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Pharm Exam 2 > Bannon: Movement Disorders > Flashcards

Bannon: Movement Disorders Flashcards

1
Q

Parkinson’s Disease

General:

A
  • Movement disorder

- Age is a prominent risk factor (5-10% of people over the age of 85)

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2
Q

Parkinson’s Disease

Clinical Features: (4)

A

Bradykinesia (slowness of movement and difficulty initiating movement)

Muscular (cogwheel) rigidity

Resting tremor (pill-rolling)

Impairment of postural stability

  • Festination (falling forward)
  • Retropulsion (falling backward)
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3
Q

Parkinson’s Disease

Clinical Presentation: (4)

A 
Early: presentation may be subtle
o	Unilateral weakness or fatigue
o	Weak voice
o	Micrographia (really small writing)
o	Olfactory losses
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4
Q

Parkinson’s Disease

Comorbidities:

A

Comorbidities: depression and dementia are common

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5
Q

Parkinson’s Disease
Clinical Course

Mean Duration (Diagnosis to Death):
Postural Instability:
Death:

A

Mean Duration (Diagnosis to Death): 15 years

  • Postural Instability: contributes to falls, immobility, constipation, dependency and depression
  • Death: due to general wasting and complications of immobility (pneumonia)
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6
Q

Parkinson’s Disease
Pathophysiology

Primarily a loss of:
Presence of:
Impact on other cells:
PNS:

A

Basics: primarily a loss of midbrain DA-producing neurons (particularly nigrostriatal DA neurons)

Presence of Lewy bodies (inclusions with radiating fibrils)

Many other cell types in other brain regions are impacted in PD (but to a lesser extent)

PNS affected as well

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7
Q

DA Pathways

Nigrostriatal DA:
Mesolimbic DA:

A

Nigrostriatal DA: modulates learning and execution of complex purposeful motor patterns and learned habits; 80% of total DA and particular affected by PD

Mesolimbic DA: modulates motivation, goal-directed thinking, affect and reward

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8
Q

DA Pathways

Mesocortical DA:
Hypothalamic DA:
Area Postrema:

A

Mesocortical DA: modulates cognition
Hypothalamic DA: hormone regulation
Area Postrema: DA receptors outside the BBB that mediate emesis

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9
Q

Effects of Loss of DA:

Direct pathway vs. Indirect pathway:

A

DA modulates EXCITATORY information from the cortex and basal ganglia sends information back to the cortex via excitation from the thalamus

  • Direct pathway ENABLES movement
  • Indirect pathway INHIBITS movement
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10
Q

Effects of Loss of DA

Loss of 70-80% if nigrostriatal DA results in:

A

Loss of 70-80% if nigrostriatal DA results in PD

  • Inhibition of the direct pathway (loss of D1 stimulation)
  • Activation of the indirect pathway (release of D2 inhibition)
  • Overall result of the above two effects is INHIBITION OF MOVEMENT
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11
Q

Effects of Loss of DA

Net Result:

A

Net Result= decreased excitation of the cortex and decreased drive to move

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12
Q

Parkinson’s Disease
Causes

Majority of Cases:
Other Causes:

A

Majority of Cases: idiopathic (we do not know the cause)

Other Causes:
o Environmental Toxins:
- MPTP (destroys DA terminals)
- Epidemiology (ie. people who drink well water have an increased risk of PD)
o Infection: post-encephalitic
o Oxidative Stress: ongoing generation of ROS may make DA cells more susceptible to damage
o Mitochondrial Defects/Damage: have been implicated
o Genetic Forms: rare but some do exist

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13
Q

Levodopa (L-dopa)

MOA:
Absorption:
Metabolism:

A

MOA: dopa is the precursor of DA (replenish DA)

Pharmacokinetics:
o Absorption: via aromatic amino acid uptake systems (affected by food)
o Metabolism: largely decarboxylated in the periphery; less than 1% reaches the brain
 Solution to this problem: almost exclusively given with carbidopa, an amino acid decarboxylase inhibitor, to all more to reach the brain

