Parkinson's Disease

Excitotoxicity
1. Calcium OVERLOAD
  1. Neuronal Death: Associated with Ca++ overload of cells and membrane damage
  2. Glutamate activates: - NMDA. - AMPA, - Metabotropic receptors
Epidemology
1. More Males are affected
2. Age of onset >50 years old
Possible Trigger Factors
1. Toxins
  1. (MPTP) •Contaminant in heroin substitute led to "frozen addict‟ syndrome •induces parkinsonism – similar to some herbicides
2. Infection
  1. Encephalitis lethargica
3. Genetic
  1. Not usually familial
4. Enviromental
  1. Dopamine oxidation
  2. MPTP
  3. Rotenone (herbicide)
Dopamine (DA) pathways
1. Due to: •Dopaminergic depletion in basal ganglia (nigro-striatal pathway) •Leading to a relative excess of acetylcholine in striatum
2. Nigrostraital – motor
  1. Lack of DA or inhibition of dopaminergic neurones may lead to parkinsonism
    1. Inhibits release of acetylcholine (ACh) from striatum
3. Mesolimbic & mesocortical – thought
  1. Excessive DA or overactive dopaminergic neurones may lead to psychosis
4. Tuberohypophyseal – hypothalamus/pituitary
  1. Prolactin release from pituitary gland - inhibited by dopamine
5. Chemoreceptor trigger zone - vomiting reflex
  1. Dopaminergic stimulation leads to vomiting
6. Metabolism of dopamine
  1. Dopamine eventually metabolised to Homovanillic acid
  2. Metabolic Pathways
    1. Catechol-o-methyltransferase
    2. Monoamine oxidase
    3. Aldehyde dehydrogenase
Symptoms
1. TREMOR
  1. Rigidity
    1. COGWHEEL
  2. Bradykinesia
    1. Akinesia
  3. 'Pill rolling'
2. Gait & Posture
  1. Shuffling
  2. Stooping
3. Speech
  1. Montone
Early Stages: Levodopa, Dopamine Agonists, MAO-B-I
1. Treatment
  1. Dopamine Precursors
    1. Levodopa
      1. Short Half-Life = 2 hours
      2. May enhance DA in Limbic System
      3. S.E. N+V, Cardiovascular - Hypotension
        Treat with Domperidone, does NOT cross BBB
        Psychological effects – delusions and hallucinations, but more commonly (20%) confusion, disorientation, insomnia or nightmares. Daytime drowsiness
        Dyskinesia
        Within 2 years of taking L-Dopa
        Involuntary writhing movements
        Motor Fluctuations ('On-off' effect)
      4. Dopa-decarboxylase inhibitor can be added
      5. Increases: Life expectancy. Improves: motor function, quality of life.
        Some symptoms not improved – e.g. dysphagia, cognitive decline
    2. MOA: Precursor of DA
  2. Dopa Decarboxylase Inhibitors
    1. Benserazide
      1. Can be combined with L-Dopa to make Co-beneldopa (Madopar)
    2. Carbidopa
      1. Can be combined with L-Dopa to make Co-Careldopa (Sinemet)
        Intestinal Gel - Duodopa, for late stage PD
        Directly into Duodenum
        Requires electronic pump device
        Dose
        The total morning dose is usually 5-10 ml, corresponding to 100-200 mg levodopa. (should not exceed 15 ml (300 mg levodopa)
    3. MOA: Inhibit the breakdown of L-Dopa to DA
  3. Monoamine Oxidase B Inhibitors
    1. DRUGS
      1. Selegilene
        Better with Levodopa than alone
      2. Rasagilene
        Neuroprotective properties
    2. Protect DA from intraneuronal breakdown
  4. Catechol-O-Methyltransferase Inhibitors
    1. DRUGS
      1. Entacapone
        Combo: Levodopa, Carbidopa & Entacopone - STALEVO
      2. Tolcapone
    2. MOA: Inhibits breakdown of peripheral l-dopa by COMT to increase levodopa level and enhance effect. May be able to reduce levodopa dose by 10-30%
  5. Amantadine
    1. MOA: Increase DA release inhibit amine uptake, direct action on DA receptors
    2. Limited by SE & worsening on withdrawal
    3. Anti-viral drug
  6. Dopamine Receptor Agonists
    1. Ergot-Derived (Fibrotic Reactions)
      1. Drugs
        Bromocriptine
        Cabergoline
        Lisuride
        Pergolide
      2. Increase risk of pulmonary, retroperitoneal and cardiac fibrosis
    2. Non-Ergot Derived
      1. Pramipexole
      2. Ropinirole
      3. Apomorphine
        D1 & D2 Agonist
        SC or Infusion
        Initiation - Hospital
        Discharge: Monitor, adjust dose
        Side Effects
        Nausea, vomiting, drowsiness, hallucinations, injection site nodules, < commonly postural hypotension, breathing difficulties, dyskinesias, anaemia
        Expensive
    3. Increase sleepiness
    4. Side Effects
      1. Nausea/vomiting
      2. Postural hypotension
      3. Hallucinations
      4. Confusion
      5. Dyskinesias
      6. Reckless Behaviour /Gambling
  7. Antimuscarinic Drugs
    1. DRUGS
      1. Procyclidine
      2. Orphenadrine
      3. Artane
      4. Benzatropine
    2. Ach: excitatory effect on striatal neurones. Also exerts presynaptic inhibitory effect on dopaminergic nerve terminals
    3. Treat tremor effectively
    4. SIDE EFFECTS
      1. dry mouth, urinary retention, visual disturbances, constipation - euphoria, drowsiness, confusion, hallucinations, cognitive impairment
2. Later Stages: Dopamine Agonists, COMT-I, MAO-B-I
  1. 2nd Choice: Amantadine, Apomorphine
    1. All must be used as adjunctive therapy

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Parkinson's Disease

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	Created by Affy MD about 11 years ago