Transcript No Slide Title

Pharmacological treatment for
Parkinson’s Disease
Cameroon course
29 January 2014
Professor Richard Walker
Consultant Physician and Honorary Professor of
Ageing and International Health
Northumbria Healthcare NHS Foundation Trust
Institute of Health and Society, Newcastle University
Talk content
 Drug
treatment in Parkinson’s disease
(PD)
 The Hai PD prevalence study in Tanzania
 Treatment intervention in Tanzania
When do clinical signs of
Parkinson's develop?
Striatal dopamine levels
Reduced by 80%
Cell loss in the substantia nigra
Reaches 50%
Comma shaped caudate
and putamen on
DaTSCAN
Pattern seen in healthy
indivuals and also in ET
Reduction (L>R) in putamen
but bilaterally abnormal
Patient had 2yrs symptoms,
with greater problems on right
side of body
James Fisher
Advanced case
Almost no activity in
putamen and bilaterally
reduced in caudate
Diagnosis of
Parkinsonism - signs
 BRADYKINESIA
 Muscular
and one of:
rigidity
 4-6Hz rest tremor
 Postural instability
Probable most important
diagnostic criteria
 Asymmetrical
onset
 Progressive
condition
 Responsive
to levodopa
Speech
Motor symptoms of Parkinson’s
Postural
instability
Hypomimia
Micrographia
Reduced arm
swing
Turning in bed
Posture
Tremor
Arising from
a chair
Motor
symptoms
of Parkinson's
Turning
Freezing
Gait festination
Bradykinesia
Shuffling gait
Rigidity
Falls
The most important partnership
Person with
PD
Person who knows
about PD
Continuous release of dopamine
in the healthy striatum
Dopamine synthesis
Continuous
dopamine
release
Pre-synaptic
membrane
Dopamine
Vesicles containing
dopamine
Post-synaptic
membrane of the
neurone
Adapted from Thanvi BR et al. Postgrad Med J 2004;80:452–8
Drug classes in Parkinson’s
Levodopa
DAs
Dopamine agonists
MAO-B inhibitors
Monoamine oxidase B
inhibitors
Anticholinergics
COMTs
Catechol-Omethyltransferase
inhibitors
Central effects: sites of drug
action
6
Levodopa
DOPA decarboxylase (DDC)
Dopamine
Tyrosine hydroxylase
Tyrosine
Metabolites of dopamine,
caused by MAO-B and
COMT enzymes
Dopamine agonists:
apomorphine
bromocriptine
cabergoline
pergolide
pramipexole
ropinirole
rotigotine
Blocked by MAO-B
inhibitor: rasagiline
and selegiline
Dopamine receptors
Blocked by COMT
inhibitor: tolcapone
Brain
Levodopa
Blood
Blood brain barrier
Adapted from Edwards et al. Parkinson’s disease and other movement disorders. Oxford University Press. 2008. pg 45
Peripheral effects: sites of
drug action
6
Levodopa
Blood brain barrier
Brain
Blood
+ COMT enzyme
=
3-O-methyldopa
- metabolite
Blocked by COMT inhibitor:
entacapone and tolcapone
Levodopa
preservation
Levodopa
Blocked by decarboxylase inhibitor:
carbidopa and benserazide
+ DOPA decarboxylase =
Dopamine
- cannot cross the blood
brain barrier
Adapted from Edwards et al. Parkinson’s disease and other movement disorders. Oxford University Press. 2008. pg 45
Efficacy of levodopa
 It
is the precursor of dopamine
 A symptomatic treatment for PD for over
40 years, still gold standard treatment
 It does not cross the blood brain barrier
 Decarboxylase inhibitor is combined with
levodopa to prevent peripheral conversion
of levodopa to dopamine
Specifics of L dopa prescribing
 Sinemet
110, 125, 275 Halfs etc etc
 Start low go slow
 What dose do you go to?
 CR preparations
 Dispersible madopar
Co-careldopa
Sinemet
Sinemet – co-careldopa
62.5mgs - 50 mg levodopa/12.5 mg
carbidopa tablet
110mgs - 100 mg levodopa/10 mg
carbidopa tablet
125mgs - 100 mg levodopa/25 mg
carbidopa tablet
275mgs - 250 mg levodopa/25 mg
carbidopa tablet
Sinemet CR – co-careldopa
125mgs - 100 mg levodopa/25 mg
carbidopa tablet
250mgs - 200 mg levodopa/50 mg
carbidopa tablet
Duodopa – co-careldopa
5mgs caridopa//20mg levodopa intestinal
gel
100ml cassette
Co-beneldopa
Madopar
Madopar – co-beneldopa
62.5mgs - 50 mg levodopa/12.5 mg
benserazide Capsules
125mgs - 100 mg levodopa/25 mg
benserazide Capsules
250mgs - 200 mg levodopa/50 mg
benserazide Capsules
Madopar dispersible
62.5mgs - 50 mg levodopa/12.5 mg
benserazide dispersible tablet
124mgs - 100 mg levodopa/25 mg
benserazide dispersible tablet
Madopar CR – co-beneldopa
125mgs - 100 mg/25 mg Prolonged
Release Hard
Capsules
Levodopa side effects
 Short

