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Special Populations > Parkinsons Med Chem > Flashcards

Parkinsons Med Chem Flashcards

1
Q

What is the pathophysiology of PD since it is a neurodegenerative disorder?

A

progressive and irreversible loss of neurons

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2
Q

Neuronal loss in what area of the brain results in loss of control of movement?

A

basal ganglia

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3
Q

Neuronal loss in what area of the brain results in cognitive impairment?

A

cortex

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4
Q

What are the 4 major features of PD?

A
  1. resting tremor
  2. brady kinesia
  3. muscular rigidity
  4. Postural imbalance leading to problems with gait and falling
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5
Q

How many neurons are lost before PD is typically diagnosed?

A

80% of DA neurons

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6
Q

What other diseases or drugs may cause Parkinsonism?

A
  1. stroke
  2. other Lewy body producing neurodegenerative disorder
  3. DA antagonists
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7
Q

Identification of what is confirmatory of PD?

A

Lewy bodies

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8
Q

What is a Lewy body?

A

clumps of individual misfolded a- synuclein proteins; can continue to recruit misfolded proteins

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9
Q

What areas do Lewy bodies form in early PD?

A
  1. brain stem
  2. olfactory bulb
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10
Q

What areas do Lewy bodies form in the clinical stage?

A
  1. misotemporal cortex
  2. midbrain
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11
Q

What areas do Lewy bodies form in late stage PD?

A

cerebral cortex

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12
Q

The loss of what major dopaminergic pathway causes motor symptoms?

A
  1. Nigrostriatal- substantia nigra to striatal pathways
  2. A9 cell bodies die in substantia nigra- loss DA production and of DA1 and DA2 receptors in the cortex and stiatum
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13
Q

The loss of what major dopaminergic pathway causes non-motor symptoms like emotional responsiveness?

A

Mesocortical (reward pathway)- VTA to olfactory bulb, amygdala, hippocampus, and medial prefrontal areas

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14
Q

What enzymes responsible for DA metabolism do we inhibit when treating PD?

A
  1. MAO-B inhibitor
  2. COMT inhibitor
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15
Q

What genetic factors lead to PD?

A
  1. mutations
  2. genetic risk (park genes: a- synuclein processing)
  3. epigenetic changes
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16
Q

What environmental factors lead to PD?

A

Mitochondrial disruptors:
1. MPTP found in street drugs
2. Paraquat in fertilizer

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17
Q

What are the normal roles of a- synuclein protein?

A
  1. protects DNA/ RNA from oxidative stress
  2. clustering and release of synaptic vesicles
  3. stabilization of electron transport chain
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18
Q

What is the normal structure and function of Park-1 gene?

A
  1. amphipathic region- lipid membrane-binding region
  2. hydrophobic region- fibrillation core
  3. Acidic region- N-terminus interacting region interacts with DNA/RNA
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19
Q

How do Selegiline, Deprenyl, and Rasagiline inactivate MAO-B to increase DA?

A

propargyl amine mimics DA and covalently modifies the active site of the enzyme resulting in an imine and MAO-B Flavin

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20
Q

Why is Deprenyl considered a selective MAO-B inhibitor?

A

Ki Deprenyl&raquo_space;> Ki Selegiline, Rasagiline

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21
Q

What is a by-product of the inhibition of MAO-B with selegiline and Deprenyl ?

A

L-amphetamine due to first pass metabolism resulting in amphetamine-like side effects

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22
Q

What are the side effects of Selegiline and Rasagiline inactivating MAO-A?

A
  1. cheese effect- taste aversion to cheese, pickled fish, cured meat
  2. increased Tyramine –> release of NE and EP —> may cause hypertensive crisis
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23
Q

Why does Rasagiline not produce amphetamine-like byproducts?

A

different base, same propargyl amine; no first pass metabolism

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24
Q

What is the MOA of Safinamide XADAGO?

A

a-aminoamide (AAA) inhibitors:
1. reversible, MAO-B selective inhibitor
2. inhibits DAT
3. inhibits voltage-dependent sodium channel blocker
4. blocks glutamate release

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25
Q

What is the MOA of Levodopa?

