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1-Parkinson's

Parkinson's

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1-Parkinson's

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  1. Muhammad Ali Parkinson´s Disease Michael J. Fox

  2. Objectives  Discuss the epidemiology, etiology, pathophysiology, s/sx, and treatment of PD  Compare and contrast pharmacological options for Parkinson’s disease  Be able to differentiate counseling points pertinent to each medication class  Formulate recommendations to manage the early and late phases of PD  Manage motor and non-motor symptoms of PD

  3. What is Parkinson’s Disease? • A degenerative brain (extrapyramidal motor system) disorder affecting movement.

  4. Neurodegenerative diseases Are conditions in which cells of brain or spinal cord are lost as a result of deterioration of neurons or their myelin sheaths, which may eventually lead to CNS related dysfunction

  5. History; • First described in 1817 by an English physician, James Parkinson, in the case series “An Essay on the Shaking Palsy.” • The famous French neurologist, Charcot, further described the syndrome in the late 1800s.

  6. Intro: • Symptoms are slowly progressive, and within 10-20 years, significant immobility results for most patients. • Although PD is predominantly a movement disorder, other impairments frequently develop including psychiatric problems such as depression and dementia. Autonomic disturbances and pain may later ensue. • More rapid rates of symptom progression and motor disability are observed in patients who are older at the onset of the disease. • There is no cure, and treatment is aimed at controlling symptoms and slowing disease progression. • Itself, it does not cause death, however death often results from complications related to impaired mobility

  7. Etiology • Unknown, and referred to as idiopathic parkinsonism. • However many theorieshave been advanced regarding the origin of PD. • And many risk factors have been implicated. • Environmental (viruses-toxins). • Genetics (gene mutation-synuclein) • Oxidative stress (can promote cell dysfunction and death), immune system disorders

  8. Important: Parkinsonism can also be caused by drugs • It is essential to rule out drug induced PD before providing treatment because most cases are reversible. • Offending agents: • antipsychotics • Metclopramide • Antiemitics

  9. Risk factors of PD • Age -the most important risk factor • Gender (Slightly more common in men) • Positive family history (15% with first degree relative) • Race (in all countries, ethnic groups, and socioeconomic classes) • Life experiences (trauma, emotional stress, personality traits such as shyness and depressiveness)? • An inverse correlation between cigarette smoking and caffeine intake in case-control studies.

  10. Prevalence of PD • The age of onset of PD is variable, usually between 40 and 70, with a mean onset in the sixth decade. On the other hand, about 10% of people with PD are younger than 45. • Prevalence rates in men are slightly higher than in women; reason unknown, though a role for estrogen has been debated. • The most common movement disorder affecting 1-2 % of the general population over the age of 65 years. • The second most common neurodegenerative disorder after Alzheimer´s disease (AD).

  11. Annual incidence of PD Incidence / 100 000 Age

  12. Pathophysiology of PD • In PD, there is a loss in the cells that make and store dopamine in the substantia nigra. • At time of diagnosis, patients have lost 50 to 60% of dopaminergic neurons in the substantia nigra and the remaining neurons in the basal ganglia, spinal cord….. are not functioning properly………….

  13. Pathophysiology of PD • Additionlly, at the basal ganglia Motor symptoms

  14. On the other hand, Non motor symptoms

  15. Neuropathology of PD • Post mortem examination of the basal ganglia reveals the presense of protein aggregates called lewy bodies and lewy neurites prevents the normal functioning of brain cells. • PD symptoms become manifest when about 50-60 % of the DA-containing neurons in the substantia nigra and 70-80 % of striatal DA are lost. • This finding suggests that adaptive mechanisms may somehow influence disease progression during the preclinical stages. • Upregulation of dopamine synthesis • Downregulation of synaptic dopamine reuptake

  16. Clinical features of PD Patients with PD display both motor and nonmotor symptoms. The nonmotor symptoms may precede the motor symptoms. • Motor Symptoms: Four classic cardinal symptoms (TRAP): T = Tremor at rest R = Rigidity A = Akinesia or bradykinesia (generalized slowness of movements) P = Postural instability and gait abnormalities The onset is gradual and present with impairment of movement that might go unnoticed.

