Pharmacotherapy of Parkinson’s disease
•
19 j'aime•3,626 vues
Lecture slides for Medical Undergraduate teaching in Pharmacology. Study material is based on Essentials of medical pharmacology by KD tripathi and Katzung. Figures are obtained from google image search and above mentioned textbooks.
Recommandé
Contenu connexe
Tendances
Tendances (20)
En vedette
Similaire à Pharmacotherapy of Parkinson’s disease
Similaire à Pharmacotherapy of Parkinson’s disease (20)
Plus de Mayur Chaudhari
Dernier
Dernier (20)
Pharmacotherapy of Parkinson’s disease
- 1. Parkinson’s Disease Dr. Mayur Chaudhari Assistant Professor Department of Pharmacology Government Medical College, Surat
- 2. Learning Objectives Pathophysiology Objectives of therapy Levodopa Comt and mao inhibitors Anticholinergics
- 6. Parkinson’s Disease Extrapyramidal motor disorder Progressive, Degenerative Rigidity, tremor and Hypokinesia Defective posture, Gait, Mask like face Sialorrhoea, Dementia.
- 7. Environmental Toxins Protein Damage Lipid Peroxidation DNA Damage AgingNeuronal Metabolism Selective Vulnerability of neuronal cells Free radical formation, Oxidative stress Excitotoxicity Cell death
- 10. Non motor Symptoms Cognitive Mood Behavioral Disabilities Dementia
- 11. Begins between 40-70 years of age Peak onset 6th decade Infrequent before 30 years More common in men
- 13. ACh DA
- 14. Objectives Of Therapy Increase Dopamine activity Replenish dopamine – Levodopa Dopamine agonist Inhibit metabolism Release DA and Prevent Reuptake Decrease Cholinergic activity
- 15. Classification Dopamine precursor : Levodopa (l-dopa) Peripheral decarboxylase inhibitors : Carbidopa, Benserazide Dopaminergic agonists: Bromocriptine, Ropinirole, Pramipexole MAO-B inhibitor: Selegiline, Rasagiline
- 16. Classification COMT inhibitors: Entacapone, Tolcapone Glutamate (NMDA receptor) antagonist (Dopamine facilitator): Amantadine. Central anticholinergics: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden. Antihistaminics : Orphenadrine, Promethazine
- 17. Levodopa Inactive, Precursor of Dopamine 95% converted into dopamine peripherally by decarboxylation Which exerts systemic action Remaining enters brain, converted into dopamine
- 18. Levodopa: CNS Symptomatic relief in Hypokinesia, rigidity and tremors Person become more alert Gradual Normalization of symptoms No effect on dementia
- 19. Levodopa 2. CVS Tachycardia Postural Hypotension 3. CTZ Nausea and Vomiting Tolerance develops chronically
- 20. Levodopa: Pharmacokinetic Rapidly absorbed through GIT Food affect absorption Undergoes high 1st pass metabolism Only 1 % Levodopa enters brain T1/2 is 1-2 hours
- 21. Levodopa: ADRs Initial Stages Nausea , Vomiting – Tolerance develops Postural Hypotension Arrhythmia Worsening of Angina Altered taste
- 22. Levodopa: ADRs After Chronic Use •Abnormal movements •Behavioral abnormalities •Fluctuations in Beneficial effects •Wearing off phenomena •On-off phenomenon
- 23. Wearing off (End of Dose) Occur at later stage on chronic use Each dose improves mobility Rigidity and akinesia return at the end of dosing interval
- 24. On-OFF Phenomena All or None response On phase may be complicated by dyskinesia Off phase with severe disease
- 26. Levodopa: Interactions Pyridoxine Dopamine receptor antagonists Non selective MAO inhibitors Antihypertensive Anticholinergics
- 27. Carbidopa, Benserazide Peripheral decarboxylase inhibitor Given in combination of Levodopa Increases t1/2 of Levodopa in periphery More levodopa available for entering CNS
- 28. Amount of Levodopa in CNS ↑ , so dose ↓ up to 1/4th Systemic ADRs of Levodopa ↓ Minimization of cardiac ADRs Minimization of on-off effect Degree of improvement higher
- 29. Carbidopa, Benserazide Abnormal movements and behavioral abnormality not resolved Postural Hypotension Levodopa always used with Carbidopa – Co careldopa
- 30. Dopamine Agonist Can act on striatal DA receptors Even in advanced patient who lost ability to synthesize, Store and Release DA Longer acting Exert Subtype selective activation of DA receptors
- 31. Bromocriptine Potent D2 agonist, Partial agonist/antagonist at D1 receptor Symptomatic improvement with in 30-60 minutes, last for 6-10 hours High dose needed for monotherapy, which produces intolerable side effects Vomiting, Hallucinations, Hypotension, Nasal Stuffiness Used to smoothen ‘on off’ fluctuations with l-dopa
- 32. Ropinirole & Pramipexole Selective D2/D3 agonist Pramipexole has greater affinity for D3 receptors Used as supplementary drug to L-dopa with tolerable S/E in advanced cases Dose titration take 1-2 weeks
