Parkinsonism

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  • Parkinsonism

    1. 1. DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC
    2. 2. ANTI-PARKNSONIAN DRUGS <ul><li>PARKINSONISM </li></ul><ul><li>1. Selective loss of dopaminergic neurons in the nigro-striatal fibers. </li></ul><ul><li>2. Clinical picture is rigidity, bradykinesia, </li></ul><ul><li>tremor and postural instability. </li></ul><ul><li>TYPES: </li></ul><ul><ul><li>Idiopathic </li></ul></ul><ul><ul><li>Drug induced </li></ul></ul>
    3. 3. <ul><li>Imbalance primarily between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia </li></ul>Dopamine Acetylcholine
    4. 4. GABA DOPAMINE ACETYLCHOLINE PARKINSONISM + -
    5. 5. <ul><li>The Dopaminergic Neurons in the Basal Ganglia Are mainly affected </li></ul><ul><li>Acetylcholine within striatum is a tonically activated neuron </li></ul><ul><li>It impinges on GABA Neuron by an Excitatory Action </li></ul><ul><li>GABA Neuron Has an Inhibitory Action on the Substantia Nigra from Substantia Nigra, Has a Dopaminergic Feed Back Loop Back to Striatum Which Gets Loss Giving Signs and Symptoms of Parkinson Disease </li></ul>
    6. 6. DRUGS <ul><li>Levodopa </li></ul><ul><li>Dopamine Agonists </li></ul><ul><li>MAO Inhibitors </li></ul><ul><li>COMT Inhibitors </li></ul><ul><li>Amantadine </li></ul><ul><li>Acetylcholine Blocking Drugs </li></ul>
    7. 7. <ul><li>Dopamine and Tyrosine Are Not Used for Parkinson Disease Therapy Dopamine Doesn't Cross the Blood Brain Barrier </li></ul><ul><li>Huge amount of tyrosine decreases activity of rate limiting enzyme Tyrosine Hydroxylase That normally Converts Tyrosine to dopamine by overwhelming enzyme tyrosine hydroxylase, has a feedback loop that will turn off tyrosine hydroxylase </li></ul>
    8. 8. <ul><li>LEVODOPA </li></ul><ul><li>MECHANISM: </li></ul><ul><li>1. Levodopa crosses blood brain barrier and is decarboxylated to dopamine in the CNS. </li></ul><ul><li>2. Dopamine stimulates postsynaptic D2 </li></ul><ul><li>receptors in the nigro-striatal neurons </li></ul>
    9. 9. <ul><li>ADVERSE EFFECTS </li></ul><ul><li>1. Anorexia, nausea, vomiting </li></ul><ul><li>2. Tachycardia, ventricular extra-systoles, atrial </li></ul><ul><li>fibrillation, postural hypotension, hypertension 3. Dyskinesias like chorea, ballismus, athetosis dystonia, myoclonus, tics, tremor. </li></ul><ul><li>4. Depression, anxiety, insomnia, somnolence, </li></ul><ul><li>delusions, hallucinations, euphoria. </li></ul><ul><li>5. On-off phenomenon ( fluctuations in clinical state). “On” means improved mobility with </li></ul><ul><li>marked dyskinesia. “Off” means marked akinesia. They alternate with each other. </li></ul>
    10. 10. <ul><li>DRUG INTERACTIONS </li></ul><ul><li>1. Pyridoxine (B6) increases extracerebral </li></ul><ul><li>metabolism of levodopa. </li></ul><ul><li>2. MAOIs with levodopa will cause hypertensive </li></ul><ul><li>crisis. </li></ul><ul><li>CLINICAL USES </li></ul><ul><li>1. Parkinsonism </li></ul><ul><li>CONTRAINDICATIONS </li></ul><ul><li>1. Psychosis </li></ul><ul><li>2. Angle closure glaucoma </li></ul><ul><li>3. Malignant melanoma </li></ul><ul><li>4. Peptic ulcer </li></ul><ul><li>5. Cardiac arrhythmias </li></ul>
    11. 11. <ul><li>DOPAMINE AGONISTS </li></ul><ul><li>1. Bromocriptine* 3. Pramipexole** </li></ul><ul><li>2. Pergolide* 4. Ropinirole** </li></ul><ul><li>This group directly stimulates dopamine receptors </li></ul><ul><li>Bromocriptine a D2 receptor agonist, is excreted in bile and feces. Pergolide stimulates both D1 & </li></ul><ul><li>D2 receptors. Pramipexole has more affinity for D3 receptors. Ropinirole is a D2 receptor agonist. </li></ul><ul><li>ADVERSE EFFECTS* </li></ul><ul><li>GIT upsets, peptic ulcer with bleeding, postural </li></ul><ul><li>hypotension, painless digital vasospasm, oedema </li></ul><ul><li>dyskinesias, hallucinations, delusions, erythro- </li></ul><ul><li>-myalgia, retroperitoneal fibrosis. </li></ul>
