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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
Tolcapone risks
Tolcapone has considerable hepatotoxicity and patients must be monitored for signs of liver damage
26
MAO-B plus L-dopa
Block DA degradation in brain with MAOB inhibitors and COMT inhibitors = increased striatal DA
27
AADC + COMT inhibitors
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)
28
MAOB inhibitors: examples
selegiline, rasagiline
29
MAOB inhibitors: Role
- Block oxidative deamination of dopamine increasing its half-life in the brain - Antioxidant properties. Anti-apoptotic and neuroprotective activity
30
Selegiline: side effects
MAOBI is partially metabolized to amphetamine and methamphetamine which may cause insomnia and anxiety
31
Rasagiline vs. selegiline
Rasagiline is a newer related compound with less side effects (no undesired metabolic products) unlike selegiline (which can form meth and amphetamine)
32
Dopamine agonists: Role
- 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
Dopamine agonist: older drugs
Ergot derivatives: - Bromocriptine (D2 agonist, D1 antagonist) - Pergolide (D2 and D1 agonist)
34
Dopamine agonists: new
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
Pramipexole, Ropinirole
Selective D2 agonists
36
Apomorphine
D2 and D1 agonist
37
Rotigotine
- can be delivered transdermally | - D2 receptor agonist and partial agonist of 5HT1A receptor
38
Dopamine agonists advantages over L-DOPA
- 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
Dopamine agonists disadvantages vs L-DOPA
- 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
When are DA agonists most used
- 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
When is L-DOPA chosen over DA agonists
L-dopa is the drug of choice in patients that also present with dementia or hallucinosis
42
Uses of DA agonists in Late PD
- 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
Anticholinergics: Role
Decreasing cholinergic inputs on D2 neurons helps decreasing their firing and activation of the indirect pathway
44
Anticholinergics: examples
Muscarinic cholinergic antagonists - trihexyphenidyl - benzotropine
45
Anticholinergics: efficacy
Less effective than other drugs | BUT Drug of choice for the treatment of parkinsonism induced by D2 antagonists
46
Anticholinergics: Side effects
Side effects related to anticholinergic properties are sedation and mental confusion, constipation, dry mouth etc. fewer side effects than other options
47
What drug is best for the treatment of parkinsonism induced by D2 antagonists
Anticholinergics
48
Amantadine--drug type
'other' doesn't fall into other categories of anti-PD drugs | Originally introduced as an anti-influenza agent
49
Amantadine--mechanism
- 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
Amantadine-efficacy
- Overall modest effects on PD symptoms. | - Sometimes used at early stages of PD or in combination with L-DOPA to decrease dyskinesia
51
Deep Brain Stimulation (DBS)--how
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
Effects of DBS
- triggers neighboring astrocytes to release a wave of calcium that promote local release of NTs (increase NTs) - increases blood flow - stimulates neurogenesis
53
DBS efficacy
- 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
Ideal Candidate for DBS
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
Side effects of DBS
- Cognitive impairment, memory defects, mania, depression, anxiety - Modest risk of surgery-related adverse events, including infection and intracranial hemorrhage (~1-5% of cases)
56
Amantadine use
rarely used | used mainly in combination with L-dopa to prevent dyskinesia due to fluctuating DA levels
57
When looking for novel mechanisms and drugs for PD consider
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
affected protein: a-synuclein function?
Synaptic function--synaptic vesicle | formation and recycling, axonal transport
59
affected protein: parkin function?
E3 ubiquitin ligase, mitophagy
60
affected protein: DJ1 function?
Chaperone, oxidative stress sensor
61
affected protein: PINK1 (PTEN-induced kinase 1) function?
Mitochondrial kinase (phosphorylation of mitochondrial proteins), mitophagy
62
affected protein: LRRK2/dardarin | (leucine-rich repeat serine/threonine kinase) Function?
Kinase. Involved in intracellular vesicle trafficking, mitochondria and microtubules dynamics
63
affected protein: ATP13A2 Function?
``` ATPase important for lysosomal function and mitochondrial dynamics ```
64
affected protein: VPS35 (vacuolar | sorting protein 35) Function?
Intracellular vesicle trafficking. | Regulates LRRK2 activity.
65
affected protein: Glucocerebrosidase Function?
Lysosomal enzyme | RISK FACTOR
66
Dopaminergic (TH+-neurons) are highly sensitive to oxidative stress, due to:
- high concentration of iron in SNc neurons (amplifies ox stress) - oxidative metabolism of DA and the generation of DA-derived ROS (produces ROS)
67
Genes/proteins involved in PD suggest
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
ROS production in DA metabolism
spontaneous DA breakdown at neutral pH to dopamine-quinone, superoxide and hydrogen peroxide + MAOB-dependent deamination of DOPAC and H2O2 --> ROS
69
DA can damage mitochondrial ____
chaperones; can't cycle
70
DA hanging aorund intracellularly is ___
BAD b/c it breaks down and forms ROS
71
Ways to prevent ROS products from DA metabolism
Sequester DA in vessicles --> no DA hanging around --> no breakdown/DA oxidation
72
How MPP causes oxidation
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
Rotenone and Paraquat effects in oxidative stress
similar structure to MPP | Also, inhibit VMAT and block DA storage as well as complex I activity
74
Major mechanisms of Neurodegeneration in PD--3 major pathways
- mitochondrial dysfunction - misfolding of proteins and issues with chaperones - lysosomal dysfunction WORK in concert for neurodegen
75
Therapeutic approaches for disease-modifying treatments: mit dysfunction
IMPROVEMENT OF MITOCHONDRIAL | FUNCTION AND MITOPHAGY
76
Therapeutic approaches for disease-modifying treatments: Oxidative stress
Anti-oxidants
77
Therapeutic approaches for disease-modifying treatments: Protein misfolding and aggregation (α-synuclein)
Reduction of α-synuclein expression, misfolding and spreading
78
``` Therapeutic approaches for disease-modifying treatments: Dysfunction of proteostatic mechanisms (chaperones, autophagy, proteasomes, lysosomes) ```
Enhancement of proteostatic mechanisms
79
Therapeutic approaches for disease-modifying treatments: directly affecting neurodegen
Pro-survival factors for DA neurons

PMCOL 412 (35 decks)

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