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Parkinson's Disease


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[Front]


What is a progressive neurodegenerative disorder?
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Parkinson's Disease

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Parkinson's Disease - Details

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What is Parkinson's diseases caused by?
By degeneration of substantia nigra in the midbrain, with irreversible loss of DA-containing neurons in the nigrostrial pathway.
What part does dopamine play in the prevention of Parkinson's disease?
Dopamine reduces resting tremor by potentiating inhibitory mechanisms in a cerebellar nucleus of the thalamus ( ventral intermediate nucleus)
The symptoms of Parkinson's disease result from what?
Loss of nigrostrial neurons and DA depletion. ACh predominates
What are the secondary manifestations of Parkinson's disease?
Defective posture and gait, mask-like face and sialorrhoea, dementia ( in some cases)
What is the etiology of Parkinson's disease?
1) Genetics: 2) Environmental Factors 3) Toxins 4) Drugs
What is alpha-synuclein?
Deposited in dopaminergic neurons of substantia nigra with loss of pigmentation leading to the formation of Lewy bodies ( the pathological hallmark of PD) and dopaminergic cell death
What is Lewy neurite?
Swollen nerve fibers that contain alpha-synuclein and other proteins which interfere with transmission of nerve signals and neuronal functions.
Does dopamine pass the blood-brain barrier?
NO. Dopamine must be produced within the CNS in order to act in the striatum
What is the final inactive metabolite of dopamine?
Homovanillic acid by either MAO or COMT
What are the clinical manifestations of Parkinson's disease?
Tremor- "Resting tremor Rigidity Bradykinesia
What are the five dopamine receptor subtypes?
D1, D2 ( found in corpus striatum) D3, D4, and D5
What is the function of D1 and D5?
Activates adenlyl cylcase to produce cAMP
What is the function of D2, D3 and D4?
Inhibits adenlyl cyclase to produce less cAMP
Where is dopamine produced?
Cells in the PARS COMPACTA of the SUBSTANTIA NIGRA.
What are the two pathways through which striatal information reaches Globus Pallidum Internal?
Direct Pathway ( excitatory) and Indirect Pathway ( inhibitory)
What are the objectives of antiparkinsonian pharmacotherapy?
1) Enhance DA-ergic activity 2) Reduce cholinergic activity
What are examples of DA agonists?
Bromocriptine and cabergoline
What is LEVODOPA?
Natural AA precursor of DA Crosses the BBB via L-amino acid transporter effective in treating symptoms of rigidity and bradykinesia seen in PD 1-3% only oral dose reaches the brain
What are the adverse effects of L-DOPA?
Nausea, Vomiting; nearly 80% patients Postural Hypotension Cardiac Arrhythmias Anxiety, Agitation, Hallucinations/ mood changes
What is the main adverse central adverse reaction of L-dopa?
Athetosis: a condition where the patient experience slow, convulated, involuntary and writhing movements of the hands, fingers, feet and toes
What is the wearing- off phenomenon?
Increasingly shortened benefit period following each dose of l-dopa due to l-dopa's short half life.
What is L-Dopa Honeymoon?
Early phase of treatment (lasts 5-6 years typically)
What is On-Off Fluctuations?
Characterized by sudden, unpredictable shifts of mobility between undertreated and treated states- sudden, unpredictable and very difficult to treat.
What are examples of dopamine agonists?
Ropinirole,pramipexole,rotigotine
What are L-Dopa Interactions?
Avoid high protein meals; AA's compete with L-dopa for entry to the brain. Take on empty stomach or reduce dietary protein. Vitamin B6: metabolizes L-dopa Hypertensive crisis if MAOIs are given concomitantly L-dopa should not be prescribed to treat the extrapyramidal effects of antipsychotics since l-dopa enhances dopamine and its interaction with D2 receptors in the mesolimbic and mesocortical pathways. Antipsychotics block these receptors and their efficacy could be compromised
What dopamine agonists are ergot-derivatives?
Bromocriptine and Carbergoline
What dopamine agonists are non-ergot-derivatives?
Pramipexole and Ropinirole and Apomorphine
What is the difference between dopamine agonists and l-dopa?
1) They act directly at dopamine receptors, therefore, it does not need metabolic conversion to an active moiety as in the case of L-DOPA 2) They do not undergo oxidation and thus avoid the generation of free radicals that may contribute to neuronal degeneration 3) Their longer half-life causes fewer motor complications as they provide continuous stimulation of striatal dopamine receptors and reduce frequency of dosing required to maintain adequate drug levels 4)DAs do not require carrier-mediated transport for GI absorption or entry into the BBB; thus dietary restrictions are not required 5) DAs usage is associated with more hallucinations, somnolence, and edema than with levodopa therapy.
What is Bromocriptine?
D2- receptor agonist, but weak alpha-adrenoceptor anatagonist. Commonly used with l-dopa started at low doses at night, titrating up according to clinical response
What is Bromocriptine also used for?
Prolactin-secreting adenomas,amenorrhea/galactorrhea to hyperprolactinemia, to stop lactation, acromegaly
What are the adverse reactions of bromocriptine?
Nausea, vomitting which may be prevented by domperidone, postural hypotension
What is cabergoline
Better than bromocriptine Longer half life. Used once or twice a week Alleviates night -time problems in PD due to lack of l-dopa
What is pramipexole?
Non-ergot D2 and D3 receptor agonist more effective against tremors Allows dose of LD to be reduced and smoothens out fluctuations
What is ropinirole?
New non-ergot direct D2 receptor agonist metabolized by CyP450 so clearance may be reduced if used with simultaneous metabolisers
What are the adverse effects of dopamine agonists?
Drowsiness, nausea, vomiting, dry mouth, dizziness, leg swelling, orthostatic hypotension. sleepiness compulsive behaviors- shopping, binge eating, gambling, sexual activities
What is apomorphine?
Used in emergency cases "rescue" medication
What is amantadine?
Antiviral agent used for influenzea
What are central antimuscarinic drugs?
Shows modest improvement in tremor, rigidity and sialorrhea and muscular stiffness