Parkinson’s Flashcards
(33 cards)
Overview and Context
Dopamine deficiency in the CNS, particularly the substantia nigra.
All major PD therapies aim to manipulate dopamine signalling to restore motor function.
Dopamine & L-dopa Key Neurochemical Concepts
Even tho lmw, Dopamine itself is not CNS-permeable due to:
High polarity (log D < 0), -2
4 H-bond donors,
Low lipophilicity,
High ionisation at physiological pH.
——
L-Dopa (levodopa) is:
A prodrug of dopamine,
Not passively CNS permeable due to being zwitterionic and highly polar,high hydrogen divers
But Mimics amino acids and uses active transporters to enter CNS (same as tyrosine).
Oral bioavailable
Bloodstream
Transported into CNS
Converted into dopamine
L-Dopa Pharmacokinetics and Challenges
Converted in periphery to dopamine via AAD (Aromatic Amino Acid Decarboxylase, removes carboxyl group) in liver
Causes nausea, vomiting, other dopamine-related toxicities.
Short half-life (~2 hrs) → leads to on/off motor fluctuations.
Cannot simply increase dose due to severe peripheral side effects.
———-
Rapid clearance means effects of levodopa diminish rapidly (and in some cases suddenly)
several hours after dosing. (6/8hrs after it’s been removed)
Rapid on and off state as symptoms initially rapidly improved
High Cmax concentration (and associated high dopamine levels) cause undesired effects - dose cannot just be increased. (Too toxic)
Relative contribution of central and peripheral metabolism and signaling further complicate the efficacy/side effect relationships.
Despite these drawbacks L-DOPA remains the most effective treatment for Parkinsons
The majority of other drugs used in PD aim to alter the metabolism or manage side effects
associated with its use
Fluoxetine
Likely to be brain penetrating as:
Low molecular weight (309)
High lipophilicity
Low number of hydrogen doners
Levodopa metabolism
Based on this a peripherally selective inhibitor of AAD should reduce rate of L-DOPA metabolism (prolonging half life) and reduce peripheral dopamine levels
(improving side effect profile)
Peripheral (not in brain) metabolism undesired:
AAD (aromatic L-amino acid decarboxylase) could transfer some to dopamine in the liver
But also, methyltransferase can methylate some Ldopa to covert it into an inactive metabolite (methyldopa)
Some levopoa will reach CNS brain
Methylation & oxidation can deactivate some dopamine in the CNS
IDEALLY: to improve levels of dopamine in CNS reduce peripheral metabolism (longer duration in body to be taken up to brain + reduce peripheral formation of dopamine & its side effects so can allow increase dose)
In brain: Conversion to dopamine & prevent metabolism of dopamine to prolong exposure
Peripheral Modulation Strategies
- Carbidopa – potent AAD Inhibitor
Inhibits peripheral AAD, reducing dopamine formation (levodopa metabolism)outside CNS.
Structurally similar to L-Dopa, but:
Cannot cross BBB (brain) & CNS due to low lipophilicity, high polarity, and lack of transporter uptake as not recognised by amino acid transporters
Not passively permeable, low PKA, high hydrogen doners
Extends L-Dopa half-life slightly (~2 hrs), reduce peripheral Levodopa metabolism, reduce peripheral dopamine formation & associated side effects
Used in combination formulations (e.g. Sinemet). - COMT Inhibitors – Inhibit Catechol-O-methyl Transferase (PERIPHERAL & CENTRAL)
Prevent peripheral and central (brain) metabolism of L-Dopa and dopamine
Inhibition of peripheral COMT should further extend the exposure of L-DOPA, while inhibition of central COMT could increase duration of dopamine exposure
Entacapone: Low molecular weight, not too many HD but Peripheral only as low lipophilicity
Tolcapone: Structurally better as higher Central and peripheral exposure ; better CNS penetration but hepatotoxic → limited use.Livertoxicity.
