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Pharmacology II > Parkinson's Disease > Flashcards

Parkinson's Disease Flashcards

1
Q

Dr. James Parkinson described parkinson’s disease as having what symptoms?

A

Tremor, bradykinesia, gait, and postural disturbances.

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2
Q

When does Parkinson’s Disease normally onset?

A

Early 60’s

10% prior to age 40

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3
Q

What are the impacts of Parkinson’s on the individual, family, and society?

A

Financial burden
Need for care giving
Changes in family roles/activities
Changing cognitive/psychological functioning of patient

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4
Q

What are the ADLs affected by in Parkinson’s?

A

Speech and tremor

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5
Q

What are the risk factors of Parkinson’s disease?

A

AGE- most important
Positive family hx
Male gender
Environmental exposure- herbacide and pesticide exposure, metals (mg, fe), well water, farming, rural residence, wood pulp mills; and steel alloy industries
Race
Life experiences (trauma, emotional stress, personality traits like shyness and depression)
Inverse correlation: smoking, caffeine

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6
Q

What pathway is the most affected by age?

A

Dopamine

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7
Q

What type of receptors are lost progressively in Parkinsons?

A

Dopamine

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8
Q

What are the clinical symptoms of parkinsons?

A

Resting tremor, bradykinesia, cogwheel rigitiy and postural instability

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9
Q

What is the most common first symptom of PD, usually asymmetric and most evident in one hand with arm at rest?

A

Resting tremor

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10
Q

What is difficulty with daily activities such as writing, shaving, using knife and fork, and opening buttons; decreased blinking, masked facies, slowed chewing and swallowing?

A

Bradykinesia

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11
Q

What is muscle tone that is increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints; stooped posture, anteroflexed head, and flexed knees and elbows?

A

Cogwheel rigidity

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12
Q

What is caused by the loss of postural reflexes in PD?

A

Postural instability

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13
Q

What does TRAP stand for in PD clinical presentation?

A 
Tremor (rest)
Rigidity- increased muscle tone
Akinesia- lack of spontaneous movement
Bradykinesia-slowness of movement
Postural instability- doesnt develop until later stages
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14
Q

What are other clinical features associated with PD?

A 
Masked facies
Drooling
Hypophonia
Micrographia
Depression
Fatigue
Difficulty w/ ADLs
Decreased arm swing
Difficulty rolling in bed
Slowness of gait
PAIN
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15
Q

What are the advanced symptoms of PD?

A 
Dysphagia
Falls
Freezing in gaits
Dementia
Psychosis
Postural hypotension
Sexual dysfunction
"Wearing off"
Dyskinesias
Bladder dysfunction
Anal Dysfunction
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16
Q

What stage of PD has no clinical signs that are evident?

A

Stage 0

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17
Q

What stage of PD has no unilateral involvement?

A

Stage I

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18
Q

What stage of PD has bilateral involvement w/o postural abnormalities?

A

Stage II

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19
Q

What stage of PD has bilateral involvement w/ mild postural imbalance on exam or hx of poor balance/falls; patient leads independent life?

A

Stage III

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20
Q

What stage of PD has bilateral involvement w/ postural instability; patient requires considerable assistance?

A

Stage IV

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21
Q

What stage of PD has severe, fully developed, end-stage disease; bed or wheelchair confined?

A

What stage of PD

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22
Q

In the non-disease state of PD what is there a balance between?

A

The inhibitory dopaminergic and excitatory cholinergic systems

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23
Q

What is the basic pathophysiology for PD?

A
  • Loss of nigrostriatal DA neurons in basal ganglia
  • Primary loss of DA leads to secondary increase in Ach in the basal ganglia
  • Loss of pigmented DA neurons in the pars compaca of the substantia nigra
  • Lewy body formation
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24
Q

If you develop PD at a young age is it from neurotoxicity?

A

No its genetic

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25
Q

What imaging is needed for preclinical PD disease diagnosis?

A

PET; SPECT imaging

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26
Q

What are the mechanisms for treatment for PD?

