Lecture 12 - Parkinson's Disease Drugs Flashcards
1
Q
Parkinson’s disease is a _____ disorder
A
movement
2
Q
When do symptoms usually appear?
A
60 yrs old
3
Q
List 5 symptoms of Parkinson’s
A
- rhythmic tremor
- leaning forward
- difficulty rising
- muscle rigidity
- shrinkage of handwriting
4
Q
List 4 voluntary motor pathways
A
- upper motoneurons
- lower motoneurons
- corticospinal pathway
- piramidal tracts
5
Q
List 4 involuntary motor pathways
A
- extrapiramidal system
- basal ganglia
- reticular system
- vestibular system
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)
7
Q
When do parkinson’s symptoms occur?
A
when about 70% of nigrostriatal neurons are lost
8
Q
Abnormal signalling leads to ??
A
impaired mobility
9
Q
Describe the normal path of neurons
A
GABA neurons are inhibited by dopamine and stimulated by acetylcholine
10
Q
Describe the path of neurons in parkinson’s disease
A
dopaminergic neurons die, leaving a relative excess of ACh
11
Q
Describe the path of neurons in huntington’s disease
A
GABA neurons die as well as some ACh neurons
12
Q
Symptoms amenable to drug therapy
A
- bradykinesia
- resting tremor
- muscle rigidity
- abnormal posture
- early treatment for ‘neuronal sparing’
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
14
Q
dopamine receptors are ______
A
metabrotropic
15
Q
D1 subfamily members
A
D1
D5
16
Q
Describe D1 subfamily
A
Gs
Increase cAMP
17
Q
D1 subfamily members
A
D2
D3
D4
18
Q
Describe D2 subfamily
A
Gi
Decrease cAMP
19
Q
Striatum has what kind of dopamine receptors
A
D1
D2
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
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
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
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
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