Nausea and vomiting, postural hypotension,
somnolence, altered sleep pattern
 Long





term
term
psychiatric disturbances
Wearing off
Dyskinesias
Dystonia
Factors associated with motor complications

Duration of disease, therapy, severity of disease
Typical pattern of wearingoff during the day
Unpredictable Motor fluctuations in
Advanced Parkinson’s - “on/off”
phenomena
“On” time
“Off” time
Morning
dose
1112 1
2
10
9
3
8
4
7 6 5
Lunch-time
dose
Evening
dose
1112 1
2
10
9
3
8
4
7 6 5
1112 1
2
10
9
3
8
4
7 6 5
Return of symptoms
“off” state
“Wearing off”
Dopamine Agonists (non-ergot)
Immediate release
Ropinirole
Requip
Dose range 2-24mgs
Pramipexole
Mirapexin
Dose range:
base 0.26 - 3.15mgs
Salt 0.088 – 4.15mgs
Rotigotine
Neupro patch
Controlled release
Starter pack
2mgs, 4mgs 8mgs
1mgs, 2mgs, 5mgs
Base dosage
0.088mgs,
0.18mgs, 0.35
mgs, 0.7mgs
Base dosage
0.26mgs, 0.52mgs,
1.05mgs, 1.57mgs,
2.1mgs,2.62mgs,
3.15 mgs
Starter pack
2mgs, 4mgs, 6mgs,
8mgs
Other Dopamine Agonists
Apomorphine
Apo-go
10mg/ml in 3ml Apogo pen
Intermittent injection
5mg/ml in 10ml prefilled syringe;
10mg/ml in 2ml and
5ml ampoules
Via syringe driver
Ergot derived
Cabergoline
Cabaser
Pergolide –
Celance
Bromocriptine Paroldel
1mg, 2mgs, 3mgs
Starter pack
50, 250,1000mcg tablets
1,2.5mg tablet
5,10mg capsule
Dopamine Agonist Side effects
 Confusion,
hallucinations, impulse control
disorder
 Postural hypotension
 Fibrotic changes due Ergot derived
agonists
 Nausea and vomiting
 Somnolence
 Leg oedema
Impulse Control Disorder
•
•
•
•
A person’s inability to resist a temptation or impulse
More likely to happen in those with a previous history
of novelty
seeking or risk – taking behaviours
Compulsive behaviours have been reported as a side
effect with levodopa and dopamine agonists
Behaviours can include:
 Pathological gambling
 Hypersexuality
 Compulsive eating
 Compulsive shopping
 Punding
Mechanism of action:
MAOB inhibitor
Metabolites of dopamine,
caused by MOA-B enzyme
Blocked by MOAB inhibitor
rasagiline and selegiline
Brain
Blood
Blood brain barrier
Adapted from Edwards et al. Parkinson’s disease and other movement disorders. Oxford University Press. 2008. pg 45
MAOB inhibitors
Selegiline
Eldepryl
5, 10mg tablet
10mg/5ml syrup
Selegline
Zelepar
1.25mgs Oral Lyophilisate
Rasagline
Azilect
1mgs (only dose)
(dissolves on the tongue)
MAOB side effects
 Hypotension
 Nausea
 Dyspepsia
– hallucinations
 Rasagiline – headache and flu-like
symptoms
 Selegiline
Mechanism of action - COMT
inhibitor
6
Metabolites of dopamine,
caused by COMT enzyme
Blocked by COMT inhibitor:
tolcapone
Blood brain barrier
Levodopa
Brain
Blood
+ COMT enzyme =
3-O-methyldopa
- metabolite
Blocked by COMT inhibitor = Levodopa
entacapone / tolcapone
preservation
Adapted from Edwards et al. Parkinson’s disease and other movement disorders. Oxford University Press. 2008. pg 45
COMT inhibitors
Entacapone - comtess
200mgs tablet
Tolcapone - tasmar
100mgs tablet
200mgs tablet
Stalevo – combination of
carbidopa, levodopa and
entacapone
50mgs - 50mg levodopa/12.5mg
carbidopa/200mg entacapone tablets
75mgs – 75mg levodopa/18.75mgs
carbidopa/200mgs entacapone
100mgs - 100mg levodopa/25mg
carbidopa/200mg entacapone tablets
125mgs – 125mg levodopa/31.25mg
carbidopa/200mg entacapone
150mgs - 150mg levodopa/37.5mg
carbidopa/200mg entacapone tablets
200mgs - 200mg levodopa/50mg
carbidopa/200mg entacapone tablets
COMT side effects
 Same
as levodopa
 Discolouration of urine
 GI


