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Tuesday, August 19, 2025

Antiparkinson agents


Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency in the striatum. This imbalance between dopamine (inhibitory) and acetylcholine (excitatory) causes the classic motor features:

  • Resting tremor

  • Bradykinesia (slowness of movement)

  • Rigidity

  • Postural instability

Non-motor symptoms include depression, sleep disturbances, autonomic dysfunction, and cognitive decline.

Antiparkinson agents are medications designed to restore dopaminergic function, correct neurotransmitter imbalance, or improve motor control. While none cure the disease, they significantly improve quality of life and delay disability.

Classification of Antiparkinson Agents

1. Dopaminergic Agents

  • Levodopa (L-DOPA)

  • Carbidopa (given with levodopa; inhibits peripheral dopa-decarboxylase)

  • Benserazide (alternative to carbidopa)

2. Dopamine Agonists

  • Ergot derivatives: Bromocriptine, Cabergoline, Pergolide (rarely used now due to fibrosis risks)

  • Non-ergot agents: Pramipexole, Ropinirole, Rotigotine (transdermal), Apomorphine (subcutaneous, rescue therapy)

3. MAO-B Inhibitors (Monoamine Oxidase B Inhibitors)

  • Selegiline

  • Rasagiline

  • Safinamide

4. COMT Inhibitors (Catechol-O-methyltransferase Inhibitors)

  • Entacapone

  • Tolcapone

  • Opicapone

5. Amantadine

  • Antiviral drug with dopaminergic and antiglutamatergic properties

6. Anticholinergics

  • Trihexyphenidyl (Benzhexol)

  • Benztropine

  • Procyclidine

  • Biperiden

Mechanisms of Action

  • Levodopa: Dopamine precursor; crosses blood–brain barrier and is converted to dopamine in the brain.

  • Carbidopa/Benserazide: Inhibit peripheral metabolism of levodopa → increase CNS availability and reduce peripheral side effects.

  • Dopamine agonists: Directly stimulate dopamine receptors (D2/D3).

  • MAO-B inhibitors: Prevent dopamine breakdown in the brain, prolonging its action.

  • COMT inhibitors: Inhibit peripheral (and central, in tolcapone) metabolism of levodopa, extending its effect.

  • Amantadine: Enhances dopamine release, blocks reuptake, and antagonizes NMDA glutamate receptors → reduces dyskinesia.

  • Anticholinergics: Block muscarinic acetylcholine receptors, reducing tremor by restoring balance between dopamine and acetylcholine.

Clinical Uses

  • Levodopa + Carbidopa/Benserazide: Gold standard, especially effective for bradykinesia and rigidity.

  • Dopamine agonists: First-line in younger patients, or adjunct to levodopa to reduce fluctuations.

  • MAO-B inhibitors: Early mild PD, or adjunct to levodopa for “wearing off.”

  • COMT inhibitors: Only used with levodopa to prolong its duration.

  • Amantadine: Used for levodopa-induced dyskinesias, modest effect on symptoms.

  • Anticholinergics: Best for tremor-dominant PD in young patients.

Dosage Examples

  • Levodopa/Carbidopa: Start with 100/25 mg orally 2–3 times daily, titrate; typical maintenance 300–1000 mg levodopa daily.

  • Pramipexole: Start 0.125 mg three times daily, titrate to 0.75–4.5 mg/day.

  • Ropinirole: Start 0.25 mg three times daily, titrate up to 24 mg/day.

  • Rotigotine patch: 2–8 mg/24h transdermal.

  • Apomorphine: 2–6 mg SC as needed for “off” episodes.

  • Selegiline: 5 mg orally twice daily (morning and noon).

  • Rasagiline: 1 mg orally once daily.

  • Safinamide: 50–100 mg orally once daily.

  • Entacapone: 200 mg orally with each levodopa dose.

  • Tolcapone: 100–200 mg orally three times daily (with monitoring for hepatotoxicity).

  • Amantadine: 100 mg orally once or twice daily.

  • Trihexyphenidyl: 1 mg orally, increased gradually to 6–10 mg/day.

