Pharmacology of Drugs for Parkinson’s Disease

Jul 13, 2024

Pharmacology of Drugs for Parkinson’s Disease

Overview of Parkinson’s Disease

  • Neurological disorder causing progressive loss of coordination/movement
  • Affects neurons in the striatum
  • Striatum receives information from the neocortex and substantia nigra
    • Cortex: relays sensory info and plans future actions
    • Substantia nigra: sends dopamine to coordinate inputs
  • Parkinson's results from degeneration of neurons connecting the substantia nigra to the striatum
    • Leads to reduced dopamine
    • Causes increased GABA and acetylcholine levels
    • Results in symptoms: resting tremor, rigidity, postural instability, slowed movement

Dopamine Synthesis and Degradation

  • Dopamine production pathway:
    1. Tyrosine converted to L-dopa/levodopa by tyrosine hydroxylase (TH)
    2. L-dopa converted to dopamine by aromatic L-amino acid decarboxylase (AADC)
  • Dopamine stored in synaptic vesicles and released upon stimulation
  • Excess dopamine metabolized by:
    • Monoamine Oxidase (MAO)
    • Catechol-O-methyltransferase (COMT)
    • MAO exists in types A and B; type B found in glial cells

Classes of Drugs for Parkinson’s Disease

Levodopa

  • Precursor to dopamine used due to blood-brain barrier limitations
  • Administered with Carbidopa (inhibits peripheral DDC)
  • Often combined with Entacapone (inhibits COMT)
  • Levodopa transport: crosses blood-brain barrier via amino acid transporter

Enzyme Inhibitors

  • Selegiline, Rasagiline: Inhibit MAO-B
  • Tolcapone: Inhibits COMT, penetrates BBB better than Entacapone

Dopamine Agonists

  • Mimic dopamine and stimulate receptors
  • Examples: Bromocriptine, Ropinirole, Pramipexole, Rotigotine, Apomorphine

Antimuscarinic Agents

  • Block muscarinic acetylcholine receptors to reduce tremors/rigidity
  • Examples: Benztropine, Biperiden, Procyclidine, Trihexyphenidyl

Amantadine

  • Mechanism isn't fully understood
  • Speculated actions: prevents dopamine reuptake, facilitates presynaptic release, blocks NMDA receptors

Side Effects

  • Levodopa + Carbidopa: Nausea, loss of appetite, hypotension, mental disturbances, discoloration of urine/sweat/saliva
  • Selegiline, Rasagiline: Nausea, insomnia, dyskinesia, visual hallucinations
  • Entacapone, Tolcapone: Discoloration of urine/sweat/saliva, diarrhea, liver toxicity (Tolcapone)
  • Dopamine Agonists: Nausea, orthostatic hypotension, mental disturbances, daytime sleepiness, pulmonary/cardiac fibrosis (Bromocriptine)
  • Antimuscarinics: Constipation, urinary retention, dry mouth, blurred vision