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Premium member Presentation Transcript PARKINSON’S DISEASE: PARKINSON’S DISEASE Presented by M.RANGALAKSHMI NAIDU I/II M.PHARM(PHARMACOLOGY) SIMS GROUP OF INSTITUTIONS GUNTURDefinition: Definition Idiopathic Symptoms : Tremors,Rigidity,Bradykinesia,loss of postural balance. Due to decreased production of Dopamine in Substantia nigra. So less dopamine action on Basal ganglia .History of Parkinson´s disease (PD) : History of Parkinson´s disease (PD) First described in 1817 by an English physician, James Parkinson, in “An Essay on the Shaking Palsy.” The famous French neurologist, Charcot, further described the syndrome in the late 1800s.Epidemiology: Epidemiology 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). May be less prevalent in China and other Asian countries, and in African-Americans. Prevalence rates in men are slightly higher than in women; reason unknown, though a role for estrogen has been debated.Incidence of PD: Age Incidence / 100 000 Incidence of PDPathogenesis: 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 4 Accelerated agingPathophysiology: Pathophysiology Imbalance of dopamine and acetylcholine Loss of 80 to 90% of dopaminergic production in the substantial nigra Lewy BodiesDiagnostic Features: Diagnostic Features Four Cardinal Signs T remor R igidity A kinesian and bradykinesia P ostural instabilityFunctional Neuroanatomy of PD : Functional Neuroanatomy of PD Substantia nigra: The major origin of the dopaminergic innervation of the striatum. Part of extrapyramidal system which processes information coming from the cortex to the striatum, returning it back to the cortex through the thalamus. One major function of the striatum is the regulation of posture and muscle tonus.Neurochemistry of PD : Neurochemistry of PD Late 1950s: Dopamine (DA) present in mammalian brain, and the levels highest within the striatum. 1960, Ehringer and Hornykiewicz: The levels of DA severely reduced in the striatum of PD patients. 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.Dopamine pathways in human brain: Dopamine pathways in human brainPowerPoint Presentation: Dopamine acts as inhibitory neurotransmitter in the CNS Four pathways 1.Nigrostriatal pathway 2.Mesolimbic-mesocorticalpathway 3.Tuberoinfundibular pathway 4.Chemoreceptor trigger zoneCharacteristic Problems: Characteristic Problems Micro graphia-small handwriting Hypomimia-decreased facial animation Hypophonia-soft speech Dysarthria-unclear pronunciation Dyspnea-labored breathing Festination-Shuffling gait Dopamine synthesis : Dopamine synthesisDiagnosis of PD : Diagnosis of PD Anamnesis and clinical examination No disease-specific biological marker available Positron Emission Tomography (PET) or Single-photon Emission Computed Tomography (SPECT) with dopaminergic radioligands Exclusion of several causes of secondary Parkinsonism: Precursor of Dopamine: L-dopa Inhibitors of Dopamine metabolism: i)MAO-B inhibitor: Selegiline ii)COMT inhibitors:Tolcapone ,Entacapone Dopamine releaser: Amantadine Dopamine agonists:Bromocriptine,Pergolide, Lysuride. Anti cholinergic drugs: Benztropine, Trihexyphenidyl,Biperiden,Ophenadrine CLASSIFICATION OF ANTIPARKINSONISM DRUGSTherapy of PD: levodopa : Therapy of PD: levodopa Late 1950s: L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of DA that crosses the blood-brain barrier, could restore brain DA levels and motor functions in animals treated with catecholamine depleting drug (reserpine). First treatment attempts in PD patients with levodopa resulted in dramatic but short-term improvements; took years before it become an established and succesfull treatment. Still today, levodopa cornerstone of PD treatment; virtually all the patients benefit.LEVODOPA (L-DOPA): LEVODOPA (L-DOPA) 3,4 di hydroxy phenyl-L-alanine. L-dopa Dopamine ( by Dopa decarboxylase) Dopamine acts on D2 receptors in basal ganglia. only 1-3 % of L-dopa enters CNS. Remaining L-dopa is converted to Dopamine in peripheral tissue. Dopamine does not cross blood brain barrier. Carbidopa : inhibitor of Dopa decarboxylase in peripheral blood. Carbidopa does not crosses blood brain barrier. Tolcapone & Entacapone: COMT inhibitorsAdverse effects:: Adverse effects: L-DOPA: Dyskinesias(choreoathetosis) Psychosis Prolactin Nausea,Vomitings Tachycardia, ventricular arrhythmias Hypotension On-off phenomenon Tolcapone : HepatotoxicDrug interactions: Drug interactions 1.Pyridoxine (B6) - Metabolism of L- dopa in peripheral blood. 2. L- dopa + MAO -A inhibitors - Severe Hypertension 3.Aminoacids decreases absorption of L-dopa. 4.Anti psychotics decreases action of Levodopa.PowerPoint Presentation: Contra indications: 1. Psychosis. 2. Angle closure glaucoma. 3.Melanoma. Precaution: Peptic ulcer.Dopamine Agonists “Synthetic Dopamine”: Dopamine Agonists “Synthetic Dopamine” Bromocriptine Mesylate (Parlodel) Pergolide Mesylate (Permax) Pramipexol (Mirapex) Ropinirole HCL (Requip)Dopamine Agonists: Dopamine Agonists 1.Ergot derivatives:Bromocriptine,Pergolide,Lysuride. Indications: Parkinsons,Hyperprolactinemia. Adverse effects: Dyskinesias, Psychosis, Emesis, Hypoprolactinemia, Hypotension , Arrhythmias , Pul.Infiltrates,Erythromelalgia. Contraindications:1.Psychosis 2.Recent M I. 2.Non-ergot drugs: Pramipexole ,Ropinirole No vasoconstriction. Side effects: Hypotension,Peripheral edema,Dyskinesias.