Which two main groups of drugs are important in the treatment of Parkinsonism?

• Drugs that increase dopamine activity
• Drugs that decrease acetylcholine activity

In what way does Amantadine act as an antiparkinsonism drug?

Amantadine is an antiretroviral drug that has a broad mechanism of action. This drug improves the patient’s rigidity, tremors & bradykinesia – however it is only effective for a few weeks.

MoA = Amantadine is a metaffinoid potentiator of dopamine by means of the following actions:

• Increases the release of dopamine
• Increases the synthesis of DA
• Inhibits the reuptake of DA
• Anticholinergic
• Antiviral
• NMDA antagonist

Discuss the MoA of the antiparkinsonism drugs that indirectly increase dopamine concentration:

• Amantadine (MoA explained above)
• Safinamide = increases DA release and decreases glutamate release.
• Istradefyllin = adenosine A2 antagonist (adenosine inhibits D2 function).
• L-dopa = metabolic precursor of DA, it replenishes the DA stores.
• Selective MAO-B inhibitors = the MAO-B enzyme has a preference for DA as substrate, thus by inhibiting this enzyme, DA won’t be metabolized and thus the concentration of DA in the CNS increases. Examples: Selegiline & Rasagiline.
• COMT-inhibitors = COMT metabolizes l-dopa to 3-O-methyl dopa (3OMD). Increased plasma levels of 3OMD weak therapeutic response with l-dopa (3OMD competes with l-dopa for active transport processes). COMT-inhibitor extend the duration of action of l-dopa, ↓ peripheral metabolism, improved bio availability. Examples: Entacapone.

Which of the dopamine agonists are ergot derivatives and which are not?

• Ergot derivative = Bromocriptine
• Non ergot derivatives = Pramipexole & Ropirinole

List the specific dopamine receptors that are stimulated by each agonist.

• Bromocriptine = potent agonist on the D2 receptors.
• Pramipexole = direct agonist on D3 receptors.
• Ropirinole = D2 agonist

Which of these drugs are classified as neuron protecting drugs? What does this mean?

Selective MAO-B inhibitors such as Selegiline & Rasagiline, as well as Pramipexole.

Neuroprotective therapy means that these drugs slow down the disease progression by preventing neuronal death via intervening in and inhibiting the pathogenic cascade that results in cell dysfunction and eventual death.

In general, these agents reduce oxidative stress, mitochondrial dysfunction, protein aggregation, inflammation, excitotoxicity, cell death, iron accumulation, or neurotrophic factors.

What is the importance of MAO-B selective drugs in the treatment of Parkinsonism?

Monoamine oxidase B is an enzyme that is metabolized in the human body into various chemicals in the brain, including dopamine. Thus by administering medication that blocks the effects of this enzyme – a MAO-B inhibitor – a higher concentration of dopamine is available for use in the brain. This can improve many motor symptoms of PD.

How do the COMT-inhibitors act in Parkinsonism?

COMT metabolizes l-dopa to 3-O-methyl dopa (3OMD). Increased plasma levels of 3OMD weak therapeutic response with l-dopa (3OMD competes with l-dopa for active transport processes). COMT-inhibitor extend the duration of action of  l-dopa, ↓ peripheral metabolism, improved bio availability. Additional drug together with l-dopa, improved response and extended on-time. COMT-inhibitors work in an indirect way.

How does istradephyllin act?

This drug is an adenosine alpha 2 antagonist – thus the concentrations of dopamine will increase (since adenosine inhibits D2 function). Thus if adenosine’s action is inhibited, D2 action won’t be blocked and dopamine will increase.

Discuss the MoA of safinamide?

Safinamide is a novel dual MoA.

• Increases DA
  • potent reversible inhibition of MAO-B
  • Inhibition of DA uptake
• Decreases glutamate release