Drugs in movement disorders

Question 1

What are the two neurotransmitters that influence the direct and indirect pathway of the basal ganglia? What are the net effects of these neurotransmitters? Based on these NTs, how would you manipulate them to treat Parkinson’s disease?

Answer 1

Dopamine - stimulates the direct pathway (D1/subP MSNs) and inhibits the indirect pathway (D2/enkephalin MSNs). Net effect is to increase movement
Acetylcholine - stimulates the indirect pathway (muscarinic receptors on MSNs). Net effect is to decrease movement
Either stimulate dopaminergic function or inhibit acetylcholine function

Question 2

How can you stimulate dopaminergic function? How can you inhibit cholinergic function?

Answer 2

dopaminergic - increase dopamine synthesis, decrease dopamine degradation, directly stimulate dopamine receptors (D2 receptors)
cholinergic - block muscarinic receptors, address the dopamine/ACh imbalance within the basal ganglia indirect pathway

Question 3

Although Ldopa can cross the BBB much better than dopamine, it is quickly broken down in the periphery before it can reach the brain when taken orally. What enzymes are degrading Ldopa in the periphery? How do pharmacologists solve this?

Answer 3

COMT (catechol-o-methyltransferase) breaks Ldopa into an inactive substance
DOPA decarboxylase breaks Ldopa down into dopamine which is a very strong emetic.
Carbidopa is a peripheral inhibitor of DOPA decarboxylase (can’t cross the BBB). Allows a much smaller oral dose of Ldopa to be given.

Question 4

After a while, Ldopa loses it’s efficacy. What is the difference between “wearing off” effect and “on-off” effect?

Answer 4

wearing off - mobility declines after a shorter amount of time; correlated with dosing schedule; increase dosing regimen will fix this
on-off - unpredictable, sudden periods of immobility; not correlated with dosing schedule; typically occurs later in disease progression than the “wearing off” effect

Question 5

What are the side effects of Ldopa?

Answer 5

nausea and vomiting
postural/orthostatic hypotension
arrhythmias (high levels of dopamine will activate Beta receptors)
dyskinesias
compulsive behaviors
psychosis - anxiety, hallucinations, insomnia, somnolence (sleep attacks)

Question 6

When do you use direct dopamine agonist drugs?

Answer 6

early in disease progression - monotherapy

Later in disease progression - adjunct to carbidopa/levodopa for wearing off effect

Question 7

What are the direct dopamine agonists drugs? What receptor(s) do they act on? How are they metabolized? What are their adverse effects?

Answer 7

act on D2&raquo_space;> D1
Pramipexole - not metabolized/excreted unchanged; same adverse effects as Ldopa also pronounced somnolence
ropinerole - metabolized by the same P450 enzyme that metabolized caffeine and warfarin; same adverse effects as Ldopa
apomorphine - used to terminate “off” periods when nothing else works because it is administered sub cutaneously and works quickly; eliminated very quickly and unchanged; same adverse effects as Ldopa

Question 8

How is MAO-B different from MAO-A? What are the MAO-B inhibitors used for?

Answer 8

MAO-B degrades dopamine only
MAO-A degrades dopamine, serotonin and norepinephrine
Used as adjuncts to carbidopa/levodopa for wearing off effects. NOT used in early disease

Question 9

What drug has a very serious interaction with MAO inhibitors? What can happen if taken together?

Answer 9

Meperidine (synthetic opioid)

Can result in serotonin syndrome (agitation and delirium progressing to coma and death)

Question 10

What are the MAO-B inhibitor drugs? How are they metabolized? What are their adverse effects?

Answer 10

Selegiline - metabolized into amphetamine/methamphetamine so given as a transdermal patch to prevent first pass metabolism; risk of tyramine related hypertensive crisis and serotonin syndrome when combined with SSRIs. Side effects of amphetamines are insomnia and anxiety.
Rasagiline - more selective for MAO-B than selegiline so safer; no amphetamine metabolites;

Question 11

What happens to COMT enzymes after long term treatment with carbidopa/levodopa?

Answer 11

Suppressing the DOPA decarboxylase for a long time will cause up regulation of COMT enzymes, negating the effect of carbidopa. Thus, you only give COMT inhibitors as adjunct therapy in the later stages of disease

Question 12

What are the COMT inhibitors?

Answer 12

Tolcapone - inhibitor in CNS and periphery; can cause hepatotoxicity and several cases of fulminant hepatic failure
Entacapone - inhibitor in periphery, NOT CNS; no evidence of hepatotoxicity

Question 13

When is amantadine used?

Answer 13

as monotherapy in the very early stages of parkinson’s disease.

Question 14

What are the drug(s) that inhibit the muscarinic cholinergic receptor on medium spiny neurons?

Answer 14

trihexyphenidyl - mostly works in CNS, does not have much peripheral effects; significant CNS side effects of confusion and sedation; cannot be used in patients with closed angle glaucoma