JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD Pharm. D IV Year PHARMACOTHERAPEUTICS - III Previous Question Paper (December - 2022 - R08)

Parkinson's disease is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. This leads to a severe depletion of dopamine in the striatum, causing an imbalance between excitatory cholinergic and inhibitory dopaminergic pathways in the basal ganglia, which disrupts motor control.

Clinical features are categorized into cardinal motor symptoms: resting tremor, bradykinesia (slowness of movement), rigidity (cogwheel or lead-pipe), and postural instability. Non-motor symptoms include depression, sleep disturbances, cognitive impairment, and autonomic dysfunction.

The treatment strategy focuses on symptomatic relief by restoring dopaminergic neurotransmission and managing non-motor symptoms:

• Levodopa/Carbidopa: The gold standard therapy; Levodopa crosses the blood-brain barrier and is converted to dopamine, while Carbidopa prevents peripheral metabolism.
• Dopamine Agonists: Agents like Pramipexole or Ropinirole directly stimulate dopamine receptors.
• MAO-B Inhibitors: Selegiline or Rasagiline inhibit the breakdown of dopamine in the brain.
• COMT Inhibitors: Entacapone extends the half-life of Levodopa by inhibiting peripheral dopamine degradation.
• Anticholinergics: Trihexyphenidyl is used primarily for tremor management in younger patients.

Drug discovery for Alzheimer's disease faces significant hurdles due to the following factors:

• Blood-Brain Barrier (BBB): Many potential therapeutic agents are unable to cross the BBB in sufficient concentrations to reach the target sites in the brain.
• Complex Pathophysiology: The disease involves multifactorial processes, including amyloid-beta plaque deposition, tau protein neurofibrillary tangles, neuroinflammation, and oxidative stress, making it difficult to identify a single effective drug target.
• Late Diagnosis: By the time clinical symptoms appear, significant irreversible neuronal loss has already occurred, limiting the efficacy of neuroprotective interventions.
• Heterogeneity: High variability in disease progression and genetic factors among patients makes clinical trial design and patient stratification extremely challenging.