Week 9 - Parkinson's Disease Flashcards
Parkinson’s Disease (PD) Background INFO
onset, risk factors, diagnostic characteristic
Is a chronic, progressive neurodegenerative disease
- ONSET: ≥60 yo
- disease of elderly BUT can have early onset (< 60 yo)
- RISK FACTOR: genetic, head injury, exposure to neurotoxins
- Treatment only improves symptoms, does NOT stop disease progression
- Loss of dopaminergic neurones in nigro-striatum pathway
- motor symptoms only seen 60-80% loss - Presence of lewy bodies
- clumps of misfolded proteins (α synuclein)
- when clumps build up in neurone = dysfunction = cell death
What are the 3 motor symptoms
- Tremor
- on one side (asymmetrical)
- coarse tremor
- Rigidity
- jerky movements
- Bradykinesia
- slow movements
- struggle to initate movement e.g. getting up
What are the non-motor symptoms
- Monotone / unexpresive face
- Small handwriting
- Swallowing + speech problems
- Drooling
- Loss of smell, excessive sweating
- Depression, anxiety
- Memory problems
- Sleep disturbances
- Constipation, urinary problems
- seen first - Dizziness + falls
List the treatment options for patients newly diagnosed with PD
Drugs ONLY started once motor symptoms affects patients daily function
AIM: ↑ dopamine level in brain
- Levodopa (L-dopa) = 1st line
- MAO-B Inhibitors
- Dopamine agonists
- DDC Inhibitors
- DDC = dopa decarboxylase - COMT Inhibitors
- Amatadine
- Anticholinergics (rarely used)
WHEN newly diagnsoed pick from the following:
1. L-Dopa (w/ DDC-i)
2. MAO-B inhbitor
3. Dopamine agonist
NOTE:
- if taking dopanergic drug do NOT stop abruptly = neuroelectric malignant syndrome
How does L-Dopa work in PD
NOTE: MUST be administered with DDC inhibitor (ineffective on its own)
ALWAYS adminstered WITH DDC inhibitor
- L-Dopa adds to endogenous dopamine levels increasing levels to normal dopamine levels rewuired for function
- MOST commone + effective treatment
- relieves motor symptoms
- start with low dose, then titrate up
- due to SE = may not be tolerated well
- can cause psychosis due to ↑ dopamine
- SE occur when dopamine is formed outside of CNS (hence why adminster with DDC = ↓ peripheral dopamine formation
NOTE: take L-dopa away from food to ↑ absorption
- protein competes with L-dopa for amino acid transporter
Explain how DDC Inhibitors works in PD
NOTE: MUST be administered with L-dopa (ineffective on its own)
- When L-Dopa adminstered enters periphery (liver) where it can be broken down (decarboxylated) by DDC
- Do NOT want L-Dopa broken down here, want L-Dopa to cross BBB and be converted into dopamine in CNS
MoA:
- DDC inihbitor prevents breakdown of L-Dopa in periphery
- limits peripheral L-dopa metabolism = ↓ peripheral dopamine levels
- more L-Dopa crosses BBB = more dopamine formed + acting in CNS
- prolongs L-Dopa half life
EXAMPLE:
- Carbidopa
Explain how MAO-B Inhibitors works in PD
- Can be used as monotherapy
- Is more tolerable than L-dopa
- Better for milder symptoms
- Prefere rasagiline due to less severe side effects
MoA:
- MAO-B inihbitor prevents dopamine breakdown / metabolism (in CNS)
= dopamine levels remain high in synapse = ↑ dopamine activating receptors
Explain how dopamine agonist work in PD
Use non-ergot drugs due to better tolerability / less SE
- Monotherapy
- has less long-term issues compared to L-dopa
- less effective in improving motor symptoms like L-dopa
- start with low dose + titrate up
MoA:
- mimic dopamine action at post-synaptic neurone
Explain how COMT Inhibitors works in PD
COMT = Catechol-o-methyl transferase inhibitors
- When L-Dopa adminstered enters periphery (liver) where it can be broken down by COMT (a.k.a methylation)
- forming methyldopa
- COMT also can breakdown L-Dopa and dopamine in CNS - Do NOT want L-Dopa broken down
MoA:
- COMT inihbitor inhibits COMT (enzyme) = prevents metabolism of dopamine (in CNS) and breakdown of L-Dopa in periphery
- = dopamine levels remain high in CNS
- = in periphery more L-dopa can cross BBB
NOTE:
- start patient on separate COMT-i tablet
- if tolerated switched to combined tablet (COMT-i, DDC-i and L-Dopa)
Explain how anticholinergics work in PD
MoA:
- used for tremor (in young patients)
NOTE:
- AVOID in elderly (risk of falls, anticholinergic burden)
NICE Treatment SUMMARY
- L-dopa (w/ DDC-I) OR Dopamine agonist (monotherapy)
- L-Dopa AND Dopamine agonist (combination therapy)
- ADD COMT-i or MAO-B inhibitor or amantadine (to above)
- Advanced theapy e.g. amorphine, duodopa
List side effects (SE) associated with drugs used in PD
- N&V
- hallucinations, psychosis
- postural hypertension
- sudden sleep onset
- issue if drive - dopamine dysregulation syndrome
- occurs if take excess L-dopa
List the treatment options for later-stage manifestations of PD
As PD progresses, response to treatment declines
- endogenous (body made) dopmine declines = exogenous (externally given) dopamine plasma levels fluctuate
- motor symptoms come back
To manage above:
- Shorten interval between drug doses (take drug more often)
- Use drug combinations
Drugs Used:
1. Amantadine
2. Duodopa
3. Apomorphine
How does Duodopa work in later stage PD
MoA, Challenges
Used in PD with severe fluctuaions
Is a fixed dose combination that pro-longs exposure to L-dopa
- Is a gel formulation, delivered directly to GI tract (via tube inserted into tract)
- via perm. PEG-J tube
- given a trial with NG tube before invasive procedure to insert PEG tube
- dont have to take multiple tablets a day
MoA Duodopa:
- Get smooth level of L-dopa in bloodstream that can get across BBB = levels out peaks and trough = no fluctuations
- Have a smooth exposure profile (no peaks)
- used for up to 16hrs a day
- have slightly higer dose in morning
- then slow steady rate throughout day
CHALLENGES:
- infection
- intrusive (pts rather take tablet)
- more expensive than generic meds.
- need to remeber how to operate machine
How does ProDuodopa work in later stage PD
MoA, Challenges
Used in PD with severe fluctuaions
Is a fixed dose combination that pro-longs exposure to L-dopa
- Is a S/C infusion formulation
- adminstered as phosphate pro-drug = improved solubility
- phosphate groups damages permeability = dephosphorylating enzyme removes group once drug enters plasma - reduces invasiveness (dont need tube fitted)
- little device is inserted under the skin
MoA ProDuodopa:
- combination of Duodopa AND Apomorphine
- combats fluctuations (“on-off”)
- Newer PD drug
- used if the above drugs arent suitable / tolerated
- increases duration of L-Dopa effect
CHALLENGES:
same as Duodopa
