Basal Ganglia Pharmacology

Question 1

What are the negative signs of basal ganglia disorders?

Answer 1

akinesia

bradykinesa

masked facies

dystonia

Question 2

What are the positive signs of basal ganglia disorders?

Answer 2

lead-pipe rigidity

cog-wheel rigidity

athetosis

dystonia

chorea

ballismus

Question 3

What is the primary goal of Parkinsons treatment?

Answer 3

restore dopaminergic activity

neuroprotective interventions are not yet available

Question 4

What are the three strategies you can use to increase dopaminergic activity?

Answer 4

1. replacement therapy with L-DOPA
2. Inhibition of dopamine breakdown (selegiline)
3. Activation of dopamine receptors (pramipexole)

Question 5

Levodopa is a prodrug that is converted to dopamine by what enzyme?

Answer 5

L-aromatic amino acid decarboxylase (AAAD)

Question 6

What is the issue with giving L-Dopa alone?

Answer 6

there is significant AAAD decarboxylase activity in the GI tract, so you don’t hardly get any of the L-DOPA reaching the CNS

Question 7

What drug can you give in combo with LDOPA to increae the amount that reaches the CNS? How?

Answer 7

Carbidopa

it inhibits AAAD in the periphery, but can’t cross the BBB, so doesn’t block it in the brain.

allows you to reduce the LDOPA dose by 75%!

the combo is called sinemet and is the current standard treatment for PD

Question 8

What dopamine receptors does dopamine activate and which does it inhibit?

Answer 8

activates D1 receptors of the direct pathway

inhibits D2 receptors of the indirect pathway

Question 9

When is LDOPA most effective in disease treatment? Why?

Answer 9

most effective early in therapy

it becomes less effective over time because you have a progressive loss of dopaminergic neurons over time, which is where the vast majority of the LDOPA to dopamine conversion occurs

Question 10

What are the adverse effects of L-DOPA?

Answer 10

1. dyskinesia - abnormal involuntary movements that increase with higher dose and with longer time on therpy
2. “on-off” phenomenon
3. “wearing off” phenomenon where drug wears off and you get symptoms flucutation
4. Side effects: confusion, anxiety, agitation, insonia, nightmares, depression, hallucinations, orthostatic hypotension, nausea, vomiting, anorexia

Question 11

What drug can you use to decrease peripheral metabolism of L-DOPA by catechol-O-methyltransferase (COMT)?

Answer 11

Entacapone - it’s a COMT inhibito

Question 12

Why does a COMT inhibitor usually need to be used when treating with carbidopa?

Answer 12

inhibition of AAAD by carbidopa is associated with a compensatory activation of COMT

Question 13

What type of MAOI is useful in PD?

Answer 13

MAO-B inhibitors:

B primarily metabolizes dopamine, so blocking it is useful in PD

selegiline is an example

Question 14

What is an example of a D2 agonist that can be used to treat PD after synthesis of dopamine form LPDOA is lost when dopaminergic neurons are gone?

Answer 14

pramipexole

Question 15

Why can muscarinic antagonists like anticholinergics be used to treat PD?

Answer 15

because ACh is used as an NT by a small but important subgroup of striatal interneurons

It also seems to be the case that when you lose dopaminergic neurons, you get an excess of ACh activity

trihexyphenidyl is an example

Question 16

What antiviral drug has been used for PD although the mechanism is unclear?

Answer 16

amantadine (symmetrel)

not as effective as LDOPA and benefits are short lived, but can be used in combo