Bloated painful abdomen
Explosive diarrhoea
 Sweating
Anticholinergics
•
•
•
•
•
Trihexyphenidyl – (formally Benzhexol),
Orphenadrine and Procyclidine
Rarely used but can be effective in younger
patients
Widely used to treat symptoms of Parkinson’s
prior to the introduction of levodopa
Modest benefit in improving bradykinesia and
rigidity, helpful in treating tremor
At the expense of impaired cognitive function,
difficult to withdraw
Other drugs - Amantadine
Amantadine
•
•
•
•
•
Antiviral agent
Anti-Parkinsonian effect is mild
Anti dyskinetic effect lasts up to 9 months
Twice daily dosing, last dose at midday to prevent
sleep problems
Side effects caused by high doses include:
• Visual hallucinations
• Confusion and agitation
• Discolouration of the legs – livedo reticularis
• Lower leg oedema
Apomorphine

Extensive first pass metabolism

So given subcutaneously

For patients with advanced PD with severe
motor fluctuations
 Can be given as:

Bolus SC injections; ‘rescue’ therapy for wearing
off
• Patients with max 6 OFF periods per day

Continuous waking day SC infusion
• Patients with so many OFF periods that injections are
inappropriate
Duodopa

Advanced PD:



Severe motor
fluctuations
Poor control despite
optimal medications
Administered via
portable pump directly
into duodenum

Inserted via
percutaneous
endoscopic
gastrostomy (PEG)
Drug management

36
As responses to drugs are variable, treatment
regimes differ from person to person
 The timing of drugs is important in order to
achieve continuous dopaminergic stimulation
 Nurses have a key role in helping the patients
manage complex drug regimes
 Sudden discontinuation of treatment should be
avoided as it can result in Neuroleptic Malignant
Syndrome, which can be fatal
Drugs to avoid
Anti-emetics
Anti-depressants others
Prochloperazine
(stemetil)
Fluphenazine (motival)
Chlorpromazine
(largactil)
Metroclopramide
(maxalon)
Perphenazine (triptafen)
Fluphenazine (moditen)
Flupentixol (fluanxol,
depixol)
Haloperidol (serenace,
haldol)
Perphenazine (fentazin)
36
Key points

The findings of PDLIFE study suggest that early initiation of
treatment may be beneficial in terms of health-related quality of
life

Levodopa restores the dopamine lost due to degeneration of
striatonigral cells

Dopamine agonists are useful for smoothing the ‘on/off’
fluctuations secondary to levodopa therapy, some may offer
continuous dopaminergic stimulation

Treatment decisions should always be based on the degree of
disability

The treatment of non motor symptoms is also as important at all
stages of Parkinson's
Surgery

Thalamotomy


drug-resistant unilateral tremor
Pallidotomy

drug-induced dyskinesias

Sub-thalamotomy - experimental

Stimulation - bilateral



thalamic (tremor)
bilateral subthalamic nucleus
(parkinsonism, tremor, dystonia)
pallidal (dyskinesias)
What is Deep Brain Stimulation?


