Transcript Management and treatment of Parkinson`s Disease

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
• 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 hydroxylase
Phenylalanine
Tyrosine
Tyrosine hydroxylase
DOPA
Dopa decarboxylase
Levodopa
COMT
AADC
3-O-methyldopa
Dopamine
MAO
3,4-dihydroxyphenylacetic acid
COMT
3-methoxytyramine
MAO
Homovanillic acid
Levodopa preparations in UK
Brand name
Release
mechanism
Levodopa 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 levodopa
Short-term
Long-term
• GI
• Involuntary movements
– 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
– 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)
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
Tend to avoid in the elderly
- Postural hypotension, nausea, confusion
Use 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 agonists
Dopamine 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: 10mg
Total 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
Citalopram
Acetylcholinesterase inhibitors
– 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
Quetiapine, clozapine
clonazepam
Oxybutynin, tolterodine
movicol
Drugs to avoid in PD!!
• Anything that blocks dopamine
Domperidone is the anti-emetic of
• Anti-emetics
choice in PD
– Prochlorperazine
– Metoclopramide, cyclizine
• Antipsychotics
– Chlorpromazine, promazine
– Fluphenazine, perphenazine, prochlorperazine,
and trifluoperazine
– Haloperidol
Use 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
Significant functional disability
Dopamine agonist
Disease progression
MAO-B inhibitor
Levodopa (max 600mg/day)
Add levodopa (max 600mg/day)
Motor complications develop
Guidelines for drug
management of PD
Add DA or entacapone
Add entacapone or DA
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.