Parkinson's Disease

Question 1

Pathophysiology of PD

Answer 1

Neurogenerative disease characterized by a loss of dopaminergic neurons at the pars compacta of the substancia nigra.

• > decrease stimulation of the motor cortex by basal ganglia; usually due to inadequate production and action of Dopamine.
• High presence of Lewy bodies in dopaminergic cells
• Also recorded a very high activity in the cell of subthalamic nucleus which inhibits movements
• an imbalance in 1 system cause imbalance in the others, in particular what is affected is the cholinergic system

Question 2

Mechanism of neuronal vulnerability in neurodegenerative disease

Answer 2

Environmental toxins, neuronal metabolism, aging will contribute to increase oxidative stress and free radicals. This lead to vulnerability wich results in DNA damage, lipid peroxidation, protein damage -> cell death

Question 3

Decarboxylase inhibitors

Answer 3

Carbidopa and Benserazide
Blockage of DOPA decarboxylase → ↓ peripheral conversion of L-DOPA to dopamine →↑ bioavailability and ↓ peripheral side effects of L-DOPA (e.g., orthostatic hypotension, nausea, vomiting)
Always administered alongside L-DOPA

Question 4

L-DOPA (levodopa): mechanism of action, indication, side effects, administration

Answer 4

• L-DOPA is converted to dopamine by DOPA decarboxylase at the presynaptic neuron → direct dopaminergic effect (especially at D2 receptors)
• L-DOPA, in contrast to dopamine, can cross the blood-brain barrier.
• Predominantly controls bradykinetic symptoms
• First-line treatment for patients > 65 years of age or patients with comorbidities
• Second-line treatment for patients < 65 years of age
  Mostly given as monotherapy in combination with decarboxylase inhibitors
  Most effective drug for reducing symptoms

Side effects: Nausea and vomiting, orthostatic hypotension, psychotic symptoms, dyskinesia, hypokinesia (end of dose, freezing, on/off), akinetic crisis.
Increased risk of severe motor dysfunction with long-term use

Administer between meals (e.g., 30 minutes before a meal) to increase gastrointestinal absorption (→ avoid high-protein diets)

Question 5

Dopamine agonists

Answer 5

(Ropinirole, Pramipexole, Rotigotine)
Act directly at striatal dopamine receptors
Predominantly control bradykinetic symptoms

First-line treatment for patients < 65 years of age
Adjunctive treatment for patients of any age
Second-line treatment for patients < 70 years of age

Less effective than L-DOPA, but fewer motor side effects
Effective in advanced disease stages

Question 6

COMT inhibitors

Answer 6

Entacapone and Tolcapone

Inhibition of catechol-O-methyltransferase (COMT) → ↓ peripheral metabolization of L-DOPA to 3-O-methyldopa (3-OMD) → ↑ availability
Tolcapone also prevents central COMT from breaking down dopamine to 3-methoxytyramine (3-MT) by crossing the blood-brain barrier → ↑ dopamine effect → ↓ demand for L-DOPA and longer therapeutic effect for each dose

Entacapone: If L-DOPA loses effect or motor symptoms fluctuate during L-DOPA therapy
Tolcapone: for refractory Parkinson disease

COMT inhibitor monotherapy is ineffective; therefore, it should always be combined with L-DOPA and carbidopa.