Implanted electrode delivers
continuous high frequency
stimulation which over rides the
abnormal inter-neuronal signals that
cause cardinal symptoms:

Tremor

Bradykinesia

Rigidity
DBS can provide effective symptom
control in drug resistance PD but
neither treatment provides a cure for
the disease

Cost of surgery is estimated within
the region of £30,000
MOTOR COMPLICATIONS
PROBLEM
SOLUTION

Wearing off








Agonists
Multiple small doses
COMT inhibitor
CR preparations
Liquid formulations
MAO B inhibitor
Apomorphine
Surgery
Dyskinesia
 Decrease
dopaminergic medication at
appropriate time
 Consider Amantadine
NEUROPSYCHIATRIC
COMPLICATIONS
Depression, Anxiety and Apathy
Associated with Parkinson's
Dysphoria
Sadness
Depression
•
The prevalence is estimated
at between 30 and 40%
Anxiety
•
Genralised anxiety, agitation, panic
attacks and phobic disorders can occur
in up to 40% of people with PD
In Parkinson's patients with depression
there is a higher frequency of
Irritability
Pessimism about
the future
Apathy
• more likely to be a direct consequence of
disease related physiological changes than
a psychological reaction or
adaptation to disability
 Depression
 Anxiety
and agitation
 Sleep disturbances
 Vivid dreams
 Hallucinations
 Delirium
 Dementia
Treatment of hallucinations
 Decrease
PD medication in following
order:





Amantadine
MAOIBs
Dopamine agonists
COMT – Is
Levodopa
 Consider
atypical neuroleptic, eg
Quetiapine
Cholinesterase Inhibitors
 Rivastigmine
license for PD dementia in
Europe (2006)
 Improvement in cognition, behaviour and
hallucinations
 Appear to be more effective in PD
dementia and Lewy Body dementia than in
AD and vascular dementia
 Relative cholinergic excess in PD
Treatment of nausea
 Anti-emetics
make Parkinson’s symptoms
worse
 Use Domperidone 10mgs tds (or rectally)
Methods 1
 Door-to-door
community based prevalence
studies are the gold standard
 Hai
district, an area in rural northern
Tanzania with a population of 160,000, used
as demographic surveillance site for over 10
years
 Research
infrastructure set up by the Adult
Morbidity and Mortality Project (AMMP)
Methods 2





A census was carried out in August 2005 in the
Hai district
Along with the census, six screening questions
for Parkinson’s disease were asked
Positive responders were then asked by the
research doctor (CD) for further history and
examination
UK Brain Bank criteria used to make diagnosis
Scripted video recording of all cases and some
false positive reviewed by an expert in
movement disorders blinded to the diagnosis
made by CD
Screening questions
1.
2.
3.
4.
5.
6.
Do your arms or legs shake, except after drinking
alcohol?
Do you shuffle or take tiny steps when you walk?
Have you ever been told you have Parkinson’s
disease?
Do you have difficulty standing up or fall easily apart
from maybe when drinking alcohol?
Do you walk more slowly than other people your
age?
Does your head shake?
Methods 3
 Positive
cases then invited to take part in
study with more thorough history, risk
factor profille and examination
 To
ensure we had not missed any cases
several other overlapping case
ascertainment methods were also used
 Blood
tests and CT brain scans carried
out on each patient
Case finding methods
Family
history
PT and OT
records
1
0
Screening
questionnaire
22
Village elders
6
1
1
Medical
records
1
1
Stroke
study
Results








33 Cases of idiopathic PD identified1
23 male, 10 female
1 female died before the prevalence date – excluded from
further analysis
Mean age 74.3 years (range 38-94)
Mean age at onset of symptoms 69 years (range 30-90)
Number who had been diagnosed prior to the study 8
Number receiving medication 5 (previously), currently only
3
Number under long-term follow up 2
C Dotchin et al Movement Disorders 2008; (11): 1567-72
Population age structures
45
40
35
30
25
20
UK
Tanzania
15
10
5
0
%under 15
%over 65
Crude and age-standardised
prevalence rates
Crude
prevalence
rate /100,000
Age-standardised
(to UK population)
prevalence /100,000
Male
14
64
Female
11
20
Combined
20
40
Physiotherapy