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14
Q

Levodopa (L-dopa)
Efficacy

Early On:
Over Time:

A

Early On: very effective, although more so for bradykinesia than for tremor

Over Time: reduced efficacy (wearing off effect after 2-5 years)

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15
Q

Levodopa (L-dopa)
Adverse Effects

Major Issues:
Other Effects:

A

Major Issues:

  • On-off phenomenon (follows reduced efficacy)
  • Dyskinesias (in up to 80% of patients after 5-8 years of treatment)
  • Related to dopa-PD (drug-disease) interaction

Other Effects:

  • Early: anorexia, nausea, hypotesion
  • Chronic: hallucinations, delusions, agitations, insomnia, pathologic gambling and hypersexuality
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16
Q

Levodopa (L-dopa)

Formulations: (3)

A

Sinemet/Atamet
Parcopa
Lodosyn

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17
Q

Sinemet/Atamet:

A

Sinemet/Atamet: levodopa + carbidopa combination (needs to be dosed 3-6 times per day)
- Sinemet CR (sustained release formulation) now available, but shows erratic absorption

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18
Q

Parcopa:

A

Parcopa: immediate-release levodopa/carbidopa that can be taken w/o water (manage acute events)

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19
Q

Lodosyn:

A

Lodosyn: carbidopa alone that can be added to regimen if needed (not often)

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20
Q

Direct Acting DA Receptor Agonists

Ergots:

A

Ergots: first used DA receptor agonists

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21
Q

Direct Acting DA Receptor Agonists
Ergots

Bromocriptine:
Current Use:

A

Bromocriptine: not typically used for PD anymore (SE profile)

Current Use: rescue from neuroleptic malignant syndrome (due to APDs)

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22
Q

Direct Acting DA Receptor Agonists
Ergots

Pergolide:
Current Use:

A

Pergolide: not FDA approved for PD anymore due to incidence of cardiac valve regurgitation

Current Use: low doses for hyperprolactinemia

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23
Q

Direct Acting DA Receptor Agonists
Non-Ergot

Currently Used Agents: (2)

A

Pramipexole: D3>D2
Ropinirole: D2

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24
Q

Direct Acting DA Receptor Agonists
Non-Ergot

Efficacy:
PD:
Other:

A

Efficacy: probably less effective than dopa, but less side effects make them first line monotherapy

Current Use:

  • PD: first used as an adjunct, now first line monotherapy
  • Other: Restless Legs Syndrome
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25
Q

Direct Acting DA Receptor Agonists
Non-Ergot

Side Effects: (5)

A 
Nausea
Edema
Hypotension
Pathologic gambling and other compulsions
Somnolence (drowsiness)
26
Q

Direct Acting DA Receptor Agonists
Non-Ergot
Treatment of Side Effects

Daytime Sleepiness (Sleep Attacks): 
Peripheral DA Effects:
A

Daytime Sleepiness (Sleep Attacks): modafinil (CNS stimulation)

Peripheral DA Effects: trimethobenzamide (anti-emetic) or domperidone (antidopaminergic)

27
Q

Direct Acting DA Receptor Agonists
Apomorphine

Administration:
MOA:
Use:

A

Administration: injectable (subQ)

MOA: dopamine agonist with some preference for D2 receptors

Use: FDA-approved for “off” episodes

28
Q

Direct Acting DA Receptor Agonists
Apomorphine

Side Effects:

Treatment of Side Effects
Emesis/Nausea:
Ondansetron:

A

Side Effects: similar to above, plus yawning and hypersexuality

Treatment of Side Effects:

  • Emesis/Nausea: trimethobenzamide (anti-emetic)
  • Ondansetron: contraindicated because combination with apomorphine results in severe hypotension
29
Q

Direct Acting DA Receptor Agonists

Rotigone:

A

Rotigone: once daily transdermal patch (similar efficacy and adverse effects, but more convenient)

30
Q

Monoamine Oxidase-B Inhibitors: (2)

