Parkinson's Disease by Minwoldu

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Information about Parkinson's Disease by Minwoldu

Published on February 27, 2014

Author: minwoldu


Parkinson’s Disease: Parkinson’s Disease Minyahil A Woldu B.Pharm, Msc in Clinical Pharmacy 1 Historical Perspective: Historical Perspective Dr. James Parkinson (1755-1828) 1817 “involuntary tremulous motion” “pass from a walking to a running pace” “shaking palsy” 2 Epidemiology: Epidemiology Average incidence is 20 per 100,000 in North America 1 Million affected in the United States 50,000 new cases per year Cost estimated to exceed $5.6 Billion annually 3 Epidemiology: Epidemiology Average age of onset 62.5 Men and women affected equally Genetic Link Incidence in: African-Americans and Asians less likely than Caucasians to develop Parkinson’s Effect of Caffeine and smoking shows some protective effects 4 PD in Ethiopia……the Good News…: PD in Ethiopia……the Good News… Ethiopia has the world's lowest recorded prevalence of Parkinson's Disease. At a rate of only 7 per 100,000 it is far below the world's highest prevalence rate of 329 per 100,000 in Nebraska, U.S.A.. For most African countries the figures are not known. 5 Parkinson’s Disease - Symptoms: Parkinson’s Disease - Symptoms Patients initially present with a triad of motor impairments: T remor R igidity A kinesian and bradykinesia P ostural instability During walking, the head and shoulders are stooped, the gait is short and shuffling, and there is a loss of automatic movements, such as arm swinging. Symptoms worsen as ……….disease progresses. 6 PowerPoint Presentation: Tremors – Usually the first symptom Usually unilateral Becomes bilateral Worsens with stress Usually -- occurs in the hands or arms can occur in head, face, jaw, & leg ♦ disappears with purposeful movement such as picking up an object Parkinson’s Disease - Symptoms Pictures used with permission from 7 PowerPoint Presentation: Postural manifestations – ■ postural instability ■ rigidity ■ stooped Parkinson’s Disease - Symptoms Postural changes cause balance instability 8 Characteristic Problems: Characteristic Problems Micrographia-small handwriting Hypomimia-decreased facial animation Hypophonia-soft speech Dysarthria-unclear pronunciation Dyspnea-labored breathing Festination-Shuffling gait 9 Parkinson’s Disease - Symptoms: Parkinson’s Disease - Symptoms Patients also suffer from non-motor symptoms such as: ♦ cognitive impairments ♦ olfactory impairments ♦ dysphagia ♦ GI dysfunction ♦ sleep disturbances ♦ depression Microsoft© 10 Parkinson’s Disease – Stages of Symptoms: Parkinson’s Disease – Stages of Symptoms Stage Symptoms One Unilateral Two Bilateral No balance impairment Three Balance impairment Mild to moderate disease Physically independent Four Severe disability Still able to walk & stand unassisted Five Wheelchair-bound or bedriddened unless assisted 11 Stages of Parkinson’s Disease: Stages of Parkinson’s Disease Mild symptoms, no disability Non-pharmacological approaches Moderate symptoms with some disability Multiple treatments available including l-dopa Progression of symptoms Levodopa required +/- other meds Early Moderate Advanced Disease progresses Non-motor complications may outweigh motor disturbances 12 Parkinson’s Disease - Pathophysiology:  Substantia Nigra Thalamus Cortex Subthalamic nucleus Globus Pallidus Parkinson’s Disease - Pathophysiology The Basal Ganglia Striatum In PD the striatum portion of the basal ganglia receives an inadequate amount of nigral cells, which impairs a person’s ability to control movement. The basal ganglion’s connection to the cortex and the thalamus also affects movement . Muscle control Dopamine Nigral cells In PD, cellular degeneration starts in the substantia nigra of the basal gangla, where dopamine-producing nerve cells, called nigral cells, are formed. 