Parkinson's - Treatment Flashcards
What are the pharmacological treatment options?
Levodopa
Dopamine agonists
→ Ergots: bromocriptine, cabergoline
→ Non-ergots: ropinirole, pramipexole, rotigotine (transdermal exemption item), apomorphine (SC)
MAO-B Inhibitors: Selegiline, Rasagiline
COMT Inhibitors: Entacapone
Anticholinergics: Trihexyphenidyl
NMDA Antagonists: Amantadine
What is the MOA of levodopa?
MOA: Dopamine precursor
→ Levodopa is peripherally converted to dopamine – catalysed by DOPA decarboxylase, MAO, COMT
(Dopamine cannot be used as Tx
as it does not cross BBB)
Usually formulated with carbidopa or benserazide
→ Peripheral DOPA-decarboxylase inhibitor (DCI) – prevent systemic SE due to excess DA
→ Does not cross the BBB
→ 75-100mg daily required to saturate DOPA-decarboxylase
What are the SE of levodopa?
Short-term SE: N/V, postural hypotension, drowsiness, sudden sleep onset, hallucinations, psychosis
Long-term SE: motor fluctuations and dyskinesia – Keep dose to minimum effective dose to prevent
(but usually sets in within 3-5 years of initiation)
* “on-off” phenomenon – levodopa response randomly increasing and decreasing, unclear mechanism, difficult to control with medication, unrelated to dose/dosing interval
* “wearing off” phenomenon – effect of levodopa wanes before end of dosing interval, associated with disease progression
* Can add amantadine to help with dyskinesia
What are the DDIs for levodopa
Pyridoxine – cofactor for DOPA-decarboxylase (okay if levodopa is administered with DCI)
* Note high dose B6 for haematological problems or in high potency vitamin B complex
Iron – affects absorption of levodopa (space out)
Protein (food, protein powder) – affects absorption of levodopa (space out)
Dopamine antagonists
* Use domperidone for antiemetic in Parkinson’s
* Antipsychotics – use clozapine, quetiapine, or ziprasidone at lower initial dose if need
What is the PK of levodopa?
Absorbed in proximal part of small intestine
F – 33% alone, 75% with benserazide/carbidopa
Absorption decreases with high fat or protein meals
* Is absorbed by an active saturable carrier system for large neutral amino acids – can get saturated by amino acids from dietary intak
What is the MOA of dopamine agonists?
Act directly on dopamine receptors in the brain to reduce PD symptoms (mimic dopamine)
What is the PK of dopamine agonists?
- Ergots have lower F than non-ergots, due to extensive 1st pass metabolism
- Longer half life and duration of action than levodopa
- Ropinirole: mainly metabolised by liver to inactive metabolites – dose reductions required in hepatic impairment, but not much issues with renal function
- Pramipexole: excreted largely unchanged in the urine – dose reductions required in renal impairment, but not much issues with hepatic function
What are the common SEs of dopamine agonists?
- Peripheral Dopaminergic: N/V, orthostatic hypotension, headache, dizziness, arrhythmias
- Central Dopaminergic: Hallucinations, somnolence, daytime sleepiness, compulsive behaviours
- Non-dopaminergic: Fibrosis (pulmonary/pericardiac/retro-peritoneal, may be partially reversible on withdrawal, lower risk with non-ergots)
- Ergot SEs: peritoneal fibrosis, cardiac valve regurgitation
What is the MOA of MAO-B Inhibitors?
Inhibits enzyme monoamine oxidase B irreversibly, interferes w breakdown of dopamine
* May delay nigral brain cell degeneration
* Irreversible – short half-life (1.5-4h) but long duration of action
* Not completely selective for MAO B
What are the SEs of MAO-B Inhibitors?
Heartburn, loss of appetite, anxiety, palpitation, insomnia
* SE from having too much dopamine: nightmares, visual hallucinations
What is the difference between selegiline and rasagiline?
Selegiline is hepatically metabolised to amphetamines (stimulant), but not rasagiline
What are the DDIs with MAO-B inhibitors?
- SSRI, SNRI, TCA – washout periods recommended
- Contraindicated w oral tablet - Pethidine, tramadol, linezolid, dextromethorphan
- Dopamine – enhanced hypertensive effect, reduce dose by 1/10, or consider alternatives
- MAOis – serotonin syndrome risk
What is the MOA of Entacapone?
Selectively, reversibly, blocks COMT conversion of dopamine and L-DOPA to an inactive form
How is entacapone used for Parkinson’s?
Used as adjunct to levodopa (must take at the same time) – reduces required dose of levodopa
→ Since breakdown of dopamine is slower, easier to hit the required amount of dopamine for therapeutic effect with a smaller dose of levodopa
→ Increases the duration that each dose of levodopa lasts for – helps in treating “wearing off” of levodopa effect
What are the SEs of entacapone?
Dyskinesias (inc abnormal movements), N/D, urinary discolouration (orange), visual hallucinations, daytime drowsiness, sleep disturbances
→ Dyskinesia on initiation – may need to dec levodopa dose