Combined AAD & COMT inhibition although only increases half-life up to ~3–4 hrs Still problem of frequent dosing.
As seen in the previous lecture, central MAO inhibition and direct dopamine receptor modulation can further enhance L-DOPA efficacy and/or help control side effects
MAO-B Inhibitors – Block CNS breakdown of dopamine
Further extend dopamine presence in brain.
Examples: Selegiline, Rasagiline.
Not used as commonly like Levodopa & carbidopa combination and possibly with COMT inhibitor
Modern Formulation & Drug Delivery Advances
Formulation Goals:
Prolong exposure, flatten peaks/troughs, reduce side effects, longer term efficacy
- Triple Combo Product (Stalevo):
Contains L-Dopa + Carbidopa + Entacapone
Combined with controlled release (CR) formulation:
Prolongs absorption phase,
Improves symptom control. - Invasive GI Infusion System:
The short duration and high Cmax/Cmin ratio associated with L-DOPA (combinations) can be partially addressed using sustained release oral formulations, or more advanced/intrusive delivery mechanisms such as Duodopa - which directly delivers levodopa/carbidopa to the intestine
Drug delivered into intestine where levodopa mostly absorbed.
Direct levodopa-carbidopa-entacapone infusion via intestinal catheter.
Highly effective but invasive and infection-prone.
By passes stomach. - Phosphate Prodrugs (e.g., Pro-DuoDopa):
Eg foscarbidopa, foslevodopa
Phosphate-modified L-Dopa and Carbidopa:
Greatly improved aqueous solubility,
Administered via subcutaneous infusion (no GI access needed), less invasive
Converted back to active drug by alkaline phosphatase in blood.
Offers continuous 24h control.
Key Takeaways for Exam
• L-DOPA is a brain penetrant prodrug of dopamine. Based on its structure/properties it is apparent that this brain penetration results from active uptake mediated by amino acid transporters
• Optimisation of L-DOPA exposure can be achieved by co-administration of AAT and COMT inhibitors with controlled distribution - and this distribution can be rationalised based on the chemical structures/properties of these drugs eg carbidopa is peripheral restricted molecule so prevents dopamine formation in liver but not in brain
• More recently advanced delivery approaches have been developed that further improve L-DOPA therapy by maintaining blood levels (peak-trough ratio, continuous infusion, direct HI tract infusion, phosphate drugs to increase solubility & allow to be dosed subcutaneously by infusion) - the in case of produodopa this requires administration of highly aqueously soluble phosphate prodrugs of L-DOPA and carbidopa
• Other AAD and COMT inhibitors are approved for use in the UK - they follow the same chemistry
‘rules’ so you can/should check their structures and make sure you can understand the link between their structures and activity profiles in a similar way to discussed for carbidopa etc.
• Other dopamine modulating agents including CNS-penetrant MAO inhibitors and direct dopamine receptor agonists are also used to manage PD/L-DOPA symptoms - again it should be possible to understand their role based on their chemistry (CNS penetration) and biological targets
Desired CNS access :
Low MW < 400,
Lipophilic (logP > 2),
≤3 H-bond donors,
Moderate ionization (not too high)
Peripheral inhibitors (carbidopa, entacapone) reduce side effects and boost CNS L-Dopa.
New delivery strategies (e.g., prodrugs + subcutaneous infusion) aim to improve convenience and efficacy.
L-Dopa is the gold standard; other drugs support its CNS delivery and prolongation.
Parkinson’s pathophysiology
Chronic, progressive neurodegenerative disease
Degeneration of dopaminergic neurones in nigro-striatal pathway. Neurodegenerative disorder causing progressive loss of dopaminergic neurons in the substantia nigra.
Dopamine deficiency → impaired transmission to the striatum and basal ganglia → loss of smooth, coordinated movement.
