Introduction
Levodopa (L-3,4-dihydroxyphenylalanine) is the most effective symptomatic treatment for Parkinson's disease and remains the gold standard therapy decades after its introduction. As a metabolic precursor to dopamine, levodopa is able to cross the blood-brain barrier, unlike dopamine itself, making it essential for restoring dopaminergic neurotransmission in the nigrostriatal pathway.
Mechanism of Action
Levodopa is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase (AAAD) in both peripheral tissues and the central nervous system. This conversion increases dopamine levels in the striatum, compensating for the depleted dopamine characteristic of Parkinson's disease. The resulting dopamine activates postsynaptic dopamine receptors (D1-D5), improving motor function by restoring the balance between dopaminergic and cholinergic activity in the basal ganglia.
Indications
- Treatment of Parkinson's disease
- Treatment of parkinsonism resulting from carbon monoxide or manganese intoxication
- Treatment of restless legs syndrome (off-label)
- Diagnosis of growth hormone deficiency (as part of levodopa stimulation test)
Dosage and Administration
Initial therapy: 250 mg 2-4 times daily, increased by 100-750 mg daily every 3-7 days Maintenance: 500 mg to 1 g daily in divided doses (3-6 times daily), not to exceed 8 g daily Immediate-release formulations: Administer with food to minimize nausea Controlled-release formulations: May be administered without regard to meals Special populations: Reduce dose in renal impairment; no specific dosing recommendations for hepatic impairmentPharmacokinetics
Absorption: Rapidly absorbed from small intestine via active transport; bioavailability 30-50% Distribution: Volume of distribution 0.9-1.6 L/kg; minimal protein binding Metabolism: Extensive first-pass metabolism by aromatic amino acid decarboxylase in GI mucosa, liver, and other tissues; also metabolized by catechol-O-methyltransferase (COMT) Elimination: Half-life 1-3 hours; primarily renal excretion (70-80% as metabolites)Contraindications
- Hypersensitivity to levodopa or any component of formulation
- Concomitant use with nonselective monoamine oxidase inhibitors (MAOIs)
- Narrow-angle glaucoma
- History of melanoma or undiagnosed skin lesions
Warnings and Precautions
Boxed Warning: None- May cause orthostatic hypotension; monitor blood pressure
- May provoke psychotic episodes, particularly in elderly patients
- Monitor for signs of dopamine dysregulation syndrome (compulsive behaviors)
- Risk of impulse control disorders (gambling, shopping, eating, sexual behaviors)
- May cause somnolence and sudden sleep attacks
- Monitor for signs of melanoma regularly
- Use with caution in patients with cardiovascular disease, pulmonary disease, or psychiatric disorders
Drug Interactions
Major interactions:- MAOIs: Risk of hypertensive crisis (avoid concomitant use)
- Antipsychotics: May diminish therapeutic effects
- Antihypertensives: Additive hypotensive effects
- Iron salts: May decrease levodopa absorption
- Protein-rich meals: May decrease levodopa absorption and efficacy
Adverse Effects
Common (>10%): Nausea, vomiting, orthostatic hypotension, dizziness, headache, insomnia Less common (1-10%): Dyskinesias, anxiety, depression, hallucinations, confusion Serious (<1%): Neuroleptic malignant syndrome (upon withdrawal), cardiac arrhythmias, gastrointestinal bleeding, hemolytic anemiaMonitoring Parameters
- Motor function and Parkinson's disease symptoms
- Blood pressure (sitting and standing)
- Mental status and psychiatric symptoms
- Complete blood count, liver and renal function tests
- Skin examinations for melanoma
- Signs of impulse control disorders
- Development of dyskinesias and motor fluctuations
Patient Education
- Take with food to minimize gastrointestinal upset
- Do not abruptly discontinue medication
- Rise slowly from sitting or lying position to prevent dizziness
- Report any new skin lesions or changes in existing moles
- Be aware of potential for drowsiness and avoid driving if affected
- Report any unusual urges or compulsive behaviors
- Maintain consistent protein intake throughout the day
- Inform all healthcare providers about levodopa use
References
1. Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376. 2. Poewe W, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. 3. FDA Prescribing Information: Carbidopa-Levodopa. 4. Olanow CW, et al. Levodopa in the treatment of Parkinson's disease: current controversies. Mov Disord. 2004;19(9):997-1005. 5. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311(16):1670-1683. 6. National Institute for Health and Care Excellence. Parkinson's disease in adults: diagnosis and management. NICE guideline [NG71]. 2017.