Management and treatment of Parkinson’s Disease

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. 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

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, 12-18 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)

12. DIRECT PATHWAY INDIRECT PATHWAY

13. 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

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

16. Dopamine metabolism Phenylalanine hydroxylase Phenylalanine Tyrosine Tyrosine hydroxylase DOPA Dopadecarboxylase Levodopa COMT AADC 3-O-methyldopa Dopamine COMT MAO 3-methoxytyramine 3,4-dihydroxyphenylacetic acid MAO Homovanillic acid

17. Levodopa preparations in UK

18. 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

19. 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)

20. 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

21. 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)

22. 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

23. Dopamine agonists • Common side effects • N&V, loss of appetite • Postural hypotension • Confusion, hallucinations • Somnolence • Impulse control disorders

24. Dopamine agonists

25. 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

26. 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

27. 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!

28. 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

29. Non-motor symptoms in PD Citalopram Quetiapine, clozapine • 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 Acetylcholinesterase inhibitors clonazepam Oxybutynin, tolterodine movicol

30. 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 egquetiapine

31. 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

32. 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

33. 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

34. 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

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

36. 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?

37. 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?

38. 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

39. Dopamine agonist Disease progression Guidelines for drug management of PD Significant functional disability MAO-B inhibitor Levodopa (max 600mg/day) Add levodopa (max 600mg/day) Motor complications develop 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

40. 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

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