50-80% loss before symptoms apparent
Presence of Lewy bodies in neurons
Lewy bodies = “clumps” of proteins made up mainly of alpha synuclein
Changes in GABA glutamate pathway may contribute to some non-motor and axial symptoms
Parkinson’s associated with:
Lewy bodies (alpha-synuclein aggregates).
Neuroinflammation.
GABA and glutamate pathway changes (axial + non-motor symptoms).
Risk factors
Men > Women.
Genetics: ~15% have a family history.
Environmental neurotoxins.
Head trauma.
Gut-brain axis theory (alpha-synuclein starts in gut → vagus nerve → brain).
Motor symptoms
Tremor: coarse, usually unilateral at rest.
Rigidity: cogwheel rigidity on passive movement.
Bradykinesia: slow movement, difficulty initiating actions.
Non-motor symptoms
Micrographia, monotone voice, mask-like face.
Swallowing & speech problems.
Drooling, dysphagia, anosmia (early sign).
Loss of smell
Excessive sweating
Memory problems
Sleep disturbances
Dizziness & falls
Constipation, urinary issues, orthostatic hypotension.
Depression, REM sleep disorder, Parkinson’s dementia.
Psychosis from disease or dopaminergic meds.
Restless legs, sexual dysfunction, impulse control disorders (e.g., gambling, hypersexuality).
Initiating Treatment
Start when motor symptoms impair daily living.
No cure; symptomatic management only. Disease progression not affected as disease modifying only.
Aim: ↑ dopamine availability in CNS.
Levodopa & peripheral dopa-decarboxylase inhibitor with either MOA-B inhibitor / dopamine agonist
Motor symptoms drug treatments
Levodopa
MAO-B inhibitors
Dopamine agonists
COMT inhibitors
Amantadine
Anticholinergics
Levodopa + DDCI treatment
Levodopa combined with peripheral dopa-decarboxylase nhibitor E.g. Madopar®
(co-beneldopa), Sinemet® co-
careldopa), Duodopa®, Produodopa®
• DD inhibitors (benserazide, carbidopa) limit peripheral metabolism of levodopa to dopamine; metabolised to dopamine after crossing BBB Most effective treatment - relieves motor symptoms of tremor, bradykinesia, rigidity
Low dose then titrated up to limit side effects of postural hypotension, nausea, vomiting and psychiatric effects
Initiate when symptoms interfere with daily activities. Until then, use other first line therapies due to long term problems (decreased efficacy and dyskinesias)
………….
Madopar (benserazide), Sinemet (carbidopa)
Gold standard, most effective for motor symptoms. Can cause dyskinesias, wearing off, psychosis, hypotension.
COMT Inhibitors
Entacapone (taken at exact same time as levodopa) ,Opicapone
Only with levodopa. ↑ duration of action. May cause diarrhoea, dyskinesias.
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Catechol-o-methyl transferase inhibitors
Use in combination with levodopa
Prevent metabolism of levodopa to 3-0-methyldopa
Entacapone
Opicapone
Entacapone + levodopa + carbidopa combination product - Stavelo
allows & in levodopa dose
Side effects - dyskinesias, nausea, diarrhoea
MOA-B Inhibitors
Rasagiline (preferred), Selegiline can cause hallucinations & insomnia (amphetaminelike metabolites)
Selegiline last dose 1pm to avoid insomnia
Prevents metabolism of dopamine = increase in dopamine at receptors
Monotherapy in early PD , better for milder initial symptoms
Useful in advanced to minimise Levodopa
Mild effect. Used early or as add-on. Selegiline → hallucinations (amphetamine metabolite).
