Dopaminergic antiparkinsonism agents

Dopaminergic antiparkinsonism agents are a key drug class used in the treatment of Parkinson’s disease (PD), a progressive neurodegenerative disorder marked by a deficiency of dopamine in the substantia nigra pars compacta. These agents act by either replacing dopamine, stimulating dopamine receptors, or prolonging dopamine action at synapses. They are also employed in parkinsonism syndromes of other origins, such as drug-induced parkinsonism or secondary parkinsonism.

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1. Classification of Dopaminergic Agents

Dopaminergic antiparkinsonism drugs fall into several mechanistic classes:

A. Dopamine precursors

• Levodopa (in combination with dopa decarboxylase inhibitors such as carbidopa or benserazide)

B. Dopamine receptor agonists

• Non-ergot: pramipexole, ropinirole, rotigotine, apomorphine

• Ergot derivatives: bromocriptine, cabergoline (less favored due to side effects)

C. MAO-B inhibitors (monoamine oxidase B)

• Selegiline, rasagiline, safinamide

D. COMT inhibitors (catechol-O-methyltransferase)

• Entacapone, tolcapone, opicapone

E. Dopaminergic reuptake inhibitors

• Amantadine (also exhibits NMDA antagonism and anticholinergic effects)

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2. Mechanism of Action

Levodopa: Prodrug converted to dopamine in the brain. Combined with a peripheral dopa decarboxylase inhibitor (carbidopa/benserazide) to prevent peripheral conversion and enhance CNS availability.

Dopamine agonists: Directly stimulate D2-like dopamine receptors in the striatum, mimicking the action of endogenous dopamine.

MAO-B inhibitors: Irreversibly inhibit monoamine oxidase B in the brain, reducing breakdown of dopamine.

COMT inhibitors: Inhibit peripheral metabolism of levodopa, prolonging its half-life and CNS availability.

Amantadine: Promotes dopamine release, inhibits dopamine reuptake, and exerts NMDA receptor antagonism, useful in dyskinesias.

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3. Approved and Common Generic Drug Names

Levodopa-based therapy:

• Levodopa + Carbidopa (Sinemet)

• Levodopa + Benserazide (Madopar)

• Extended-release formulations: Rytary, Duopa (enteral suspension)

Dopamine agonists:

• Pramipexole (Mirapex)

• Ropinirole (Requip)

• Rotigotine (Neupro – transdermal patch)

• Apomorphine (Apokyn – subcutaneous injection)

• Bromocriptine, Cabergoline (rarely used)

MAO-B inhibitors:

• Selegiline (Eldepryl)

• Rasagiline (Azilect)

• Safinamide (Xadago)

COMT inhibitors:

• Entacapone (Comtan)

• Tolcapone (Tasmar)

• Opicapone (Ongentys)

Other dopaminergic agents:

• Amantadine (Symmetrel, Gocovri)

• Amantadine ER (for levodopa-induced dyskinesia)

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4. Clinical Indications

• Parkinson’s Disease (idiopathic)

• Parkinsonism from antipsychotics or neuroleptic drugs

• Restless Legs Syndrome (RLS): dopamine agonists (e.g., ropinirole, pramipexole)

• Dystonia syndromes

• Dopamine-responsive dystonia

• Freezing of gait (advanced PD): Apomorphine

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5. Pharmacokinetics Overview

Drug Class	Route	Half-life	CNS Penetration	Metabolism
Levodopa	Oral, Enteral	~1.5 hrs	Yes	Peripheral + hepatic
Dopamine agonists	Oral, Patch, SC	6–10 hrs	Yes	Hepatic (CYP1A2, CYP3A4)
MAO-B inhibitors	Oral	10–40 hrs	Yes	Hepatic
COMT inhibitors	Oral	2–3 hrs	Peripheral action	Hepatic
Amantadine	Oral	10–15 hrs	Yes	Renal excretion

6. Adverse Effects

Levodopa:

• Nausea, hypotension

• Dyskinesias (with long-term use)

• Motor fluctuations (“wearing off,” “on-off”)

• Neuropsychiatric: hallucinations, impulse control disorders

Dopamine agonists:

• Daytime somnolence

• Hallucinations, psychosis

• Peripheral edema

• Impulse control disorders (gambling, hypersexuality)

MAO-B inhibitors:

• Insomnia (especially selegiline)

• Serotonin syndrome (if combined with SSRIs)

• Hypertensive crisis (rare, high doses)

COMT inhibitors:

• Orange discoloration of urine (entacapone)

• Diarrhea

• Hepatotoxicity (tolcapone; monitor LFTs)

Amantadine:

• Livedo reticularis

• Edema

• Confusion, dizziness

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7. Contraindications

• Levodopa: narrow-angle glaucoma, history of melanoma

• Dopamine agonists: uncontrolled psychosis, severe hypotension

• Selegiline: with meperidine, tramadol, or serotonergic agents

• Tolcapone: active liver disease

• Amantadine: ESRD (requires dose adjustment)

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8. Drug Interactions

• Levodopa: antagonized by antipsychotics (esp. typicals), reduced absorption with high-protein meals

• Dopamine agonists: additive sedation with CNS depressants

• MAO-B inhibitors: avoid serotonergic agents (SSRIs, SNRIs, TCAs), meperidine, and dextromethorphan

• COMT inhibitors: additive effect with levodopa, monitor for enhanced dyskinesia

• Amantadine: increased anticholinergic and CNS effects with other agents

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9. Dosing and Titration

• Levodopa/Carbidopa: initiate at 100/25 mg TID; titrate based on response

• Ropinirole: start at 0.25 mg TID, max ~24 mg/day

• Pramipexole: start at 0.125 mg TID, titrate to 1.5 mg TID

• Selegiline: 5 mg BID (morning and noon)

• Entacapone: 200 mg with each levodopa dose

• Amantadine: 100–400 mg/day in divided doses

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10. Therapeutic Strategies

Patient Stage	Preferred Dopaminergic Agents
Early PD (<65 years)	MAO-B inhibitors, dopamine agonists
Elderly or Cognitive Risk	Levodopa/carbidopa (monotherapy)
Motor fluctuations	Add COMT inhibitors, MAO-B inhibitors, amantadine
Dyskinesia	Amantadine (Gocovri ER)
Freezing episodes	Apomorphine injection

11. Role in Advanced Parkinson’s Disease

• Continuous dopaminergic stimulation with levodopa intestinal gel (Duopa)

• Apomorphine subcutaneous infusion

• Combination with deep brain stimulation (DBS)

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12. Monitoring and Precautions

• Motor complications: monitor for “wearing off,” “on-off,” and dyskinesia

• Neuropsychiatric status: hallucinations, depression, impulse control

• Liver function: required for tolcapone

• Renal function: monitor in patients on amantadine