Antiparkinsonian Drugs

Parkinson's Pathophys & Levodopa - Brain Balancers

• Pathophysiology: Dopamine (DA) depletion in nigrostriatal pathway (substantia nigra pars compacta → striatum); Lewy bodies. Imbalance: ↓DA, relative ↑Acetylcholine (ACh).
• Levodopa (L-DOPA):
  • MOA: Metabolic precursor of DA; crosses Blood-Brain Barrier (BBB); converted to DA by DOPA decarboxylase in brain. Most effective drug.
• Carbidopa/Benserazide:
  • MOA: Peripheral DOPA decarboxylase inhibitors.
  • Benefits: ↓ L-DOPA dose required, ↓ peripheral side effects (Nausea/Vomiting, arrhythmias), ↑ L-DOPA reaching brain.
• L-DOPA Adverse Effects:
  • Peripheral: Nausea/Vomiting, postural hypotension, cardiac arrhythmias.
  • Central: Dyskinesias (chorea, dystonia), psychosis (hallucinations), 'on-off' phenomenon (📌 like a faulty switch), 'wearing-off' phenomenon.
• Interactions:
  • Pyridoxine (Vitamin B6): Enhances peripheral L-DOPA metabolism (if L-DOPA given alone), ↓ efficacy.
  • Non-selective MAOIs: Risk of hypertensive crisis.

⭐ The 'on-off' phenomenon, characterized by unpredictable fluctuations between mobility and immobility, is a significant challenge in long-term Levodopa therapy.

Dopamine Agonists - Dopamine's Deputies

• MOA: Directly stimulate DA receptors in striatum.
• Types & Key Drugs:

  Category	Examples	Key Features
  Non-Ergot	Pramipexole (D2/D3), Ropinirole (D2), Rotigotine (D1-3 patch), Apomorphine (D1/D2 SC rescue)	Preferred; lower fibrosis risk
  Ergot	Bromocriptine (D2)	Less used; ⚠️ risk of fibrosis (cardiac, pulmonary)

• Pros vs. Levodopa: Longer action; potentially ↓ motor fluctuations/dyskinesias (early).
• Cons: Less potent (motor); ↑ somnolence (sleep attacks), hallucinations, edema, 📌 impulse control disorders.
• Use: Early PD monotherapy (<65-70 yrs); adjunct in advanced PD (↓ 'off' time, ↓ L-DOPA dose).

⭐ Impulse control disorders (e.g., pathological gambling, compulsive shopping, hypersexuality) are a distinctive and serious adverse effect class associated with dopamine agonists.

Enzyme Inhibitors & Amantadine - Helper Crew Drugs

• MAO-B Inhibitors (Selegiline, Rasagiline, Safinamide):
  • MOA: Inhibit MAO-B → ↑brain DA. Safinamide: also ↓glutamate.
  • Use: Early PD; adjunct to L-DOPA (↓'wearing-off').
  • SE: Nausea, insomnia (Selegiline). Serotonin syndrome risk (SSRIs/TCAs). Rare tyramine reaction.
• COMT Inhibitors (Entacapone, Tolcapone, Opicapone):
  • MOA: Inhibit COMT → ↓L-DOPA metabolism (Entacapone/Opicapone: peripheral; Tolcapone: P+C) → ↑L-DOPA bioavailability & t½.
  • Use: With L-DOPA for 'wearing-off'.
  • SE: Dyskinesias (↑L-DOPA), N/D. Brownish-orange urine (Entacapone).

  ⭐ Tolcapone, a COMT inhibitor, carries a significant risk of hepatotoxicity, necessitating regular liver function monitoring, unlike Entacapone.

• Amantadine:
  • MOA: ↑DA release, ↓DA reuptake, NMDA antagonist, anticholinergic.
  • Use: Mild early PD; L-DOPA-induced dyskinesia.
  • SE: Livedo reticularis, ankle edema, confusion.

Anticholinergics & Management - Tremor Tamers & Tactics

• Anticholinergics (Central Muscarinic Receptor Antagonists)
  • MOA: Block striatal muscarinic receptors; restore Dopamine/Acetylcholine balance. ↓ tremor, rigidity.
  • Examples: Trihexyphenidyl, Benztropine, Procyclidine, Biperiden.
  • Use: Younger patients (<65-70 yrs) with predominant tremor. Drug-induced parkinsonism (not tardive dyskinesia).
  • Side Effects: Dry mouth, blurred vision, constipation, urinary retention, tachycardia, confusion (elderly). 📌 Mnemonic: 'Can't see, can't pee, can't spit, can't shit'.
  • Contraindications: Narrow-angle glaucoma, prostatic hyperplasia, paralytic ileus.

⭐ Central anticholinergics are particularly effective against tremor in Parkinson's disease but are poorly tolerated in elderly patients due to cognitive side effects and other peripheral anticholinergic effects.

• Overall Management Strategy
  • Initial: MAO-B inh, Amantadine, DA agonist, Levodopa (age, symptoms, preference).
  • Motor Complications ('wearing-off', 'on-off', dyskinesias): Adjust L-DOPA; add COMT/MAO-B inh, DA agonist; Amantadine (dyskinesia); Apomorphine rescue.
  • Refractory: Deep Brain Stimulation (DBS).

High‑Yield Points - ⚡ Biggest Takeaways

• Levodopa: Most effective drug, but efficacy wanes with motor fluctuations ("on-off" phenomenon).
• Carbidopa/Benserazide: Peripheral decarboxylase inhibitors; ↓ Levodopa's side effects, ↑ brain availability.
• Dopamine Agonists (e.g., Pramipexole, Ropinirole): Monotherapy in early PD or adjuncts to Levodopa.
• MAO-B Inhibitors (e.g., Selegiline, Rasagiline): Prevent dopamine breakdown; mild symptomatic relief.
• COMT Inhibitors (e.g., Entacapone): Prolong Levodopa's action; Tolcapone: hepatotoxicity risk.
• Amantadine: Useful for Levodopa-induced dyskinesia; modest antiparkinsonian effects.
• Anticholinergics (e.g., Trihexyphenidyl): Best for tremor and rigidity; less for bradykinesia.