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/dNonergot Agonist Dosing: Nonergot Agonist Dosing Pramipexole (Mirapex) Monotherapy or Adjunct Initial dose of 0.125 mg TID and increased every 5 to 7 days as tolerated up to 3 to 4.5mg/d Higher doses are not more effective than 1.5mg/d and are associated with more side effects Mean 27% reduction of L-Dopa Decrease dose with renal function impairment Drugs that are secreted by the cationic transport system may decrease the clearance of pramipexole by 20%. These include cimetidine, diltiazem, quinidine, quinine, ranitidine, triamterene, and verapamil.Nonergot Agonist Dosing: Nonergot Agonist Dosing Ropinirole (Requip) Monotherpy or Adjunct Initial dose of 0.25mg TID and increased by 0.25mg TID on a weekly basis. After the fourth week doses may be increased by 1.5mg/d up to 9mg/d. Further adjustment may be obtained by 3mg/d increases up to 24mg/day Mean 19% reduction of L-dopa Drugs that inhibit or induce CYP1A2 will affect the clearance of ropinirole. Inhibitors such as cimetidine, ciprofloxacin, clarithromycin, diltiazem, enoxacin, erythromycin, fluvoxamine, mexiletine, norfloxain, omeprazole, ritonavir, and troleandomycin. Inducers such as carbamazepine, phenobarbital, phenytoin, and rifampin. If therapy is stopped, discontinue over seven daysAmantadine: Amantadine Amantadine HCL (Symmetrel) Inhibits dopamine recapture 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 reticularisLIVEDORETICULARIS : SIDE EFFECT OF AMANTADINE: LIVEDORETICULARIS : SIDE EFFECT OF AMANTADINEAnticholinergics: Anticholinergics Drugs: Benztropine, Trihexyphenidyl, Biperiden,Ophenadrine, Diphenhydramine. Clinical use: Reduce rigidity and tremor but less effective in resolving bradykinesia Useful in Rx of drug induced Parkinsonism. Adverse effects: Dry mouth,Dry skin,dry eyes,blurring of near vision,mydriasis,urinary retention, constipation,tachycardia. Contraindications: Prostatic hyperplasia, angle closure glaucoma.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. Possible adverse effects include dry mouth, blurred vision, somnolence, hallucinations, memory impairment, confusion, urinary retention, and constipation. 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 daily dosage of 6mg. Possible adverse effects include dry mouth, blurred vision, somnolence, hallucinations, memory impairment, confusion, urinary retention, and constipation.Selegiline: Selegiline Selective MAO-B inhibitor Increases dopamine levels in the brain Clinical use: used in conjunction with other drug Only drug known to arrest the progression of the disease.Selegiline: Selegiline Selegiline HCL (Eldepryl) Monotherapy or adjunct MOA-inhibits monoamine oxidase-B (MAO-B) Inhibition of MAO-A does not occur Dosage of 5 mg BID with breakfast and lunch When used as monotherapy delays the need of L-dopa by an average of nine months. Possible adverse effects include nausea, dizziness, abdominal pain, confusion, and exacerbation of L-dopa side effects Controversial theory of decreased rate of neuronal death due to a reduction of free radicals.Ayurvedic treatment for PD: Ayurvedic treatment for PD The Mucuna Pruriens plant, also known as Atmagupta Kapikacchu is largely used in the treatment of Parkinson's Plants like Sida Cordifolia, and Ashwagandha , which contribute towards the Ayurvedic treatment of Parkinson's disease too, Brahmi (Hydrocotyle Asiatica) and Jatamansi (Nardostachys Jatamansi) are also given.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 Two methods: Ablation and deep brain stimulationGrafting: Grafting Suprarenal to brain transplantation Fetal tissue transplantation Cell culture transplantationClinical Research: Clinical Research Animal models Gene Therapy Neuroprotective Treatments Neural TransplantationUnder 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 researchReferences: References GOODMAN&GILLMANS’THE PHARMACOLOGICAL BASIS OF THERAPEUTICS,TENTH EDITION Pg no:552-560. RANG AND DALES PHARMACOLOGY,SIXTHEDITION Pgno:517-521. Essentials of MEDICAL PHARMACOLOGY,Tripathi TEXT BOOK OF PHARMACOLOGY by LIPPINCOT pgno:93-100 BASICS OF CLINICAL PHARMACOLOGY ,KATZUNG www.wikipedia.com http://www.buzzle.com/article Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp. 101-1332001 Cotzias, G. C. et al. Modification of parkinsonism: chronic treatment with L-DOPA. N. Engl. J. Med. 280, 337-345, 1969 Contd…PowerPoint Presentation: Marsden, C. D. Parkinson's disease. Lancet 335, 948-952, 1990. Reprinted with permission from Elsevier. Forno, L. S. Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. 55, 259-272, 1996 Lewy, F. in Handbuch der Neurologie Vol. 3 (eds Lewandowski, M. & Abelsdorff, G.) pp. 920-933, Springer Verlag, Berlin 1912 Tretiakoff 1919 Parkinson . An Essay on the Shaking Palsy. Sherwood, Neely & Jones, London, 1817, JPowerPoint Presentation: THANK`U’ You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.