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PMCOL 412 > PD II > Flashcards

PD II Flashcards

1
Q

Why use L-Dopa over DA

A

L-dopa can cross the BBB (transport through aromatic aminoacid transporter)

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2
Q

L-Dopa converted to DA by

A

AADC in the brain

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3
Q

L-dopa admin–efficacy

A

Good to excellent symptomatic response at the beginning of treatment (“honeymoon” phase) BUT over time, most patients will eventually develop complications

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4
Q

T/F L-Dopa corrects non-motor symptoms as well

A

FALSE
Non-motor symptoms are not corrected (depression, dementia, autonomic dysregulation etc.) and the underlying neurodegenerative process is not affected

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5
Q

Effects of L-dopa in early PD

A

In early PD, improvement motor responses exceed the plasma lifetime of the drug, as DA is stored in neurons and can be released after there is no more circulating L-DOPA.

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6
Q

Complications of L-DOPA

A

Occur over time and include:
- motor and non-motor fluctuations
- L-DOPA induced dyskinesia (LID, involuntary hyperkinetic movements).
- Neuropsychiatric problems (psychosis,
hallucinosis, etc.) tend to develop over time, but are less pronounced than with dopamine agonists

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7
Q

what is LID

A

L-DOPA induced dyskinesia (LID) involuntary hyperkinetic movements
LID is mainly due to D1R supersensitivity and hyperactivation–occurs at peak dose

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8
Q

Why is there a difference b/t the initial L-DOPA effects and later complications

A

Likely due to fluctuation in DA concentration and intermittent stimulation of receptors, which lead to:
- plastic changes in gene expression in the
striatum
- overall changes in the firing pattern of striatal neurons

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9
Q

L-DOPA metabolism

A

AADC converts L-dopa to DA
COMT converts L-DOPA to 3-OMD (3-)-methyldopa)
Both occur peripherally

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10
Q

How LID effect L-dopa use

A

As LID is as disabling as PD itself, delay L-dopa use until PD effects are worse to prevent dyskinesia (wait to use it until absolutely necessary due to complications)

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11
Q

Peripheral L-Dopa side effects

A
  • nausea and vomiting
  • hypotension
  • cardiac arrhythmias
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12
Q

What causes the peripheral side effects of L-dopa

A

Conversion to dopamine or to 3-O-methyl dopa in the periphery is responsible for side effects associated with L-DOPA
administration in high doses

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13
Q

Peripheral side effects of L-Dopa: nausea and vomiting

A

Caused by the action of dopamine on D2 receptors in the area postrema of the medulla (chemoreceptor trigger zone)

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14
Q

Peripheral side effects of L-Dopa: hypotension

A

Activation of vascular dopamine receptors and vasodilation

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15
Q

Peripheral side effects of L-Dopa: Cardiac arrhythmias

A

Activation of peripheral adrenergic

receptors

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16
Q

How to decrease peripheral metabolism of L-Dopa

A

Prevent peripheral metabolism of L-DOPA by COMT and AADC and prevent central metabolism of L-DOPA by COMT BUT not AADC (need central AADC for DA production)

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17
Q

HOW do we alter L-dopa metabolism

A

use pharmacological inhibitors of DA metabolism

incl. carbidopa, benserazide, entacapone, tolcapone

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18
Q

L-DOPA administration to prevent side effects

A
  • Side effects can be reduced by administering lower doses of L-dopa in association with inhibitors of peripheral DA metabolism
  • Most L-dopa doses are now associated to carbidopa or benserazide
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19
Q

Inhibitors of aromatic amino acid decarboxylase (AADC): Role

A

Prevent excess peripheral dopamine formation

Want central AADC to work so use ones that don’t cross BBB

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20
Q

Inhibitors of aromatic amino acid decarboxylase (AADC): examples

A

carbidopa, benserazide

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21
Q

COMT inhibitors: Role

A

Increase half-life and concentration of L-Dopa and dopamine

Inhibits BOTH peripheral and brain COMT (or just peripheral)

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22
Q

COMT inhibitors: examples

A

entacapone, tolcapone

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23
Q

Difference between entacapone, tolcapone

A

entacapone–peripheral only

tolcapone–can cross BBB

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24
Q

When are COMT inhibitors used most

A

Tolcapone or entacapone are often co-administered at later disease stages to
reduce “on/off” fluctuations.

