Pharmacotherapy of Parkinson's

Question 1

What is the place in therapy of anticholinergic agents and which ones are used most commonly?

Answer 1

Think of the shaking car with three hexagons - Benztropine and Trihexyphenidyl

Best used for tremors > rigidity, does not help with bradykinesia - helps restore the cholinergic:dopamine ratio in the brain

Question 2

What is the first line treatment for early mild to moderate symptoms of Parkinson’s? What is the mechanism of action?

Answer 2

Amantadine - think of the manatees breaking the rope box open

• > Increase dopamine release and decrease dopamine reuptake
• > mild cholinergic antagonism

Question 3

What is the toxicity associated with amantadine?

Answer 3

Ataxia, livedo reticularis

Question 4

What is the gold-standard treatment for Parkinson’s and how does it work?

Answer 4

Levodopa - L-DOPA rope

Carbidopa - Police car in the periphery in the scene

->carbidopa scares the L-Dopa guys in to bank vault (brain) by inhibiting L-Dopa conversion to dopamine peripherally (inhibits DDC - Dopa DeCarboxylase)

Question 5

What would be the side effects of levodopa given alone?

Answer 5

Nausea, vomiting - trigger of chemoreceptor trigger zone
Hypotension - beta agonism
Cardiac arrhythmias

Question 6

What side effects does Levodopa / carbidopa have even despite DDC blockade?

Answer 6

Peripheral effects are lessened

Central effects - Dyskinesias (think of guy with strange movements around his face), response fluctuations, and psychiatric complications (disturbed hostage) i.e. hallucinations, anxiety.

Question 7

What are the response fluctuations which can occur due to longterm levodopa/carbidopa?

Answer 7

1. Peak dose dyskinesia - can occur 30 min after dosing due to huge CNS rush
2. Wearing off - end of dose deterioration
3. On-off effect - random and unpredictable fluctuations occur with no relation to dosing

Question 8

How can end of dose deterioration be combated?

Answer 8

1. Shorten dosing interval
2. Add dopamine agonist
3. Add MAO-B inhibitor
4. Add COMT inhibitor
5. Apomorphine rescue

Question 9

What can cause delayed onset of response with levodopa / carbidopa?

Answer 9

Eating with a full stomach -> delayed gastric emptying

Too much dietary protein -> inhibits dopamine uptake

Ferrous sulfate -> chelates the drug and leads to decrased absorption

Anticholinergics -> alter absorption and lead to dumping a massive dose in duodenum

Question 10

Why do peak dose dyskinesias occur more frequently in later treatment with levodopa/carbidopa and how do you combat this?

Answer 10

Because the therapeutic window of dopamine becomes smaller -> always overshooting.

Want to maintain a more constant dopamine concentration via addition of COMT inhibitor or not starting levodopa/carbidopa til later in treatment regimen

Question 11

What is Hedonistic Homeostatic Dysregulation?

Answer 11

Especially in younger patients, dopamine therapy may cause drug hoarding and overdose, with manic psychosis
-> gambling, shopping, hypersexuality, etc

Question 12

What are the hallucinations which can happen with dopaminergic treatment and how can they be treated?

Answer 12

Usually visual hallucinations, though they may become distressing

Treat with clozapine or quetiapine -> atypical antipsychotics less likely to block D2 and worsen symptoms

Question 13

What is duodopa?

Answer 13

Surgically implantable pump with carbidopa/levodopa for continuous infusion - less fluctuation

Question 14

Who are direct dopamine agonists the firstline treatment for?

Answer 14

Patients under age 65 -> delay the need for levodopa/carbidopa, and don’t require functioning neurons

Question 15

What dopamine agonists are most commonly used for longterm management and which is not preferred? Why?

Answer 15

Preferred: Ropinirole (D2 agonist, two ropes), Pramipexole (pecs)

Not preferred: Bromocriptine -> ergot alkaloid, partial agonism at alpha and serotonin receptors and causes more hallucinations

Question 16

What is apomorphine used for and what do you need to give with it?

Answer 16

Used for acute, rapid relief of “off periods”, but is a very potent trigger of area postrema and needs to be given with an antiemetic (non-D2, i.e. ondansetron)

Question 17

What does COMT do? MAO-B?

Answer 17

It is an enzyme in that breaks down both L-Dopa and Dopamine in the PNS and CNS.

MAO-B only breaks down dopamine in the CNS and PNS

Question 18

What is the role of COMT inhibitors in therapy?

Answer 18

They are used only as adjuncts to levodopa/carbidopa

-> smooth out the curve, have no role as a monotherapy

Question 19

What are COMT inhibitors, how are they different, and what are their side effects of concern?

Answer 19

Tolcapone - Tall Al Capone - inhibits peripheral AND central breakdown of L-dopa and dopamine, but causes hepatic dysfunction (handle of gun)

Entacapone - Al Capone - stays in periphery blocking COMT, preferred agent with fewer side effects

Question 20

What is the role of MAO-B inhibitors in therapy? What is the argument behind this?

Answer 20

Can be used alone in early therapy, or as an adjunct to levodopa/carbidopa

MAO-B inhibitors may have a disease-modifying effect if given early since breakdown of dopamine by MAO probably creates damaging ROS

Question 21

What are the two MAO-B inhibitors and which is preferred? Why?

Answer 21

Selegiline - extensive first pass metabolism and production of amphetamine metabolites

Rasagiline - good bioavailability and no toxic breakdown agents -> drug of choice

Question 22

What consideration of levodopa/carbidopa dosing needs to be made with MAO-B inhibitors / COMT inhibitors?

Answer 22

Need to reduce it by about 30% before dosing -> massive increase in dopamine can induce dyskinesias