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MD4001 Week 5 > 1. Treatment of Parkinson's Disease > Flashcards

1. Treatment of Parkinson's Disease Flashcards

1
Q

Other forms/types of parkinson’s disease?

A
  • Extrapyramidal
  • Akinetic-rigid syndromes
  • Parkinsonism: Only present with some/mild symptoms
  • Parkinson’s plus: Have additional features and symptoms that are associated with other ilnesses
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2
Q

What are other symptoms seen in parkinson’s plus syndrome?

A

• Multiple system atrophy (MSA)- a-syn: Can involve cerebellum, ask about postural hypotension
• Progressive Supranuclear Palsy (Steele-Richardson Olszewski): Difficulty with vertical gaze, axial stiffness. Often fall backwards.
- tau
• Cortical Lewy body disease - a-syn : Cortex patholigy
• Drug-induced Parkinsonism: Related to major tranquillisers
• Corticobasal degeneration - tau: Often have alian limb, not recognised as own

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3
Q

Histology of parkinsons

A

Loss of dopaminerigic cells of substantia nigra.

Appearance of lewy bodies that contain proteins.

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4
Q

Gene association with PD?

A 
Genes containing mutations associated with PD:
(Autosomal dominant)
-SNCA (PARK1, PARK4)
-LRRK2 (PARK8)
-VPS35
-EIF4G1
(Autosomal recessive)
-PARKIN (PARK2)
-PINK1 (PARK6)
-DJ1 (PARK7)
Presentation in 20-30s means genetic disorder.
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5
Q

Features of PD?

MAIN 3

A 
*****
• Tremor at rest (not intention!)
• Rigidity – cogwheel, limbs>axial
• Bradykinesia:  Affected arm may not move when walking
********
  • Asymmetry:
  • Loss righting reflex (Unable to stabilise self if pushed)
  • 30% cognitive decline
  • Hypomimia (lack facial expression)
  • Glabellar tap (tap finger on central forehead, blink reflex should stop with continual tapping. PD blinking doesn’t stop)
  • Quiet Speech
  • Micrographia (small writing)
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6
Q

Describe the direct pathway present at the basal ganglia controlled excitation of the motor cortex

A

Excitation of the striatum (Caudate/putamen) causes inhibition of the Globus pallidus –inhibition–> VAVL motor thalamus pathways. This double inhibition leads to motor cortex excitation.

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7
Q

Influence of substantia dopaminergic effect on motor activity?

I.e. the pars compacta of the substantia nigra

A

Excites the DIRECT pathway
Inhibits the INDIRECT pathway
Increased Va/VL drive to cortex
More motor activity

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8
Q

Possible causes of PD?

A
  1. Progression of disease from brainstem to basal ganglia then to cortex. Suggests there is a spreading agent to allow this distribution
  2. Accumulation of alpha-synuclein is the bowel of patients in pre-clinical phase of PD. Spread to nervous system
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9
Q

Contributions to neurog

degeneration?

A 
Oxidation stress
Excito toxicity
Lack of growth factors
Ionic dysequilibrium
Mitochondrial dysfunction
Activation of cell death pathways
Immune attack
Anormal protein handling
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10
Q

Main strategy of PD treatment?

A

Main strategy is to counteract the deficiency in dopamine in the basal ganglia.

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11
Q

Drug treatment options for PD?

A
  • Levodopa (in combination with carbidopaor benserazide)
  • Dopamine agonists (e.g. pramipexole, ropinirole and bromocriptine)
  • Monoamine oxidase B (MAO-B) inhibitors (e.g. selegiline and rasagiline).
  • Amantadine-releases dopamine
  • Muscarinic Ach Antagonsist (benzhexol)
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12
Q

Why do people not vomit on ldopa?

A 
it's a precursor for dopamine 
and
Administered in combination in carbidopa or benserazide
and
gradual increase in prescription
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13
Q

Examples of dopamine agonist?

A

(e.g. pramipexole, ropinirole and bromocriptine)

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14
Q

Example of MOA-B inhibition used for PD treatment?

A

(e.g. selegiline and rasagiline)

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15
Q 
Role of the following therapies for PD:
Levodopa?
Amantadine?
Selegine/rasagaline?
COMT inhibitors?
DA agonist?
ACH inhibitors?
A

Levodopa: Increases L-dopa levels –> increasse in dopamine
Amantadine: Stimulate release of DA and inhibits uptake. So more in cleft
Selegine/rasagaline: Inhibits MAO-B which degradates DA
COMT inhibitors: Block degredation of DA and L-dopa
DA agonist: Bind to DA receptors to excite postsynpatic membrane
ACH inhibitors: Block ACh

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16
Q 
Levodopa:
Use?
In combination with? why?
Initial success?
Problem?
Effect on neurodegeneration?
A

Use:
First line treatment for PD

combined with a dopa decarboxylase inhibitor (carbidopa or benserazide).
• This combination lowers the dose needed and reduces peripheral system effects.

