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

- Drugs that increase the activity of Dopamine.

- Drugs that lower the Cholinergic (Ach) activity.

• In what way does amantadine act as a antiparkinsonism drug?

Amantadine is a metaffinoid potentiator of dopamine, which therefore has the effect of increasing the release of dopamine, increasing the synthesis of dopamine and inhibiting the reuptake of dopamine. Can also act as an anticholinergic. Can also act as an NMDA antagonist, as it has antidyskinetic effects, which will therefore help with movement disorders of Parkinsonism. It can also act as an adenosine α2-A antagonist, which inhibits D2 function and thus results in increased dopamine.

• Discuss the mechanisms of action of the antiparkinsonism drugs that indirectly increase dopamine concentration.

• Amantadiene:

Metaffinoid potentiator of dopamine, which therefore has the effect of increasing the release of dopamine, increasing the synthesis of dopamine and inhibiting the reuptake of dopamine.

• Selective MAOB inhibitors (eg Rasagiline and Selegiline):

Selectively inhibits MAO-B enzymes that result in dopamine metabolism being suppressed and dopamine levels being high in the central nervous system.

• COMT inhibitors (eg Entacapone):

COMT metabolizes l-dopa to 3-oxygen (O) -methyl dopa (3OMD), so the increased levels of 3OMD have a poor therapeutic response with l-dopa, because they compensate for the active transport processes. Thus, by using a COMT inhibitor, it prevents competition with l-dopa and thus l-dopa's duration of action will be prolonged, peripheral metabolism will be reduced and improved bioavailability will occur.

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

Ergot derivatives: Bromocriptine

Non-ergot derivatives: Pramipexole and Ropinirole

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

D2 receptor agonists:

-Ropinirole

-Bromocriptine

D3 receptor agonists:

-Pramipexole

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

Selective Monoamine Oxidase B (MAO-B) inhibitors (eg Rasagiline). This means that the MAO-B inhibitor prevents MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) from being converted to MPP + (N-methyl-4-phenylpyridium), which can therefore protect against the prevalence of Parkinsonism.

• What is the importance of monoamine oxidase B (MAO-B) selective drugs in the treatment of Parkinsonism?

MAO-B has a preference for Dopamine as a substrate, so the Dopamine concentration in the central nervous system will be increased.

• How do the COMT-inhibitors act in Parkinsonism?

COMT metabolizes l-dopa to 3-oxygen (O) -methyl dopa (3OMD), so the increased levels of 3OMD have a poor therapeutic response with l-dopa, as they compensate for the active transport processes. Thus, by using a COMT inhibitor, it prevents competition with l-dopa and thus l-dopa's duration of action will be extended, peripheral metabolism will be reduced and improved bioavailability will occur.

• How does istradephyline act?

The drug is an adenosine α2-A antagonist, which therefore inhibits D2 function. The drug can also be used as additional therapy in l-dopa / carbidopa therapy.

• Discuss the MOA of safinamide

Safinamide has a dual mechanism of action:

1. The drug increases the Dopamine activity, through the potent reversible inhibition of MAO-B, as well as the inhibition of Dopamine reuptake.

2. The drug also lowers glutamate release.