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Flashcards in Parkinson's Disease Deck (51):
1

When do Parkinson's symptoms appear?

Around age 60 but can present in much younger people

2

What are the symptoms of Parkinson's disease?

Pill rolling motion, tremor at rest, not sleep and reduce or stop when movement begins
Muscle rigidity (cogwheel)
Loss of facial expression and fidgety movement
Difficulty getting out of chair (initating movement), shrinkage of handwriting
Stooped posture, problems with balance, weak voice, shuffling steps

3

What is involved in the involuntary motor pathway?

Extrapiramidal system, basal ganglia, reticular system, vestibular system

4

What occurs in the brain in Parkinson's disease?

Loss of neuron in the substantia nigra and thus loss of dopamine innervation of the striatum (basal ganglia)
Other neurons are lost in the cortex and other parts of the brain
Lewy bodies are present

5

What does the appearance of parkinson's correlate with in the brain?

When about 70% of nigrostriatal neurons are lost

6

What abnormal signalling leads to impaired mobility?

The balance between acetylcholine and dopamine is lost. Increased GABA output from excess acetylcholine

7

What is the cause of parkinsons?

Actual cause is not known
Metabolism of dopamine by MAO B produces free radicals leading to abnormal accumulation and production of proteins
Environmental toxin (MPTP)
Genetics (GBA, LARK2 both involved in autophagy)
Dopamine itself (oxidant)
Autophagy/lysomal pathway gets messed up (destroys and recycles parts of cell that aren't working)

8

Which symptoms of parkinson's can be amended by drug therapy?

Bradykinesia (slow initiation of movement)
Tremor at rest
Muscle rigidity
Abnormal posture

9

What are the pharmacological targets for Parkinson'?

Increase dopamine signalling in the brain
Decrease cholinergic activity
Decrease peripheral dopamine effects at D1/D2 receptors
Decrease peripheral L-DOPA metabolism

10

How is dopamine synthesized in the smooth muscle cells?

Tyrosine is converted to L-DOPA which can then be converted to Dopamine by dopa decarboxylase or 3-methyldopa by catechol-o-methyltransferase (don't want build up)

11

How is dopamine synthesized in the brain?

Tyrosine is converted to L-DOPA by tyrosine hydroxylase and then it is converted to dopamine by dopa decarboxylase

12

How does dopamine leave the presynaptic terminal in the brain?

Via a synaptic vesicle or monoamine oxidase (MAOB)

13

What are the subtypes of dopamine receptors?

All are metabotropic, are also present in the periphery smooth muscle
D1: Excitatory (Gs, increases cAMP) D1, D5
D2: Inhibitory (Gi, decreases cAMP) D2, D3, D4

14

What are some examples of MAO B inhibitors?

Rasagiline, selegiline

15

What are some examples of levodopa combination therapies?

Levodopa/carbidopa
Levodopa/benserazide

16

What are some examples of dopamine agonists (D2/D3)?

Pramipexole, ropinirole

17

What are some examples of anticholinergics?

Benztropine, ethopropzine, procycline, trihexyphenidyl

18

What are the disposition characteristics of L-dopa?

Rapidly absorbed in small intestine, crosses BBB
Peak concentration in 1-2 hours, half-life in 1-3 hours

19

What causes bioavailability issues with L-dopa?

Metabolism in intestine, blood and peripheral tissues
Concurrently ingested food (protein, iron)
Very small portion gets into brain (combo therapy helps more get in)

20

What are the effects of the use of L-dopa?

Reduces rigidity and bradykinesia
Improves motor function and speech
Return of facial expression

21

What are some of the side effects of L-dopa?

Wearing off more and more, hypotension and cardiac arrhythmias, anorexia, behavioral changes, insomnia, confusion, psychosis, hallucinations

22

What side effects cause patients to be moved to a different drug from L-dopa?

Dyskinesias (abnormal involuntary movements)
"On-off" effect (taking the medication does nothing

23

What can patients be given if they're experiencing hallucinations and stuff from L-dopa?

