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Parkinsons Disease Resting tremor, bradykinesia, rigidity. Loss

of postural reflexes. Death due to

complications of immobility. Degeneration of dopaminergic neurons of

the nigro-striatal pathway. Decrease indopamine content of the

Imbalance between dopaminergic andcholinergic innervation in the striatum.

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Pathophysiology of Parkinsons Disease

Increased production of free radicals (reactive oxygen species)

and deficiency of antioxidant mechanisms

O2 O2 H2O2 OH- 2H2OHydroxyl

radical

Hydrogen

peroxide

Superoxide

radical

+e- +e-

+ OH-2H+

+e- +e-

Natural Antioxidant mechanisms:

1. In mitochondria radicals are tightly bound and reduced towater

2. O2- dismutated by SOD to H2O2 and then cleared by catalase

or glutathione peroxidase

3. Free radical scavengers (vit. E, ascorbate) which can react

directly with free radicals

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Evidence for Free Radical Hypothesis

Polyunsaturated fats major constituent andsubstrate for lipid peroxidation free radicals

Free Fe++ level high in S. nigra promotes radicalformation

Fe++binding capacity is limited in brain

Brain contains almost no catalase, and low levels

of glutathione, glutathione peroxidase and vit. E Oxidative metabolism of dopamine potential to

generate radicals

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Dopamine Metabolism

DA +O2 + H2O 3,4 dihydroxyphenyl acetaldehyde + NH3 + H2O2MAO

Enzymatic Oxidation of Dopamine

Auto-oxidation of Dopamine

DA + O2 SQ + O2- + H+

DA + O2- + 2H+ SQ + H2O2

Clearance of Peroxide

2 GSH + H2O2 GSSG + 2 H2OGPO

Fenton Reaction

H2

O2

+ Fe2+ OH + OH- + Fe3+

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GSH

Mitochondrial

Damage H2O2

FREE RADICALS

Cell

Death

Mitochondrial

Damage

Excitotoxicity Cytosolic Ca2+

Ca2+ activated

Degradative enzymes

DAFe2+

Free radical

Production (?PD)

Free radicalDefenses (?ALS)

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ATP Ca2+

ATPATP

Na+

Normal Conditions Energy Failure

Glutamate

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Treatment of Parkinsons Disease Levodopa: Dopamine precursor

Levodopa + Carbidopa (Sinemet)

Selegiline: MAO-B selective inhibitor Amantadine: Dopamine release (also antiviral)

Dopamine receptor agonists: bromocriptine,pergolide, lisuride

Tolcapone: COMT Inhibitor

Trihexphenidyl: anticholinergic

Surgery: fetal transplants.

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L-Dopa

Selegiline

Carbidopa

Tolcapone

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Adverse effects of L-Dopa Nausea and vomiting

Tachycardia, increased contractility,

arrhythmias

Orthostatic hypotension

Dyskinesias

Behavioral disturbances (hallucinations,paranoia, mania, insomnia, anxiety,nightmares)

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Late Complications of L-Dopa Wearing Off and On-Off Phenomena

Pharmacokinetic explanation

Pharmacodynamic explanation

Strategies to manage:

Infusion, sustained release, or multiple short

interval doses of L-Dopa Add selegiline to prevent metabolism

Use receptor agonists

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Other DrugsSelegiline

Blocks MAO-B (found in CNS) not MAO-A also found in

periphery Provides symptomatic benefit and/or slows progression of

the disease.

Of limited value in advanced disease

Trihexphenidyl

Additive effect to others at any stage of the disease

All symptoms relieved but less effective than L-Dopa

Anticholinergic side effects

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Dopamine receptor agonists Especially useful in advanced stages of PD

Bromocriptine: D1, Pergolide: D1 & D2 agonists

In general less effective than L-Dopa Same pattern of adverse effects as L-Dopa. First

dose phenomenon: sudden cardiovascular collapse

Bromocriptine: Inflammatory pleuropulmonary

reactions and fibrosis Bromocriptine also used in the treatment of

hyperprolactinemia and acromegaly

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Drugs for Spasticity Baclofen: derivative of GABA activates GABA-B

receptors. Acts in spinal cord at presynaptic terminals toinhibit motoneuron firing by decreasing release of

excitatory neurotransmitter. Mechanism: hyperpolarization by K+ conductance and

inhibition of Ca++ channels.

Drowsiness, insomnia, ataxia, confusion. In overdose:

coma, respiratory depression and seizures. Benzodiazepines.

Dantrolene: acts on muscle. Generalized muscle weakness.

Others: Clonidine, botulinum toxin.

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Baclofen interferes

with release of

excitatory transmitters

EPSP

IPSP

Diazepam facilitates

GABA-mediated

presynaptic inhibitionInterneuron