1. Management and treatment of Parkinson’s Disease
SAHD
Naghme Adab

2. 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

3. Incidence rates ≈ 20 / 100 000 / year
Overall prevalence ≈ 160 /
Incidence rates ≈ 20 / / 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

4. 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

5. What would you do?

6. Case History 2 76 year old female, RH
Right sided tremor, walking slow, difficulty dressing, months
Right sided signs of PD, slow to rise from chair, slow, small steps
BP on ACEI, well controlled

7. 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

8. When to Start circumstances risk/benefit ratio
usually depends on functional impairment
No real evidence for neuroprotection BUT…..

9. 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

11. 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)
The GPI is inhibitory on the thalamus which in turn results in cortical activity
A decrease in GPI activity leads to less inhibition of the thalamus and an increase in cortical activity

12. DIRECT PATHWAY INDIRECT PATHWAY
GPI is inhibitory- an increase in its activity cause decrease in thalamic and cortical activity/ a decrease in its activity leads to increased thalamic/cortical activity
IN normal BG, 2pathways ie direct ( GO – net result to inhibit Gpi ) pathway and indirect ( no Go Pathway- net result is to excite GPi).
Dopamie acts in opposite ways on the 2 pathways.
In direct –( via D1 receptors) it inhibits Gpi leading to decreased inhibition of thalamus and thus increase in cortical activity
In indirect pathway ( via D2 receptors) inhibits the indirect pathway resulting the suppression of the Subthalamic nucleus leading to reduced GPI activity
In PD there is less dopamine available due to death of neurons in SN so net effect is less movement
INDIRECT PATHWAY

15. 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

16. Classes of drug in PD Levodopa/carbidopa Dopamine agonists
MAO-B inhibitors
COMT inhibitors
Amantadine
Continuous dopaminergic stimulation (CDS)
Acetylcholinesterase inhibitors

17. Has plasma half-life of 60 mins. Absorbed from small bowel
Has plasma half-life of 60 mins. Absorbed from small bowel. Levodopa crosses the BBB but dopamine does not.
Want to reduce the metabolism of Levodopa as much as possible to ensure it gets to the brain. Thus stop peripheral breakdown of levodopa by using DDC inhibitors, MAO-B inhibitors and COMT inhibitors.

18. Dopamine metabolism Phenylalanine Tyrosine DOPA Levodopa
Phenylalanine hydroxylase
Phenylalanine
Tyrosine
Tyrosine hydroxylase
DOPA
Dopa decarboxylase
Levodopa
COMT
AADC
3-O-methyldopa
Dopamine
Has plasma half-life of 60 mins. Absorbed from small bowel. Levodopa crosses the BBB but dopamine does not.
Want to reduce the metabolism of Levodopa as much as possible to ensure it gets to the brain. Thus stop peripheral breakdown of levodopa by using DDC inhibitors, MAO-B inhibitors and COMT inhibitors.
COMT
MAO
3,4-dihydroxyphenylacetic acid
3-methoxytyramine
MAO
Homovanillic acid

19. 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
100 10
Sinemt ®Plus, Sinemet ®125 25
Sinemet® 275
250
Half Sinemet® CR
Modified
Sinemet® CR
200
Madopar® Disp 62.5
Rapid
Madopar ®Disp 125
Madopar ®62.5
Madopar ®125
Madopar ®250
Madopar ®CR

20. 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

21. Side effects of levodopa
Short-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)

22. 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 instead

23. MAO-B inhibitors - Rasagiline
10-15 fold more potent than selegiline
No amphetamine metabolites
1mg daily
Monotherapy
Adjuvant treatment
Reduces off time by 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)
PRESTO study
Rasagiline v placebo
1mg rasagiline ↓ off time by 0.94 hrs/day v placebo
LARGO study
Rasagiline v entacapone
1mg rasagiline same as entacapone in reducing off time and increasing on time without troublesome dyskinesias
Rasagiline neuroprotective? ADAGIO study

24. Dopamine agonists Ergot-derived DAs Non-ergot 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

25. Dopamine agonists Common side effects Impulse control disorders
N&V, loss of appetite
Postural hypotension
Confusion, hallucinations
Somnolence
Impulse control disorders
ICD in up to 15%

26. 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

27. 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

28. COMT inhibitors Side effects Hepatic toxicity (tolcapone)
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
Tolcapone: 2 weekly for first year; 4 weekly for next 6 months; 8 weekly thereafter

29. 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!

30. Amantadine Used for dyskinesia in advanced PD
100mg bd (2nd dose no later than 2pm)
Side effects
Confusion, hallucinations, insomnia
Ankle oedema, livedo reticularis

31. 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

32. Apomorphine Short-acting dopamine agonist
Extensive first-pass metabolism (ie cannot give orally)
Onset of action ~ 10 mins
Duration of action ~ 60 mins
Domperidone 30mg tds 2-3 days
Rescue injections (pen) or continuous (pump)
Aim to reduce oral meds
Usually run up to 16 hrs/day
Skin problems
Cost ~ £12,000/year

33. Duodopa Intrajejunal infusion of levodopa gel
Avoids problems of gastric emptying
100ml cassette = 2000mg levodopa
Cost ~ £30,000/year
In-patient admission for titration and placement of PEJ tube

34. Surgery for PD
Bilateral subthalamic nucleus stimulation (deep brain stimulation)
Good for pts with
Severe tremor
Dyskinesias
On/off fluctuations
Medical failures
Not for
> 70 yrs
Sig. cognitive impairment/mood disorder
Dopamine dysregulation syndrome
Realistic expectations
Does not improve non-motor symptoms
Not neuroprotective (ie disease continues to progress)
Does not help axial symptoms (postural instability, freezing, falling)
£37,000 one-off cost

35. Acetylcholinesterase inhibitors
For use in PD dementia
Don’t know about MCI in PD yet
Acetylcholinesterase inhibitors
Rivastigmine (licensed for PD dementia)
Tablets: 1.5mg bd (max 6mg bd)
Patch: 4.6mg/24 hours (max 9.5mg/24 hours)
Donepazil, galantamine
NMDA receptor antagonists
Memantine

36. 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
Citalopram
Quetiapine, clozapine
Acetylcholinesterase inhibitors
clonazepam
Oxybutynin, tolterodine
movicol

37. 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 PD
Use atypicals if needed eg quetiapine

38. Summary Initiate treatment with Add other oral treatments as required
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

39. 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

40. Case History 2 76 year old female, RH
Right sided tremor, walking slow, difficulty dressing, months
Right sided signs of PD, slow to rise from chair, slow, small steps
BP on ACEI, well controlled

41. 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

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

43. 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?

44. 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

45. 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

46. Guidelines for drug management of PD
Dopamine agonist
Disease progression
Significant functional disability
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

47. 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

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