Chapter 18  ·  Module 1
Pathophysiology and Treatment Rationale
Parkinson's disease: what is lost and how drugs compensate
Nigrostriatal Pathway Degeneration
Normal
Healthy Nigrostriatal Pathway
  • Substantia nigra pars compacta produces dopamine
  • Dopamine neurons project to the striatum
  • Striatal dopamine facilitates smooth motor control
  • Dopamine and acetylcholine are in balance
Parkinson's Disease
Nigrostriatal Degeneration
  • 70 to 80% of substantia nigra pars compacta neurons lost before symptoms appear
  • Dopamine input to striatum severely reduced
  • Lewy bodies (alpha-synuclein) in surviving neurons
  • Relative cholinergic excess in striatum
Striatal Neurotransmitter Imbalance
Dopamine
Severely Reduced
Loss of nigrostriatal input leaves striatum without dopaminergic modulation
vs.
Acetylcholine
Relatively Excess
Striatal interneurons unchanged — unopposed cholinergic activity drives tremor and rigidity
Cardinal Motor Features — TRAP
T
Tremor
  • Resting, pill-rolling
  • Suppressed by movement
  • 4 to 6 Hz
R
Rigidity
  • Cogwheel or leadpipe
  • Passive resistance throughout range
A
Akinesia
  • Slowness of movement
  • Most disabling feature
  • Best levodopa response
P
Postural Instability
  • Lost postural reflexes
  • Appears late in disease
  • Poor drug response
Pharmacological Strategies
Increase dopamine
Levodopa and carbidopa
Dopamine precursor — crosses blood-brain barrier
Increase dopamine
Dopamine agonists
Pramipexole, ropinirole — direct receptor activation
Extend dopamine effect
Enzyme inhibitors
Monoamine oxidase B and catechol-O-methyltransferase inhibitors
Reduce acetylcholine
Anticholinergic drugs
Benztropine, trihexyphenidyl — best for tremor