Module 4.3.2 (Management of Parkinsons)

Question 1

What are the principles of treatment?

ps: You must have bradykinesia plus either tremor or rigidity for a Parkinson’s diagnosis to be considered.

Answer 1

• Maintain function as long as possible with minimum medication
• Individualise therapy according to disease stage and main symptoms

Question 2

What examples DDI and COMT inhibitors that are used with levodopa for therapy of PD?

Answer 2

DDI: carbidopa and benserazide

COMT-I: entecapone

Question 3

Examples of ergot and non-ergot dopamine agonists?

Answer 3

Ergot: bromocriptine, cabergoline

Non-ergot: pramipexole, rotigotine (patch), apomorphine (inje)

Question 4

Examples of MAO-B inhibitors?

Answer 4

• Selegiline, rasagiline, safinamide

Question 5

What is preferred 1st line therapy for parkinsons? What is it given with?

Answer 5

Levodopa

• Always with DDI (>75 mg benserazide or carbidopa daily)

Question 6

Why is levodopa/DDI 1st line therapy? What is the AE?

Answer 6

Greatest benefit with the least adverse effects

• especially in elderly and cognitive decline

> improves bradykinesia (slowness of movement) and rigidity, reduces mortality; less effective for tremor

> ADRs: orthostatic hypotension, neuropsychiatric effects, hallucinations and confusion, impulse control disorders, dopamine dysregulation syndrome (compulsive overuse)

Question 7

Long term levodopa syndrome develops within 5 years of starting LD, what are the two major complications of this? Who is more likely to occur in?

Answer 7

1. Motor fluctuations

> Wearing OFF, delayed ON and ON-OFF swings

2. Drug-induced chorea/dyskinesias

> involuntary erratic, writhing motions usually affecting face, arms, legs or trunk

Especially in patients with earlier onset PD, more severe disease, higher LD dose, longer duration of disease

Question 8

What happens with increased duration with levodopa therapy?

Answer 8

TI window narrows

• Spend more time ‘off’ and experiencing dyskinesias than their ‘on’ state

Question 9

Describe the “Wearing OFF” stage of LD. How to manage?

Answer 9

• End of dose failure = earliest and most common motor complication
• Re-emergence of sx before next LD dose is due

> related to the progressive loss of neuronal storage capacity and short half life of LD

• first sign = early morning tremor and immobillity = improves afterr 1st morning dose

Management

• Increase levodopa/carbidopa dose
• Smaller, more frequent doses (upto 5-6) doses per day
• Add a dopamine agonist (or switch)
• Use CR product –> bedtime dose at first, then during the day. Long duration of action but lower oral bioavailability. Keeps level of dpamine more constant to control symptoms and limit dyskinesia.
• Take on an empty stomach, reduce protein intake
• Add a COMT inhibitor. Combination therapy is available (Stalevo®= levodopa + carbidopa + entacapone) which would be convenient for the patient)
• Add rasgiline or selegiline (MAO-b inhibitor). Selegilline contraindicated with an SSRI.

Question 10

When does ON-OFF swings occur when using LD? How to amnage?

on: periods during which the patient responds to levodopa and periods of
impaired motor function –> improved mobility

off: patient responds poorly to
levodopa

Answer 10

• Occur in advanced PD, after extended therapy with LD
• Rapid and sudden motor fluctuations unrelated to timing of last LD dose

> exact emchanism unclear; therapeutic challenge

Management

• DBS (deep brain stimulation)

Continuous dopaminergic therapy –> continous infusion + boluses

> SC apomorphine

> Duodenal levopdopa continuous infusions

• LD/CD gel given via percutaneous endoscopic gastronomy (PEG) tube into duodenum or jejunum
• Reduces the fluctuations in concentrations due to erratic or delayed gastric emptying
• Used only for uncontrolled advance disease with severe motor fluctuations, very expensive :(

Question 11

What is meant by ‘freezing’ in PD? How to manage?

… issa motor complication

Answer 11

• Sudden freezing of gait
• Feet are stuck, difficulty initiating steps or turning
• Exacerabted by stress or when obstacles are encountered
• Symptom of disease or drug-related event

Management

• Increase dopaminergic needs
• Physiotherapy

Question 12

What are dyskinesias/peak dose dyskinesias? How to manage?

…issa motor complication

Answer 12

Inability to control muscles giving rise to uncoordinated flailing of the arms or legs, or chorea, rapid repetitive movment of the limbs, face, tongue, mouth and neck

> not painful but very distressing

Management

• Decrease LD dose (even though may worsen PD)
• Smaller and more frequent LD doses
• Add amantadine
• Add dopamine agonists or increase dose
• Switch dopamine agonists

Question 13

How to treat advanced PD?

