Levodopa is the precursor to dopamine. Most commonly, clinicians use levodopa as a dopamine replacement agent for the treatment of Parkinson's disease. It is most effectively used to control bradykinetic symptoms that are apparent in Parkinson's disease and it is the most effective medication to improve the quality of life in patients with idiopathic PD. Levodopa is typically prescribed to a patient with Parkinson's disease once symptoms become more difficult to control with other antiparkinsonian drugs. The drug is also useful for post-encephalitic parkinsonism and symptomatic parkinsonism due to carbon monoxide intoxication.[1][2][3] Recent data have suggested that levodopa can either slow down the progression of Parkinson's disease and/or have increased benefits even after drug administration has stopped. A common off-label use for levodopa is restless leg syndrome and periodic limb movement in sleep (PLMS). Levodopa has been suggested as a reasonable treatment option for patients with intermittent restless leg syndrome who do not need regular daily therapy.[4]

Degeneration of the substantia nigra occurs in patients with Parkinson's disease. This condition results in the disruption of the nigrostriatal pathway and thus, decreasing the striatal dopamine levels. Unlike dopamine, levodopa can cross the blood-brain-barrier (BBB). Levodopa converts to dopamine in both the CNS and periphery.[5] In order to increase the bioavailability of levodopa and decrease its side effects, it is often administered in combination with peripheral decarboxylase inhibitors (such as carbidopa and benserazide). Dopamine decarboxylase inhibitors prevent the conversion of levodopa to dopamine in the periphery, allowing for more levodopa to cross the BBB. Once converted to dopamine, it activates postsynaptic dopaminergic receptors and compensates for the decrease in endogenous dopamine.[6]

Oral: usually available in combination with carbidopa or benserazide.

• Immediate-release (IR) tablets

• Disintegrating tablets 

• Controlled-release (CR) tablets

• Extended-release (ER) capsules[7][8]

Treatment should begin with small doses and the recommended dose is 300 to 1200 mg (higher if tolerated) per day, divided in 3 to 12 doses.[9] The recommended titration schedule is to increase by 100 mg every 3-4 days. Patients should take the oral form of levodopa with meals to decrease gastrointestinal (GI) upset. To improve absorption, patients should take levodopa 1 hour prior to, or 2 hours after meals containing protein.[10] Patients should avoid high-fat, high-calorie meals when taking levodopa as it can delay the absorption by 2 hours. Also, high protein diets can decrease the amount of levodopa absorbed due to competition with amino acid transporters. The orally disintegrating tablets need to be dissolved entirely on the tongue before swallowing. The extended-release capsule of levodopa can be administered with or without food. Patients who have trouble swallowing can open up the capsule and sprinkle the contents over food and consume immediately.

Oral Inhalation: Inhaled formulation of levodopa was approved by the U.S. Food and Drug Administration in 2018 for the treatment of Parkinson's disease as adjunctive therapy to levodopa/carbidopa. Inhaled levodopa bypasses the intestinal absorption and hepatic metabolism of oral levodopa and it is available in the form of dry powder[11]

Infusion: another form of administration is a 16-hour infusion through a nasojejunal tube. Research has shown that levodopa infusion is associated with low plasma trough levels seen with oral drug administration. Recent studies of such infusion have shown to decrease the adverse effects of motor complications. Some studies have even shown that pulsatile administration of levodopa can cause more motor complications as compared to the continuous administration of the drug. Administration of levodopa in the pediatric population does not have much research, and as a result, is not recommended to be administered to patients under the age of 18.

The common adverse effects of Levodopa treatment are nausea, dizziness, headache, and somnolence. Increasing carbidopa is recommended to relieve nausea, and domperidone can be helpful if additional carbidopa is ineffective. Special precaution is necessary for elderly patients because they may be more sensitive to the central nervous system (CNS) effects. The most common side effects in older patients taking levodopa can be confusion, hallucinations, delusions, psychosis, and agitation.[12][13][14] There may be a greater risk of hip fractures in older adults as well due to levodopa mildly increasing homocysteine levels as an adverse effect. Patients presenting with an idiopathic parkinsonian disorder and who are on levodopa can also develop low serum vitamin B12, elevated methylmalonic acid levels, and greater chances of sensorimotor peripheral neuropathy. 

Abrupt withdrawal or dose reduction of levodopa is associated with an increased risk of a neuroleptic malignant syndrome (NMS). This condition has been termed the parkinsonism hyperpyrexia syndrome. Hyperthermia, involuntary movements, and muscle rigidity are seen in severe cases. Management includes replacing levodopa at the prior doses and aggressive supportive care in an intensive care unit.[15]

The most common cardiovascular effects are dizziness and postural hypotension; thus, reduction or discontinuation of antihypertensive medications is required for some patients. Researchers also report cardiac arrhythmias in studies. Somnolence is another adverse effect reported with levodopa use. The onset is rapid and without warning, and thus, precaution is needed when operating motor vehicles.[16] Clinicians should discontinue the medication in patients that experience excessive daytime sleepiness. Long-term use of levodopa presents with other complications. The quality of life of patients can be negatively affected because of irreversible motor function changes from drug use. These motor complications present in about 50% of patients using levodopa for 5 to 10 years. The motor complications increase depending on whether the onset of PD was at an early age.

The use of levodopa is contraindicated with the concurrent use of monoamine oxidase inhibitors (MAOIs) because it can lead to a hypertensive crisis. There should be a 14-day washout period when switching from levodopa to an MAOI or vice versa. Patients that are on D2 antagonists may see a reduction in the effects of levodopa, and as a result, it may reduce the beneficial effects of the drug. Individuals with narrow-angle glaucoma should use levodopa with caution as it can increase ocular pressure. Extra precaution is necessary for patients with atrial nodal or ventricular arrhythmias. The recommendation is that these patients be administered levodopa in a coronary care unit. Levodopa use is also contraindicated in people with pre-existing neuropathy because symptoms have the potential to worsen. The risk of GI bleeds increases in patients who already have a history of peptic ulcer disease. Levodopa can increase the risk of psychosis in patients already diagnosed with a major psychotic disorder.

Per the Food and Drug Administration (FDA)  label, Levodopa should not be used in patients with a history of malignant melanoma due to the risk of activating melanoma. However, there are several studies that suggested drug exposure is not the reason for the increased risk of melanoma but may reflect the association of Parkinson's disease with melanoma. More studies are required to verify the correlation between levodopa and dermatologic effects.[17]