A

Selegiline

Rasagiline

31
Q

Selegiline

MOA:

A

MOA: irreversible inhibitor of MAO-B, resulting in inhibition of DA metabolism

  • Less peripheral MAO inhibition
  • Can be used in combination with dopa
  • Less interaction with tyramine-rich foods than MAO-A inhibitors
32
Q

Selegiline

Efficacy:

A

Efficacy: modest benefits as initial monotherapy OR dopa co-therapy

33
Q

Selegiline

Possible Mechanisms of Benefit: (4)

A

Possible Mechanisms of Benefit:

  • Increased DA
  • Metabolism to amphetamine (chemically similar to methamphetamine)
  • Antidepressant effects
  • Previously believed it may have neuroprotective qualities (untrue)
34
Q

Rasagiline

MOA:
Efficacy:
Adverse Effects:

A

Rasagiline: newer

MOA: same as above

Efficacy: clearly effective for the treatment of early PD or as an adjunct in advanced PD
- May have neuroprotective qualities (still an open question)

Adverse Effects:

  • Nausea
  • Orthostatic hypotension
35
Q

Catechol-O-Methyltransferase (COMT) Inhbitors:

A

Entacapone

36
Q

Entacapone

MOA:
Use:

A

MOA: given with L-dopa to increase its levels by blunting metabolism in periphery and the brain

Use: used as an ADJUNCT to Sinemet (levodopa + carbidopa) to reduce fluctuations and “off” time

37
Q

Entacapone

Side Effects:

A

May increase risk of dyskinesia (due to the fact that it increases the action of L-dopa)

Does NOT cause hepatotoxicity like earlier COMT inhibitors (Tolcapone)

38
Q

Antivirals:

A

Amantadine

39
Q

Amantadine

MOA:
Efficacy:

A

MOA: relevant MOA to the treatment of PD may be its action as an NMDA antagonist

Efficacy: modest transient benefits (may only last a few weeks); better for tremor

40
Q

Amantadine

Side Effects: (2)

A
  • Livedo reticularis (skin condition causing lace-like purple discoloration of the lower extremeties)
  • Psychosis (rare, at high doses)
41
Q

Antimuscarinics

Currently Used: (4)

A

o Benztropine
o Trihexyphenidyl
o Procyclidine
o Biperiden

42
Q

Antimuscarinics

MOA:

A

MOA: offsets neurochemical imbalance in striatum created by loss of DA (ie. decreases action of ACh)

43
Q

Antimuscarinics

Use:

A

Use: LOW DOSES useful for the following conditions (it is NOT useful for bradykinesia)
o Early onset tremor
o Rigidity
o Drooling

44
Q

Antimuscarinics

Side Effects:
CNS Effects:
PNS Effects:

A

Side Effects: prominent side effects may contraindicate its use in many patients

CNS Effects: impaired memory, drowsiness, confusion, delusions

PNS Effects: dry mouth, blurred vision, urinary retention, tachycardia

45
Q

Treatment of Comorbidities

Depression:
Psychosis:

A

Depression: SSRIs preferred

Psychosis: clozapine or other atypical antipsychotics (less risk for inducing parkinsonism)

46
Q

Treatment of Comorbidities

Dementia:
Other Therapies:

A

Dementia: cholinesterase inhibitors that are used in AD/dementia

Other Therapies:
o Physical therapy and physical/mental exercise recommended

47
Q

Surgical Interventions

DA Cell Replacement:

A

DA Cell Replacement: DA from adrenals, carotid bodies, fetal cells from human, transgenic pigs or stem cells

48
Q

Surgical Interventions

Ablations:

A

Ablations: not done anymore (irreversible and non-adjustable; replaced by deep brain stimulation)
o Helped with tremor, bradykinesia and medication response

49
Q

Surgical Interventions

Deep Brain Stimulation:
Efficacy:

A

Deep Brain Stimulation: safer, reversible and adjustable

Efficacy: more effective than ablations and with fewer complications (can be used bilaterally)

