Lecture 12 - Parkinson's Disease Drugs Flashcards Preview

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Flashcards in Lecture 12 - Parkinson's Disease Drugs Deck (56)
1

Parkinson's disease is a _____ disorder

movement

2

When do symptoms usually appear?

60 yrs old

3

List 5 symptoms of Parkinson's

-rhythmic tremor
-leaning forward
-difficulty rising
-muscle rigidity
-shrinkage of handwriting

4

List 4 voluntary motor pathways

-upper motoneurons
-lower motoneurons
-corticospinal pathway
-piramidal tracts

5

List 4 involuntary motor pathways

-extrapiramidal system
-basal ganglia
-reticular system
-vestibular system

6

What is parkinson's caused by?

by the loss of neurons in the substantia nigra and thus, the loss of dopamine innervation of striatum (part of the basal ganglia)

7

When do parkinson's symptoms occur?

when about 70% of nigrostriatal neurons are lost

8

Abnormal signalling leads to ??

impaired mobility

9

Describe the normal path of neurons

GABA neurons are inhibited by dopamine and stimulated by acetylcholine

10

Describe the path of neurons in parkinson's disease

dopaminergic neurons die, leaving a relative excess of ACh

11

Describe the path of neurons in huntington's disease

GABA neurons die as well as some ACh neurons

12

Symptoms amenable to drug therapy

-bradykinesia
-resting tremor
-muscle rigidity
-abnormal posture
-early treatment for 'neuronal sparing'

13

Discuss pharmacologic targets for parkinson's

-increase Da signalling in brain
-Levodopa therapy
-decrease cholinergic activity (striatal muscarinic receptors)
-decrease peripheral dopamine effects at D1/D2 dopamine receptors
-decrease peripheral L-dopa metabolism

14

dopamine receptors are ______

metabrotropic

15

D1 subfamily members

D1
D5

16

Describe D1 subfamily

Gs
Increase cAMP

17

D1 subfamily members

D2
D3
D4

18

Describe D2 subfamily

Gi
Decrease cAMP

19

Striatum has what kind of dopamine receptors

D1
D2

20

What kinds of medication would be used to treat the first appearance of parkinson's

MAO B inhibitors
Levodopa
Dopamine agonists
Amantadine
Anticholinergics

21

Describe the disposition characteristics of L-dopa

-rapid absorption from the small intestine by aromatic amino acid transport system
-crosses BBB
-peak plasma concentration 1-2 hr after ingestion
-plasma half life = 1-3 hrs

22

Bioavailability issues with L-dopa

-metabolism in intestine, blood, and peripheral tissues
-concurrently ingested food (protein, iron)
-only 1% actually enters the brain

23

Therapeutic effects of L-dopa

-reduces rigidity and bradykinesia
-improves motor function and speech
-return of facial expression
-first choice drug for improving motor function

24

Side effects of L-dopa

-nausea and vomiting
-anorexia
-hypotension and cardiac arrhythmias
-dyskinesias (abnormal involuntary movements)
-can have an on-off effect
-behavioural changes
-insomnia, confusion
-psychosis, schizophrenia-like behaviour, hallucinations

25

An adjunct to L-dopa = ?

carbidopa

26

How does carbidopa work?

-inhibits dopa decarboxylase (DDC or aromatic L-amino acid decarboxylase AADC)
-does not cross BBB
-reduces the amount of L-dopa required and thus, reduces the adverse effects of L-dopa

27

Describe standard adjunct therapy for parkinson's

L-dopa + carbidopa = Sinemet
L-dopa + bensarazide = Prolopa

28

Another adjunct to L-dopa = ?

Entacapone

29

Describe Entacapone

-primarily for treating later stage parkinsons' disease
-selective and reversible inhibitor of peripheral COMT
-reduces peripheral metabolism of L-dopa
-does not cross BBB
-this leads to increased conversion of L-dopa to dopamine in the brain

Entacapone - used to treat problems associated with long term therapy of L-dopa (wearing off/ on-off effects)

-can enhance adverse effects of L-dopa, such as dyskinesias, nausea, psychosis and confusion

30

Sinemet + entacapone = ?

stalevo

31

roprinirole/pramipexole are selective _______

dopamine agonists at D2/D3 receptors

32

roprinirole/pramipexole:
bioavailability ?

50%

33

roprinirole/pramipexole:
peak plasma concentration ?

1-3 hours after ingestion

34

roprinirole/pramipexole:
plasma half life

5-6 hours

35

Therapeutic effects of roprinirole/pramipexole

-act on D2 and D3 receptors in and outside of the corpus striatum
-improves depressive symptoms
-may be combined with L-dopa to treat "on-off" effects

36

Side effects of dopamine agonists (including roprinirole/pramipexole)

-action on D2 receptors outside of the corpus striatum - dyskinesia
-activates other CNS D1-D3 receptors
-suppresses prolactin secretion
-suppresses growth hormone release
-Hypotension
-visual and auditory hallucinations

37

Muscarinic antagonists:
representative drugs

-trihexyphenidyl HCl and benzatropine mesylate
-selective for muscarinic ACh type 1 receptor (M1R)
-not first line therapy

38

Muscarinic antagonists:
therapeutic effect

-used mainly in young patients with severe tremor
-inhibition of striata cholinergic activity
-improves tremor but not rigidity
-not recommended in elderly

39

Muscarinic antagonists:
side effects

dry mouth
blurred vision
urinary retention
constipation
mental confusion
hallucinations
delusions
drowsiness
glaucoma

40

MAO-A metabolizes ?

NE and 5-HT

41

MAO-B metabolizes ?

dopamine

42

Selegiline is an ?

irreversible MAO-B inhibitor

43

Bioavailability issues with Selegiline ?

-negligible bioavailability after oral ingestion
-very rapid absorption (peak conc. < 1 hr)
-plasma half-life about 2 hr

44

Therapeutic issues with Selegiline

-relatively selective inhibition of MAO-B
-enhances effects of L-dopa
-may be useful to manage the on/off effect
-increased death rate compared to L-dopa when used as first treatment for the mild disease

45

Selegiline side effects

-insomnia
-cognitive problems
-not to be used with other MAO-I drugs

46

Selegiline is superseded by _______

rasagiline

47

Explain: Selegiline is superseded by rasagiline

-less production of amphetamine-like by-products
-better bioavailability
-useful in patients with depression and/or cognitive decline

48

Amantadine is a ??

dopamine releaser

49

bioavailability issues with amantadine

-not absorbed from the stomach (variable)
-half life of 12-14 hrs with normal renal function
-virtually complete excretion by the kidney (renal function)

50

Amantadine - therapeutic effects

-increases dopamine release in the CNS
-only of short-term benefit (<6 mo)
-sometimes used together with L-dopa

51

Side effects of Amantadine (similar to L-dopa)

-psychosis, hallucinations
-confusion
-nightmares
-anorexia
-livedo reticularis (reddish-blue netlike mottling of the skin)

52

slide 35 - important

okay

53

moderate/severe disability and age 70-75+ years or with significant comorbidity including cognitive impairment = ??

begin levodopa +/- COMTI

54

mild/moderate motor disability and no cognitive impairment = ??

begin dopamine agonist

55

mild motor disability and no cognitive impairment = ??

begin MAO-B inhibitor

56

Non-pharmacological therapeutics?

surgery -ablation and/or deep brain stimulation

growth factors - glial cell line-derived neurotrophic factor (GDNF)

stem cells - replacement of dopaminergic neurons