Parkinson's Disease Drugs

Question 1

What are the symptoms of Parkinson’s?

Answer 1

Three S’s : slow, stiff, shaky

Slow = bradykinesia
Stiff = rigid
Shaky = resting tremor

This presents as motor changes:

• “Pill rolling” tremor in hands
• Slow shuffling gait
• Difficulty initiating movements (e.g. getting out of chair)
• Tiny handwriting
• Reduced facial expressions
• Soft voice

Question 2

Disease progression more rapid if:

Answer 2

-older, male patient
-rigidity is the main symptom
-other comorbidities (stroke, etc.)

Question 3

Disease progression slower if:

Answer 3

• Younger person, tremors are the primary symptom.

Question 4

What is the cause of Parkinson’s?

Answer 4

Cell death of dopaminergic neurons in the SUBSTANTIA NIGRA PARS COMPACTA

Eventually other neurons in other brain regions die too
(b/c it’s a progressive movement disorder)

*common for both hemispheres to be eventually affected

Question 5

When do symptoms appear?

Answer 5

when about 70% of nigrostriatal neurons are lost

Question 6

What are the Basal ganglia & motor control?

Answer 6

Basal ganglia are needed to INITIATE movements

At rest, the thalamus is tonically inhibited by the striatum

Outputs from the striatum lead to both activation and inhibition from the thalamus

*Dopamine from the SNpc excites the direct pathway (D1 receptors) and inhibits the indirect pathway (D2 receptors). Net result= movement

*Removes tonic inhibition

Question 7

What is Parkinson’s disease?

Answer 7

Dopamine neuron die, so the tonic inhibition is not removed.

When dopamine is lost, the thalamus remains inhibited.

Question 8

Compare the Nigrostriatal Pathway (Normal vs. Parkinson’s)

Answer 8

Normal:
- GABA neurons are inhibited by dopamine and stimulated by acetylcholine

Parkinson’s Disease
- Dopaminergic neurons die, leaving a relative excess of acetylcholine

*Not enough dopamine, too much acetylcholine in the striatum (main message for patho)

Question 9

What are the enzymes that have ~ ability to degrade dopamine? & what is the main one?

Answer 9

Main one: MAOB

Other enzymes that have ~ability to degrade dopamine: MAOA, MAOB, COMT

Question 10

How would you treat Parkinson’s disease? (i.e. where in the CNS would you target?)

Answer 10

1. Replace dopamine
2. Increase dopamine receptor activity (agonists)
3. Block dopamine breakdown
4. Enhance dopamine release

Question 11

Strategies to treat Parkinson’s Disease:

Answer 11

1. Replace dopamine
2. Increase dopamine receptor activity (agonists)
3. Block dopamine breakdown
4. Enhance dopamine release

Question 12

________ dopamine signalling in the striatum

Answer 12

INCREASE

Question 13

What is the dopamine synthesis in substantia nigra?

Answer 13

1 used (a prodrug)

Levodopa (L-DOPA)

used b/c dopamine doesn’t cross BBB

Question 14

What is the L-DOPA Pharmacology?

Answer 14

UPTAKE
- Peak plasma concentration 1-2 h after ingestion
- 1-3 h half life

Question 15

L-DOPA is always given in combo with drugs that:
________ peripheral dopamine metabolism

Answer 15

DECREASE

Question 16

What are the drugs (added to Levodopa) to increase dopamine signalling?

Answer 16

• Entacapone (blocks COMT)

-Carbidopa (blocks DOC)

• Benserazide (blocks DOC)

Question 17

Levodopa + carbidopa =

Answer 17

STANDARD therapy (peripheral metab. is inhib. & more gets to brain)

Question 18

Levodopa + carbidopa + entacapone =

Answer 18

for late stage patients

Question 19

Levodopa + carbidopa CR (controlled release)

Answer 19

…

Question 20

What are drugs to increase dopamine signalling?