Answer 13

Combination therapy often required

Question 14

What are examples of dopamine agonists used to treat advanced PD? Are they used on its own?

Answer 14

Rarely use as 1st line monotherapy (rotigotine (patch) for NBM patient, pramipexole for once-daily dosing); otherwise add on.

• Pramipexole (preferred oral agent)
• Rotigotine (transdermal patch)
• Apomorphine SC injection prn or continuous infusion

> rescue medication for severe fluctuations refractory to conventional therapy

> effective within 5-10 minutes

> requires admission to specialised clinic or hosptial for intiation of therapy

> VERY emetogenic –> domperidone required –> less likely to worsen PD symptoms –> 10mg tds for upto 7 days only

Question 15

AE of dopamine agonists? Which patients to avoid in? What to warn patients about?

> AE of dopamine agonists are 15% worse than levodopa

Answer 15

hallucinations and confusion common, impulse control disorder (ICD), sudden sleep onset, dopamine dysregulation syndrome

• ICD: problem gambling, hypersexuality, overspending, binge eating, inappropriate internet use, punding

> avoid in patients with history of ICDs or similar, warn patients and carers, monitor behaviour

> If ICD develop, stop DA, taper gradually to avoid withdrawal syndrome

Question 16

What COMT inhibitor is used to treat advanced PD? What is it given with? AE?

Answer 16

Entacapone with each LD dose

Take with each LD dose to prolong clinical response

• reduce LD dose by 10-30%

AE

• Worsens dopaminergic ADRs; also bright yellow/organge urine, increased LFTs

> taper slowly due to NMS-like withdrawal syndrome

NMS: high fever, irregular pulse, accelerated heartbeat (tachycardia), increased rate of respiration (tachypnea), muscle rigidity, altered mental status

Question 17

What MAO-B inhibitors are used to treat advanced PD? Advantage of using them? What are they used with? AE?

Answer 17

Adjunct to LD –> increase efficacy by 20% –> reduce “off” time

> may increase dopaminergic ADRs/dyskinesias

• Rasagiline
• Selegiline
• Safinamide

AE​

• Insomnia, neuro-psychiatric ADRs common
• Associated with serotonin toxicity; C/I with serotonergic agents
• Tyramine reaction rare; follow dietary restrictions if taken with moclobemide

Question 18

What is amantadine used with to treat advanced PD? When does it effectiveness reduce? What CNS side effects?

Answer 18

Adjunct therapy; useful for controlling LD-induced dyskinesias

> effectiveness drops off after 3 to 6 months

CNS side effects

• nervousness, depression, nightmares, hallucinations, insomnia, dizziness; also livedo reticularis

> mottled discolouration of the skin

Question 19

Why may anticholinergics be used to treat advanced PD? What are examples of this? Why poorly tolerated?

Answer 19

Effective against tremor, may reduce sialorrhoea (hypersalivation)

• Benzatropine
• Biperiden
• Trihexyphenidyl (benzhexol)

> poorly tolerated: blurred vision, cognitive impairment, constipation, dry mouth, urinary retention

• avoid in eldely, cognitive impairemtn

Question 20

What drugs may worsen PD?

Answer 20

• Antipsychotics (esp typical antipsychotics)
• Dopamine antagnoist antiemetics (droperidol, metoclopramide, prochlorperazine)
• Methyldopa

Question 21

What drugs not to use with MAO-B (+DDI) for PD?

Answer 21

• Non selective MAOIs (phenelzine, tranylcypromine)
• Moclobemide
• Serotonergic drugs

Question 22

What are some non-pharmacological therapies in PD?

Answer 22

CAMs

• No evidence, vitamin E/vitamin C, CoQ10 that signficantly delay PD progression

Multidisciplinary approach

• Physiotherapy, speech therapy, occupational therapty, dietetics
• Physical therapies (active music therapy, treadmill training, balance training) can improve function

Surgery (deep brain stimulation)

• high frequency DBS with an inserted electrode
• Must succeful in patients with motor fluctuations and dyskinesias
• does not alloviated cognitive deficits, NMS (non-motor symptoms) and some motor effects

> C/I in major psychatric/medical illness, cognitive impairment, PPM, levodopa-resistant parkinsonism, +/- advanced age

Question 23

How to manage the following non-motor smyptoms (NMS) in PD (lifestlye advice and also medications used):

A) orthostatic hypotension (20 mmHg fall in SBP, 10mmg Hg in DBP; risk of falls, injuries)

B) constipation

C) sleep problems

D) psychosis

E) depression and anxiety

F) dementia

Answer 23

A)

