drugs for parkinon’s disease parkinson's disease –progressive tremor –bradykinesia and...
TRANSCRIPT
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Drugs for Parkinon’s disease• Parkinson's disease
– progressive tremor– Bradykinesia and rigidity
– degeneration of the dopaminergic nigrostriatal pathway
– decrease in the striatal concentration of dopamine
– presence of Lewy bodies
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• Degeneration of the nigrostriatal pathway leads to the depletion of the neurotransmitter dopamine
• therapy involved the administration of its precursor levodopa or agents that mimic the action of dopamine
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Drug Therapy• Decrease cholinergic activity within
Basal Ganglia– Activating Dopamine receptors in
Substantia Nigra feeding back to Cholinergic Cells in the striatum
– Antagonize Acetylcholine receptors
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Antiparkinsonian Drugs • Symptomatic Therapy
– The traditional approach to treating patients with Parkinson's disease is the administration of drugs to alleviate symptoms.
• Anticholinergic Agents and Amantadine • Levodopa • Synthetic Dopamine Agonists
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Anticholinergic Agents
• Act by correcting the balance between dopamine and acetylcholine
• trihexyphenidyl and benztropine• Antagonists at muscarinic receptors• raise the concentration of dopamine in the
synaptic cleft
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Anticholinergic Agents
• adverse effects– impairment of memory and hallucinations– impaired ocular accommodation– dryness of the mouth– Constipation– urinary retention– vasodilatation
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Amantadine
• resembles the anticholinergic drugs• appears to enhance synthesis, release, or
reuptake of dopamine from the surviving Nigral Neurons
• often results in some improvement in rigidity and bradykinesia.
• induce ankle edema and livedo reticularis
of the legs
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Levodopa
• the cornerstone of symptomatic therapy• decarboxylated to dopamine• usually administered with a peripheral
decarboxylase inhibitor
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L Dopa- Pharmacokinetics
• L Dopa is readily absorbed from GI Tract• Large amount of L Dopa has to be given due to
First Pass Effect • L Dopa metabolized by dopa decarboxylase in
liver and periphery to dopamine• Secreted in urine unchanged or conjugated with
glucoronyl sulfate• Most of L Dopa converted to NE and EPI
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Effects of L Dopa on the Symptoms of Parkinson Disease
• L Dopa fairly effective in eliminating most of the symptoms of Parkinson Disease
• Bradykinesia and rigidity respond quickly• Reduction in tremor effect with continued
therapy• L Dopa less effective in eliminating
postural instability and shuffling gait
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Effects of L Dopa on Behavior
• L Dopa partially changes mood by elevating mood
• L Dopa increases patient sense of well being
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Effects of L Dopa on Cardiovascular System• cardiac stimulation due to beta adrenergic
effect on heart• Elderly- transient tachycardia, cardiac
arrhythmias and hypertension
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Effects of L Dopa on Gastrointestinal System
• Nausea, Vomiting, and Anorexia• Abdominal Pain• Diarrhea and Constipation• May cause activation of Peptic Ulcer
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Synthetic Dopamine Agonists
• mimic the effect of dopamine by binding directly with the post-synaptic dopamine receptors
• Bromocriptine, pergolide and lisuride• tetracyclic ergot derivatives• longer plasma half-lives
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Synthetic Dopamine Agonists
• The nonergot dopamine agonists ropinirole and pramipexole
• higher doses, they produce similar side effects
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Protective Therapy • treat the underlying pathogenesis of
Parkinson's disease so that neurodegeneration is prevented or delayed
• Possible mechanisms of cell damage :– Autoimmunity– excessive excitatory drive– disturbance of trophic factors– increase in the concentration of toxic free
radicals
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Protective Therapy
• vitamins• co-enzyme Q10• dopamine agonists• monoamine oxidase type B (MAOB)
inhibitors.
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Management of Different Stages of Disease
• Newly Diagnosed Parkinson's Disease – Hoehn-Yahr stage I– the patient has minor symptoms that are not
sufficiently troublesome to affect routine daily activities
– selegiline, levodopa, or a synthetic dopamine agonist or no pharmacotherapy
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• National Collaborating Centre for Chronic Conditions. Parkinson’s disease: national clinical guideline for diagnosis and management in primary and secondary care. London: Royal College of Physicians, 2006.
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Levodopa
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Dopamine Agonist
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Monoamine oxidase type B(MAOB) inhibitors
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ono
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Beta Adrenergic agents
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Amantadine
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Anticholinergics
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Severe Parkinson's Disease
• Management is directed toward decreasing the dose of the drug causing the most troublesome side effects and raising the dose of an alternative drug
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Levodopa
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Dopamine agonist
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MOAB inhibitors
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COMT
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Amantadine
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Management of Adverse Reactions to Therapy
• nausea and hypotension– associated with peak plasma concentrations
of dopaminomimetic agent– minimized by taking the medications after light
meals or snacks.– Domperidone 10 to 20 mg
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Management of Adverse Reactions to Therapy
• Hypotension– increased intake of water and salt– fludrocortisone 0.1 mg once or bid– midodrine 2.5 to 20 mg
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Management of Adverse Reactions to Therapy• Dyskinesia, fluctuations in mobility
– unpredictable "on-off" reactions– predictable "wearing-off" effects– Avoid high protein meals
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Management of Adverse Reactions to Therapy• Psychiatric side effects
– confusion, visual hallucinations, and paranoia– begin as nocturnal phenomena– Neuroleptic drugs in general are
contraindicated
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Thank you
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Calne D. N Engl J Med 1993;329:1021-1027
Structure of the Dopamine D2A Receptor
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Calne D. N Engl J Med 1993;329:1021-1027
Dopamine D1A Receptor Coupled to a G Protein and Linked to Adenylate Cyclase in a Striatal Neuron
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Calne D. N Engl J Med 1993;329:1021-1027
Dopamine D1A Receptor Coupled to a G Protein and Linked to Adenylate Cyclase in a Striatal Neuron
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Agents that Increase Dopamine functions• Increasing the synthesis of dopamine - l-Dopa• Inhibiting the catabolism of dopamine -
selegiline• Stimulating the dopamine receptor sites
directly - bromocriptine & pramipexole• Blocking the uptake and enhancing the release
of dopamine - amantadine