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Parkinson pharmacotherapy
- 1. Dr. Prerna Singh Junior Resident Department of Pharmacology JNMC, AMU Pharmacotherapy of Parkinson’s Disease
- 2. Outline Introduction Pathophysiology Clinical feature Pharmacotherapy
- 3. Introduction Paralysis agitans / shaking palsy James Parkinson Second most common neurodegenerative disease Idiopathic > Drug induced Incidence: 1% in age > 65 2.5% age > 80 Male: Female 2:1
- 4. Etiology Unknown Genetics – Important < 50 year Autosomal dominant : PARK1, LRRK2 Autosomal recessive : Parkin, PINK1, AJ1 Environmental- Pesticide(similar structure to MPTP) Protective: cigarettes, caffeine
- 5. Etiology Degeneration of dopaminergic neuron in substantia nigra pars compacta 70-80% loss for symptoms Hallmark – Lewy body
- 6. Etiology Drug induced: D2 blocker antipsychotics - Metoclopramide, Phenothiazine Neurological conditions: Multiple system atrophy, Essential tremor, supranuclear palsy Other: Excitotoxicity Inflammation Autophagy
- 10. Pathophysiology
- 11. Antioxidant role Substantia nigra pars compacta- high oxidative Free radical generation by MAO Glutathione limit this damage Parkinson: Impaired protection
- 12. Cardinal feature •Rigidity-Cogwheel •Tremor-Resting, pill rolling •Bradykinesia •POSTURAL INSTABILITY Motor symptoms Slow shuffling gait Festinating gait Dysarthria Dysphonia Flexed posture Hypophonia Hypomimia Micrographia Non motor symptomsOlfactory disturbance Constipation Sleep disorder Sexual dysfunction Anxiety Confusion Apathy Dementia DepressionDeath : Immobility – Aspiration, Pulmonary embolism, Pneumonia
- 14. DIAGNOSIS No lab test Genetic testing Neuroimaging Medication history
- 15. Treatment goal Improve motor and non motor symptom Improve mobility Minimize side effect and treatment complication NO DRUG IS NEUROPROTECTIVE Patient education
- 16. Drugs used for Parkinson’s
- 17. L-DOPA – Dopamine precursor Dopamine cant cross BBB L-dopa can cross Metabolized by DDC and COMT in periphery – side effect and low availability in brain Initial dose: 300 mg/day (100mg TDS) Max: 800- 1000 mg/day Oral disintegrating tablet: difficulty swallowing
- 18. L-DOPA – Dopamine precursor Absorption affected by- gastric emptying Absorbed via neutral amino acid transporter Extended release: RYTARY DUOPA: intestinal gel via gastrostomy tube
- 19. L-DOPA – Dopamine precursor Side effect: Nausea vomiting Postural hypotension- D1 stimulation Sedation Vivid dream
- 20. Complication of L-Dopa therapy Occur after 5-6 month treatment End of dose wearing off- Cause: loss of neuronal storage capacity and short half life of dopamine Patient dependent on exogenous dopamine Solution: Increase frequency of administration Or Add COMT or MAO inhibitor Dopamine agonist can be added CONTROLLED RELEASE DOPA
- 21. Complication of L-Dopa therapy Delayed on/ no on Cause: Delayed gastric emptying or decreased absorption Solution: Give empty stomach Oral disintegrating tablets
- 22. Complication of L-Dopa therapy Freezing Cause: Sudden inhibition of lower extremity motor function: falls Solution: Increase dose Add dopamine agonist Physiotherapy Walking aids
- 23. Complication of L-Dopa therapy Dyskinesia: Involuntary choreiform movement Distinguish form tremor Cause: Peak DA level- too much dopamine stimulation Solution: Lower dose May aggravate Parkinson- so increase frequency or add another drug
- 25. Complication of L-Dopa therapy Off period dystonia Sustained muscle contractions Cause: waning drug level- early morning Solution: Bedtime dose- sustained release
- 26. Fate of L-Dopa
- 27. Inhibition of dopamine metabolism
- 28. L- DOPA + Carbidopa Increase half life of L- dopa Half life : 1 hour Carbidopa makes it 1.5 hour Decrease side effect Peripheral decarboxylase inhibitor(not cross BBB) Dose: 10mg TDS
- 29. COMT inhibitor Increase central bioavailability of DOPA Increase half life to 2-2.5 hour ENTACAPONE- 200 mg max 8 times a day TOLCAPONE- inhibit both central and peripheral COMT HEPATOTOXIC 100-200 mg TDS
- 30. MAO –B Inhibitor Prolong dopamine activity Selegiline: 5mg BD METABOLITE: Amphetamine – anxiety insomnia High FPM: transdermal patch available Rasagiline: 0.5- 1mg OD No such metabolite Cheese reaction Serotonin syndrome with TCA Neuroprotective?