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25
Q

Tolcapone risks

A

Tolcapone has considerable hepatotoxicity and patients must be monitored for
signs of liver damage

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26
Q

MAO-B plus L-dopa

A

Block DA degradation in brain with MAOB inhibitors and COMT inhibitors = increased striatal DA

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27
Q

AADC + COMT inhibitors

A

Used to decrease peripheral effects of L-DOPA by decreasing peripheral metabolism of L-DOPA
Allow more L-DOPA to enter CNS (can then decrease the dosage)

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28
Q

MAOB inhibitors: examples

A

selegiline, rasagiline

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29
Q

MAOB inhibitors: Role

A
  • Block oxidative deamination of dopamine increasing its half-life in the brain
  • Antioxidant properties. Anti-apoptotic and neuroprotective activity
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30
Q

Selegiline: side effects

A

MAOBI
is partially metabolized to amphetamine and
methamphetamine which may cause insomnia and anxiety

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31
Q

Rasagiline vs. selegiline

A

Rasagiline is a newer related compound with less side effects (no undesired metabolic products) unlike selegiline (which can form meth and amphetamine)

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32
Q

Dopamine agonists: Role

A
  • The need for a more physiological and continuous dopaminergic stimulation has led to the extensive use of dopamine agonists
  • Stimulation of D2 receptor accounts for most or all anti-PD effects, as well as for most side effects
33
Q

Dopamine agonist: older drugs

A

Ergot derivatives:

  • Bromocriptine (D2 agonist, D1 antagonist)
  • Pergolide (D2 and D1 agonist)
34
Q

Dopamine agonists: new

A

Most used dopamine agonists:

  • Selective D2 agonists: Pramipexole, Ropinirole
  • Apomorphine (D2 and D1 agonist)
  • Rotigotine (transdermal patches; D2 receptor agonist and partial agonist of 5HT1A receptor)
35
Q

Pramipexole, Ropinirole

A

Selective D2 agonists

36
Q

Apomorphine

A

D2 and D1 agonist

37
Q

Rotigotine

A
  • can be delivered transdermally

- D2 receptor agonist and partial agonist of 5HT1A receptor

38
Q

Dopamine agonists advantages over L-DOPA

A
  • longer striatal half-life (more physiological DR stimulation)
  • direct stimulation of receptors bypassing degenerating nigrostriatal neurons
  • reduced incidence of motor complications
  • antioxidant effects, antiapoptotic and neuroprotective activity (potentially)
39
Q

Dopamine agonists disadvantages vs L-DOPA

A
  • Higher incidence of side effects such as psychosis and hallucination
  • Less effective against PD motor symptoms (except for apomorphine, which is equipotent to L-Dopa)
40
Q

When are DA agonists most used

A
  • Dopamine agonists are often administered in early PD to delay use of L-dopa and associated motor complications
  • Used to treat “off” time in late-stage patients on L-DOPA
41
Q

When is L-DOPA chosen over DA agonists

A

L-dopa is the drug of choice in patients that also present with dementia or hallucinosis

42
Q

Uses of DA agonists in Late PD

A
  • In advanced PD, dopamine agonists are used to reduce “off” time in patients with L-dopa-related fluctuations
  • Rotigotine transdermal patches are particularly useful in advanced PD patients who develop dysphagia (can’t swallow–use transdermal patch)
43
Q

Anticholinergics: Role

A

Decreasing cholinergic inputs on D2 neurons helps decreasing their firing and activation of the indirect pathway

44
Q

Anticholinergics: examples

A

Muscarinic cholinergic antagonists

  • trihexyphenidyl
  • benzotropine
45
Q

Anticholinergics: efficacy

A

Less effective than other drugs

BUT Drug of choice for the treatment of parkinsonism induced by D2 antagonists

46
Q

Anticholinergics: Side effects

A

Side effects related to anticholinergic properties are sedation and mental confusion, constipation, dry mouth etc.
fewer side effects than other options

47
Q

What drug is best for the treatment of parkinsonism induced by D2 antagonists

A

Anticholinergics

48
Q

Amantadine–drug type

A

‘other’ doesn’t fall into other categories of anti-PD drugs

Originally introduced as an anti-influenza agent

49
Q

Amantadine–mechanism

A
  • Pre-synaptically: enhances release of stored dopamine from dopaminergic terminal and inhibits reuptake
  • Post-synaptically: amantadine can activate D2 receptors by changing their conformation to a high-affinity configuration
  • Anticholinergic properties
50
Q

Amantadine-efficacy

A
  • Overall modest effects on PD symptoms.