A

-Increase endogenous DA- inhibit peripheral metabolism by DA decarboxylase, Inhibit COMT, inhibit central and peripheral MAO B
DA agonists- D1, D2, and D3, partial agonists
-Adenosine A2a
-Anticholinergics

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27
Q

What are the therapeutics of PD?

A

Non-pharmocological interventions

Pharmacotherapy

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28
Q

What is the goal of pharmacotherapy in PD?

A

To minimize disability and side effects while maintaining quality of life

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29
Q

What are the non-pharmacological interventions of PD?

A
  • Patient and caregiver education- selective info on stage of disease is least anxiety-provoking
  • supportive/counseling- peer and group, legal and financial
  • Exercise
  • Nutrition
  • Surgery
  • Psychological Support- depression, litmited social functioning, poor QOL, severe disease
  • Utilize safety devices- grab bars, bath seats, emergency systems
30
Q

How should you approach pharmacotherapy?

A
  • Treatment planning must include short-term relief and long-term management
  • Manage potential side effects
  • Provide symptom control for ADL
  • Timing of initial therapy based on patient functional ability and physician philosophy
  • Treatment can evolve as patient’s illness progresses
  • Titrate treatment over time to maximize therapeutic response
31
Q

What is the ultimate goal of pharmacotherapy for PD?

A

To slow or halt progression by replenishing dopamine

32
Q

What do you do to increase dopamine?

A

-DA precursors- Leva-Dopa with ADDC inhibitor, carbidopa (peripheral inhibitor)
-DA agonists- Bromocriptine
-Prevent DA metabolism- MAO inhibitor (selegiline),Inhibit COMT (cabergoline)
Increase DA release- Amantadine- antiviral med that is used primary because it increases release of DA.

33
Q

What does decreasing Ach do in PD?

A

Helps w/ symptomatic tremor and rigidity (anticholinergics)

34
Q

What is the GOLD STANDARD treatment of Parkinson’s disease?

A

Levodopa (L-dopa)

35
Q

Levodopa/Carbidopa (Sinemet)- MOA

A

Crosses the BBB
Taken up by dopaminergic presynaptic nerve terminals in the straitum & is converted to dopamine by aromatic L-amino acid decarboxylase
Some levodopa is converted to dopamine peripherally
Co-dependent upon enzyme inhibitor Carbidopa

36
Q

Levodopa/Carbidopa (Sinemet)- Pharmacologic effects

A
  • 75% of patients respond to L-Dopa, with >50% reduction in the severity of their symptoms. Most commonly prescribed remedy for Parkinson’s
  • Tolerance develops usually after 3-5 years of therapy.
37
Q

What is “wearing off”?

A
  • Also known as “end-of-dose wearing off”
  • Benefits from each levodopa dose get shorter over time, and symptoms return between doses
  • This may mean the disease has worsened
  • Often treatable with drug therapies
  • Affects 2 0f 3 people who have been taking levodopa for 5 or more years
38
Q

What are the symptoms of “wearing off”?

A 
Must have 1 or more b/w levodopa doses
Slowness of movement (bradykinesia)
Tremor
Feeling of internal tremor
Decreased manual dexterity
Inability to move (akinesia) early in the morning
Sudden muscle spasms (dystonia)
"Pins and needles" feeling (paresthesia)
Pain
SOB
Constipation
Voice softness
39
Q

What are the strategies to address “wearing off”

A

Increasing levodopa dose or number of daily doses
Adding a dopamine agonist or increasing its dose
Using a COMT inhibitor

40
Q

Levodopa/Carbidopa (Sinemet)- Absorption and metabolism

A

Take on an empty stomach to increase absorption and transport across blood-brain barrier
Short 1/2 life thats why its dosed frequently

41
Q

Levodopa/Carbidopa (Sinemet)- ADRs

A

Usually due to dopamine in the periphery
-N/V/anorexia- usually transient from stimulation of emetic center
-CV-tachycardia, arrhythmias
CNS- visual and auditory hallucinations, depression, mania, anxiety, and abnormal involuntary movements (dyskinesia)

42
Q

Levodopa/Carbidopa (Sinemet)- interactions

A
  • Vitamin B6 (Pyridoxine) increase peripheral breakdown of levodopa.
  • MAO Inhibitors-HTN crisis due to increase catecholamine production.
  • Antipsychotic meds work against levodopa
43
Q

Levodopa/Carbidopa (Sinemet)- Carbidopa MOA

A

An inhibitor of the aromatic L-amino acid decarboxylase, binding to the pyridoxal binding site of the enzyme.