Initial success?
• 80% of patients show initial improvement in rigidity and hypokinesia.

Problem?
• Limited in effectiveness with time as the neurodegeneration progresses. Needs increasing dose

• Overall no evidence that L-Dopa slows or accelerates neurodegeneration.

17
Q

Side effect of levodopa?

A
  • Involuntary writhing movements (dyskinesia) which may appear within 2 years. Affect face and limbs mainly. Occurs at peak therapeutic effect.
  • Rapid fluctuations in clinical state. Hypokinesia and rigidity may suddenly worsen and then improve again. This on-off effect not seen in untreated PD patients or with other PD drugs. Reflects fluctuating receptor dynamics.
18
Q

4 categories of dopamine agonists used for PD treatment?

A
  • Pramipexole and roprinirole are D2/3 selective receptor agonists that are better tolerated. Short half-life in plasma could be a problem
  • Bromocriptine,cabergoline and pergolide (ergots) are ORALLY active drugs that work on D1 and D2 receptors. They have limiting side effects – fibrotic reactions.
  • Rotigotine newer agent delivered by a transdermal PATCH
  • Apomorphine given by INJECTION sometimes given to control the off effect of levodopa.
19
Q

Problem with dopamine agonst?

A

Dopamine dysregulation syndrome

20
Q

Wat is dopamine dysregulation syndrome?

A

• Sudden onset sleep
• Impulse control disorders – gambling, binge
eating, hypersexuality.
• Hypotension
• Neuroleptic malignant syndrome if stopped abruptly.

21
Q

Name the 3 MOA-Inhibitors used for PD treatment?

How are they administered and MoA?

A
  • Selegiline is a selective MAO-B which lacks the unwanted peripheral effects of non- selective MAO inhibitors.
  • Inhibition of MAO-B protects dopamine from extraneuronal degradation .
  • Combination with levodopa is more effective in relieving symptoms and prolonging life.
  • Rasagiline is an alternative and may retard the disease progression.
22
Q

How is amantadine useful in PD treatment?

A
  • Antiviral drug discovered to be beneficial in PD.
  • Increased dopamine release is primarily responsible for its therapeutic effect.
  • Less effective than levodopa or bromocriptine and action declines with time.
23
Q

How are ACH antagonists useful is PDF treatment?

Name 3 used

A
  • Muscarinic acetylcholine receptors exert an inhibitory effect on dopaminergic nerves suppression of which compensates for a lack of dopamine.
  • Benzhexol, Orphenadrine and procyclidine can all be used, with usual anti-cholinergic side effects.
24
Q

How does neural transplantation help treat PD?

A

Some transplants have been shown to survive and establish functional dopaminergic connections and clinical benefit.
Note: Not known yet if the transplanted cells will be prone to the neurodegeneration already going on.

• Stem cell technology is the great hope.

25
Q

How does brain stimulation treat PD?

DBS: Deep brain stimulation

A

• Electrical stimulation of the subthalamic or Gpi nuclei by inserted electrodes (DBS) is used in severe cases. Can improve motor dysfunction.

Usually to the sub-thalamuc nucleus

26
Q 
Drug that:
• Dopamine precursor?
• Dopa decarboxylase inhibitor?
• COMT inhibitor?
• Dopamine agonists?
• MAO-B inhibitors?
• Dopamine release enhancer?
• Muscarinic antagonists?
A
  • Dopamine precursor: Levodopa
  • Dopa decarboxylase inhibitor: Carbidopa
  • COMT inhibitor: Entacapone
  • Dopamine agonists: Pramipexole, ropinirol, rotigotine, bromocriptine
  • MAO-B inhibitors: selegine, rasagiline
  • Dopamine release enhancer: Amantadine
  • Muscarinic antagonists: Benzhexol (Trihexyphenidyl hydrochloride).
27
Q

Within Basal Ganglia Inhibition with ____, Excitation with _______

A

Within Basal Ganglia Inhibition with GABA, Excitation with Glutamate

28
Q

Describe the indirect pathway in which the basal ganglia control the excitation of motor output from cortex?

A

Cortex stimulates striatum via corticostriate pathway.
This Inhibits the indirect loop between the globus pallidus and subthalamic nucleus, which excites cortex.
The gp inhibits thalamic stimulation to cortex via lenticular fasciculus. So indirect loop stimulation encourages the inhibition and control.

29
Q

Striatal internerons cholinergic effect on motor activity?

A

Inhibts the DIRECT pathway
Excites the INDIRECT pathway
Decreases Va/VL drive to cortex
Less motor activity

30
Q

Result of parkinson’s disease on Substantia dopaminergic effect on motor activity?

A

SN dopamine cells lost

Indirect pathway released from inhibition. So is excited.
ACh excitation is also unopposed.

Leads to less motor activity!

MD4001 Week 5 (11 decks)

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