Treatment of Parkinson's Disease l Flashcards
Potential diagnosis of patients with parkinsonian symptoms
- Idiopathic PD
- Parkinson’s Plus
- have specific symptoms - Parkinsonism
- drug-induced
- toxin-induced
- vascular
Parkinson’s Disease features
- idiopathic
- neurodegenerative
- CNS disorder
- 4 characteristic features :
1. Muscular rigidity
2. Rest tremors - disappears with movement
3. Slow movements & poverty of movement (bradykinesia)
4. Postural instability
Diagnosis of PD
- Clinical signs, physical examinations & history
- must have at least 2 of the 3 cardinal signs (tremors, rigidity & bradykinesia/akinesia)
Akathesia = Akinesia?
No.
Akinesia is no movement
Akathisia is movement disorder that makes it hard to stay still
Dyskinesia = Bradykinesia?
No.
Dyskinesia is involuntary movements
Bradykinesia is slow movement
IDP INITIAL clinical presentations (3)
- Asymmetric
- Positive response to Levodopa / Apomorphine (dopamine agonist)
- Less rapid progression (rapid = H&Y 3 in 3 years)
Morbidities of IDP (3)
- Unable to perform ADL or unable to perform ADL safely
- Dysphagia
- increase risk of pneumonia - Falls
- due to gait instability
Pathological cause of IDP (3)
At least 50-80% loss of dopaminergic neurones in substantia nigra
- leads to clinical symptoms
1. Age-related loss of neurons
2. Environmental toxin/insult - pesticides/herbicides
3. Genetics - genetics abnormalities
H&Y staging (5)
H&Y 1
- symptoms on one side of body
H&Y 2
- symptoms on both sides of body
- no balance impairment
H&Y 3
- balance impairment
- physically independent
H&Y 4
- severe disability but still can walk/stand unassisted
H&Y 5
- wheelchair bound
- bedbound
Measuring PD using H&Y staging (3)
- assess mobility
- if not on treatment, assess when the person is in “on” and “off” state
- no need to reassess on every visit
Non-motor symptoms of PD (4)
- Psychiatric impairment
- depression - Cognitive impairment
- dementia - Sleep disorders
- Autonomic dysfunction
- constipation
PD rating scales (3)
- H&Y
- Unified Parkinson’s Disease Rating Scale (UPDRS)
- MDS-UPDRS
Is there predromal symptoms of PD?
Examples of predromal symptoms (3)
Possible.
Can be unmasked by drug-induced parkinsonism
eg hyposmia, constipation, bladder disorder
Early/Young onset of PD
- slower disease progression
- common initial presentation is dystonia (compared to falls & freezing in late-onset)
- less cognitive decline but earlier motor complications
- treatment : dopamine agonist > levodopa
Goal of PD treatment (2)
- Manage symptoms
2. Maintain function & autonomy (increase independence)
Can PD treatment cure PD?
No. There is no treatment for PD that has clear evidence to be neuroprotective. PD treatment cannot : - replace dopamine - cure PD
Pharmacological treatments for PD (6)
Increase central dopamine, dopaminergic transmission
- Levodopa + peripheral decarboxylase inhibitor (DCI)
- Dopamine agonist
- ergot-derivative (bromocriptine, cabergoline, pergolide)
- non-ergot derivative (ropinirole, pramipexole, apomorphine, rotigotine) - COMT-i
- Entacapone
- Tolcapone (not in SG) - MAO-i
- Selegiline (stimulating)
- Rasagiline
Correct imbalance in other pathways - Acetylcholinergics
- Benztropine
- Trihexyphenidyl - NMDA antagonists
- Amantadine
- Memantine
Non-pharmacological treatment for PD
Involve several professionals as the impact of PD is wide
eg physiotherapy, speech therapy, nutrition therapy, occupational therapy
Why dopamine cannot be used a direct treatment?
Dopamine cannot cross BBB.
