PD II Flashcards
Why use L-Dopa over DA
L-dopa can cross the BBB (transport through aromatic aminoacid transporter)
L-Dopa converted to DA by
AADC in the brain
L-dopa admin–efficacy
Good to excellent symptomatic response at the beginning of treatment (“honeymoon” phase) BUT over time, most patients will eventually develop complications
T/F L-Dopa corrects non-motor symptoms as well
FALSE
Non-motor symptoms are not corrected (depression, dementia, autonomic dysregulation etc.) and the underlying neurodegenerative process is not affected
Effects of L-dopa in early PD
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.
Complications of L-DOPA
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
what is LID
L-DOPA induced dyskinesia (LID) involuntary hyperkinetic movements
LID is mainly due to D1R supersensitivity and hyperactivation–occurs at peak dose
Why is there a difference b/t the initial L-DOPA effects and later complications
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
L-DOPA metabolism
AADC converts L-dopa to DA
COMT converts L-DOPA to 3-OMD (3-)-methyldopa)
Both occur peripherally
How LID effect L-dopa use
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)
Peripheral L-Dopa side effects
- nausea and vomiting
- hypotension
- cardiac arrhythmias
What causes the peripheral side effects of L-dopa
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
Peripheral side effects of L-Dopa: nausea and vomiting
Caused by the action of dopamine on D2 receptors in the area postrema of the medulla (chemoreceptor trigger zone)
Peripheral side effects of L-Dopa: hypotension
Activation of vascular dopamine receptors and vasodilation
Peripheral side effects of L-Dopa: Cardiac arrhythmias
Activation of peripheral adrenergic
receptors
How to decrease peripheral metabolism of L-Dopa
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)
HOW do we alter L-dopa metabolism
use pharmacological inhibitors of DA metabolism
incl. carbidopa, benserazide, entacapone, tolcapone
L-DOPA administration to prevent side effects
- 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
Inhibitors of aromatic amino acid decarboxylase (AADC): Role
Prevent excess peripheral dopamine formation
Want central AADC to work so use ones that don’t cross BBB
Inhibitors of aromatic amino acid decarboxylase (AADC): examples
carbidopa, benserazide
COMT inhibitors: Role
Increase half-life and concentration of L-Dopa and dopamine
Inhibits BOTH peripheral and brain COMT (or just peripheral)
COMT inhibitors: examples
entacapone, tolcapone
Difference between entacapone, tolcapone
entacapone–peripheral only
tolcapone–can cross BBB
When are COMT inhibitors used most
Tolcapone or entacapone are often co-administered at later disease stages to
reduce “on/off” fluctuations.
Tolcapone risks
Tolcapone has considerable hepatotoxicity and patients must be monitored for
signs of liver damage
MAO-B plus L-dopa
Block DA degradation in brain with MAOB inhibitors and COMT inhibitors = increased striatal DA
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)
MAOB inhibitors: examples
selegiline, rasagiline
MAOB inhibitors: Role
- Block oxidative deamination of dopamine increasing its half-life in the brain
- Antioxidant properties. Anti-apoptotic and neuroprotective activity
Selegiline: side effects
MAOBI
is partially metabolized to amphetamine and
methamphetamine which may cause insomnia and anxiety
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)
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
Dopamine agonist: older drugs
Ergot derivatives:
- Bromocriptine (D2 agonist, D1 antagonist)
- Pergolide (D2 and D1 agonist)
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)
Pramipexole, Ropinirole
Selective D2 agonists
Apomorphine
D2 and D1 agonist
Rotigotine
- can be delivered transdermally
- D2 receptor agonist and partial agonist of 5HT1A receptor
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)
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)
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
When is L-DOPA chosen over DA agonists
L-dopa is the drug of choice in patients that also present with dementia or hallucinosis
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)
Anticholinergics: Role
Decreasing cholinergic inputs on D2 neurons helps decreasing their firing and activation of the indirect pathway
Anticholinergics: examples
Muscarinic cholinergic antagonists
- trihexyphenidyl
- benzotropine
Anticholinergics: efficacy
Less effective than other drugs
BUT Drug of choice for the treatment of parkinsonism induced by D2 antagonists
Anticholinergics: Side effects
Side effects related to anticholinergic properties are sedation and mental confusion, constipation, dry mouth etc.
fewer side effects than other options
What drug is best for the treatment of parkinsonism induced by D2 antagonists
Anticholinergics
Amantadine–drug type
‘other’ doesn’t fall into other categories of anti-PD drugs
Originally introduced as an anti-influenza agent
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
Amantadine-efficacy
- Overall modest effects on PD symptoms.
- Sometimes used at early stages of PD or in combination with L-DOPA to decrease dyskinesia
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
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
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.
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)
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)
Amantadine use
rarely used
used mainly in combination with L-dopa to prevent dyskinesia due to fluctuating DA levels
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
affected protein: a-synuclein function?
Synaptic function–synaptic vesicle
formation and recycling, axonal transport
affected protein: parkin function?
E3 ubiquitin ligase, mitophagy
affected protein: DJ1 function?
Chaperone, oxidative stress sensor
affected protein: PINK1 (PTEN-induced kinase 1) function?
Mitochondrial kinase (phosphorylation of mitochondrial proteins), mitophagy
affected protein: LRRK2/dardarin
(leucine-rich repeat serine/threonine kinase) Function?
Kinase. Involved in intracellular vesicle trafficking, mitochondria and microtubules dynamics
affected protein: ATP13A2 Function?
ATPase important for lysosomal function and mitochondrial dynamics
affected protein: VPS35 (vacuolar
sorting protein 35) Function?
Intracellular vesicle trafficking.
Regulates LRRK2 activity.
affected protein: Glucocerebrosidase Function?
Lysosomal enzyme
RISK FACTOR
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)
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
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
DA can damage mitochondrial ____
chaperones; can’t cycle
DA hanging aorund intracellularly is ___
BAD b/c it breaks down and forms ROS
Ways to prevent ROS products from DA metabolism
Sequester DA in vessicles –> no DA hanging around –> no breakdown/DA oxidation
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
Rotenone and Paraquat effects in oxidative stress
similar structure to MPP
Also, inhibit VMAT and block DA storage as well as complex I activity
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
Therapeutic approaches for disease-modifying treatments: mit dysfunction
IMPROVEMENT OF MITOCHONDRIAL
FUNCTION AND MITOPHAGY
Therapeutic approaches for disease-modifying treatments: Oxidative stress
Anti-oxidants
Therapeutic approaches for disease-modifying treatments: Protein misfolding and aggregation (α-synuclein)
Reduction of α-synuclein expression, misfolding and spreading
Therapeutic approaches for disease-modifying treatments: Dysfunction of proteostatic mechanisms (chaperones, autophagy, proteasomes, lysosomes)
Enhancement of proteostatic mechanisms
Therapeutic approaches for disease-modifying treatments: directly affecting neurodegen
Pro-survival factors for DA neurons
