Levodopa (L-Dopa)

Mechanism of Action

Degeneration of the substantia nigra occurs in patients with Parkinson disease. This condition results in the disruption of the nigrostriatal pathway and thus decreases 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] 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]

Administration

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 into 3 to 12 doses.[9] The recommended titration schedule is to increase the dose by 100 mg every 3 or 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 before or 2 hours after meals containing protein.[10] Patients should avoid high-fat, high-calorie meals when taking levodopa as it can delay 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, sprinkle the contents over food, and consume it immediately.

Oral Inhalation: Inhaled formulation of levodopa was approved by the U.S. Food and Drug Administration in 2018 to treat Parkinson 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 been shown to decrease the adverse effects of motor complications. Some studies have even shown that the pulsatile administration of levodopa can cause more motor complications than the continuous administration of the drug. Administration of levodopa in the pediatric population does not have much research, and as a result, it 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. 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 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 neuroleptic malignant syndrome (NMS). This condition has been termed 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, reducing or discontinuing 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 can lead to other complications. The patients' quality of life 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 Parkinson disease was at an early age.

Contraindications

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 taking 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, several studies suggested drug exposure is not the reason for the increased risk of melanoma but may reflect the association of Parkinson disease with melanoma. More studies are required to verify the correlation between levodopa and dermatologic effects.[17]

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 essential to test for intraocular pressure in patients with glaucoma. Testing patients for peripheral neuropathy before and while on levodopa is also necessary. Patients should also have regular monitoring of dyskinesia. Patients need to be observed for psychotic behavior and hallucinations while taking dopaminergic medications. Hallucinations can accompany confusion and excessive dreaming. Thus, patients with a history of past psychiatric disorders should not receive treatment with levodopa. As an extra precaution, patients require monitoring for melanoma. It is unknown whether the risk of melanoma increases 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 undergoes decarboxylation in the periphery. The rise in catecholamines activates alpha and beta-adrenergic receptors and results 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 medication to nursing women. Supportive measures are necessary to treat toxicity, such as gastric lavage, maintenance of airways, and administering intravenous (IV) fluids.

Enhancing Healthcare Team Outcomes

While the initial treatment of a patient with Parkinson disease is by a neurologist, outpatient monitoring and continued care are often accomplished by the primary care provider or nurse practitioner/physician assistant; these and other caregivers need to function as an interprofessional team when managing patients on levodopa therapy. When patients start on L-dopa, Frequent monitoring of BUN, creatinine levels, and hepatic function is necessary. Additionally, the patient must obtain a referral to the ophthalmologist for glaucoma screening. Patients on L dopa may develop mood changes and should be closely followed by a mental health nurse.

The primary care provider needs to know the Parkinson disease symptoms because L-dopa usually works for a short period, and patients may have to start on other medications. This situation is where ongoing monitoring by nursing can inform the clinician promptly of status changes so that additional interventions can commence. Also, the pharmacist should verify potential drug-drug interactions and dosing and consult with the clinician as more agents may be needed. Also, patients with Parkinson disease may develop a variety of autonomic symptoms and may need a referral to a gastroenterologist and urologist. Overall, there is no cure for Parkinson disease, and eventually, most patients succumb to the disorder, but interprofessional teamwork can optimize the outcome within these limitations.[18][19] [Level 5]