  • Increases bioavailability of levodopa by blocking the enzyme in the periphery but not the CNS thus making more levodopa available for the CNS.
  • Decreases the amount of levodopa needed approximately 75%.
  • Greatly reduces the incidence of N/V and untoward effects on the heart.
44
Q

Levodopa/Carbidopa (Sinemet)- Carbidopa ADRs

A

Increases the incidence &/or severity of behavioral ADRs of L-dopa
Increases dyskinesias produced by L-dopa

45
Q

What are the direct dopamine agonists and what do they do?

A 
Directly stimulate DA receptors 
Used alone of in combo w/ carbidopa/levodopa
-Pergolide (permax)
-Bromocriptine (parlodel)
-Pramipexole (Mirapex)
-Ropinirole (Requip)
-Apomophine (Apokyn)
-Cabergoine (Dostinex)
46
Q

What are the risks/benefits associated with dopamine agonists?

A

-Reduced risk of motor complications and dyskinesias vs. Carbidopa/Levodopa

  • Combination with Carbidopa/Levodopa:
  • Increased symptom management
  • Minimized motor complications
  • Increase “time on”
  • Decrease need of Carbidopa/Levodopa

May be beneficial as monotherapy in early disease

47
Q

Are dopamine agonists potentially neuroprotective?

A

Yes

  • Interact w/ presynaptic DA autoreceptors and decrease autooxidation, free radical formation
  • Reduce levodopa requirements, reducing toxic levodopa-mediated metabolites
  • Antioxidant properties
48
Q

Dopamine agonist- Side effects/ADRs

A 
Similar to levodopa
N/V, orthostasis, psychosis
Epidoses of narcolepsy reported w/ pramipexole and ropinirole
Incidence 30-50%
Higher dose or rapid titration
49
Q

Dopamine agonist- Side effects/ADRs continued

A

Possible increased risk of compulsive gambling
Proposed mechanism: stimulation of dopamine release in the mesolimbic DA pathway
Treatment: reduce DA agonist dose or switch to different DA agonist
Inform patient of this potential risk

50
Q

Ropinirole

A

Dopamine Agonist

CYP1A2

51
Q

Bromocriptine

A

Dopamine Agonist

High first-pass metabolism, highly protein bound

52
Q

Pramipexole

A

Dopamine Agonist

Renally excreted

53
Q

What are the adverse effects of dopamine agonists?

A 
Adverse effects often limiting factor…
Sedating effects, including somnolence and unintended sleep episodes
Hypotension
Hallucinations or psychosis
May cause dyskinesias
N/V
Leg edema
54
Q

Rotigotine (Nuepro)- MOA and ROA

A

Dopamine agonist-transdermal
High affinity for all dopamine receptor subtypes
Once daily transdermal delivery
Benefit is you dont have to remember to take the pills but it still has the same side effects as other dopamine agonists
More continuous dopaminergic stimulation, thought to lessen possibility of motor fluctuation and dyskinesias associated with pulsatile dopamine agonist treatment long-term

55
Q

Rotigotine (Nuepro)- AEs

A

Application-site reactions, nausea, somnolence

Serious AEs- sudden onset of sleep and brief LOC while driving

56
Q

Selegiline (Deprenyl; Eldepryl)- MOA

A

MAO-B inhibitor
MOA: Irreversible MAO-B inhibitor that blocks dopamine breakdown and can extend the actions of L-Dopa up to 1 hour
Can extend the time before L-Dopa is needed by about 9 months