13 Pathogenesis: Pathogenesis Four Theories Oxidative damage - Impaired protection Environmental toxins - MPTP-Methyl-phenyl tetrahydropyridine Genetic predisposition - Mutations in the gene for the protein alpha-synuclein located on chromosome Accelerated aging Imbalance of dopamine and acetylcholine Loss of 80 to 90% of dopaminergic production in the substantia nigra. 14 Diagnosis: Diagnosis Bradykinesia must be present with at least two of the following: limb muscle rigidity, resting tremor (abolished with movement), or postural instability. Need to eliminate secondary causes; Drug-Induced Toxic Stroke Trauma Neoplasm Other neurodegenerative conditions Alzheimer’s Lewy Body dementia 15 Schwab & England Activities of Daily Living Scale: Schwab & England Activities of Daily Living Scale 100% Completely independent. Able to do all chores without slowness, difficulty or impairment. Essentially normal. Unaware of any difficulty 80% Completely independent in most chores. Takes twice as long. Conscious of difficulty and slowness 60% Some dependency. Can do most chores, but exceeding slowly and with much effort. Error; sometimes impossible 40% Very dependent. Can assist with all chores, but few alone 20% Nothing alone. Can be slight help with some chores. 0% Cannot swallow, bladder and bowel not functioning, Bed-ridden. 16 Pharmacotherapy : Pharmacotherapy Levodopa Dopamine agonists COMT inhibitors Amantadine Anticholinergics Selegiline 17 PowerPoint Presentation: DA GABA ACh Striatum Substantia Nigra Levodopa Amantadine Selegiline Zydis selegiline Rasagiline Dopamine agonists Apomorphine Bromocriptine Pergolide Pramipexole Ropinirole Rotigotine Baclofen Anticholinergics BBB Carbidopa Benserazide Tolcapone Entacapone MAO-B Stalevo ® ( carbidopa /levodopa/ entacapone ) Parcopa® Sites of Action of PD Drugs: 2008 Adjunctive Drug Therapy for Advanced PD 18 Early or Moderate Stage Management of PD: Early or Moderate Stage Management of PD Level A – MAO-B inhibitors – selegiline , rasagiline Level A – Dopamine agonists – pramipexole , ropinirole , rotigotine – caution in elderly, cognitive impairment, young males (?) Level A - Carbidopa /levodopa – immediate release Level B - Carbidopa /levodopa – controlled release Recommended Years 1-5 (possibly more?) 19 Advanced Management of PD Treating Motor Fluctuations: Advanced Management of PD Treating Motor Fluctuations Level A – entacapone, rasagiline Level B – pramipexole, ropinirole, tolcapone - caution hepatotoxicity Level C – apomorphine, cabergoline, and selegiline Level C (surgical) – STN deep brain stimulation Level C (dyskinesias) - amantadine Disregarded – bromocriptine, sustained release carbidopa/levodopa Evidence Years 1-3 and following Adjunctive Drug Therapy for Advanced PD Pahwa, R., et al., Neurology 2006;66:983–995 20 Levodopa: Levodopa Introduced in the late 1960s “Gold Standard” Crosses the blood-brain barrier Adverse effects such as nausea, vomiting, postural hypotension, involuntary movements, restlessness, and cardiac arrhythmias 21 Levodopa: Levodopa L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia. Pyridoxal phosphate (vitamin B6) is a required cofactor in this reaction, and may occasionally be administered along with L-DOPA, usually in the form of pyridoxine. 