Parkinson’s 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 in dopamine content of the • Imbalance between dopaminergic and cholinergic innervation in the striatum.
Parkinson’s 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 in dopamine content of the •Imbalance between dopaminergic and cholinergic innervation in the striatum.
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Parkinson’s 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 in dopamine content of the
• Imbalance between dopaminergic and cholinergic innervation in the striatum.
Pathophysiology of Parkinson’s Disease
Increased production of free radicals (reactive oxygen species) and deficiency of antioxidant mechanisms
O2 O2 H2O2 OH•- 2H2OHydroxyl radical
Hydrogenperoxide
Superoxideradical
+e- +e-
+OH -2H+
+e- +e-
Natural Antioxidant mechanisms:1. In mitochondria radicals are tightly bound and reduced to
water2. 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
Evidence for Free Radical Hypothesis
• Polyunsaturated fats major constituent and substrate for lipid peroxidation → free radicals
• Free Fe++ level high in S. nigra –promotes radical formation
• 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
• 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
Other Drugs
Selegiline• 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
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