57
Q

Selegiline (Deprenyl; Eldepryl)-suggested uses and ADRS

A

Suggested for: pts whose cognition is intact
Pts with “Wearing-off” of L-dopa actions
ADRs- Insomnia, jitteriness, HTN, also can worsen preexisting sx such as hallucinations and delusions. Rare serotonin syndrome w// concomitant SSRI treatment

58
Q

Emsam (Transdermal selegiline)

A

MAO-B inhibitor

Approved fro adjunctive tx (not given alone only w/ levodopa) of PD at low doses

59
Q

Rasagiline (Azilect)

A 
MAO-B inhibitor
Selective, irreversible MAO-B inhibitor
5x more potent than selegiline
Used for first time tx of pts w/ early PD (2006), and also as an adjunct to levodipa in moderate to advanced PD
Expensive and not used often
60
Q

Amantadine (Symmetrel) (Symadine)- MOA

A

Originally developed as antiviral, effective in treating influenza
MOA: unknown but appears to enhance the synthesis & release of dopamine; inhibits reuptake of dopamine; blocks cholinergic receptors and inhibits NMDA receptors
Less efficacious than L-Dopa
Slightly more efficacious than anticholinergic agents
Adjunct to L-Dopa
Relieves symptoms of bradykinesia, rigidity and tremor

61
Q

Amantadine (Symmetrel) (Symadine)- ADRs

A

Fewer side effects than L-dopa or anticholinergic agents
When administered w/anticholinergic, hallucinations, confusion and nightmares may occur
Insomnia, dizziness, and slurred speech
Administer w/ caution in patients w/ renal disease

62
Q

Catochol-O-methytranferase inhibitors (COMT Inhibitor)- MOA

A

Indicated for treatment of patients with PD experiencing end-of-dose “wearing off” with levodopa
Inhibits COMT both peripherally and centrally. These agents work to reduce the concentration of 3-O-methyldopa which competes w/L-Dopa for active transport; also blocks metabolism of DA
Increase levodopa bioavailability in brain
NO ROLE AS MONOTHERAPY

63
Q

Tolcapone (Tasmar)

A

COMT inhibitor- peripheral and central
Readily absorbed
Highly protein bound (99%)
Strict LFT monitoring-DC if elevated or sign of liver failure
Informed consent available package insert (due to liver failure)
Delayed onset diarrhea (6-8 weeks, 5%)
Brownish orange fluid discoloration common (tears, saliva)
Orthostasis

64
Q

Entacapone (Comtan)- MOA

A

COMT inhibitor
adjuncts to carbidopa/levodopa to prevent peripheral conversion of levodopa to its metabolite thus prolonging the action of levodopa and decreasing the amount needed.

65
Q

Entacapone (Comtan)- ADRs

A

Diarrhea & orthostasis
Brownish-orange urine discoloration
No evidence of hepatotoxicity

66
Q

Stalevo®

A

Combination carbidopa, levodopa, entacapone

67
Q

Anticholinergics- MOA

A

Blocking the cholinergic effect is an attempt to rebalance the decrease in dopaminergic effects

68
Q

Trihexphenidyl (Artane) & benztropine (Cogentin)- uses

A

Anticholinergics
Not as effective as L-Dopa
Can be effective against tremor and dystonic features
Usually ineffective against bradykinesia and other disabilities.

69
Q

Trihexphenidyl (Artane) & benztropine (Cogentin)- ADRs

A

ADRs often limit use
Antimuscarinic effects: dry mouth, blurred vision, constipation and urinary retention.
Sedation, memory impairment, confusion, dysphoria, hallucinations

70
Q

What is the most commonly performed surgical procedure for PD in the US?

A

Deep brain stimulation (DBS)

71
Q

What is deep brain stimulation (DBS)?

A

Implanted electrode connected to a pulse generator that delivers current to thalamus, globus pallidus interna or subthalamic nucleus
Can adjust amplitude, frequency, and pulse width

72
Q

Do PD patients get depressed?

A

Yes and it needs to be treated.

Pharmacology II (23 decks)

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