Management and treatment of Parkinson’s Disease

SAHDNaghme Adab

Reminder- what is PD?

• UK Brain bank criteria• Bradykinesia/Akinesia is obligatory

– ( slowness of initiation, reduction in speed and amplitude of repetitive actions)

AND at least one of the following• Rigidity• 4-6Hz tremor• Postural instability

• Overall prevalence ≈ 160 / 100 000• Incidence rates ≈ 20 / 100 000 / year• 2% of people over 80 are affected…….therefore in a catchment area of ≈ 1 million people

we would expect 1600 patients with PD and 200 new cases per year

• Mean age at onset 60• <5% of PD in under 40s

Case History 1

• 55 year old man, RH• Plumber• Tremor, right sided, 9-12 months• Difficulty holding spanner, manipulating small objects• Difficulty bending/getting up off floor etc• Otherwise well, no medication• Right sided rest tremor, bradykinesia/rigidity

What would you do?

Case History 2

• 76 year old female, RH• Right sided tremor, walking slow, difficulty

dressing, 12-18 months• Right sided signs of PD, slow to rise from chair,

slow, small steps• BP on ACEI, well controlled

Case History 3

• 68 year old man, RH• Left sided tremor for 2 years• OK with ADL’s, mobility not affected• Tremor embarrassing• Retired, not on medication• Left sided rest tremor, mild bradykinesia,

normal gait

When to Start

• circumstances• risk/benefit ratio• usually depends on functional impairment• No real evidence for neuroprotection BUT…..

General Principles

• low and slow• titrate to response or SE• unlike epilepsy, PD is chronic and progressive• most pts will need drugs altered over a period

of years

Pathways

• The basal ganglia receive huge no of inputs and produce outputs back to cortex and brainstem

• Part of an information loop that takes info from cortex processes it and feeds it back

• dopamine is produced by substantia nigra in brain stem

• modulates output of striatum (caudate + putamen)• The main input system is the striatum• The main output system is the Globus Pallidum ( Gpi)

DIRECT PATHWAY INDIRECT

PATHWAY

Drugs used in management of PD

• Classes of PD drugs available– PD motor symptoms– Dementia, psychosis, non-motor

• What to use when– New diagnosis– Adjuvant therapy– Complex disease

• Suggested flow chart for treatment of PD

Classes of drug in PD

• Levodopa/carbidopa• Dopamine agonists• MAO-B inhibitors• COMT inhibitors• Amantadine• Continuous dopaminergic stimulation (CDS)• Acetylcholinesterase inhibitors

Dopamine metabolism

Phenylalanine Tyrosine

Levodopa

DOPA

3-O-methyldopa

3-methoxytyramine

Dopamine

3,4-dihydroxyphenylacetic acid

Homovanillic acid

COMT

Phenylalanine hydroxylase

AADC

Dopa decarboxylase

Tyrosine hydroxylase

MAO COMT

MAO

Levodopa preparations in UKBrand name Release

mechanismLevodopa dose

(mg)Decarboxylase

dose (mg)

Sinemet ®LS, Sinemet 62.5 Immediate 50 12.5

Sinemet ®110 Immediate 100 10

Sinemt ®Plus, Sinemet ®125 Immediate 100 25

Sinemet® 275 Immediate 250 25

Half Sinemet® CR Modified 100 25

Sinemet® CR Modified 200 50

Madopar® Disp 62.5 Rapid 50 12.5

Madopar ®Disp 125 Rapid 100 25

Madopar ®62.5 Immediate 50 12.5

Madopar ®125 Immediate 100 25

Madopar ®250 Immediate 200 50

Madopar ®CR Modified 100 25

L-Dopa

• always given with a decarboxylase inhibitor• sinemet (carbidopa) co-careldopa• madopar (benserazide) co-beneldopa• Madopar dispersible may have slightly quicker

onset of action• can be given in slow release prep ( Sinemet CR)-

but usually reserved for overnight symptoms

Side effects of levodopaShort-term• GI

– N&V– Loss of appetite

• Cardiovascular– Postural hypotension

• Sleep – Somnolence– Insomnia– Vivid dreams, nightmares– Inversion of sleep-wake cycle

