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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.