    12. 12. <ul><li>CONTRAINDICATIONS </li></ul><ul><li>1. Psychotic illness </li></ul><ul><li>2. Recent myocardial infarction </li></ul><ul><li>3. Active peptic ulceration </li></ul><ul><li>4. Peripheral vascular disease </li></ul><ul><li>MAOIs </li></ul><ul><li>1. Selegiline (Deprenyl) 2. Rasagiline </li></ul><ul><li>Selegiline inhibits MAO-B which metabolizes </li></ul><ul><li>dopamine, so dopamine is increased in the CNS. It has also neuroprotective effect. </li></ul><ul><li>Rasagiline is more potent than selegiline. MAOIs </li></ul><ul><li>are not used with levodopa to avoid hypertensive crisis. </li></ul>
    13. 13. <ul><li>COMT INHIBITORS </li></ul><ul><li>1. Tolcapone 2. Entacapone </li></ul><ul><li>They prolong the actions of levodopa by decreasing its peripheral metabolism. </li></ul><ul><li>ADVERSE EFFECTS </li></ul><ul><li>Dyskinesias, nausea, confusion, diarrhea, </li></ul><ul><li>abdomonal pain, orthostatic hypotension,sleep </li></ul><ul><li>disturbances, orange colored urine. </li></ul><ul><li>AMANTADINE </li></ul><ul><li>It potentiates dopaminergic function by influenc- </li></ul><ul><li>-ing the synthesis, release or reuptake of </li></ul><ul><li>dopamine. Side effects are acute toxic psychosis </li></ul><ul><li>postural hypotension, heart failure. </li></ul>
    14. 14. <ul><li>ACETYLCHOLINE BLOCKING DRUGS </li></ul><ul><li>1. Benztropine 4. Procyclidine </li></ul><ul><li>2. Biperiden 5. Trihexyphenidyl </li></ul><ul><li>3. Orphenadrine </li></ul><ul><li>They block the muscarinic receptors in the </li></ul><ul><li>striatal cholinergic fibres. They improve tremor & </li></ul><ul><li>rigidity but have little effect on bradykinesia. </li></ul><ul><li>ADVERSE EFFECTS </li></ul><ul><li>Drowsiness, confusion, dry mouth, blurred vision, </li></ul><ul><li>mydriasis, urinary retention, constipation, </li></ul><ul><li>cardiac arrhythmias. </li></ul><ul><li>CONTRAINDICATIONS: Prostate hyperplasia, </li></ul><ul><li>pyloric stenosis, paralytic ileus. </li></ul>
    15. 15. Pathophysiology of Parkinson’s Disease Increased production of free radicals (reactive oxygen species) and deficiency of antioxidant mechanisms O 2 O 2 H 2 O 2 OH • - 2H 2 O Hydroxyl radical Hydrogen peroxide Superoxide radical +e - +e - + OH - 2H + +e - +e - <ul><li>Natural Antioxidant mechanisms: </li></ul><ul><li>In mitochondria radicals are tightly bound and reduced to water </li></ul><ul><li>O 2 - dismutated by SOD to H 2 O 2 and then cleared by catalase or glutathione peroxidase </li></ul><ul><li>Free radical scavengers (vit. E, ascorbate) which can react directly with free radicals </li></ul>
    16. 16. Evidence for Free Radical Hypothesis <ul><li>Polyunsaturated fats major constituent and substrate for lipid peroxidation -> free radicals </li></ul><ul><li>Free Fe ++ level high in S. nigra –promotes radical formation </li></ul><ul><li>Fe ++ binding capacity is limited in brain </li></ul><ul><li>Brain contains almost no catalase, and low levels of glutathione, glutathione peroxidase and vit. E </li></ul><ul><li>Oxidative metabolism of dopamine potential to generate radicals </li></ul>
    17. 17. ↓ GSH Mitochondrial Damage ↑ H 2 O 2 FREE RADICALS Cell Death Mitochondrial Damage Excitotoxicity ↑ Cytosolic Ca 2+ Ca 2+ activated Degradative enzymes DA Fe 2+ ↑ Free radical Production (?PD) ↓ Free radical Defenses (?ALS)