  17. Clinical features of PD

  18. Clinical features of PD https://www.youtube.com/watch?v=8xxe2WWWoYI&list=PLLGrjt-zFDRBsp26KSYL8wgThJ4Z5IJrL

  19. Clinical features of PD http://www.youtube.com/watch?v=j86omOwx0Hk

  20. Clinical features of PD

  21. Clinical features of PD

  22. Clinical features of PD • Non motor symptoms (SOAP) • Due to multiple neurotransmitter abnormalities throughout the brain, and some symptoms may be aggravated by PD medications. • S= Sleep and Speech disturbances • O = Other miscellaneous symptoms (problems with vision, nausea, fatigue, , pain, dysesthesias,, seborrhea) • A=Autonomic dysfunction: orthostatic hypotension, Impaired gastrointestinal motility, bladder dysfunction, dysphagia, excessive head and neck sweating, and. • P= Psychological symptoms: • (anxiety, psychosis, cognitive impairment, depression) (Meds)

  23. Clinical features of PD Response Fluctuations -Motor complication (MAD) M= Motor fluctuations • wearing off , • delayed peak response, • random unpredictable on- off, • freezing) A = Akathisia D= Dyskinesias (e.g., chorea, dystonia, diphasicdyskinesia) Response fluctuations occur with disease progression, as the patient’s dopamine reserves are depleted in the brain, and as a complication of PD treatment (L-dopa).

  24. Clinical features of PD Response Fluctuations -Motor complication (MAD) M= Motor fluctuations • wearing off , • delayed peak response, • random unpredictable on- off, or random off • freezing)

  25. Clinical features of PD Response Fluctuations -Motor complication (MAD) A = Akathisia

  26. Clinical features of PD • Response Fluctuations -Motor complication (MAD) D= Dyskinesias (e.g., chorea, dystonia, diphasic dyskinesia)

  27. Diagnosis The most useful diagnostic tool is the • history, including presenting symptoms medication history associated risk factors. • Physical examination (performed on both sides of the body • Imaging studies??????????

  28. Staging of Parkinson Disease • The degree of disability can be defined using: • The Unified Parkinson’s Disease Rating Scale (UPDRS) (six parts) • Hoehn and Yahr scale which is discussed below Mild disease that does not interfere with ADL or work. Requires minimal or no treatment Employment may be significantly affected unless effective treatment is initiated Advanced-stage disease- Combined treatment End stage Disease, pt are incapacitated, not respond well to drug therapy.

  29. Treatment • Desired Outcomes • General Approach to Treatment: The treatment of PD is categorized into three phases: • Non pharmacological intervention; education, lifestyle changes, nutrition, and exercise • Pharmacologic intervention, primarily with drugs that enhance dopamine concentrations. • Surgical treatments for those who fail pharmacologic interventions

  30. Non-pharmacological Options • Nutrition • Physical, occupational and speech therapy • Exercise

  31. Pharmacologic treatment

  32. Pharmacologic treatment Pharmacologic options include: • Levodopa (exogenous dopamine in the form of a precursor) • Dopamine agonists (stimulating dopamine receptors within the corpus striatum) • Aromatic l-amino acid decarboxylase (AAD) inhibitors/carbidopa • Catechol-O-methyltransferase (COMT) inhibitors • Monoamine oxidase type B inhibitors (MAO-B). • Amantadine. • Anticholinergic drugs (to improve tremor) Dopaminergic therapy Inhibiting the major metabolic pathways within the brain that are responsible for the degradation of levodopa and its metabolites.

  33. What the best time to initiate dopaminergic therapy? Most health care professionals (guidelines) agree that treatment should begin when the patient begins to experience functional impairment as defined by (a) threat to employment status, (b) symptoms affecting the dominant side of the body, or (c) bradykinesia or rigidity. (d) Individual patient preferences also should be considered.