Contraindications

  • Levodopa: Narrow-angle glaucoma, history of melanoma (dopamine is a melanin precursor), psychosis.

  • Dopamine agonists: History of impulse control disorders, severe hypotension, fibrotic disorders (ergot derivatives).

  • MAO-B inhibitors: Use with meperidine, SSRIs, or TCAs (risk of serotonin syndrome).

  • COMT inhibitors: Hepatic impairment (especially tolcapone).

  • Amantadine: Seizure disorders, renal impairment (dose adjustment needed).

  • Anticholinergics: Glaucoma, prostatic hypertrophy, elderly (confusion risk).

Adverse Effects

Levodopa/Carbidopa

  • Nausea, vomiting (reduced by carbidopa)

  • Orthostatic hypotension

  • Dyskinesias (involuntary movements with chronic use)

  • Motor fluctuations (“wearing off,” “on–off” phenomenon)

  • Neuropsychiatric effects (hallucinations, confusion)

Dopamine Agonists

  • Nausea, vomiting

  • Orthostatic hypotension

  • Somnolence, sudden sleep attacks

  • Impulse control disorders (gambling, hypersexuality, shopping addiction)

  • Hallucinations, confusion

MAO-B Inhibitors

  • Insomnia (especially with selegiline)

  • Hypertensive crisis (with tyramine foods, if selectivity lost at higher doses)

  • Serotonin syndrome (with SSRIs, TCAs)

COMT Inhibitors

  • Dyskinesias (due to enhanced levodopa effect)

  • Diarrhea

  • Hepatotoxicity (tolcapone)

  • Urine discoloration (orange/brown)

Amantadine

  • Livedo reticularis (mottled skin discoloration)

  • Ankle edema

  • Confusion, hallucinations

Anticholinergics

  • Dry mouth, constipation, urinary retention

  • Blurred vision

  • Cognitive impairment, confusion (especially in elderly)

Precautions

  • Levodopa: Give with food to reduce GI upset, but avoid high-protein meals (interfere with absorption).

  • Dopamine agonists: Use cautiously in psychiatric illness.

  • MAO-B inhibitors: Screen drug list for serotonergic agents.

  • COMT inhibitors: Monitor liver function (tolcapone).

  • Amantadine: Adjust dose in renal impairment.

  • Anticholinergics: Avoid in elderly due to risk of delirium and memory impairment.

Drug Interactions

  • Levodopa:

    • Reduced effect with antipsychotics (dopamine antagonists).

    • Hypertensive crisis with non-selective MAO inhibitors.

  • Dopamine agonists: Additive hypotension with antihypertensives.

  • MAO-B inhibitors: Dangerous with SSRIs, SNRIs, TCAs, meperidine.

  • COMT inhibitors: Potentiate levodopa; dose adjustment required.

  • Amantadine: Additive anticholinergic effects with other anticholinergics.

  • Anticholinergics: Interact with tricyclic antidepressants, antihistamines (additive anticholinergic burden).

Comparative Efficacy

  • Levodopa: Most effective drug; best for motor symptoms, especially bradykinesia and rigidity.

  • Dopamine agonists: Less potent than levodopa but longer duration; useful in younger patients to delay levodopa use.

  • MAO-B inhibitors: Mild benefit alone, but useful adjunct to levodopa.

  • COMT inhibitors: Not effective as monotherapy; used to manage wearing-off in levodopa users.

  • Amantadine: Modest effect; unique for reducing levodopa-induced dyskinesias.

  • Anticholinergics: Effective for tremor, but limited by cognitive side effects.

Modern Therapeutic Strategy

  • Early PD (younger patients): Start with dopamine agonists or MAO-B inhibitors.

  • Older patients: Levodopa/carbidopa is preferred due to superior symptom control.

  • Moderate to advanced PD: Combination therapy (levodopa + COMT inhibitor + dopamine agonist).

  • Dyskinesia management: Reduce levodopa dose, add amantadine.

  • Fluctuations: Use extended-release formulations or add adjuncts (COMT inhibitors, MAO-B inhibitors).




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