- Sometimes used at early stages of PD or in combination with L-DOPA to decrease dyskinesia

51
Q

Deep Brain Stimulation (DBS)–how

A

Electrodes implanted into the internal globus pallidus or in the subthalamic nucleus –> Electric field generated
around the electrodes –> changes firing pattern and rate of neurons

52
Q

Effects of DBS

A
  • triggers neighboring astrocytes to release a wave of calcium that promote local release of NTs (increase NTs)
  • increases blood flow
  • stimulates neurogenesis
53
Q

DBS efficacy

A
  • Reduces many symptoms of advanced L-Dopa-responsive PD, including tremor, on-off fluctuations and dyskinesia
  • Sustained clinical improvement for at least 10 years
  • Less active on gait impairments, balance and speech, which might worsen.
54
Q

Ideal Candidate for DBS

A

Ideal candidates for DBS are young patients, responsive to L-Dopa an with no cognitive or psychiatric impairment (psych impairment can be worsened with DBS)

55
Q

Side effects of DBS

A
  • Cognitive impairment, memory defects, mania, depression, anxiety
  • Modest risk of surgery-related adverse events, including infection and intracranial hemorrhage (~1-5% of cases)
56
Q

Amantadine use

A

rarely used

used mainly in combination with L-dopa to prevent dyskinesia due to fluctuating DA levels

57
Q

When looking for novel mechanisms and drugs for PD consider

A

The mitochondria because
- A major environmental risk factor for PD is
exposure to mitochondrial toxins (MPTP, rotenone, paraquat, etc.)
- Several genetic risk factors for PD are linked to mitochondrial function and oxidative stress
The mitochondria likely plays a critical role in PD pathogenesis

58
Q

affected protein: a-synuclein function?

A

Synaptic function–synaptic vesicle

formation and recycling, axonal transport

59
Q

affected protein: parkin function?

A

E3 ubiquitin ligase, mitophagy

60
Q

affected protein: DJ1 function?

A

Chaperone, oxidative stress sensor

61
Q

affected protein: PINK1 (PTEN-induced kinase 1) function?

A

Mitochondrial kinase (phosphorylation of mitochondrial proteins), mitophagy

62
Q

affected protein: LRRK2/dardarin

(leucine-rich repeat serine/threonine kinase) Function?

A

Kinase. Involved in intracellular vesicle trafficking, mitochondria and microtubules dynamics

63
Q

affected protein: ATP13A2 Function?

A 
ATPase important for lysosomal
function and mitochondrial
dynamics
64
Q

affected protein: VPS35 (vacuolar

sorting protein 35) Function?

A

Intracellular vesicle trafficking.

Regulates LRRK2 activity.

65
Q

affected protein: Glucocerebrosidase Function?

A

Lysosomal enzyme

RISK FACTOR

66
Q

Dopaminergic (TH+-neurons) are highly sensitive to oxidative stress, due to:

A
  • high concentration of iron in SNc neurons (amplifies ox stress)
  • oxidative metabolism of DA and the generation of DA-derived ROS (produces ROS)
67
Q

Genes/proteins involved in PD suggest

A

mitochondrial dysfunction and associated oxidative stress are central in PD
Other genes are involved in protein degradation and lysosomal enzymes–potential role of lysosomes in PD

68
Q

ROS production in DA metabolism

A

spontaneous DA breakdown at neutral pH to dopamine-quinone, superoxide and hydrogen peroxide + MAOB-dependent deamination of DOPAC and H2O2 –> ROS

69
Q

DA can damage mitochondrial ____

A

chaperones; can’t cycle

70
Q

DA hanging aorund intracellularly is ___

A

BAD b/c it breaks down and forms ROS

71
Q

Ways to prevent ROS products from DA metabolism

A

Sequester DA in vessicles –> no DA hanging around –> no breakdown/DA oxidation

72
Q

How MPP causes oxidation

A

1) MPP cations are taken up by DAT and VMAT
2) MPP inhibits complex I activity (causes ROS generation)
3) MPP interferes with VMATs ability to move DA into vesicles –> DA redistributed into cytoplasm –> DA-dependent oxidative stress

73
Q

Rotenone and Paraquat effects in oxidative stress

A

similar structure to MPP

Also, inhibit VMAT and block DA storage as well as complex I activity

74
Q

Major mechanisms of Neurodegeneration in PD–3 major pathways

A
  • mitochondrial dysfunction
  • misfolding of proteins and issues with chaperones
  • lysosomal dysfunction
    WORK in concert for neurodegen
75
Q

Therapeutic approaches for disease-modifying treatments: mit dysfunction

A

IMPROVEMENT OF MITOCHONDRIAL

FUNCTION AND MITOPHAGY

76
Q

Therapeutic approaches for disease-modifying treatments: Oxidative stress

A

Anti-oxidants

77
Q

Therapeutic approaches for disease-modifying treatments: Protein misfolding and aggregation (α-synuclein)

A

Reduction of α-synuclein expression, misfolding and spreading

78
Q 
Therapeutic approaches for disease-modifying treatments: Dysfunction of
proteostatic mechanisms (chaperones, autophagy, proteasomes, lysosomes)
A

Enhancement of proteostatic mechanisms

79
Q

Therapeutic approaches for disease-modifying treatments: directly affecting neurodegen

A

Pro-survival factors for DA neurons

PMCOL 412 (35 decks)

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