A

precursor of DA

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26
Q

What usually starts to happen around years 4-6 of L-DOPA treatment?

A

end-of-dose akinesia

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27
Q

What usually starts to happen around years 6-10 of L-DOPA treatment?

A

drug induced dyskinesia from supratherapeutic dose

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28
Q

What drugs are in Stalevo?

A

Entacapone
L-DOPA
Carbidopa

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29
Q

What is the MOA of Benserazide and Carbidopa?

A

reversible and competative inhibition of DOPA decarboxylase in the periphery

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30
Q

Why do Benserazide and Carbidopa only act in the periphery?

A

cannot cross the BBB

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31
Q

Why does reversible and competative inhibition of DOPA decarboxylase in the periphery help with PD?

A

Less L-DOPA coversion to dopamine; more L-DOPA can be transported across the BBB to be covered to DA in the brain

32
Q

What is the MOA of COMT inhibitors?

A

reversible and competative inhibition of L-DOPA degredation by inhibiting COMT in the periphery

33
Q

What are the 3 COMT inhibitor agents?

A
  1. Entacapone
  2. Tolcapone
  3. Opicapone
34
Q

Why is Tolcapone banned in Canada?

A

induces liver damage

35
Q

What is the difference between Opicapone and the other COMT inhibitors?

A
  1. 2 site binding results in high affinity
  2. pyridine N-oxide prevents CNS penetration and reduced toxicity
36
Q

What medications can cause secondary PD?

A
  1. Traditional antipsychotics
  2. anti-dopaminergic antiemetics
  3. central dopamine depleting antihypertensives (Reserpine, methyldopa)
  4. cholinesterase inhibitors
37
Q

What clinical presentations are identified by TRAP?

A
  1. Tremor (resting/ one sided tremor)
  2. Rigidity
  3. Akinesia/ bradykinesia
  4. Postural instability
38
Q

What are mental status changes seen in PD?

A
  1. confusion
  2. dementia
  3. psychosis
  4. sleep disturbances
38
Q

What are symptoms of autonomic dysfunction in PD?

A
  1. incontinence
  2. constipation
  3. orthostasis
  4. flushing
  5. sexual disturbances
39
Q

What is the gold standard for monitoring the response to medications used to decrease signs and symptoms of PD at any stage?

A

UPDRS

40
Q

When should we treat PD or increase intensity of therapy?

A

when symptoms affect quality of life

41
Q

What are the SEs of SINEMET?

A
  1. N/V
  2. orthostatic hypotension
  3. hallucinations
  4. delusions
  5. confusion
  6. agitation
  7. cardiac arrhythmias
42
Q

What are long-term effects of SINEMET?

A
  1. wearing on/off
  2. involuntary movements (dyskinesias)
43
Q

What agents are in SINEMET?

A

L-DOPA / Carbidopa

44
Q

What is the wearing off phenomenon?

A

return of PD symptoms before the next dose

45
Q

What is the on-off phenomenon?

A

unpredictable return of PD symtptoms

46
Q

What are dyskinesias?

A

drug-induced involuntary movements; dose-limiting prompts change in treatment

47
Q

What are interactions with Benserazide and Carbidopa that decrease effectiveness?

A
  1. avoid Fe salts within 3 hours
  2. excessive vit B6 decreases absorption
  3. avoid high fat meals
48
Q

What type of diet should be followed to maximize clinical effects of SINEMET?

A

lower protein meals throughout the day with main protein meal at supper

49
Q

What are advantages to using levodopa/ carbidopa CR?

A
  1. less frequent dosing results in higher morning levels
  2. less peak-trough variation
  3. less motor fluctuations
50
Q

What are disadvantages to using levodopa/ carbidopa CR?

A
  1. night time hallucinations/ vivid dreams
  2. 25-30% dose increased required
51
Q

What are the levodopa/ carbidopa extended release agents?

A
  1. SINEMET CR
  2. RYTARY
52
Q

Risk of what SE increases when using RYTARY?

A

GI bleed

53
Q

What is an advantage to the RYTARY capsule dosage form?

A

can be opened and sprinkled on applesauce

54
Q

What role does Parcopa have in therapy?

