Pharmacology  ·  Antiparkinson Drugs

Pathophysiology and Treatment Rationale

Parkinson's disease: what is lost and how drugs compensate

• Parkinson's disease results from progressive loss of dopaminergic neurons in the substantia nigra pars compacta — 70 to 80 percent of these neurons are gone before motor symptoms appear, underscoring the brain's substantial compensatory reserve.
• The core problem is a striatal neurotransmitter imbalance: dopamine input is severely reduced while striatal cholinergic interneurons remain intact, producing unopposed acetylcholine activity that drives tremor and rigidity.
• The four cardinal motor features are captured by TRAP: Tremor (resting, pill-rolling, 4–6 Hz), Rigidity (cogwheel or leadpipe), Akinesia/bradykinesia (slowest and most disabling), and Postural instability (appears late, responds poorly to drugs).
• Pharmacological strategies fall into four categories: increase striatal dopamine (levodopa/carbidopa, dopamine agonists), prolong dopamine action (MAO-B and COMT inhibitors), and reduce cholinergic excess (anticholinergic drugs for tremor).
• Akinesia responds best to dopaminergic therapy while tremor responds best to anticholinergic agents; postural instability responds poorly to any available drug.