Dopamine agonists
Non ergot: Pramipexole, Ropinirole, Rotigotine transdermal patch
Ergot: Pergolide, lisuride, bromocriptine, cabergoline
Agonists at post-synaptic dopamine receptors eg Apomorphine
Useful initial monotherapy - fewer long term problems thar levodopa (although less effective for motor symptoms
In advanced disease, used with levodopa
Available mainly as tablets; exceptions are rotigotine (24 h ransdermal patch) and apomorphine (s/c - covered later)
Slow initial dose titration needed
ergot: lung and cardiac valve fibrosis
Ergot-derivatives now rarely used
Nausea and vomiting
Psychiatric (hallucinations, psychosis)
Postural hypotension
Sudden sleep onset
Rarely, Dopamine Dysregulation Syndrome (gambling, hypersexuality, binge-eating
Most common in young males and if previous history of mental
Mimic dopamine. Risk of impulse control, sudden sleep onset, psychosis, hypotension. Rotigotine: useful if swallowing is impaired.
Anticholinergics
Procyclidine
Rare. Only in young patients with tremor. Avoid in elderly due to confusion. May be used for urinary issues.
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E.g. trihexyphenidyl, orphenadrine
Now only used for tremor, or to treat some non motor symptoms Avoid in elderly due to side effects
Side effects
anticholinergic, e.g. constipation, urinary retention psychiatric, e.g. confusion, delusions
Useful in young, tremor ++
Do not stop abruptly due to rebound symptoms
Amantadine
Weak NMDA/glutamate modulator.
Short-term help for dyskinesias.
Psychiatric side effects, rash, oedema.
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Glutamate antagonist at NMDA receptor
Treats dyskinesias in late disease
Efficacy decreases after several months
Side effects
psychiatric, e.g. confusion, hallucinations
GI, e.g. N&V
oedema, skin rash (livedo reticularis)
Tachyphylaxis - need more drug to have same effect over time
Treatment complications
Wearing Off: levodopa effects fade before next dose.
On-Off Phenomenon: unpredictable swings between “on” (dyskinesias) and “off” (immobility).
Dyskinesias: involuntary movements (peak dose effect).
Management:
Shorten dosing intervals.
Add COMT/MAO-B inhibitors.
Reduce levodopa or use amantadine.
Consider continuous therapies
————————————————————————As disease progresses, response to treatment declines Endogenous dopamine declines, plasma levels of exogenous dopamine are prone to large fluctuations
Wearing off
Plasma drug concentrations fall (trough) - patients experience akinesia and rigidity
On-off
When drug concentrations peak, patients can experience motor complications (dyskinesia and dystonia). On-off is fluctuation between peak and trough drug levels and associated symptoms
Shorten interval between drug doses or use drug combinations to manage
First line therapy
1)Dopamine agonist or
Levodopy monotherapy
Continuous therapy: Apomorphine
Subcutaneous (pump + PRN pen)
Potent D2 agonist. Good for on-off. Start with domperidone (antiemetic).
Risk: nodules, psychosis, QT prolongation.
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Subcut route only - bolus or 12 hour-infusion useful for ‘on-off’ fluctuations specialist supervision needed
Side effects (see also DA slide)
Nausea, vomiting (pretreat with domperidone PR for 3/7)
yawning, drowsiness, abscess / nodule formation
Caution: Apomorphine as well as domperidone cam prolong QT interval - may exclude pre-existing cardiac complications
Advanced & continuous therapy: Pro-Duodopa
Subcutaneous pump (24h)
Continuous carbidopa/levodopa. Easier to manage than Duodopa. Pre-programmed rates. Can have extra boost settings.
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For PD with severe motor fluctuations and dyskinesia
Subcutaneous formulation of Co-careldopa
Administered using a pump over 24hours
Used if apomorphine or DBS not tolerated or not suitable, or if these treatments no longer control symptoms
Advanced / continuous therapy: Duodopa
Intestinal gel via PEG-J
For very advanced PD. Direct to jejunum (best levodopa absorption). Invasive, requires nurse-led initiation.
During waking hours (disconnected at night)
Maintenance rate and optional booster
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For PD with severe motor fluctuations and dyskinesia
Intestinal gel formulation of co-careldopa
Delivered directly to jejunum
Administered using pump via PEG-/ tube (invasive)
Initial trial with NG tube
Can be used for up to 16 hours/day