• Psychiatric– Confusion– Visual hallucinations– Delusions, illusions

Long-term• Involuntary movements

– Peak-dose dyskinesia– Diphasic dyskinesia– Dystonia

• Response fluctuations– Wearing off– Unpredictable on/off

• Psychiatric– Confusion– Visual hallucinations– Delusions, illusions

Keep total daily dose of levodopa as low as possible (≤ 600mg)Keep total daily dose of levodopa as low as possible (≤ 600mg)

MAO-B inhibitors - Selegiline

• Monotherapy- No comparative data with other monotherapies

• Adjuvant therapy- Poor evidence base for use as adjuvant in advanced PD

• Preparations available- Selegiline PO tablets, 2.5mg – 10 mg daily- Eldepryl tablets/liquid, 2.5mg – 10 mg daily- Zelapar fast-melt tablets, 1.25mg daily

• Amphetamine metabolites- Hallucinations, insomnia, nightmares, vivid dreams- Postural hypotension, nausea, confusion Tend to avoid in the elderly

Use rasagiline insteadTend to avoid in the elderlyUse rasagiline instead

MAO-B inhibitors - Rasagiline• 10-15 fold more potent than selegiline• No amphetamine metabolites• 1mg daily• Monotherapy• Adjuvant treatment

– Reduces off time by 48-56 mins/day– Increases on time without dyskinesias– Similar in efficacy and tolerability to entacapone

• Well tolerated– Initial ‘flu-like’ symptoms in first 2 weeks – Safe with most SSRIs (avoid/use with caution with fluoxetine and

fluvoxamine: serotonergic syndrome)

Dopamine agonists• Ergot-derived DAs

– Bromocriptine, lisuride, pergolide, cabergoline– Cardiac valvulopathy– Pulmonary, retroperitoneal, and pericardial fibrotic reactions

• Non-ergot DAs– Ropinirole, pramipexole, rotigotine, apomorphine

• Monotherapy, adjuvant therapy• Mode of delivery

– Oral, patch, sub-cutaneous

• Delay onset of motor fluctuations, dyskinesias

Dopamine agonists

• Common side effects– N&V, loss of appetite– Postural hypotension– Confusion, hallucinations– Somnolence

• Impulse control disorders

Dopamine agonistsDopamine agonist Start dose Max dose

Ropinirole 0.75mg tds 8mg tds

Requip XL 2mg od 24mg od

Pramipexole 0.125mg (salt) tds 1.5mg (salt) tds

Pramipexole PR 0.375mg od 4.5mg od

Rotigotine patch 2mg patch/24 hours 16mg patch/24 hours

Apomorphine s/c variable (injection or continuous infusion)

Single injection: 10mgTotal daily dose: 100mg

COMT inhibitors

• Must be taken with levodopa• Entacapone (200mg with each levodopa dose)

– On time increased by 1hr 1 min– Off time decreased by 41 min

• Tolcapone (100mg tds)– On time increased by 1hr 38 mins– Off time decreased by 1 hr 32 mins

• Stalevo– Combines sinemet with entacapone

COMT inhibitors

• Side effects– Dyskinesia (so ↓ levodopa)– Diarrhoea– Nausea, somnolence, abdo pain– Discoloured urine (body fluids orange)

• Hepatic toxicity (tolcapone)– Only 3 pts died fulminant liver failure– Rigorous blood monitoring– Stop if AST or ALT exceed upper limit of normal

Antimuscarinics

• Dopamine loss leads to loss of inhibition of cholinergic stimulation

• may be helpful in tremor• SE confusion/cognition, dry mouth/eyes,

urinary retention• Very rarely used!

