; anti-parkinsonian
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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
      +e-                +e-            +e-                     +e-
                  -                                         -
O2             O2                H2O2           OH• + OH               2H2O
            Superoxide         Hydrogen       Hydroxyl
              radical          peroxide        radical

      Natural Antioxidant mechanisms:
      1. In mitochondria radicals are tightly bound and reduced to
      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
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
• 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
                 Dopamine Metabolism
Enzymatic Oxidation of Dopamine
DA +O2 + H2O            3,4 dihydroxyphenyl acetaldehyde + NH3 + H2O2
Auto-oxidation of Dopamine
     DA + O2           SQ• + O2- + H+
DA + O2- + 2H+         SQ• + H2O2

Clearance of Peroxide
   2 GSH + H2O2               GSSG + 2 H2O
Fenton Reaction
  H2O2 + Fe2+                 OH• + OH- + Fe3+

         Mitochondrial                                    Fe2+
                                             ↑ H2O2              DA

↓ Free radical          FREE RADICALS                     ↑ Free radical
Defenses (?ALS)                                           Production (?PD)

                               Cell           Ca2+ activated
         Mitochondrial         Death
           Damage                             Degradative enzymes

                  Excitotoxicity       ↑ Cytosolic Ca2+

           ATP      Ca2+

           ↑ATP     ↓ATP

Normal Conditions        Energy Failure
Treatment of Parkinson’s 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.
   L-Dopa   Carbidopa

Tolcapone               Selegiline
    Adverse effects of L-Dopa
• Nausea and vomiting
• Tachycardia, increased contractility,
• Orthostatic hypotension
• Dyskinesias
• Behavioral disturbances (hallucinations,
  paranoia, mania, insomnia, anxiety,
    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
                   Other Drugs
• Blocks MAO-B (found in CNS) not MAO-A also found in
• Provides symptomatic benefit and/or slows progression of
  the disease.
• Of limited value in advanced disease
• 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
  dose phenomenon: sudden cardiovascular collapse
• Bromocriptine: Inflammatory pleuropulmonary
  reactions and fibrosis
• Bromocriptine also used in the treatment of
  hyperprolactinemia and acromegaly
            Drugs for Spasticity
• Baclofen: derivative of GABA activates GABA-B
  receptors. Acts in spinal cord at presynaptic terminals to
  inhibit 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.
    Baclofen interferes
      with release of
  excitatory transmitters

                             Diazepam facilitates
                             presynaptic inhibition



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