Hence DCI added tgt with Levodopa to prevent peripheral metabolism of Levodopa to dopamine
Peripheral conversion of Levodopa to dopamine & potential ADR
Catalysed by :
- MAO
- COMT
- dopamine decarboxylase
SE :
N/V & postural hypotension due to dopamine production
Levopdopa PK (2)
- F (levodopa) = 33%
- F (levodopa + DCI) = 75%
- absorption by active saturable carrier system for large neutral amino acids (eg tryptophan)
Hence, FDI w high protein food (reduce F)
Space apart 2h
Preparations of available DCI : Levodopa (3)
Sinemet 1:4
Sinemet 1:10
Madopar 1:4
Levodopa ADR (7)
- N/V
- Orthostatic hypotension
- Drowsiness, sudden sleep onset
- Hallucinations, psychosis
- Dyskinesia (3-5years onset after taking drug)
- “on-off” phenomenon
- unpredictable - “wearing off” phenomenon
- disease progression
- decreased plasma conc at end of dose
Management of “wearing off” phenomenon (2)
- Modify dosing interval (shorten dosing interval)
2. Use modified release > immediate release preparations
PD disease progression
- narrow therapeutic window
- lower threshold conc for dyskinesia
- higher threshold conc for symptomatic relief
Sustained release Levodopa purpose
- designed to release Levodopa/DCI over a longer period of time (4-6h)
- reduce risk of “wearing off” effects
- useful to reduce stiffness on walking
- lower bioavailability
Switching between immediate release agents and SR/CR Levodopa
SR/CR to IR :
- decrease dose
IR to SR/CR :
- increase dose (25-50%)
Sinemet SR precaution
- do not crush
Madopar HBS precaution
- do not open capsule
Levodopa DDI (5)
- Vit B6 (pyridoxine)
- cofactor for doapamine decarboxylase
- generally not an issue if using DCI but do be aware of possibility of interactions with high dose vitB6 & high potency vitB complex tablets - Iron
- chelates with iron to decrease F
- space out administration - Protein
- absorption of Levodopa is by saturable carrier systems for large neutral AA
- space out administration 2h - Antidopaminergic drugs
eg metoclopramide, prochlorperazine, 1st gen antipsychotics (FGA) & risperidone
- antiemetic use domperidone - Non-selective MAOi (not registered in SG)
Dopamine agonists types
- Ergot derivatives
- bromocriptine
- cabergoline (Dostinex)
- pergolide (not in SG) - Non-ergot derivative
- ropinirole (SR & IR available)
- pramipexole (SR & IR available)
- apomorphine (SC)
- rotigotine (transdermal) (not in SG)
MOA dopamine agonists (2)
- act on D2 receptors in nigral striatum
- mimics dopamine
Dopamine agonists PK
- ergot derivative F < non-erogt derivative F due to extensive 1st pass metabolism
- longer half life & duration of action that Levodopa
- hepatic metabolism (ropinirole)
- renal excretion (pramipexole)
Dopamine agonists ADR (dopaminergic)
- Peripheral
- Central
Peripheral (3)
- N/V
- postural hypotension
- leg oedema
Central (3) - daytime drowsiness, somnolence - hallucinations (visual > auditory) - compulsive behaviours eg gambling, shopping, eating & hypersexuality
Dopamine agonists ADR (non-dopaminergic) (2)
Higher risks for ergot derivative
- Fibrosis
- may be partially reversible upon withdrawal
- pulmonary, pericardiac, retro-peritoneal - Valvular heart disease
Dopamine agonists vs Levodopa (4)
- patients type
- ADR
- Dopamine agonists less motor complications than Levodopa
- Dopamine agonists more hallucinations, sleep disturbances & leg oedema than Levodopa
- Dopamine agonists preferred in younger patients than Levodopa
- No clinical significant difference in efficacy between both agents
Why is dopamine agonists > Levodopa in younger patients? (2)
- To maximise treatment options
2. To delay the onset of Levodopa-induced motor complications
Dopamine agonists place in management of PD (3)
- Monotherapy in younger patients
- Adjunct to Levodopa in moderate/severe PD
- Can be used to manage the motor complications caused by Levodopa
Rotigotine patch uses
- used in patients not suitable for tube-feeding, cannot swallow and transition
- NIL by mouth
- not registered in SG anymore
Rate of regeneration of MAOs
14-28 days cos irreversible inhibition
MAO-A metabolism
- peripheral
- NA
- 5-HT
MAO-B metabolism
- central
- dopamine
MAO-Bi examples (2)
- Selegiline
- Rasagiline
- irreversible
MAO-B i use in PD (2)
- effective as monotherapy in early stages
- adjunct in later stages
- not totally selective for MAO-B (can cross over to MAO-A)
- no evidence of neuroprotection
Selegiline metabolism
- hepatically metabolised to amphetamines (stimulating but no effect on MAO-B)
Rasagiline metabolism
- not metabolised to amphetamines
DDI of MAO-B i (7)
- SSRI, SNRI, TCAs (washout period req)
- Tramadol, pethidine (opioids)
- Dextromethorphan
- Dopamine
- Sympathomimetics (eg pseudoephedrine, phenylephrine)
- Another MAO-i
- Linezolid
FDI of MAO-B i
- food rich in tyramines
- advice patients to avoid such foods
MAO-B i vs Dopamine agonists & Levodopa
MAO-B i < Dopamine agonists & Levodopa
COMT meaning
Catechol-O-methyl Transferase
COMT-i examples (2)
- Entacapone
2. Tolcapone (not in SG)
COMT-i MOA
- decrease “off” times & “wearing off” effect by inhibiting COMT metabolism of levodopa
- major metaboliser of Levodopa in the presence of DCI
- not effective without concurrent Levodopa
- selective, reversible COMTi
- must be taken at the same time as Levodopa
COMT-i clearance
Hepatic metabolism
COMTi ADR (6)
- Diarrhoea (entacapone)
- Urine discoloration (orange) (entacapone)
- Levodopa also cause urine discoloration - Dyskinesia upon initiation (reversible)
- may need to decrease Levodopa dose - N/V
- Orthostatic hypotension
- Hepatic impairment
- LFT monitoring for Tolcapone
- every 2-4 weeks for 6 months
Entacapone DDI
- avoid with MAOi
Tolcapone vs Entacapone (3)
Tolcapone
- more potent and longer duration of action (2-3h)
- Tolcapone require greater reduction in Levodopa dose
- Tolcapone require LFT every 2-4 weeks for 6 months
Entacapone
- less potent and shorter duration of action (1-2h)
- Entacapone require smaller reduction in Levodopa dose
- Entacapone does not require regular LFT monitoring
Early/young onset vs Late onset of PD (2)
Early/young onset
- less cognitive decline
- common presentation is dystonia
Late onset
- more cognitive decline
- common presentation (2/3 of cardinal features)
Management of tardive dyskinesia (3)
- Modified release > immediate preparations (prevention)
- Immediate release (acute symptomatic treatment)
- Amantadine (maintenance of progression of levodopa-induced dyskinesia)