22 Levodopa: Levodopa Besides the CNS, L-DOPA is also converted into dopamine from within the peripheral nervous system. In order to bypass these effects, co-administer a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa or with a benserazide. Co-administration of pyridoxine without a DDCI accelerates the peripheral decarboxylation of L-DOPA to such an extent that it negates the effects of L-DOPA administration 23 Levodopa: Levodopa Today L-dopa/carbidopa (Sinemet) used almost exclusively Initial dose 25/100mg ½ QD for 7 days increase by ½ tab daily for 7 days until up to 1 tablet TID. Extended release dosed as 25/100mg QD and titrated up to TID over a months time. Maximum dose of L-dopa is 800mg/day. Adverse effects minimized with carbidopa “End-of-dose wearing-off effect” “On-off effect” 24 Levodopa-Carbidopa ….. : Levodopa-Carbidopa ….. Is the most effective drug for Parkinson’s symptoms Can be used first-line, especially in older patients Long-term use associated with dyskinesias and motor fluctuations (on-off, wearing off). Other side effects include: nausea loss of appetite orthostasis, confusion, hallucinations, constipation, dry mouth, headache 25 Dopamine Agonists “Synthetic Dopamine”: Dopamine Agonists “Synthetic Dopamine” Bromocriptine Mesylate (Parlodel) Pergolide Mesylate (Permax) Pramipexol (Mirapex) Ropinirole HCL (Requip) 26 Dopamine Agonists: Dopamine Agonists Monotherapy or combination Are particularly useful for: Prolonging the effective treatment period in patients with deteriorating response. Delaying the onset of L-dopa therapy. Particularly in younger patients. Treating patients who cannot tolerate high doses of L-dopa. Associated with more side effects than L-dopa Potential adverse effects include somnolence, dyskinesias, nausea, vomiting, orthostatic hypotension, nightmares, hallucinations, confusion, dizziness 27 Ergot Agonist Dosing: Ergot Agonist Dosing Bromocriptine (Parlodel) Initial 1.25mg QD-BID Titrate 1.25mg to 2.5mg/d every week Average dose <30mg/day. Some patients may require up to 120mg/day Pergolide (Permax) 13 times more potent than bromocriptine Initial 0.05mg/d for 2 days, increasing by 0.1 to 0.15mg/d every 3 days over a 12 day period May increase by 0.25mg every 3 days until symptoms are eliminated or adverse effects occur Mean dose 3mg/d 28 COMT Inhibitors: COMT Inhibitors Are…….catechol-O-methyl transferase (COMT) inhibitor Drugs………… Entacapone ( Comtan ) Tolcapone ( Tasmar ) Mechanism of action……….. They inhibit COMT from metabolizing L-DOPA peripherally. 29 COMT Inhibitor - Entacapone (Comtan): COMT Inhibitor - Entacapone (Comtan) Adjunct therapy Initial dose of 200mg with each dose of levodopa up to 8 times daily Decrease dose of L-dopa …………may be necessary May lead to……Exacerbation of L-dopa side effects diarrhea, urine discoloration, abdominal pain 30 Amantadine (Symmetrel): Amantadine (Symmetrel) Inhibits dopamine recapture by…….. Blocks acetylcholine and glutamate receptors Dose 100mg BID to TID Caution in…………. renal failure patients Currently used to reduce choreic movements Narrow therapeutic range Unpleasant side effects such as nausea, dizziness, confusion, hallucinations, nightmares, dry mouth peripheral edema, and livedo reticularis 31 Anticholinergics: Anticholinergics Monotherapy or adjunct Predopaminergic therapy Most effective for reducing tremor Use Limited by side effects especially in the elderly. Drugs…….. Trihexyphenidyl HCL ( Artane ) Benztropine Mesylate (Cogentin) 32 Anticholinergics: Anticholinergics Trihexyphenidyl HCL (Artane) Initial dose of 1mg and increase by 2 mg every 3 to 5 days until 6 to 10 mg/day. Usually given TID with meals or QID with meals and at bedtime. Benztropine Mesylate (Cogentin) Initial dose of 0.5 to 1 mg at bedtime. Increase by 0.5mg every 5 to 6 days up to a total 6mg/day 33 Selegiline - (Eldepryl): Selegiline - (Eldepryl) Monotherapy or adjunct When used as monotherapy delays the need of L-dopa by an average of nine months. MOA-inhibits monoamine oxidase-B (MAO-B) Inhibition of MAO-A does not occur Dosage …… 5 mg BID with breakfast and lunch Possible adverse effects include ……… nausea, dizziness, abdominal pain, confusion, and exacerbation of L-dopa side effects 34 Parkinson's disease AFTER the "honeymoon": Parkinson's disease AFTER the "honeymoon" The first few years………. symptoms are usually well controlled with low doses of carbidopa/levodopa or a dopamine agonist (pramipexole, etc). But eventually drug efficacy decreases ……… as the disease progresses. 