  • Subthalamic nucleus (improves most Sx) > Globus pallidus > Thalamus
  • > 70% of patients improve (more “on” time per day, decreased meds)
  • However, little/no improvement in instability AND may actually cause a slight decrease in cognition
50
Q

Surgical Interventions
Deep Brain Stimulation

Use: (4)

A
  • Patients refractory to medication treatment
  • Patients with significant dyskinesia
  • Patients with significant clinical fluctuation on dopa
  • NEED TO HAVE INTACT COGNITION
51
Q

Surgical Interventions
Deep Brain Stimulation

Adverse Effects: (4)

A

Adverse Effects: less of these effects at 6 months post-surgery than 3 months (decrease with time)

  • May cause a decrease in cognition
  • Serious effects in ~40% of patients (hemorrhage, surgical site infection)
  • Increased depression and suicide (possibly unmasked due to decreased dose of DA drugs)
  • Increased impulsivity (may underlie increase in compulsive gambling and falling)
52
Q

Surgical Interventions

Neurorestoration:
Unexpected adverse effects:

A

Infusion of Trophic Factor GDNF into Putamen: had early promise but no efficacy overall

Unexpected adverse effects:

  • Surgical complications
  • Ataxia
  • GDNF Abs
53
Q

Surgical Interventions
Neurorestoration

Local Injections of AAV-GAD:
Local Injections of Transgenes:

A

Local Injections of AAV-GAD: initial findings promising but double-blind results less stellar

Local Injections of Transgenes: specificity conferred through receptor-mediated uptake (currently in trials)

54
Q

Current Management of PD Patients:

A

All current treatments are for SYMPTOMATIC relief only

Long-term goal is neuroprotection, or at least, neurorestoration

55
Q

Current Management of PD Patients

Basics:

A
  • Basics:
    o Delay treatment until necessary (try lifestyle adaptations first)
    o Consider a trial of antimuscarinic agent/MAO-B inhibitor/Amantadine ALONE to start
    o When it becomes necessary, initiate DA therapy with newer direct acting DA agonist (NOT L-dopa)
  • Pramipexole or Ropinirole
    o If necessary, add low-dose Sinemet (levodopa-carbidopa) to the direct acting DA agonist
    o Adjust Sinemet dosing as necessary
56
Q

Current Management of PD Patients

Other Additions:

A

o For long-term complications of L-dopa, add a COMT inhibitor (thought to prolong/stabilize L-dopa effects, therefore reducing “on/off” phenomena)
o SubQ apomorphine for rescue during “off” periods
o Addition of anticholinergics to treat tremor or drooling
o Consider DBS in patients with treatment failure and intact cognition

57
Q

Essential Tremor

Basics:

A

Basics: most common neurological disorder among adults (0.4-4% prevalence)

Impact is on quality of life NOT life span, and therefore is mistaken as a benign disorder

58
Q

Essential Tremor

Hallmark Feature:

A

Hallmark Feature: action/kinetic tremor in both upper limbs; less commonly in head, tongue and lower limbs

  • Often a crescendo tremor (resembling cerebellar intention tremor)
  • Aggravated by emotions, hunger, fatigue and temperature extremes
59
Q

Essential Tremor

Pathophysiology:
Causes:

A

Pathophysiology: uncertain
- Possibility: abnormal oscillations within thalamocortical and olivocerebellar loops

Causes:
- Autosomal dominant pattern of inheritance: gene defects unknown but chromosomal loci identified
o Variable penetrance (~50% of cases), but 5-10x increased risk if you have an affected 1st degree relative

60
Q

Essential Tremor

Treatments:

A

• Treatments: over 50% respond to drug therapy

  • Beta Blockers: propanolol or others
  • Anti-Seizure Drugs: low doses of primadone or topiramate
  • Refractory Patients: ventralis intermedius thalamotomy or DBS (completely effective in >80% of tx resistant patients; DBS preferred)

Pharm Exam 2 (13 decks)

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