Atypical antipsychotics like clozapoine, risperidone, dopamine antagonists

24

What does carbidopa or benserazide do for adjunct therapy?

Inhibits dopa decarboxylase in the periphery to allow it to go back to the brain (doesn't cross BBB)
Reduces the amount of L-dopa required (reduces adverse effects)

25

How is entacapone used as an adjunct therapy with L-dopa?

Selective and reversible inhibitor of peripheral COMT (reduces peripheral metabolism of L-dopa), allowing more to be sent back to the brain

26

What is entacapone-L-dopa adjunct therapy used for?

Later stage Parkinson's disease (with motor symptoms)
When wearing off and on off effects from long term L-dopa treatment

27

What is a problem with entacapone adjunct therapy?

Can enhance the adverse effects of L-dopa like dyskinesias, nausea, psychosis and confusion

28

What is amantadine?

Dopamine releaser (unknown mechanism of action)

29

What are the bioavailability issues with amantadine?

Variable absorption in the stomach
12-14 hour half life
Virtually complete excretion by the kidney

30

What are the therapeutic effects of amantadine?

Increases dopamine release in the CNS
Only short term benefit (

31

What are the side effects of amantadine?

Psychosis, hallucinations, confusion, nightmares, anorexia
Livedo reticularis (reddish blue netlike mottling of the skin of the extremities) with long term use due to vasoconstriction

32

What are the bioavailability issues with ropinirole or pramipexole?

Onset 1-3 hours after ingestion
Half life 5-6 hours

33

What are the therapeutic effects of ropinirole or pramipexole?

Act on D2 and D3 receptors in and outside of the periphery
Improves depressive symptoms

34

What can ropinirole or pramipexole be used for?

May be combined with L-dopa to treat "on-off" effects
Helpful if patient is also experiencing depression

35

What are the side effects of dopamine agonists?

Dyskinesia (action on D2 receptors outside of corpus striatum)
Activates other CNS D1-3 receptors and suppresses prolactin secretion and growth hormone release
Hypotension
Visual and auditory
Hypersexuality

36

What method of delivery of dopamine agonist can reduce dyskinesia?

Transdermal patch delivery

37

What dopamine agonist is given in an emergency situation?

Apomorphine

38

What are the therapeutic effects of muscarinic antagonists?

Inhibition of striatal cholinergic activity
Improves tremor but not
rigidity
Selective for muscarinic 1 receptor

39

What are the side effects of muscarinic antagonists?

Dry mouth, blurred vision, urinary retention, constipation, delusions, hallucinations, drowsiness

40

What is a contraindication for muscarinic antagonists?

Glaucoma
M3 receptors in iris

41

What does monoamine oxidase A do?

Metabolized norepinephrine and serotonin

42

What does monoamine oxidase B do?

Metabolizes dopamine

43

What are the bioavailability issues with selegiline?

Negligible bioavailability after oral ingestion
Very rapid absorption (

44

What does selegiline do?

Enhances effects of L-dopa in the brain, useful to manage "on-off" effect
Can be used with the doses

45

What is a therapeutic issue with selegiline?

Increased death rate compared to L-dopa when used as a first treatment for mild disease (animal studies suggested slowing of disease)

46

What are the side effects of selegiline?

Insomnia, cognitive problems
Don't use with other MAOi's (will break down enzyme)

47

What makes rasagiline better than selegiline?

Less production of amphetamine-like by-products
Better bioavailability
Useful in patients with depression and/or cognitive decline

48

What is the first line therapy for moderate to severe Parkinson's with cognitive impairment?

Levodopa with or without a COMT inhibitor (entacapone)

49

What is the first line therapy for mild to moderate Parkinson's with no cognitive impairment?

Dopamine agonist

50

What is the first line therapy for mild parkinson's with no cognitive impairment?

MAO-B inhibitor

51

What are some non-pharmacological treatments for Parkinson's?

Surgery (ablation to reduce tremor) or deep brain stimulation (parts of basal ganglia- inhibit STN to reduce dyskinesia)
Growth factors (GDNF)
Stem cells to replace dopaminergic neurons