- 33. Ropinirole & Pramipexole Used as monotherapy in early cases Lower chances of motor fluctuations and dyskinesia in comparison to L-dopa Slower rate of neuronal degeneration in clinical studies Alternative to L-Dopa for longer symptom free life
- 34. Ropinirole & Pramipexole Rapidly absorbed orally Metabolised in liver with t ½ of 6 hours Longer acting than L-dopa
- 35. Ropinirole & Pramipexole: S/E Nausea Dizziness, Hallucinations Postural hypotension Episodes of day time sleep Patients advised not drive
- 36. MAO-B Inhibitor: Selegiline Selective, Irreversible MAO-B Inhibitor Retard intracerebral degradation of dopamine In low doses does not interfere with peripheral metabolism of dietary amines Less chances of accumulation of CAs and hypertensive reactions
- 37. MAO-B Inhibitor: Selegiline Mild action as monotherapy With L-dopa, attenuates motor fluctuations, ↓ ‘wearing off’ 20-30% reduction in L-dopa dose Advanced cases with ’on-off’ effect not improved Worsening of dyskinesia, mental confusion and hallucinations
- 38. Selegiline: Adverse effects Postural hypotension, Nausea, confusion Accentuation of L-dopa induced involuntary movements and psychosis Insomnia and agitation due to metabolism into amphetamine Contraindicated in epilepsy
- 39. Selegiline Pethidine+ Selegiline: Excitement, rigidity, resp. depression and hyperthermia Interacts with TCAs and SSRis
- 40. Rasagiline 5 time potent, longer acting Not metabolised to amphetamine Does not produce excitatory side effects Some evidence of neuro protective effects
- 41. COMT Inhibitors
- 42. Entacapone, Tolcapone Selective, reversible inhibitors of COMT Prevent metabolism of L-dopa by COMT peripherally Preserve DA formed in striatum Enhance therapeutic effect of L-dopa
- 43. Entacapone, Tolcapone Smoothen ‘wearing off’ Increase ‘on’ time, decrease ‘off’ time Improves daily activities Dose of L-dopa can be decreased Not given for early cases
- 44. Entacapone, Tolcapone: A/Es Worsening of L-dopa A/Es Nausea, Vomiting, Dyskinesia, Postural Hypotension, Hallucinations Diarrhoea Orange yellow discoloration of urine Acute fatal hepatitis and Rhabdomyolysis: Tolcapone
- 45. NMDA antagonist: Amantadine Rapidly acting, lower efficacy than L-dopa Tolerance develops in months and efficacy is lost Promotes presynaptic synthesis and release of DA in brain, Has some anticholinergic property Inhibit NMDA glutamate receptors
- 46. Amantadine Can be used in mild cases Short course to supplement L-dopa Supress motor fluctuations and abnormal movements S/Es – Insomnia, restlessness, confusion, nightmares, Anticholinergic effects Livedo reticularis – Local release of Cas, edema of ankles
- 47. Central anticholinergics Higher central: peripheral anticholinergic ration Reduce the unbalanced cholinergic activity Efficacy is lower than Levodopa Only drug effective in drug induced parkinsonism Trihexyphenidyl, Procyclidine, Promethazine
- 48. Central anticholinergics 10-25 % improvement symptomatically for 4-8 hours Tremor is well controlled than rigidity, Hypokinesia not affected Sialorrhoea controlled by peripheral action Monotherapy in mild cases or when L-dopa is contraindicated Combined with L-dopa to reduce the dose
- 49. Central Anticholinergics S/E – similar to atropine Impairment of memory, confusion and blurred vision in elderly Urinary retention in elderly males
- 50. No drug can alter basic pathology of disease Drugs used to provide symptomatic relief, additional happier and productive life In case of mild cases – anticholinergics or Selegiline Ropinirole/ Pramipexole in early cases in young patients Selegiline can be combined with L-dopa to overcome ‘ wearing off’ phenomena
- 51. L-dopa+ Decarboxylase is standard therapy, Combination reduces early complications not late Start with lower dose and titration in 2-3 months Benefit last for 2-3 years before decline Subsequently ‘wearing off’ is seen, dyskinesia appear Drug holiday not practised now
- 52. L-dopa alone used only in patients who develop intolerable dyskinesia Amantadine used for brief period of exacerbation Ropinirole/ Pramipexole – to supplement L-dopa in late cases to smoothen ‘on off’, to reduce the dose and dyskinesia Entacapone in advanced cases with L-dopa+ carbidopa – Prolong action and smoothen ‘on off’ fluctuations
Notes de l'éditeur
- first clear medical description was written in 1817 by James Parkinson.
- Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes.
- - Extrapyramidal motor disorder characterized by rigidity, tremor and Hypokinesia with secondary manifestations like defective posture and gait, mask like face and Sialorrhoea and dementia.
- Functional circuitry between the cortex, basal ganglia, and thalamus. The major neurotransmitters are indicated. In Parkinson’s disease, there is degeneration of the pars compacta of the substantia nigra, leading to overactivity in the indirect pathway (red) and increased glutamatergic activity by the subthalamic nucleus. Striatum receive Excitatory Glu input from motor cortex and modulatory Dopaminergic input from SN-PC. Balancing Cholinergic interneurons in striatum Output from Stritum to GP I and SN-PR via direct and indirect pathway. Direct pathway releases GABA while dominant indirect pathway hay GABA (Inhibitory) and Glu (Excitatory) relay. Degenrative lesion in SN-PC decreases dopaminergic input to the striatum leading to imbalance between DA and Ach and producing Hypokinesia, Rigidity and tremor.
- Direct pathway facilitates BG output to the thalamus and motor areas Indirect pathway disinhibits the STN and in turn inhibits thalamus and motor areas. BG plays a important role in planning and programming of movement by selecting and inhibiting specific motor strategies. BG plays a role in some cognitive processes in awareness of body orientation in space, ability to adapt behaviour as task requirements change and motivation Loss of dopamine results in an overactive indirect pathway that is thought to underlie Akinesia and Rigidity. Underactive direct pathway is responsible for Bradykinesia.
- Posture, Gait, Handwriting, Speech, Facial expression, Mood and self-care gradually normalize some patients this progresses to excitement— frank psychosis may occur. Embarrassingly disproportionate increase in sexual activity has also been noted
- Dopamine decrease central sympathetic outflow Gradual tolerance develops to both cardiac stimulant and hypotensive actions.
- AbN Movt – fascial tics, grimacing, tounge thrusting, Choreoathetoid movt, - develops within months. Behavioral AbN – Mild anxiety, Nightmares, Depression, Mania, Hallucination, Confusion, Psychosis Fluctuation in motor fn – after 2-5 yrs of therapy.
- Increasing the dose and frequency can give relief but limited by development of dyskinesia
- Reflection of progression of disease Neurons loss ability to store and release DA Dose fractionation and frequent administration tends to diminish this for a time.
- Pyridoxine – nullify therapeutic effect by enhancing per. Decarboxylation Phenothiazines, butyrophenones and Metoclopramide Mao Inhibitors – HTN crisis can occur due to inhibition of peripheral DA AntiHTN – Postural Hypotension Atropine – Retard absorption,More time available for per degradation
- Two isoenzyme forms of MAO, termed MAO-A and MAO-B are recognized; both are present in peripheral adrenergic structures and intestinal mucosa, while the latter predominates in the brain and blood platelets.
- clinical benefits derived from selegiline are short lived (6–26 months). Based on the hypothesis that oxidation of DA and/or environmental toxins (MPTP-like) in the striatum by MAO to free radicals was causative in parkinsonism, it was proposed that early therapy with selegiline might delay progression of the disorder. However, no difference in the course of the disease has been detected on follow up of selegiline treated patients in large multicentric studies