L04 Antiparkinsons Flashcards
Define Parkinson’s disease.
Briefly, a neurodegenerative disease characterised by disorders of movement, as well as gait.
James Parkinson (1817): Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported with a propensity to bend the trunk forwards to pass from a walking to a running pace: the senses and intellects being uninjured.
Current characterisation:
- Neurodegenerative disease characterised by lack of dopamine
- Tremors
- Stiffness in motion; hesitation to start motion
- Gait disorder
- Disorders of movement
- No cognitive disorder in early stages
- Intellects may be affected in late stages -> Parkinson’s Disease dementia
There is no association between the prevalence of Parkinson’s disease (PD) with age. True or false?
False.
Worldwide, incidence & prevalence of PD increases with age.
- Average age of onset: Early to mid-60s
At what ages do young-onset PD begin to manifest in 5-10% of patients diagnosed with PD?
21-40 y/o
At what ages do juvenile-onset PD begin to manifest in patients diagnosed with PD?
Before 20 y/o.
- Frequency of genetically inherited PD are higher amongst this sub-population of PD patients.
Explain the pathophysiology of Parkinson’s disease.
At intracellular level:
- Common end-mechanism of impaired clearing of abnormal/damaged intracellular proteins by ubiquitin-proteasomal system
- Failure to clear toxin proteins allows the accumulation of aggresomes (i.e. Lewy bodies), leading to apoptosis
- Leads to degeneration of dopaminergic neurons with Lewy body inclusions
Within nigrostriatal pathway:
- Since substantial nigra has dopaminergic projections to basal ganglia (i.e. nigrostriatal pathway), the accumulations of Lewy body inclusions cause the loss of dopaminergic neurons, thus the loss of dopamine found within synpases & subsequently the loss of dopaminergic projections.
- Basal ganglia is impt. in movement control that facilitates & modulates motor movements initiated by motor cortex
- Without dopamine, motor movement are no longer regulated, resulting in movement disorders.
Explain how PD is diagnosed.
No reliable diagnostic marker available
- Based on presence of clinical features
- AND exclusion of alternative diagnoses
All patients with parkinsonian syndrome have PD. True or false?
False!
- 10-25% of patients with parkinsonian syndrome do NOT have PD!
- Common differential diagnoses are atypical parkinsonian disorders.
What are the three cardinal features of PD?
Rest tremors
Rigidity
Bradykinesia (slowness of movement)
Describe the non-motor manifestations of PD & its incidence.
Involves the autonomic, neuropsychiatric, olfactory & sensory systems.
- E.g. Falls, postural instability, postural hypotension, confusion, dementia, suboptimal nutrition, speech & sleep disorders
Common in PD patients (as many as 88% have at least one non-motor smx & 11% w/ five non-motor smx)
- More prominent in later stages of PD
- Relatively resistant to & maybe worsened by dopaminergic agents -> dilemma
- Cause significant disability, BUT often neglected in PD management
Explain the general progression of PD.
Progressive disorder w/ rate of disability progression most marked in the early years of disease.
- Significant disability 10-15 years after onset
- At later stages, PD pt becomes increasingly dependent on caregivers’ aid in their activities of daily living.
- Motor fluctuation, dyskinesia & non-motor symptoms are common at later stages.
Explain the therapeutic rationale behind the treatment of PD.
Individualised Tx according to:
- Age
- Stage of disease
- Level of activity
- Associated psychological factors
- Associated medical conditions
- Patient factors
START LOW, GO SLOW!!
For early symptomatic PD pt w/o complications:
- May NOT need to start on PO medications if coping well, to minimise risk of developing cumulative ADR from anti-PD medications
- Maintain physiotherapy & exercise regime by stretching, maintaining balance & posture –> Start w/ better baseline w/ greater muscle mass
- Healthy & balanced diet
- Knowledge of disease
- Social support
List the classes of anti-PD medications available for the Tx of Parkinson’s disease.
Dopaminergic MOA:
1) Levodopa (L-dopa) -> agonist
2) MAO-B inhibitors
3) Catechol-O-methyltransferase (COMT) inhibitors
4) Dopamine agonists
Non-dopaminergic / Mixed MOA:
5) Anticholinergics
6) Amantadine
What are the indications for levodopa?
Gold standard in symptomatic combination therapy both early & late PD.
- Co-formulated with a dopa-decarboxylase inhibitor
Describe the mechanism of action of levodopa.
Dopaminergic MOA:
Levodopa is a dopamine precursor that helps increase the synthesis of dopamine neurotransmitters by increasing the number of dopamine precursors.
Levodopa is usually formulated without any additional potentiators. True or false?
False.
Often prepared as a “2-in-1” preparation that includes a peripheral dopa-decarboxylase inhibitor e.g. benserazide or carbidopa.
Explain why a dopa-decarboxylase inhibitor is co-formulated with levodopa for the Tx of PD.
- Dopamine itself cannot cross the blood-brain barrier (BBB)
- If levodopa is peripherally converted by dopa-decarboxylase before entry into BBB, it cannot exert its therapeutic effect.
- Peripheral dopa-decarboxylase inhibitors prevents levodopa from converting into active dopamine too early, resulting in greater amounts of levodopa entering the BBB, which allows for a lower dose of levodopa being administered.
