Parkinson's - Treatment

Question 1

What are the pharmacological treatment options?

Answer 1

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

Question 2

What is the MOA of levodopa?

Answer 2

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

Question 3

What are the SE of levodopa?

Answer 3

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

Question 4

What are the DDIs for levodopa

Answer 4

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

Question 5

What is the PK of levodopa?

Answer 5

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

Question 6

What is the MOA of dopamine agonists?

Answer 6

Act directly on dopamine receptors in the brain to reduce PD symptoms (mimic dopamine)

Question 7

What is the PK of dopamine agonists?

Answer 7

• 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

Question 8

What are the common SEs of dopamine agonists?

Answer 8

• 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

Question 9

What is the MOA of MAO-B Inhibitors?

Answer 9

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

Question 10

What are the SEs of MAO-B Inhibitors?

Answer 10

Heartburn, loss of appetite, anxiety, palpitation, insomnia
* SE from having too much dopamine: nightmares, visual hallucinations

Question 11

What is the difference between selegiline and rasagiline?

Answer 11

Selegiline is hepatically metabolised to amphetamines (stimulant), but not rasagiline

Question 12

What are the DDIs with MAO-B inhibitors?

Answer 12

• 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

Question 13

What is the MOA of Entacapone?

Answer 13

Selectively, reversibly, blocks COMT conversion of dopamine and L-DOPA to an inactive form

Question 14

How is entacapone used for Parkinson’s?

Answer 14

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

Question 15

What are the SEs of entacapone?

Answer 15

Dyskinesias (inc abnormal movements), N/D, urinary discolouration (orange), visual hallucinations, daytime drowsiness, sleep disturbances

→ Dyskinesia on initiation – may need to dec levodopa dose

Question 16

What are the DDIs of entacapone?

Answer 16

→ Iron – dec entacapone conc
→ Contraindicated w concurrent non-selective MAOi – decreases catecholamine metabolism, increases hypertensive effects (MAO-Bi okay)
→ Catecholamines (epinephrine, dopamine etc) – inc risk of tachycardia, HTN, arrhythmias
→ Warfarin – increased warfarin exposure and increased risk for bleeding.

Question 17

What are the SEs of trihexyphenidyl?

Answer 17

SE (esp elderly): dry mouth, sedation, C, urine retention, delirium, confusion, hallucination

Question 18

What is the MOA of amantadine?

Answer 18

• Enhance release of stored dopamine
• Inhibit presynaptic uptake of catecholamine
• Dopamine receptor agonist
• NMDA receptor antagonist (antiglutamate)

Question 19

What are the SEs of amantadine?

Answer 19

• Nausea, light-headedness, livedo reticularis
• Inability to concentrate, confusion, hallucination, nightmares, insomnia

Question 20

What are the considerations in prescribing amantadine?

Answer 20

• Renally excreted – reduce dose in renal impairment
• Stimulating effect – 2nd dose given in the afternoon instead of at night so that can sleep
• Avoid concurrent use with memantine