CNS V: Drugs for Parkinson’s disease

Question 1

Contrast normal and Parkinson’s Caudate Putamen and the activity of D1 and D2 receptors

Answer 1

Normal

• D1: Enables movement (direct pathway)
• D2: Inhibits movement (indirect pathway)

Parkinson’s

• D1: Movement inhibited by reduced activity
• D2: Activity increased because of release of D2 inhibition (movement inhibited)

Question 2

Give 5 possible causes of parkinson’s disease

Answer 2

• Exact cause unknown
• Genetic factors
• Exposure to neurotoxin
• Oxidation reactions resultign in free radical production
• Disease is progressive

Question 3

In Parkinson’s, what is the imbalance of neurotransmitter in the Basal Ganglia?

Answer 3

• Less dopamine (inhibits GABA cells)
• MORE acetylcholine (activates GABA cells)

Gaba cells in basal forebrain inhibit movement

Might play a part:

• NE
• 5-HT
• GABA

Question 4

What is the the amino acid that gets converted to L-DOPA?

Answer 4

tyrosine

Question 5

Give the dopamine synthetic and degradation pathways.

How can these be manipulated to treat Parkinson’s?

Answer 5

Synthesis

• L-Tyrosine
• DOPA (tyrosine hydroxylase)
• Dopamine (DOPA decarboxylase)

Degradation

• Dopamine
• DOPAC (MAO) or 3-methoxytyramine (COMT)
• Homovanillic acid (MAO or COMT, which ever one did not catalyse the step before)

Parkinson’s Treatment

• Increase DOPA and DOPA decarboxylase activity
• Inhibit MAO and/or COMT

Question 6

What are three types of drugs used to treat Parkinson’s?

Answer 6

• Drugs that increase dopamine levels in the brain
• DA receptor agonists
• Acetylcholine antagonists

Question 7

Describe the use of L-DOPA for Parkinson’s

Answer 7

• Levodopa
• Metabolized in periphery before CNS by LAAD and COMT (first pass)
• Adverse effects due to increased DA and NE in peripheral
• Carbidopa (analog of L-DOPA) inhibits conversion of L-DOPA to dopamine in periphery and DOES NOT CROSS THE BLOOD BRAIN BARRIER
• COMT inhibitors (eg. tolcapone) block conversion of LDOPA to 3-O-mDOPA and maximizes bioavailability of LDOPA to be transported into the brain

Question 8

What is Selegiline?

Answer 8

Parkinson’s drug

Irreversible inhibitor of MAO-B in striatum
- Inhibits oxidation of DA to DOPAC

Question 9

Describe the use of dopamine receptor agonists for treating Parkinson’s.

Answer 9

• Directly activate DA receptors
• Can be used with L-DOPA
• Act at postsynaptic dopamine receptors
• Activation of specific DA receptors may limit adverse effects of these drugs

Question 10

Describe the use of antimuscarinic drugs for Parkinson’s

Answer 10

• Block striatal muscarinic receptors
• Not as effective as L-DOPA/carbidopa treatment
• Efficient in control of tremors
• Alleviates extrapyramidal effects caused by older anti-psychotics

Question 11

What is amantadine?

Answer 11

A parkinson’s drug.

• OFten combined with levodopa-carbidopa therapy
• Used in patients who do not respond well to levodopa
• Inhibits dopamine re-uptake and facilitates pre-synaptic DA release