• review medications (antiparkinsond drug, antiHTN drugs)
• avoid heat, alcohol, large meals, straining, standing up rapdily
• increase sodium and water intake
• smaller, more frequent meals
• exercise in horizontal position (swimming)
• compression sotckings
• sleep with head of the bed raised

drug treatment:

> fludrocortisone 0.1 mg daily, increasing to 0.2 mg daily if needed

AE of fludrocortisone: sodium and water retention, oedema, hypokalaemia and hypertension

> alternatives: pyridostigimine, midodrine, ephedrine, octreotide

B)

• Increse fluids, dietary fibre
• remove anticholinergics
• osmotic laxatives –> PEG, macrogol

C)

• insomnia, RLS, hypersomnia
• Parasomnia (REM sleep behaviour disorders) –> clonazepam 0.25mg nocte (monitor for decline in cognition and symptom control)
• sleep hygiene

D)

• common in PD, eldely have cognitive disturbance and anticholinergic drugs wihich worsen cogntive function
• often drug induced –> reduce LD dose, simplify regimen

> withdrawl anticholinergics and DAs

Antipsychotic therapy (low dose second gen antipsychotics)

• clozapine most effective but difficult to use, needs regular blood monitoring
• quetiapine useful and often used empirically
• avoid other second gen and first gen antispychotics

E)

• Treat with standard pharmacotherapy
• Common and often undertreated

F)

• 2-6x increased risk with PD –> increases with time
• cholinesterase inhibitors have mild-mod benefit

> donepezil, rivastigmine –> fewer ADRs –> can exacerbate motor symptoms in PD e.g. tremor

> Trial for 2-3 months; taper slowly if no benefit

check if patient on anticholinergic as it worsens cognitive function

Question 24

Use levodopa or dopamine agonists as initial treatments?

Answer 24

• Because of the increased risk of neuropsychiatric adverse effects from dopamine agonists in late-onset PD, levodopa is often started first. Levodopa achieves somewhat better control of motor symptoms of PD than dopamine agonists and MAO-B inhibitors, but dyskinesias and motor fluctuations develop after long-term use or highdose treatment.
• Because patients with early-onset disease are more likely to develop levodopa induced abnormal movements (dyskinesia), dopamine agonists are sometimes introduced as initial treatment; however, this early advantage of dopamine agonists over levodopa diminishes over time (about 10 yr).
• In practice, dopamine agonists are generally preferred in younger patients and levodopa in those >70 years, although individual factors such as disease severity, comorbidities and adverse effects must be taken into account.

> eTG only recommends dopamine agonists as first-line therapy in “exceptional circumstances” and recommends levodopa as first-line therapy

Question 25

What drugs to avoid in Parkinson’s disease?

Answer 25

Drugs that block dopamine receptors can result in parkinsonism or substantially worsen motor symptoms in patients with Parkinson disease and may lead to neuroleptic malignant syndrome.

These include neuroleptics, such as haloperidol, thioridazine, chlorpromazine, promethazine, fluphenazine, risperidone and olanzapine; antiemetics, such as prochlorperazine and metoclopramide; tetrabenazine; and antihypertensives, such as methyldopa. Meperidine (pethidine) should be avoided in those receiving monoamine oxidase B inhibitors.

Question 26

True or false

Theoretically, use of high dose selegiline could increase systemic exposure to sumatriptan through MAO-A inhibition.

Monoamine oxidase (MAO) inhibitors, including procarbazine, and selegiline (concurrent use of any of these agents with sumatriptan may lead to a potentially dangerous hyperserotonergic state or other adverse effects; sumatriptan should be used with caution in patients receiving these medications)

> sumatriptan not recommended for use during or within 14 days following administration of a MAO inhibitor

Answer 26

True

Question 27

How to manage sialorrhoea

Answer 27

Refer for specialist assessment of sialorrhoea

Speech therapist and occupational therapists can assist patients to improve their swallowing

First line therapy is botulinum toxin type A injection into salivary glands

Question 28

How to manage incontinence?

Answer 28

• Assess any underlying physical causes of incontinence
• Use appropriate non-pharmacologic therapies and continence aids
• Restricting fluid intake in the evening may be sufficient
• Anticholinergic drugs and mirabegron could exacerbate the patient’s glaucoma and are best avoided. (They may be contraindicated if the patient has closed angle glaucoma).
• Anticholinergic drugs are also often poorly tolerated in the elderly and could also exacerbate constipation and lead to a decline in cognitive function.
• Botulinum toxin and sacral neuromodulation are less commonly used therapies for patients with PD that possibly could be tried.