- 31. MAO-B Inhibitor Safinamide: newly approved 50mg OD
- 32. Dopamine agonist Ergot derivative: Bromocriptine- Pulmonary fibrosis Pergolide – valvular heart disease, cardiac valve fibrosis Non ergot derivative: Pramipexole 0.125mg TDS Ropinirole- 0.25mg TDS Rotigotine- high FPM (transdermal patch)
- 33. Dopamine agonist Adjuvant to L-Dopa Mild to moderate PD - may be used as monotherapy PREFFERED IN YOUNG PATIENT Old patient – more chance of side effect so avoided Combination with L- Dopa: increased risk of dyskinesia Side effects – compulsive behaviors/ gambling
- 34. Apomorphine Non ergot DA agonist Approved as rescue therapy for off period High First pass metabolism: Subcutaneous 2-6mg Can cause injection site reaction and orthostatic hypotension
- 35. Amantadine Antiviral Mechanism in Parkinson : ? Inhibition of NMDA receptor???? Facilitate dopamine release???? 300mg/day Useful in dopamine induced dyskinesia- anti-glutamate mechanism Side effect: livido reticularis(vasoconstriction)
- 36. Anticholinergics Benztropine- 0.5-4mg/day Trihexyphenidyl – 1-6mg/day Cause of tremor Side effect: Blur vision Constipation Urinary retention Dry mouth Confusion Sedation Acetyl choline Dopamine
- 38. Thank you!
- 39. Surgery Deep brain stimulation Adjuvant
- 40. New drugs Adenosine A2A receptor antagonist : Istradefylline Preladenant 5HT1A antagonist : Aarizotan Glutamate receptor antagonist
Editor's Notes
- NEURODEG DIS: PROGRESSIVE IRR. LOSS OF NEURON Estrogen protective
- Cigg. Inv in dopamine signaling Coffee neuroprotection
- Pathology appears first in ant. Olfactory n. & lower brainstem. Lewy body : aggregates of alpha synuclein Eosinophilic cytoplasmic inclusions , in nerve cell
- Schematic wiring diagram of the basal ganglia. e striatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of cerebral cortex. e striatum contains projection neurons expressing predominantly D1 or D2 DA receptors, as well as interneurons that use ACh as a neurotransmitter. Out ow from the stria- tum proceeds along two routes. e direct pathway, from the striatum to the SNpr and GPi, uses the inhibitory transmitter GABA. e indirect pathway, from the striatum through the GPe and the STN to the SNpr and GPi, consists of two inhibitory GABA-ergic links and one excitatory Glu projection. e SNpc provides dopaminergic innervation to the striatal neurons, giving rise to both the direct and the indirect pathways, and it regulates the relative activity of these two paths. e SNpr and GPi are the output structures of the basal ganglia and provide feedback to the cerebral cortex through the VA/VL nuclei of the thalamus. et e ect of stimulation of the direct pathway at the level of the striatum is to increase the excitatory out ow from the thalamus to the cortex net e ect of stim- ulating the indirect pathway at the level of the striatum is to reduce the excitatory out ow from the thalamus to the cerebral cortex.
- DA released in the striatum tends to increase the activ- ity of the direct pathway and reduce the activity of the indirect pathway, whereas the depletion that occurs in PD has the opposite e ect. e net e ect of the reduced dopaminergic input in PD is to increase markedly the inhibitory out ow from the SNpr and GPi to the thalamus and reduce excitation of the motor cortex.
- Rigidity- Increased muscle resistance Cogwheel Constipation cooz bowel muscle rigid Involvement of extranigral areas plays an important role in non-motor features & levodopa nonresponsive motor aspects. Tremor- rhythmic oscillatory movement around a joint Resting, pin rolling Bradykinesia – slowness in movement
- GENETIC : NOT MUCH USEFUL NEUROIMAGING FOR OTHER CAUSES
- Side effect; nausea, orthostatic hypotension Not cross transmucosal memb – has to reach duodenum]
- Separate dose with protein meal
- Drug holiday- risk of neurolept malignant syndrome
- 10/100 MG TDS 25/100 TDS
- Tyramine not metabolized in moa I presence Gets accumulated Dispalce NE HYPERTENSIVE CRISIS TREATMENT PHENTOLAMINE SEROTONIN SYNDROME DELIRIUM AGITATION TACHYCARDIA DIARRHOEA TREATMENT CYPROHEPTADINE
- Istradefylline new approval
- Ropinirole is metabolized by CYP1A2: Inducer- cigarettes Inhibitor: Flouroquinolones
- Inncreased ch activity
- IN SUBTHALAMUS AND GLOBUS EXTERNUS