RESCUE trial carried out in European centres
shows that cueing is effective in treated patients
with PD1
No previous data on effectiveness in untreated
PD
Easy to deliver in the patient’s home, relatively
low cost, no side effects
Would it be possible to deliver in Tanzania?
Would it be effective if the patient has never had
drug treatment?
1 Nieuwboer et al., 2007
Methods
Cueing training
•3 weeks
•At home (therapy & assessment)
•19 participants
•Age 76.4 (12.9)
•H&Y 2.4 (.7)
Home Practice
•Dual-tasks
•Stop-start
•Heel strike & push off
•Sideways &backwards
•Turning & tight spaces
•Different surfaces &
distances
Results: Effect of therapeutic cueing
P value
Therapeutic cueing improved
Step length 0.7 m
<.0001
•
Speed
0.17 m/s
<.0001
Step
frequency
7.8 steps/min
0.046
UPDRS III
6
0.004
Outcome
Change
•
•
•
Walking
Motor severity
ADL
Similar results for dual task gait
Drug treatment follow up1






First reviews April and July 2007
One year follow up July 2008
Two year follow up May 2009
Three year follow up January 2010
Four year follow up July 2011
Five year follow up April 2012
Catherine Dotchin, Ahmed Jusabani, Richard Walker. Three year follow up of Levodopa
plus Carbidopa treatment in a prevalent cohort of patients with Parkinson’s disease inHai, Tanzania.
Journal of Neurology 2011; 258 (9): 1649-56
African Task Force






Ratified April 2012
Expand training in Africa – doctors, nurses, other
healthcare professionals
PDNS courses – East Africa (Tanzania) 2012,
Anglophone West Africa (Ghana) 2013
Non-specialist doctor courses – Ghana 2013,
Ethiopia 2015
Tele-health training courses for Cameroon
Explore options for drug treatment – donated
drugs for pilot scheme in Nigeria September
2012
References
1
2
3
4
Parkinson’s Disease Society. The Professional’s Guide to Parkinson’s Disease.
November 2007. pg38
NICE. Parkinson's disease. Quick reference guide. June 2006.
Clough et al. Fast Facts: Parkinson’s disease. Health Press. April 2007. pp 40 -47
Edwards et al. Parkinson’s disease and other movement disorders. Oxford University
Press. 2008. pg 66
5
Thanvi BR et al. Postgrad Med J 2004;80:pp452–8
6
Edwards et al. Parkinson’s disease and other movement disorders. Oxford University
Press. 2008. pg 45-55
Parkinson’s Disease Society. The Professional’s Guide to Parkinson’s Disease;
November 2007. pp 39-41
Clarke C. Parkinson’s disease in Practice. The Royal Society of Medicine Press
limited. 2007. pp45-49
Madopar capsules. Summary of Product Characteristics. September 2007
Madopar CR capsules. Summary of Product Characteristics. April 2009
Sinemet. Summary of Product Characteristics. May 2008
Sinemet CR. Summary of Product Characteristics. January 2009
Duodopa intestinal gel. Summary of Product Characteristics. April 2008
EPDA. Taking Control. Parkinson’s leaflet information series.
Clough et al. Fast Facts: Parkinson’s disease. Health Press. April 2007. pp 90-91
Requip XL. Summary of Product Characteristics. May 2008
Neupro. Summary of Product Characteristics. April 2009
Mirapexin. Summary of Product Characteristics. April 2008
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References
Requip tablets. Summary of Product Characteristics. August 2008
Apo-go. Summary of Product Characteristics. June 2008
Cabaser. Summary of Product Characteristics. March 2007
Celance. Summary of Product Characteristics. January 2008
Paroldel. Summary of Product Characteristics. January 2008
Clarke C. Parkinson’s disease in Practice. The Royal Society of Medicine Press
limited. 2007. pp54-55
Parkinson’s Disease Society. Information sheet – Compulsive Behaviour and
Parkinson’s. March 2008
Comtess. Summary of Product Characteristics. May 2007
Tasmar. Summary of Product Characteristics. January 2006
Stalevo. Summary of Product Characteristics. June 2008
Azilect. Summary of Product Characteristics. September 2007
Eldepryl. Summary of Product Characteristics. September 2006
Zelapar. Summary of Product Characteristics. April 2009
Schapira HV. Principles of Treatment in Parkinson’s disease. Butterwort Heinemann.
2006. pg 130
Amantadine. Summary of Product Characteristics. February 2008
Clough et al. Fast Facts: Parkinson’s disease. Health Press. April 2007. pp 61-64
Parkinson’s Disease Society. The Drug Treatment of Parkinson’s Disease, for people
living with Parkinson’s. September 2008. pg 31
Parkinson’s Disease Society. The Professional’s Guide to Parkinson’s Disease.
November 2007. pp 44-46