Levodopa (L-Dopa)

Article Author:
Kavita Gandhi
Article Editor:
Abdolreza Saadabadi
Updated:
10/27/2018 12:31:40 PM
PubMed Link:
Levodopa (L-Dopa)

Indications

Levodopa is the precursor to dopamine. Most commonly, Levodopa is used as a dopamine replacement agent for the treatment of Parkinson disease. It is most effectively used to control bradykinetic symptoms that are apparent in Parkinson disease. Levodopa is typically prescribed to a patient with Parkinson disease once symptoms become more difficult to control with other antiparkinsonian drugs. The drug can also be used for postencephalitic parkinsonism and symptomatic parkinsonism due to carbon monoxide intoxication. Recent data have suggested that levodopa can either slow down the progression of Parkinson 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).

Mechanism of Action

Degeneration of the substantia nigra occurs in patients with Parkinson disease. This 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 is converted to dopamine in both the CNS and periphery. Levodopa is commonly administered with carbidopa, a dopamine decarboxylase inhibitor, to decrease the amount of levodopa that is converted to dopamine in the periphery. This would allow for more levodopa to cross the BBB. Once converted to dopamine, it activates postsynaptic dopaminergic receptors and compensates for the decrease in endogenous dopamine. Levodopa administration should be discontinued for about 12 hours before carbidopa is administered to decrease the adverse reactions.

Administration

The oral form of levodopa is given with meals to decrease gastrointestinal (GI) upset. Patients are recommended to 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. 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 negative effects of motor complications. Some studies have even shown that pulsatile administration of levodopa can cause more motor complications when compared to continuous administration of the drug. Administration of levodopa in the pediatric population has not been well researched and as a result, is not recommended to be administered to patients under the age of 18.

Adverse Effects

The common adverse effects of Levodopa treatment are nausea, dizziness, headache, and somnolence. Special precaution should be used in elderly patients because they may be more sensitive to central nervous system (CNS) effects. The most common side effects in older patients taking levodopa can be confusion, hallucinations, delusions, psychosis, and agitation. 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. If levodopa is suddenly stopped, a commonly reported adverse effect is neuroleptic malignant syndrome (NMS). Hyperthermia, involuntary movements, and muscle rigidity are seen in severe NMS cases. The most common cardiovascular effects are dizziness and postural hypotension. Cardiac arrhythmias have also been reported in studies. Somnolence is another adverse effect that has been reported with levodopa use. The onset is rapid and without warning and thus, precaution is needed when operating motor vehicles. Medication should be discontinued 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 are seen 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.

Contraindications

The use of levodopa is contraindicated with the congruent use of monoamine oxidase inhibitors (MAOIs) because it can lead to 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, the beneficial effects of the drug may be reduced. Individuals with narrow-angle glaucoma should use levodopa with caution as it can increase ocular pressure. Extra precaution should be taken in patients with atrial nodal or ventricular arrhythmias. It is recommended 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 is heightened in patients who already have a history of peptic ulcer disease. Levodopa can increase the risk of psychosis in patients who are already diagnosed with a major psychotic disorder.

Monitoring

Frequent monitoring of BUN, creatinine levels, and hepatic function is necessary for individuals taking Levodopa. Good hepatic function is crucial in patients taking levodopa because it is where the drug is decarboxylated. Also, it is important to test for intraocular pressure in patients with glaucoma. Testing for peripheral neuropathy before and while on levodopa is also very important. Patients should also be regularly monitored for dyskinesia. Patients need to be observed for psychotic behavior and hallucinations when on dopaminergic medications. Confusion and excessive dreaming can be accompanied with hallucinations. Thus, patients with a history of past psychiatric disorders should not be treated with levodopa.  As an extra precaution, patients should be monitored for melanoma. It is not known yet whether the risk of melanoma is increased due to levodopa use or Parkinson disease.

Toxicity

Studies have shown that levodopa toxicity can damage neuronal cells. The formation of free radicals once the body oxidizes levodopa can induce apoptosis. Also, dopamine, norepinephrine, and epinephrine levels can rise in the blood when levodopa is decarboxylated in the periphery. The rise in catecholamines activate alpha and beta-adrenergic receptors and result in toxic effects. In pregnant women, levodopa does cross the placenta and can potentially be metabolized by the fetus. Unfortunately, there is insufficient information to make an appropriate decision regarding the use of levodopa in pregnant women. The drug is excreted in breast milk, and thus, caution is advised when administering the drug to women who are nursing. To treat toxicity, supportive measures should be taken such as gastric lavage, maintenance of airways, and administration of intravenous (IV) fluids.