Answer 20

2. Increase dopamine receptor activity (agonists)
3. Block dopamine breakdown
4. Enhance dopamine release

Question 21

Monoamine Oxidase A (MAOA):

Answer 21

Metabolizes norepinephrine (noradrenaline) and serotonin (5-HT)

Question 22

Monoamine Oxidase B (MAOB):

Answer 22

Metabolizes dopamine

Question 23

Monoamine oxidase B inhibitors:

Answer 23

Rasagiline, selegiline

• Rasagiline (2nd gen) - better bioavailability, fewer side effects
• Monotherapy or adjunct that enhances effects of L-DOPA

(drug to increase dopamine signalling)

Question 24

Dopamine agonists:

Answer 24

Ropinirole (po), rotigitine (patch)

• Second generation drugs, better than first (bromocriptine)
• Act on D2 receptors (inhibitory receptors; seems to be more effective for initiating movement)
• Often preferred by young PD patients (due to less motor complications (“wearing off”) (fewer SE’s)

Question 25

Enhance dopamine release:

Answer 25

Amantadine

• Only of short-term benefit (< 6 months) (therefore, not readily used)
• Better for younger PD patients because of anti-cholinergic side effects

Question 26

What are the common side effects of increasing dopamine signalling?

Answer 26

• Dyskinesias (ABNORMAL INVOLUNTARY MOVEMENTS)
  (b/c of too much dopamine)

CNS effects
- NAUSEA & VOMITING (area postrema; 80% of patients)
- Anorexia
- Behavioral changes
- Insomnia, confusion, dizziness
- Psychosis, schizophrenia-like behavior, hallucinations

Peripheral effects
- Hypotension (postural) and cardiac arrhythmias

Most can’t sit still b/c of the drugs

Question 27

What are the unique SE’s?

Answer 27

Levodopa
- Wearing off or “on-off” effect (15-20% of patients)
- Give with entacapone or switch to ropinirole
Increased libido

Ropinirole
- Increased libido (sometimes inappropriate sexual behavior)
- Pathological gambling or spending (due to overactivation of reward pathway)

Amantadine
- Less dyskinesia
- Increased confusion (in the eldery, due to anticholinergic effects)
- Nightmares
- Rose coloured mottling of the legs (livedo reticularis)

Question 28

What is Domperidone(peripheral D2 receptor antagonist)?

Answer 28

Many drugs that increase dopamine signalling cause nausea and hypotension due to activity on peripheral dopamine receptors

Therapeutic effects
- Does not cross the BBB
- Blocks peripheral dopamine receptors
- Decreases nausea, increases blood pressure

Question 29

What are the drug interactions of Parkinson’s dopamine treatments?

Answer 29

How to treat psychosis? MOST ANTI-PSYCHOTICS ARE DOPAMINE ANTAGONISTS.

SSRIs (especially rasagiline, ropinirole)- can lead to serotonin syndrome (=> death due to too much serotonin in their brain; anti-depressants)

Monoamine oxidase A inhibitors- a problem with rasagiline, ropinirole, levodopa (increased toxicity

Question 30

Drugs to increase dopamine signalling:

Answer 30

• Entacapone
• Carbidopa
• Domperidone (peripheral D2 antagonists)
• Amantadine
• Levodopa
• Rasagiline
• Ropinirole

Question 31

_______ cholinergic activity in the striatum

Answer 31

Decrease

Question 32

What is Benztropine or Trihexyphenidyl(Muscarinic Antagonists) Therapeutic Effect?

Answer 32

• Not a first line therapy
• Used mainly in young patients with severe tremor
• NOT RECOMMENDED in elderly (can amplify confusion and memory deficits)
• Inhibition of striatal cholinergic activity

Question 33

What is Benztropine or Trihexyphenidyl(Muscarinic Antagonists) SE’s?

Answer 33

• Dry mouth
• Blurred vision
• Urinary retention
• Constipation
• Mental confusion, hallucinations, delusions
• *Contradindicated in Glaucoma (M3 receptors in iris)

Question 34

What are the 1st LINE drugs to increase dopamine in the striatum?

Answer 34

• Levodopa (prodrug)
  – Peripheral L-dopa enzyme inhibitors (carbidopa, entacapone)
• MAO-B inhibitors (rasagiline)
• D2 receptor agonists (ropinirole)

Question 35

What are the 2nd LINE drugs to increase dopamine in the striatum?

Answer 35

• Dopamine releaser (amantadine)

Drugs to decrease acetylcholine activity in the striatum
- Anticholinergics (benztropine)

Question 36

Drugs to help with side effects (due to peripheral activity)

Answer 36

Peripheral D2 receptor antagonist (domperidone)