Continuous dopaminergic stimulation• Pulsatility of oral treatments• In early disease, remaining dopaminergic

neurons can store excess dopamine and act as ‘buffer’ to low dopamine levels

• As disease progresses, more neurons die and buffer capacity is lost

• Apomorphine• Duodopa• Deep brain stimulation

Non-motor symptoms in PD• Depression, psychosis• Dementia• Sleep disorders

– Restless legs syndrome– Periodic limb movements of sleep– REM sleep behaviour disorder

• Falls• Autonomic disturbance

– urinary dysfunction– weight loss, dysphagia– constipation– erectile dysfunction– orthostatic hypotension– excessive sweating– sialorrhoea

clonazepamclonazepam

movicolmovicol

CitalopramCitalopram Quetiapine, clozapineQuetiapine, clozapine

Acetylcholinesterase inhibitorsAcetylcholinesterase inhibitors

Oxybutynin, tolterodineOxybutynin, tolterodine

Drugs to avoid in PD!!

• Anything that blocks dopamine• Anti-emetics

– Prochlorperazine– Metoclopramide, cyclizine

• Antipsychotics– Chlorpromazine, promazine– Fluphenazine, perphenazine, prochlorperazine,

and trifluoperazine– Haloperidol

Domperidone is the anti-emetic of choice in PDDomperidone is the anti-emetic of choice in PD

Use atypicals if needed eg quetiapineUse atypicals if needed eg quetiapine

Summary • Initiate treatment with

– Levodopa– Dopamine agonist– Rasagiline

• Add other oral treatments as required– Fluctuations, dyskinesias– Neuropsychiatric problems– Falls, postural instability– Speech/swallowing problems

• Consider– Manipulating dosages (limit to fractionation!!)– Manipulating timings– Enzyme inhibition (MAO-B and COMT inhibitors)

• When PD becomes advanced consider– Apomorphine, Duodopa, DBS

Case History 1

• 55 year old man, RH• Plumber• Tremor, right sided, 9-12 months• Difficulty holding spanner, manipulating small objects• Difficulty bending/getting up off floor etc• Otherwise well, no medication• Right sided rest tremor, bradykinesia/rigidity

Case History 2

• 76 year old female, RH• Right sided tremor, walking slow, difficulty

dressing, 12-18 months• Right sided signs of PD, slow to rise from chair,

slow, small steps• BP on ACEI, well controlled

Case History 3

• 68 year old man, RH• Left sided tremor for 2 years• OK with ADL’s, mobility not affected• Tremor embarrassing• Retired, not on medication• Left sided rest tremor, mild bradykinesia,

normal gait

• MDT required for effective managment• PD nurse is very useful!• Role of AHP eg PT, SALT

Case History 4

• 71 year old• 1997 diagnosed with PD, right sided tremor,

bradykinesia/rigidity-all mild• L-dopa started after 10 months as symptoms worsened,

problems with stairs• Started on sinemet 62.5mg od then incresed to tds over

1 week. • No response after 2 weeks• What next?

• Dose incresed to 125mg tds with good response• Stable over 2 years then mobility worsened and patient

getting slow and stiff before next drug dose• What next?• 1999 Increase sinemet to qds• (OR add entacapone)• Over next 3 years, dose increased to sinemet 250, 125,

250, 125 plus sinemet CR nocte• 2002- fluctuations in response- drugs not always

helping him switch on, extra movements an hour after taking his medications, switched off prior to his next dose

• What next?

• Sinemet decreased to 125 qds plus CR nocte• Entacapone added• No improvement, slightly worse over 6 months• What next?• Ropinirole added• Dose slowly increased over 8 months• 2004 (79 yrs old), hallucinations, mild cognitive

decline• Ropinirole decreased, symptoms worsened• Quetiapine added• Sinemet levels maintained

Guidelines for drug management of PD

Significant functional disability Disease progressionDopamine agonist

Add levodopa (max 600mg/day)

Motor complications develop

Add DA or entacapone

MAO-B inhibitor

Add entacapone or DA

Levodopa (max 600mg/day)

Switch to tolcapone if entacapone fails

Add MAO-B inhibitor if not already given

Add amantadine for dyskinesia

Severe motor complications

Consider apomorphine, Duodopa, DBS

Prescribe on Kardex

• Sinemet to 125 qds • Sinemet CR nocte• Add the Entacapone• Instead of ropinirole prescribe pramipexole• Prescribe a suitable anti-emetic• Prescribe a suitable anti-depressant

References

• Parkinson’s disease in Practice. Carl Clarke.2nd edition 2007.