Antiparkinsons Flashcards
Pathophysiology of Parkinson’s Disease
- Impaired clearing of abnormal/damaged IC proteins by ubiquitin-proteasomal system
- Failure to clear toxic proteins
- -> Accumulation of aggresomes & finally apoptosis
Lewy bodies: Aggresomes containing alpha-synuclein & ubiquitin
- Degeneration of dopaminergic neurons* (with Lewy bodies inclusion in the substantia nigra)
- > Substantia nigra has dopaminergic projections to the basal ganglia [Important in facilitating & modulating motor movement]
Clinical Features of Parkinson’s Disease
- 3 Cardinal Features*:
i) Rest tremors
ii) Rigidity
iii) Bradykinesia (slowness of movement)
Non-motor manifestations:
- Autonomic, neuropsychiatric, olfactory, sensory
- Common & > prominent in later stages of PD
- > Relatively resistant to & may be worsened by dopaminergic agents
- > Can cause significant disability but it is often neglected in PD management
List the treatment options of Parkinson’s Disease
1) Levodopa (eg. Madopar)
2) Anticholinergics (eg. Artane)
3) Dopamine agonists
4) COM-T inhibitors (eg. Entacapone, Tolcapone)
5) MAO-B inhibitors (eg. Selegiline, Rasagiline)
6) Amantadine
How is treatment individualised according to?
- Age
- Stage of disease
- Level of activity
- Associated physiological factors/medical conditions
- Patient factors
Course of Parkinson’s Disease
- Progressive disorder
- Rate of disability progression is most marked in the early years (Significant disability 10-15yrs > onset)
- PD pts become increasingly dependent in their activities of daily living
Common @ later stages:
Motor fluctuation, dyskinesias, non-motor symptoms
When might oral medications not be needed for Parkinson’s Disease?
Early symptomatic disease w/o complications
- Physiotherapy & exercise
- Healthy & Balanced diet
- Knowledge on disease
- Social support
Levodopa
Eg. Madopar, Sinemet
What: Analogue of L-dopa, precursor to be synthesised to Dopamine
- “2-in-1” preparation with peripheral decarboxylase inhibitor to prevent L-dopa from being converted in periphery so that > avail in brain
Side Effects:
Short-term - N/V, Postural hypotension
Long-term - Motor fluctuations & dyskinesia (10%/yr)
IMPORTANT:
- Risk of dyskinesia increase with longer use & becomes chronic even if you stop using the medication
- Keep to lowest dose
Levodopa for Parkinson’s Disease
Eg. Madopar, Sinemet
What: Analogue of L-dopa, precursor to be synthesised to Dopamine
- “2-in-1” preparation with peripheral decarboxylase inhibitor to prevent L-dopa from being converted in periphery so that > avail in brain
Side Effects:
Short-term - N/V, Postural hypotension
Long-term - Motor fluctuations & dyskinesia (10%/yr)
IMPORTANT:
- Risk of dyskinesia increase with longer use & becomes chronic even if you stop using the medication
- Keep to lowest dose
Anticholinergics for Parkinson’s Disease
Eg. Trihexyphenidyl (Artane)
Use: i) Symptomatic monotherapy ii) (+) Levodopa
Advantages:
- May be effective in controlling tremor & treating sialorrhoea (excessive saliva secretion)
Side Effects (Especially elderly) : - Dry mouth, sedation, constipation, urinary retention, delirium, confusion, hallucinations
MAO-B Inhibitors for Parkinson’s Disease
Eg. Selegiline (Jumex), Rasagiline
Use: Symptomatic monotherapy in EARLY stages of PD
- Mild Anti-Parkinson activity
MOA: Inhibits MAO-B, interfere with breakdown of dopamine, > dopamine available in synaptic space
Advantages:
- May delay nigral brain cell degeneration (may have some disease modifying effect)
Side Effects:
- Heartburn, loss of appetite, nausea, constipation, dizziness, anxiety, HA, palpitation, insomnia, confusion, nightmares, visual hallucination
COMT Inhibitors for Parkinson’s Disease
Eg. Entacapone (Comtan), Tolcapone (Tasmar)
Use: (+) Levodopa
- Blocks enzyme that converts Levodopa into an inactive form, > levodopa avail to enter brain
Advantages:
- Increases duration of each dose of levodopa, beneficial in treating “wearing off” responses
Side Effects:
- Increase abnormal movements (dyskinesias)
- Nausea, diarrhoea
- Urinary discolouration
- Visual hallucinations
- Daytime drowsiness, sleep disturbances
- (Tolcapone) Liver dysfunction
Dopamine Agonists for Parkinson’s Disease
Eg. Bromocriptine, Pergolide, Piribedil, Ropinirole, Pramipexole
Use: i) Symptomatic monotherapy ii) (+) Levodopa
- *Should commence therapy with Dopamine Agonists 1st instead of Levodopa for younger PD pts
(Antiparkinson effect not superior to Levodopa)
MOA: Acts directly on dopamine receptors to reduce symptoms of PD. Prevents/delay onset of motor complications
Side Effects (Similar to levodopa)
- ‘ergot’ derivative -> fibrosis
- Pedal edema (in extremities especially legs)
- (Ropinirole, Pramipexole) Somnolence
- Arrhythymia
- (Pergolide) Restrictive valvular heart disease
Amantadine for Parkinson’s Disease
Use: i) Monotherapy ii) (+) Levodopa
- Mild anti-PD effect (tremor, rigidity, bradykinesia, dyskinesia)
- *Need to screen pts for seizures/psychiatric symptoms
MOA:
- Enhance release of stored dopamine
- Inhibit presynaptic uptake of catecholamine
- Dopamine receptor agonist
- NMDA receptor antagonist
- Antidyskinetic (note: Amantadine may be considered as therapy to REDUCE dyskinesia in PD pts with motor fluctuations)
Side Effects (Limits its use):
- Cognitive impairment (inability to concentrate)
- Hallucination
- Insomnia
- Nightmares
- Livedo reticularis (spasm of blood vessels/ abnormal circulation of blood at the surface)
- Venule swelling due to thromboses -> Mottled reticulated discolouration of limbs