  34. What pharmacologic option should we start with? • Only for patients with mild symptoms????? • Initiatig treatment with: • Anticholinergic • MAOI • Amantadine

  35. What is the best dopaminergic therapy to start with? • Levodopa remains the most effective antiparkinsonian agent • Dopamine agonists The American Academy of Neurology and NICE Guidelines : It depends on Patient’s age Younger patients (age <75 years) Older patients (age >75 years) Dopamine agonist Levodopa Why????????

  36. What is the best dopaminergic therapy to start with? • Can we start with both L dopa and dopaminergic agonists? • Dosing for all pharmacological options????? • Dose timing and frequency?

  37. Dopamine Agonists • As a class, dopamine agonists provide adequate control of symptoms when given as monotherapy in up to 80% of patients with early-stage disease. These benefits are sustained for 3 years or more (5 years) in most patients. However, with disease progression, levodopa therapy will eventually be required. • Two generations of dopamine agonists have been used for the treatment of idiopathic, early-stage PD. Retroperitoneal Fibrosis Pleuropulmonary Fibrosis Cardiac Fibrosis

  38. Rules for (apomorpine) Use • The onset of effect is within 10 to 20 minutes, and the duration of effect is about 60 minutes. • Rescue agent in the treatment for acute off episodes in patients with advanced stages of PD. • It requires premedication with an antiemetic because it causes nausea and vomiting.

  39. Adverse effects of dopamine agonists • Nausea • Vomiting • Sedation • Pedal edema • Orthostatic hypotension (Counseling Point) • CNS effects (hallucinations-night mares- confusion) more than with L dopa • Enhanced risky behavior as gambling or compulsive shopping. (Counseling Point) apomorphine Pramipexole & carbegoline Black box warning Excessive daytime sleepiness (Sleep attacks) occurs in 50% of PD. (Counseling Point) Adding modafinil (100–200 mg twice daily) or possibly selegiline can improve alertness but remain controversial

  40. Dopamine Agonists Pros • Has levodopa sparing effect • Can assist with levodopa related issues • Apomorphine is useful for off episodes Cons • Side effects: postural hypotension, confusion, hallucinations, daytime sedation, pedal edema

  41. Levo-dopa • It is a dopamine precursor; • We can't use DOPMAINE itself ???

  42. Problems in levodopa therapy: carbidopa more levodopa reaches the brain. less drug is required [so  its dose &  it side effects]. More dose More side effects

  43. Carbidopa/Levodopa Supplied as tablets in three strengths: 25/100 • Starting: ½ tab BID/week……. ½ tab TID/week then inc by ½ tab daily every week • - Usual main. dose: 300-2000 mg/day • - or to individual requirements, or as tolerated. • Levodopa is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. • Immediate release (standard formulations) has an onset of 15-30 min • Controlled release CR formulation (SR or ER) has a delayed onset (45-60 min) and longer duration!!! • Rate of absorption????

  44. Counseling Points with Carbidopa/Levodopa • Take 30 minutes before or 60 minutes after meals!!! • Anticholinergic medications!!! • Iron supplements!!! • Amino acids • What about antacids???? (Protein rich food)

  45. other formulas of Carbidopa/Levodopa • Enteral • Duodenal (duodopa)® • Advantages of switching from oral to enteral or duodenal formulas?? • Candidates for this formulas??

  46. LEVODOPA: Pros • It is the most effective therapy for managing PD motor symptoms Cons Initial side effects: • GI………….(50%) • Discoloration of urine/sweat./saliva ( (darker colour) 50% of patients • Postural hypotension /diziness(30% of patients); • How to manage????? • later, mental disturbances ( (15% of patients)

  47. LEVODOPA: Adverse effects Cons: later on…………… • Efficacy tends to decrease as the disease progresses. • Motor fluctuations(on–off effect and the wearing off/or end-of-dose deterioration effect, delayed peak) • Akathisia • Dyskinesias 'peak-dose dyskinesia‘.

  48. Dyskinesias Dyskinesias https://www.youtube.com/watch?v=w1TX8iLTarE https://www.youtube.com/watch?v=wfYNgYgEUoQ&list=PLLGrjt-zFDRBsp26KSYL8wgThJ4Z5IJrL http://www.youtube.com/watch?v=koL0PWCJ4lo

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