivative – D1 & D2 agonist
Use:- Low dose mono-therapy in early disease, or in combo w/ l-DOPA
- High dose in late disease when pt is unresponsive to l-DOPA

• Bromocriptine is given in low doses to tx antipsychotic-induced hyperprolactinemia

Toxicity: - Mesolimbic & mesocortical effects (more than l-DOPA): depression, anxiety, insomnia, anxiety, hallucination

• Somnolence &/or cognitive disturbances (punding)
• Hypoprolactinemia
• Cardiac valve fibrosis (pergolide only)
• Less likely to cause dyskinesia compared to l-DOPA

Metabolism:
Interaction:
CI: psychiatric history

Ciprofloxacin & fluvoxamine increase plasma levels of ropinirole by inhibiting CYP1A2

Ropinirole & pramipexole & slow the loss of DA neurons.

Question 6

Apomorphine

Answer 6

Mechanism:Non-ergot derivative – D1 & D2 agonist
Use:- Low dose mono-therapy in early disease, or in combo w/ l-DOPA
- High dose in late disease when pt is unresponsive to l-DOPA

• Bromocriptine is given in low doses to tx antipsychotic-induced hyperprolactinemia

Toxicity: - Mesolimbic & mesocortical effects (more than l-DOPA): depression, anxiety, insomnia, anxiety, hallucination

• Somnolence &/or cognitive disturbances (punding)
• Hypoprolactinemia
• Cardiac valve fibrosis (pergolide only)
• Less likely to cause dyskinesia compared to l-DOPA

Metabolism: Given via injection to pts who are immobile

Interaction:
CI: psychiatric history

Ciprofloxacin & fluvoxamine increase plasma levels of ropinirole by inhibiting CYP1A2

Ropinirole & pramipexole & slow the loss of DA neurons.

Question 7

Ropinirole

Answer 7

Mechanism: Non-ergot derivative - D2 & D3 agonist
Use:- Low dose mono-therapy in early disease, or in combo w/ l-DOPA
- High dose in late disease when pt is unresponsive to l-DOPA

• Bromocriptine is given in low doses to tx antipsychotic-induced hyperprolactinemia

Toxicity: - Mesolimbic & mesocortical effects (more than l-DOPA): depression, anxiety, insomnia, anxiety, hallucination

• Somnolence &/or cognitive disturbances (punding)
• Hypoprolactinemia
• Cardiac valve fibrosis (pergolide only)
• Less likely to cause dyskinesia compared to l-DOPA

Metabolism: Metabolized by CYP1A2
Interaction:
CI: psychiatric history

Ciprofloxacin & fluvoxamine increase plasma levels of ropinirole by inhibiting CYP1A2

Ropinirole & pramipexole & slow the loss of DA neurons.

Question 8

Pramipexole

Answer 8

Mechanism: non-ergot derivative - D2 & D3 agonist
Use:- Low dose mono-therapy in early disease, or in combo w/ l-DOPA
- High dose in late disease when pt is unresponsive to l-DOPA

• Bromocriptine is given in low doses to tx antipsychotic-induced hyperprolactinemia

Toxicity: - Mesolimbic & mesocortical effects (more than l-DOPA): depression, anxiety, insomnia, anxiety, hallucination

• Somnolence &/or cognitive disturbances (punding)
• Hypoprolactinemia
• Cardiac valve fibrosis (pergolide only)
• Less likely to cause dyskinesia compared to l-DOPA

Metabolism:
Interaction:
CI: psychiatric history

Ciprofloxacin & fluvoxamine increase plasma levels of ropinirole by inhibiting CYP1A2

Ropinirole & pramipexole & slow the loss of DA neurons.

Question 9

Amantadine

Answer 9

antiviral;
- increases DA release, has muscarinic effect, antagonizes NMDA receptors
- helps alleviate mild akinesia and rigidity
Does NOT affect tremor!
- short term use for 6-12 months before L-DOPA
CI: renal failure

Question 10

Benztropine

Answer 10

Muscarinic receptor antagoinst (anticholinergic)
-useful for patients with tremor and drooling
- short-term monotherapy in pts with “tremor-predominant” P.D.
SE: dry mouth, blurred vision, constipation, difficulty urinating, exacerbates glaucoma; impairs memory in elderly***