    18. 18. &quot;On/off&quot; Effect: <ul><li>&quot;On/off&quot; Effect Is like a Light Switch ; Without Warning, All of a Sudden, Person Goes from Full Control to Complete Reversion Back to Bradykinesia, Tremor, Etc. Lasting from 30 Minutes to Several Hours and Then Get Control Again </li></ul><ul><li>&quot;On/off&quot; Effect Occurs after usually after 2 or more years on L Dopa </li></ul><ul><li>Related to Denervation Hypersensitivity </li></ul>
    19. 19. <ul><li>Treat by Giving Small Dose Regimens from 16 to 20 Hours </li></ul><ul><li>&quot;On/off&quot; Effect May Be Due to Composite of Amino Acids That Use Same Dopamine Transporter across Gastric Mucosa causing extremely low levels of L Dopa in CNS thereby causing symptoms of Parkinson Disease to reappear. </li></ul><ul><li>Changing diet (to low protein), may cause large conc of L Dopa in CNS Giving thus producing an 'off' Effect of Symptoms of Parkinson Disease </li></ul>
    20. 20. DRUG INTERACTIONS WITH L DOPA: <ul><li>Vitamin B6 - Vitamin B6 Is a Cofactor for Decarboxylation of L Dopa; Vitamin B6 Enhances Conversion of L Dopa to Dopamine in Periphery Making it less Readily for Use in the CNS </li></ul><ul><li>L Dopa Is co-administered with Carbidopa </li></ul><ul><li>Carbidopa Is Antagonistic to Peripheral L Dopa Decarboxylation Carbidopa Doesn't Cross Blood Brain Barrier </li></ul><ul><li>By co-administering Carbidopa, will decrease metabolism of L Dopa in GI Tract and Peripheral Tissues thereby increasing L Dopa conc. into CNS; meaning we can decrease L Dopa dose and also control the dose of L Dopa to a greater degree. </li></ul>
    21. 21. DRUG INTERACTIONS CONT…… <ul><li>Antipsychotic Drugs - Antipsychotic Drugs Block Dopamine Receptor </li></ul><ul><li>Reserpine -Reserpine Depletes Dopamine Storage </li></ul><ul><li>Anticholinergics - Used Synergistically with L Dopa as an Antiparkinson Agent, but Anticholinergics Act to decrease L Dopa absorption since Anticholinergics have an effect on gastric emptying time which delays crossing of GI Membrane by L Dopa </li></ul>
    22. 22. DRUG INTERACTIONS CONT……. <ul><li>Nonspecific MAO Inhibitors - Interfere with L Dopa Breakdown and exaggerate the CNS effects the Nonspecific MAO Inhibitors Can Precipitate Hypertensive Crisis by the tyramine-cheese effect (Tyramine Is Found in Cheese, Coffee, Beer, Pickles, Chocolate, and Herring), when given to a person taking a MAO Inhibitor Tyramine Is not broken down therefore producing a tremendous release of Norepinephrine) </li></ul>
    23. 23. On the Horizon <ul><li>A number of potential Parkinson's treatments in research laboratories now show much promise. They include: </li></ul><ul><ul><li>Neurotrophic proteins -- These appear to protect nerve cells from the premature death that prompts Parkinson's. One hurdle is getting the proteins past the blood-brain barrier. </li></ul></ul><ul><ul><li>Neuroprotective agents -- Researchers are examining naturally occurring enzymes that appear to deactivate &quot;free radicals,&quot; chemicals some scientists think may be linked to the damage done to nerve cells in Parkinson's and other neurological disorders. </li></ul></ul>
    24. 24. <ul><li>Classify Drug used in treatment of parkinsonism .Explain the mechanism of action & ADRs of L-dopa (2+2+2+=6 ) </li></ul><ul><li>Mention two atropine substitutes used in parkinsonism. Explain the rational of it’s use (4 marks) </li></ul><ul><li>L-dopa is not useful in treatment of drug induced parkinsonism. Why? Explain (4 marks). </li></ul><ul><li>What is the rationale of use of Carbidopa with Levodopa? (4 marks) </li></ul><ul><li>Write briefly on (4 marks each) </li></ul><ul><li>On/off phenomenon during L-dopa therapy. </li></ul><ul><li>Selegilline (Deprenyl) </li></ul><ul><li>COMT-inhibitors </li></ul><ul><li>Ropinirole & paramipexole </li></ul>
    25. 25. THANK YOU

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