management and treatment of parkinson’s disease
DESCRIPTION
Management and treatment of Parkinson’s Disease. SAHD Naghme 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 - PowerPoint PPT PresentationTRANSCRIPT
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.