10th Medicine Review Course 2018 21 st July 2018 Drug Therapy for Parkinson's disease Prakash Kumar National Neuroscience Institute Singapore General Hospital Sengkang General Hospital Singhealth Duke-NUS Academic Medical Centre
Outline Brief overview of Parkinson s disease (PD) Drug therapy for motor symptoms Drug therapy for non-motor symptoms Take home message
What is Parkinson s disease? Progressive neurodegenerative disease, unknown cause Progressive neuronal loss involving dopaminergic and non-dopaminergic neurotransmitters Causing motor symptoms (tremors, rigidity and bradykinesia, gait freezing, postural instability, speech and swallowing problems) And various non-motor symptoms (autonomic, cognitive, behavioural, sleep and pain)
Epidemiology 2 nd most commonest neurodegenerative disease after Alzheimer's disease Average age of onset early to mid-60s 1% of population aged > 60 years have PD No significant difference in prevalence rates between different ethnicity Worldwide, the incidence and prevalence of PD increase with age Mayeux et al. Arch Neurol. 1992
Pathological progression of PD
Clinical progression of PD Kalia et al. The Lancet. 2015
Progression of motor problems 1. Progression of medication responsive motor problems (bradykinesia, rigidity, tremors) 2. Progression of medication-refractory motor problems (gait & postural instability, dysarthria, dysphagia) 3. Medication-related motor complications (fluctuation: wearing OFF, delayed ON, short ON, dose failure; dyskinesia) which initially are predictable but become unpredictable later on
medscape
Progression of non-motor problems 1. Non-motor problems resulting from medications (cognition, psychosis, sleepiness, constipation, orthostatic hypotension, impulse control disorders) 2. Non-motor symptoms arising in the medication OFF state (insomnia, anxiety, panic, pain, dyspnoea, sudden excessive sweating or cold feeling) 3. Non-motor complications unrelated to medical therapies (cognitive, behaviour, fatigue, urinary problems, constipation, decreased libido, erectile dysfunction)
Treatment To date no cure, no neuroprotective treatment Purely symptomatic
Symptomatic treatment Nonpharmacological Pharmacological Device assisted (Deep Brain Stimulation, Duodopa, Apomorphine Pump) Multidisciplinary
Nonpharmacological treatments Patient/caregiver education Physical therapy Exercise Occupational therapy Speech/language therapy Diet and nutrition Psychosocial interventions
Pharmacological treatment for motor symptoms Treatment should be individualized for both timing and choice of drugs
Goals of treatment Conventional control signs and symptoms Current improve QoL Future slowing disease progression and restoring function
Reasons to consider pharmacological treatment Symptoms (motor/ non-motor) affecting quality of life Impaired job performance Impaired recreational activities Social impairment
Parkinson s disease medication DDC inhibitors Benserazide Carbidopa Dopamine Agonists Bromocriptine (ergot) Pramipexole (non-ergot) Ropinirole (non-ergot) Rotigotine (non-ergot)
Pros and cons of available therapy Drugs Pros Cons MAO-B Inhibitors Anticholinergic Dopamine agonist Levodopa Convenient dosing, Relative lack of sideeffects Predominantly for tremors Inexpensive Less likely motor fluctuation and dyskinesia Most effective, easily titrated Modest symptomatic benefit Side effects Less effective than levodopa Side effects Motor fluctuation and dyskinesia
What drug to choose?
Factors that influence choice of drugs Patient factors Age Level of disability of patient Drug factors Efficacy of drug Potential side effects short and long term Convenience of administration Cost
Age influencing choice of drugs <65 y-o Levodopa sparing agent >65 y-o Levodopa Dopamine-agonists MAO-B inhibitor - Selegiline, rasagiline Anticholinergic Amantadine
Psychiatric Times 2007
Management of medication responsive motor problems Under treatment Increasingly common Concern about levodopa induced toxicity Also preconceived with delaying levodopa related motor complications quality of life Management: increase dopaminergic medication (including COMT-I & MAO-B-I) with quality of life as endpoint.
Management of medication-related motor complications (1) Wearing off / predictable fluctuation Increase frequency of levodopa dosing Increase individual dosages of levodopa Add controlled release levodopa Add COMT-I (entacapone) Add MAOB-I (rasagiline, selegiline) Add or increase dopamine agonist (ropinirole, pramipexole, rotigotine) Night-time offs use bedtime controlled released levodopa, or regular levodopa through the night
Management of medication-related motor complications (2) Unpredictable Fluctuations (Increased latency to benefit, Dose failures, On-off) Avoid levodopa close to mealtime Chew / crush L-dopa with carbonated drink Intraduodenal administration of levodopa Transdermal (patch) agonist - rotigotine Apomorphine injection/ infusion
Management of medication-related motor complications (3) Dyskinesias Reduce total dopaminergic load parkinsonism worsens Reduce individual levodopa doses / increase dopamine agonist Amantadine Clozapine
Pharmacological treatment for nonmotor symptoms Excessive daytime sleepiness Exclude reversible pharmacological and physical cause Modafinil Rapid eye movement sleep behaviour disorder Clonazepam Melatonin
Orthostatic hypotension Review existing meds: antihypertensive, dopaminergics Midodrine Fludrocortisone Drooling Sublingual atropine drops Ipratropium bromide spray into mouth Botulinum toxin to salivary glands
Depression Consider psychiatrist referral Cognitive behavior therapy (CBT) Consider targeting antidepressant to accompanying symptoms Sleep difficulties +/- significant anxiety: Mirtazapine Fatigue or apathy: Fluoxetine Generalized anxiety disorder: Venlafaxine Avoid SSRI + selegiline serotonin syndrome (extremely rare however)
Psychotic symptoms (hallucination and delusion) Treat trigger conditions; infection, metabolic Eliminate narcotics Eliminate/reduce less potent meds: anticholinergics, amantadine, MAO-B inhibitors, COMT inhibitor Reduce dopamine agonist Reduce levodopa Consider antipsychotics: quetiapine, clozapine (need FBC monitoring) Consider cholinesterase inhibitor if there is accompanying dementia
Dementia Discontinue trihexyphenidyl Discontinue all other drugs with low effectiveness (Amantadine, MAO-B inhibitor,s dopamine agonists) Consider cholinesterase inhibitor: rivastigmine, donapezil (or memantine if cholinesterase inhibitors are not tolerated or are contraindicated)
Constipation Prokinetics, macrogol, stool softeners Bladder instability Consider urology referral Oxybutynin, tolterodine Erectile dysfunction sildenafil
Take home message To date there is no cure for PD and treatment is purely symptomatic Pharmacological treatment should be individualized for both timing and choice of drugs The primary goal of symptomatic treatment is to improve quality of life Start drugs low dose and titrate slowly