L9- Parkinson's Disease Treatment (DA precursors)

Question 1

describe the primary goals and difficulties with the current PD treatment

Answer 1

-usually symptomatic treatment –> helps improve quality of life

• no or minimal effect against disease progression –> therefore more difficult to manage more advanced PD
• later features like dementia, cognitive impairment don’t respond well to treatment

Question 2

describe the main drug / treatment for PD

Answer 2

Levodopa- dopamine precursor (L-DOPA)

• restores dopamine levels in brain
• more effective in early PD since dopaminergic neurons are required for efficacy
• only works when it is in the body (therefore frequent doses required)

Question 3

why is dopamine not given as a treatment for PD

Answer 3

dopamine does not cross the BBB, but its precursor L-dopa does (levodopa)

Question 4

describe the fate and effects of levodopa if given alone

Answer 4

-most is decarboxylated (dopa decarboxylase) into dopamine in the periphery
=> side-effects: n/v, cardiac arrhythmias, hypotension

Question 5

______ is always given along with levodopa, explain

Answer 5

carbidopa:
-inhibits dopa decarboxylase
-doesn’t cross BBB, so only works in periphery
=> more levodopa conversion to dopamine in CNS + dec peripheral side-effects + smaller levodopa doses

Question 6

levodopa + carbidopa = ______

Answer 6

Sinemet (carbidopa:levodopa = ~1:10 or 1:4)

Question 7

levodopa alone:

• (1)% metabolized in GIT
• (2)% conversion in periphery
• (3)% conversion in brain

Answer 7

1- 70%
2- 27-29%
3- 1-3%

Question 8

levodopa in combination (Sinemet):

• (1)% metabolized in GIT
• (2)% conversion in periphery
• (3)% conversion in brain

Answer 8

1- 40%
2- 50%
3- 10%

Question 9

describe the pharmacokinetics of levodopa

Answer 9

• rapidly absorbed from SI
• food delays appearance of levodopa in plasma as certain AAs compete with it for absorption through GIT and BBB –> ideally avoid protein rich meals

Question 10

when and why might the effects of levodopa decrease over time

Answer 10

When: in the 3rd-5th year of therapy

Why: (2-fold)

• loss of dopaminergic nigrastrital neurons
• tolerance and sensitization

Question 11

Levodopa AEs: GI

Answer 11

• anorexia

- n/v

Question 12

Levodopa AEs: CVS

Answer 12

• tachycardia and ventricular extrasystoles

- hypotension

Question 13

Levodopa AEs: CNS

Answer 13

• visual, auditory hallucinations (inc mesocortical pathway)
• dyskinesias
• mood changes, depression, anxiety, agitation, insomnia

Question 14

what are the main issues with levodopa and its treatment regimen

Answer 14

1) Wearing-Off Reactions // End-of-Dose Akinesia
- fluctuations related to timing of levodopa intake: consequence of large infrequent doses
- —> therefore take small, frequent doses

2) On-Off Phenomenon:
- fluctuations not related to timing of levodopa intake
- unknown mechanism- currently under research
- Pts w/ severe off-periods and unresponsive to other measures –> give Apomorphine

Question 15

what are the main concerns with levodopa in terms of drug interactions (hint- 2)

Answer 15

VitB6 (PLP): co-factor for DOPA decarboxylase –> inc peripheral metabolism of levodopa

MAOIs: cheese reaction (tyramine) –> hypertensive crisis

Question 16

what are the main contraindications of levodopa (hint- 4)

Answer 16

• psychotic Pts => exacerbates mental disturbances
• Antipsychotic drugs => Parkinsonian syndrome
• angle-closure glaucoma
• monitor cardiac Pts for arrhthymia