A

levodopa/ carbidopa ODT:
1. first morning dose
2. PRN for acute wearing off effects associated with freezing
3. can be a substitute for IR Sinemet

55
Q

What are disadvantages to Parcopa?

A
  1. more peak dose dyskineasia
  2. hypotension
56
Q

What role does Inbrija have in therapy?

A

levodopa/ carbidopa orally inhaled powder:
1. rescue for severe “off” episodes
2. NOT a substitute for IR Sinemet

57
Q

What are SEs / exacerbations seen with Inbrija?

A
  1. falling asleep
  2. IOP in glaucoma
  3. invoke bronchospasm
  4. low BP
  5. hallucinations
  6. uncontrollable impulses
  7. dyskinesia
  8. change in sputum color
58
Q

What can be done if Sinemet dose modifications do not help with hypotension proportional to blood peak?

A
  1. fludrocortisone
  2. midodrine
  3. droxidopa
59
Q

How can wearing off be managed with Sinemet?

A
  1. add dopamine agonist
  2. MAO-B inhibitor
  3. COMT inhibitor
  4. increase frequency / dose
  5. change to CR
60
Q

How can on-off be managed with Sinemet?

A
  1. add COMT inhibitor- Entacapone
  2. add MAO-B inhibitor rasagiline/ selegiline
  3. add DA agonist- pramipexole/ ropinrole
  4. redistribute dietary protein
61
Q

How can dyskinesias with Sinemet be managed?

A
  1. decrease levodopa dose
  2. add amantadine
62
Q

What are SEs with Amatadine?

A
  1. dry mouth
  2. sedation
  3. vivid dreams
  4. LIVIDO RETICULARIS RASH
63
Q

What is the role of Istradefylline in PD?

A

for off episodes

64
Q

How are hallucinations/ delusions managed from Sinemet and PD?

A
  1. avoid nighttime dosing especially ER
  2. Antipsychotics (Clozapine, Quetiapine)
  3. Pimvanserin
65
Q

What are the SEs with Pimvanserin?

A
  1. QT prolongation
  2. interacts with CYP3A4 inhibitors and inducers
66
Q

What is the MOA of Pimvanserin?

A

serotonin 2A inverse agonist/ antagonist atypical antipsychotic

67
Q

What is Selegilene and Rasagliline role in therapy?

A
  1. younger patients/ early theray
  2. adjunct to allow for Sinemet dose reduction
68
Q

What are SEs with MAO-B inhibitors Selegiline, Rasagiline, Safinamide?

A
  1. hallucinations
  2. anxiety
  3. insomnia (amphetamine-like metabolites)
  4. dyskinesia
  5. delirium
  6. hypertensive crisis
69
Q

What increases the risk of hyperensive crisis?

A

concurrently or within 14 days of:
1. antidepressants
2. narcotics (meperidine)
3. MAO inhibitors (also linezolid)
4. cyclobenzaprine
5. DM
6. St. John’s wort
7. general anesthesia
tyramine containing foods

70
Q

What is the role of Safinamide in therapy?

A

add-on treatment in patients expirencing wearing off from Sinemet

71
Q

What role do dopamine agonists have in PD?

A
  1. first line monotherapy in younger patients
  2. add on for late stage allowing for lower doses or longer intervals
  3. some evidence in secondary parkinsonism due to ischemic brain trauma
72
Q

What are SEs of non-ergot DA agonists Pramiprexole, Ropinerole, Rotigotine?

A
  1. somolence
  2. nausea
  3. hypotension
  4. compulsive behaviors (gambling, sex, substance abuse)
73
Q

How are oral DA agonists dosed when starting therapy?

A

titrated from low to high at weekly increments as tolerated

74
Q

What is the role of injectable Apomorphine?

A

acute on-off dyskinesias (mostly freezing episodes in patients on high dose Sinemet

75
Q

What are SEs with Apomorphine injection?

A
  1. dyskinesias
  2. falls
  3. hallucinations
  4. headaches
  5. injection site reaction
  6. N/V
  7. somnolence
76
Q

What are CIs to using Apomorphine inj?

A
  1. sodium metabisulfite allergy
  2. 5HT3 antagonists including antiemetics (ondencetron etc) and alosetron

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