Parkinson's Disease

Question 1

When do Parkinson’s symptoms appear?

Answer 1

Around age 60 but can present in much younger people

Question 2

What are the symptoms of Parkinson’s disease?

Answer 2

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

Question 3

What is involved in the involuntary motor pathway?

Answer 3

Extrapiramidal system, basal ganglia, reticular system, vestibular system

Question 4

What occurs in the brain in Parkinson’s disease?

Answer 4

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

Question 5

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

Answer 5

When about 70% of nigrostriatal neurons are lost

Question 6

What abnormal signalling leads to impaired mobility?

Answer 6

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

Question 7

What is the cause of parkinsons?

Answer 7

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)

Question 8

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

Answer 8

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

Question 9

What are the pharmacological targets for Parkinson’?

Answer 9

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

Question 10

How is dopamine synthesized in the smooth muscle cells?

Answer 10

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)

Question 11

How is dopamine synthesized in the brain?

Answer 11

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

Question 12

How does dopamine leave the presynaptic terminal in the brain?

Answer 12

Via a synaptic vesicle or monoamine oxidase (MAOB)

Question 13

What are the subtypes of dopamine receptors?

Answer 13

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

Question 14

What are some examples of MAO B inhibitors?

Answer 14

Rasagiline, selegiline

Question 15

What are some examples of levodopa combination therapies?

Answer 15

Levodopa/carbidopa

Levodopa/benserazide

Question 16

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

Answer 16

Pramipexole, ropinirole

Question 17

What are some examples of anticholinergics?

Answer 17

Benztropine, ethopropzine, procycline, trihexyphenidyl

Question 18

What are the disposition characteristics of L-dopa?

Answer 18

Rapidly absorbed in small intestine, crosses BBB

Peak concentration in 1-2 hours, half-life in 1-3 hours

Question 19

What causes bioavailability issues with L-dopa?

Answer 19

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

Question 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

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

Answer 22

Dyskinesias (abnormal involuntary movements)

“On-off” effect (taking the medication does nothing

Question 23

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

Answer 23

Atypical antipsychotics like clozapoine, risperidone, dopamine antagonists

Question 24

What does carbidopa or benserazide do for adjunct therapy?

Answer 24

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)

Question 25

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

Answer 25

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

Question 26

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

Answer 26

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

Question 27

What is a problem with entacapone adjunct therapy?

Answer 27

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

Question 28

What is amantadine?

Answer 28

Dopamine releaser (unknown mechanism of action)

Question 29

What are the bioavailability issues with amantadine?

Answer 29

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

Question 30

What are the therapeutic effects of amantadine?

Answer 30

Increases dopamine release in the CNS | Only short term benefit (

Question 31

What are the side effects of amantadine?

Answer 31

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

Question 32

What are the bioavailability issues with ropinirole or pramipexole?

Answer 32

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

Question 33

What are the therapeutic effects of ropinirole or pramipexole?

Answer 33

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

Question 34

What can ropinirole or pramipexole be used for?

Answer 34

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

Question 35

What are the side effects of dopamine agonists?

Answer 35

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

Question 36

What method of delivery of dopamine agonist can reduce dyskinesia?

Answer 36

Transdermal patch delivery

Question 37

What dopamine agonist is given in an emergency situation?

Answer 37

Apomorphine

Question 38

What are the therapeutic effects of muscarinic antagonists?

Answer 38

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

Question 39

What are the side effects of muscarinic antagonists?

Answer 39

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

Question 40

What is a contraindication for muscarinic antagonists?

Answer 40

Glaucoma | M3 receptors in iris

Question 41

What does monoamine oxidase A do?

Answer 41

Metabolized norepinephrine and serotonin

Question 42

What does monoamine oxidase B do?

Answer 42

Metabolizes dopamine

Question 43

What are the bioavailability issues with selegiline?

Answer 43

Negligible bioavailability after oral ingestion | Very rapid absorption (

Question 44

What does selegiline do?

Answer 44

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

Question 45

What is a therapeutic issue with selegiline?

Answer 45

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

Question 46

What are the side effects of selegiline?

Answer 46

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

Question 47

What makes rasagiline better than selegiline?

Answer 47

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

Question 48

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

Answer 48

Levodopa with or without a COMT inhibitor (entacapone)

Question 49

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

Answer 49

Dopamine agonist

Question 50

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

Answer 50

MAO-B inhibitor

Question 51

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

Answer 51

``` 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 ```