35 "Wearing off": "Wearing off" Occurs after about ……….5 years of levodopa... where its effects start to "wear off" sooner after the last dose. Management of “Wearing off” time….. Change levodopa dosing INTERVAL ( 30 to 60 min). Use of sustained-release levodopa ( Sinemet CR ) to reduce off-time... Doesn’t help!! Dopamine agonist - extends"on" time & prevents "deep" offs. 36 "Wearing off": "Wearing off" Management …..Next recommendation is adding…. COMT inhibitor...or an MAO-B inhibitor. Comtan (entacapone) or the combo product Stalevo (carbidopa/levodopa/entacapone). Tasmar (tolcapone)... Effect on liver MAO-B inhibitor, selegiline or rasagiline ( Azilect ). Rasagiline has better evidence for reducing off time… but Selegiline (costs less) 37 Dyskinesias : Dyskinesias Define as…. diminished voluntary movements Dyskinesias occur when patients get …. too much……. dopamine. Decreasing the levodopa dose may …… help...but ….. It may mean more Parkinson's symptoms, such as tremor, stiffness, and rigidity. 38 Dyskinesias…. diminished voluntary movements: Dyskinesias…. diminished voluntary movements If dyskinesias are a problem, suggest …….. decreasing the levodopa dose ...and adding a dopamine agonist. These cause fewer dyskinesias than levodopa...and also help decrease Parkinson's symptoms. Or suggest adding amantadine ...but watch for CNS side effects. COMT inhibitors might contribute to dyskinesias. Suggest reducing the dose or stopping the COMT inhibitor if necessary . 39 Medication-Induced PD: Medication-Induced PD Meds cause about 10% of cases of Parkinson-like motor symptoms...instead of Parkinson's disease itself. This is most common in the elderly...women...and with high doses. The biggest offenders are the older antipsychotics, such as haloperidol, fluphenazine, and perphenazine. Atypical antipsychotics can also cause Parkinson's symptoms...especially risperidone and olanzapine. Antiemetics such as ………….metoclopramide and prochlorperazine can also be a problem.       40 Medication-Induced PD: Medication-Induced PD Less common culprits are ……valproate, lithium, SSRIs, and others. Drug-induced symptoms are often ……symmetrical and occur within wks to months after starting a med. Suggest stopping or lowering the dose of possible drug culprits. symptoms usually go away within a few months of stopping the drug...unless permanent movement disorder, such as tardive dyskinesia. Use alternatives….. quetiapine (Seroquel, etc) or clozapine (Clozaril, etc) if an antipsychotic is needed. 41 Surgical Options: Surgical Options Pallidotomy and Pallidal Stimulation Thalamotomy and Thalamic Stimulation Introduced in 1950 Pallidotomy improves tremor, rigidity, and bradykinesia Thalamotomy relieves tremor, rigidity, but not bradykinesia Neurosurgical treatment came to a end with the introduction of L-dopa in late 1960s Resurgence of neurosurgical intervention with the failure of pharmacological treatments after 10 to 15 years of disease progression 42 Under Investigation: Under Investigation Implantable pumps Implantable capsules containing dopamine-producing cells New medications to target one of the five individual brain receptors for dopamine Continued genetic research 43 The End!: The End! Thank you!! 44

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