Drugs of Parkinson's Disease

DRUG CLASSES AT A GLANCE

1. LEVODOPA (+ Carbidopa)

• Mechanism: Dopamine itself cannot cross the blood-brain barrier. Levodopa (L-DOPA), its precursor, crosses via the L-amino acid transporter (LAT) and is decarboxylated to dopamine in the brain.
• Why combine with carbidopa? Carbidopa is a peripheral DOPA decarboxylase inhibitor that cannot cross the blood-brain barrier. It prevents peripheral conversion of levodopa to dopamine, thereby:
  • Reducing peripheral side effects (nausea, vomiting, hypotension)
  • Increasing the fraction of levodopa reaching the brain
  • Allowing a 75% dose reduction of levodopa
• Brand names: Sinemet (carbidopa/levodopa), Rytary (extended-release)

Adverse Effects of Levodopa

Motor Complications

• Wearing-off (end-of-dose akinesia): Benefit duration shortens; symptoms worsen before next dose
• On-off phenomenon: Unpredictable, abrupt swings between mobility ("on") and immobility ("off")
• Management of fluctuations: Increase dose frequency, use controlled-release preparations, add COMT inhibitor, add MAO-B inhibitor, or consider continuous intestinal gel infusion

Key point: Levodopa does not alter disease progression, but it is the most effective symptomatic treatment even after 20+ years. - Goldman-Cecil Medicine

2. DOPAMINE RECEPTOR AGONISTS

• Lower risk of dyskinesias compared to levodopa (non-pulsatile stimulation)
• Useful as initial monotherapy (especially in younger patients <65 yrs)
• Used adjunctively when levodopa response fluctuates

Non-ergot Agonists (Preferred)

Ergot Agonists (Less used / Avoided)

• Bromocriptine: D2 agonist; rarely used now
• Pergolide: D1+D2 agonist; withdrawn from US market due to valvular heart disease (fibrotic reactions)
• Cabergoline: Long-acting; similar cardiac valvulopathy risk

Adverse Effects of Dopamine Agonists

• Nausea, postural hypotension, somnolence ("sleep attacks" while driving!)
• Psychiatric: hallucinations, psychosis, confusion (more than levodopa)
• Impulse control disorders (gambling, hypersexuality, binge eating) - specific to non-ergot agonists
• Peripheral edema
• Contraindicated in psychotic illness, recent MI, active peptic ulcer

3. MAO-B INHIBITORS

• Selegiline is metabolized to amphetamine metabolites - can cause insomnia (avoid evening dosing), anxiety
• Rasagiline is not metabolized to amphetamine; cleaner profile
• All three: do not combine with meperidine, tramadol, SSRIs, TCAs (risk of serotonin syndrome), or non-selective MAO inhibitors

4. COMT INHIBITORS (Catechol-O-Methyltransferase Inhibitors)

• Adverse effects: worsening levodopa side effects (dyskinesias, nausea, hallucinations), diarrhea, orange discoloration of urine
• Tolcapone: black-box warning for fulminant hepatic failure - restrict use

5. ANTICHOLINERGICS (Antimuscarinic Agents)

• Best for: Tremor (less effective for bradykinesia and rigidity)
• Most useful in: Drug-induced parkinsonism, younger patients with tremor-predominant disease
• Adverse effects: Dry mouth, urinary retention, constipation, blurred vision, confusion, memory impairment, hallucinations
• Avoid in: Elderly (cognitive side effects), patients with dementia, prostatic hypertrophy, glaucoma

6. AMANTADINE

• Mechanism: NMDA glutamate receptor antagonist; also enhances dopamine release and has mild anticholinergic properties
• Uses:
  • Mild early Parkinson's disease (modest benefit)
  • Reduces levodopa-induced dyskinesias (primary current use)
  • Extended-release form (Gocovri) is FDA-approved specifically for dyskinesias
• Adverse effects: Livedo reticularis, leg edema, confusion, hallucinations
• Eliminated renally - reduce dose in renal impairment

7. NEWER/ADJUNCT AGENTS

Istradefylline

• Adenosine A2A receptor antagonist
• Approved as adjunctive therapy with levodopa/carbidopa to reduce "off" time
• Mechanism: A2A receptors modulate dopamine signaling in basal ganglia; blocking them enhances dopaminergic tone
• Adverse effects: Dyskinesias, dizziness, nausea

Apomorphine (rescue)

• Potent D1+D2 agonist; subcutaneous injection (or sublingual film - Kynmobi)
• Acts within minutes; used for sudden, unpredictable "off" episodes
• Must pretreat with antiemetic (trimethobenzamide, NOT domperidone with certain preparations)

TREATMENT STRATEGY SUMMARY

Early disease (mild symptoms)
    ├── Age <65 years, cognitively intact
    │       → Start dopamine agonist (pramipexole/ropinirole)
    │         OR MAO-B inhibitor (rasagiline) if very mild
    │
    └── Age >65 years OR cognitive dysfunction OR severe disability
            → Start Levodopa/Carbidopa (Sinemet)

Motor fluctuations develop
    → Add COMT inhibitor (entacapone)
    → Add MAO-B inhibitor (rasagiline/selegiline)
    → Add dopamine agonist
    → Consider extended-release levodopa (Rytary)
    → Apomorphine for rescue

Dyskinesias develop
    → Reduce levodopa dose + add dopamine agonist
    → Add amantadine
    → Consider deep brain stimulation (DBS)

DRUGS TO AVOID IN PARKINSON'S DISEASE

• Antipsychotics (haloperidol, phenothiazines) - block D2 receptors
• Metoclopramide - dopamine blocker
• Reserpine, tetrabenazine - deplete monoamines
• Non-selective MAO inhibitors combined with levodopa - hypertensive crisis

• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 28 (Pharmacology of Parkinson Disease)
• Goldman-Cecil Medicine, 2-Vol Set, Chapter 378 (Parkinson Disease - Medical Treatment)