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Pharmacology > Lecture 12 - Parkinson's Disease Drugs > Flashcards

Lecture 12 - Parkinson's Disease Drugs Flashcards

1
Q

Parkinson’s disease is a _____ disorder

A

movement

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2
Q

When do symptoms usually appear?

A

60 yrs old

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3
Q

List 5 symptoms of Parkinson’s

A
  • rhythmic tremor
  • leaning forward
  • difficulty rising
  • muscle rigidity
  • shrinkage of handwriting
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4
Q

List 4 voluntary motor pathways

A
  • upper motoneurons
  • lower motoneurons
  • corticospinal pathway
  • piramidal tracts
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5
Q

List 4 involuntary motor pathways

A
  • extrapiramidal system
  • basal ganglia
  • reticular system
  • vestibular system
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6
Q

What is parkinson’s caused by?

A

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

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7
Q

When do parkinson’s symptoms occur?

A

when about 70% of nigrostriatal neurons are lost

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8
Q

Abnormal signalling leads to ??

A

impaired mobility

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9
Q

Describe the normal path of neurons

A

GABA neurons are inhibited by dopamine and stimulated by acetylcholine

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10
Q

Describe the path of neurons in parkinson’s disease

A

dopaminergic neurons die, leaving a relative excess of ACh

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11
Q

Describe the path of neurons in huntington’s disease

A

GABA neurons die as well as some ACh neurons

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12
Q

Symptoms amenable to drug therapy

A
  • bradykinesia
  • resting tremor
  • muscle rigidity
  • abnormal posture
  • early treatment for ‘neuronal sparing’
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13
Q

Discuss pharmacologic targets for parkinson’s

A
  • 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
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14
Q

dopamine receptors are ______

A

metabrotropic

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15
Q

D1 subfamily members

A

D1

D5

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16
Q

Describe D1 subfamily

A

Gs

Increase cAMP

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17
Q

D1 subfamily members

A

D2
D3
D4

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18
Q

Describe D2 subfamily

A

Gi

Decrease cAMP

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19
Q

Striatum has what kind of dopamine receptors

A

D1

D2

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20
Q

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

A 
MAO B inhibitors
Levodopa
Dopamine agonists
Amantadine
Anticholinergics
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21
Q

Describe the disposition characteristics of L-dopa

A
  • 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
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22
Q

Bioavailability issues with L-dopa

A
  • metabolism in intestine, blood, and peripheral tissues
  • concurrently ingested food (protein, iron)
  • only 1% actually enters the brain
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23
Q

Therapeutic effects of L-dopa

A
  • reduces rigidity and bradykinesia
  • improves motor function and speech
  • return of facial expression
  • first choice drug for improving motor function
24
Q

Side effects of L-dopa

A
  • 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
Q

An adjunct to L-dopa = ?

A

carbidopa

26
Q

How does carbidopa work?

A
  • 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
Q

Describe standard adjunct therapy for parkinson’s

A

L-dopa + carbidopa = Sinemet

L-dopa + bensarazide = Prolopa

28
Q

Another adjunct to L-dopa = ?

A

Entacapone

29
Q

Describe Entacapone

A
  • 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
Q

Sinemet + entacapone = ?

A

stalevo

31
Q

roprinirole/pramipexole are selective _______

A

dopamine agonists at D2/D3 receptors

32
Q

roprinirole/pramipexole:

bioavailability ?

A

50%

33
Q

roprinirole/pramipexole:

peak plasma concentration ?

A

1-3 hours after ingestion

34
Q

roprinirole/pramipexole:

plasma half life

A

5-6 hours

35
Q

Therapeutic effects of roprinirole/pramipexole

A
  • 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
Q

Side effects of dopamine agonists (including roprinirole/pramipexole)

A
  • 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
Q

Muscarinic antagonists:

representative drugs

A
  • trihexyphenidyl HCl and benzatropine mesylate
  • selective for muscarinic ACh type 1 receptor (M1R)
  • not first line therapy
38
Q

Muscarinic antagonists:

therapeutic effect

A
  • used mainly in young patients with severe tremor
  • inhibition of striata cholinergic activity
  • improves tremor but not rigidity
  • not recommended in elderly
39
Q

Muscarinic antagonists:

side effects

A 
dry mouth
blurred vision
urinary retention
constipation
mental confusion
hallucinations
delusions
drowsiness
glaucoma
40
Q

MAO-A metabolizes ?

A

NE and 5-HT

41
Q

MAO-B metabolizes ?

A

dopamine

42
Q

Selegiline is an ?

A

irreversible MAO-B inhibitor

43
Q

Bioavailability issues with Selegiline ?

A
  • negligible bioavailability after oral ingestion
  • very rapid absorption (peak conc. < 1 hr)
  • plasma half-life about 2 hr
44
Q

Therapeutic issues with Selegiline

A
  • 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
Q

Selegiline side effects

A
  • insomnia
  • cognitive problems
  • not to be used with other MAO-I drugs
46
Q

Selegiline is superseded by _______

A

rasagiline

47
Q

Explain: Selegiline is superseded by rasagiline

A
  • less production of amphetamine-like by-products
  • better bioavailability
  • useful in patients with depression and/or cognitive decline
48
Q

Amantadine is a ??

A

dopamine releaser

49
Q

bioavailability issues with amantadine

A
  • 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
Q

Amantadine - therapeutic effects

A
  • increases dopamine release in the CNS
  • only of short-term benefit (<6 mo)
  • sometimes used together with L-dopa
51
Q

Side effects of Amantadine (similar to L-dopa)

A
  • psychosis, hallucinations
  • confusion
  • nightmares
  • anorexia
  • livedo reticularis (reddish-blue netlike mottling of the skin)
52
Q

slide 35 - important

A

okay

53
Q

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

A

begin levodopa +/- COMTI

54
Q

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

A

begin dopamine agonist

55
Q

mild motor disability and no cognitive impairment = ??

A

begin MAO-B inhibitor

56
Q

Non-pharmacological therapeutics?

A

surgery -ablation and/or deep brain stimulation

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

stem cells - replacement of dopaminergic neurons

Pharmacology (21 decks)

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