Levodopa As A Treatment For Parkinson's Disease

Introduction

Parkinson's disease is a condition where cells in the central nervous system cease to function properly or die off. It mostly presents in later life with generalised slowing of movements and at least one other symptom of resting tremor (shaking while being at rest) or rigidity. Other associated features are a loss of smell, sleeping difficulties, mood disorders, producing too much saliva, constipation, and excessive periodic movements of the arms and legs during sleep.¹

Parkinson’s disease affects at least 1% of the population over the age of 60. The disorder is linked to the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. The cause of most cases is unknown. Only around 10% of cases are caused by genetics, and these usually happen in young people.¹

The condition starts slowly but gets worse over time. Tremors often show up first, and later on they might come with slower movements and stiffness. Difficulty maintaining balance is seen late in the disease and can seriously affect the quality of life. Additionally, some patients may experience autonomic symptoms before they notice movement-related symptoms. The diagnosis is mainly based on history and clinical presentation. SPECT scans can be done in doubtful cases or to exclude other brain-related disorders.¹

Parkinson’s disease is a complex disorder with a broad spectrum of features that require an individualised treatment approach. The main medications used for the treatment of movement-related symptoms of the disease are levodopa, dopamine agonists, catechol-o-methyltransferase inhibitors, monoamine oxidase inhibitors, amantadine and anticholinergics.²

Levodopa is the most efficacious medication for the management of symptoms of Parkinson’s disease. Levodopa treatment helps patients to be more active, independent, and able to work, leading to a better quality of life.²

This article will delve into the workings of levodopa, its administration methods, common side effects, situations where it should be avoided, and what to monitor while using it. 

How does levodopa work?

In Parkinson's disease, there's a breakdown of the substantia nigra, disrupting the nigrostriatal pathway and leading to decreased dopamine levels in the striatum. Levodopa can pass through the blood-brain barrier and is converted into dopamine both in the brain and elsewhere in the body. To enhance its effectiveness and minimise side effects, levodopa is often combined with medications like carbidopa and benserazide, which block its conversion to dopamine outside the brain. This allows more levodopa to reach the brain, where it is converted into dopamine, thereby alleviating symptoms by compensating for the reduced natural dopamine levels.³

How is levodopa administered?

Levodopa comes in oral form and is typically combined with either carbidopa or benserazide. There are different types of oral formulations available, such as immediate-release tablets, disintegrating tablets, controlled-release tablets, and extended-release capsules.³

Treatment should start with small doses, and the recommended dose is 300 to 1200 mg (higher if tolerated) per day, divided into 3 to 12 doses. The recommended way to increase the dose is by adding 100 mg every 3 or 4 days. Patients should take the oral form of levodopa with meals to minimise gastrointestinal upset. For better absorption, patients should take levodopa 1 hour before or 2 hours after protein-containing meals. Patients should avoid high-fat, high-calorie meals when consuming levodopa as it can delay absorption. Also, high-protein diets can decrease the absorption of levodopa. The orally disintegrating tablets should dissolve completely in the tongue before swallowing. The extended-release capsule of levodopa can be administered with or without food. Patients who have swallowing problems can open up the capsule, sprinkle the content over food, and consume it immediately.³

In 2018, the FDA approved oral inhalation formulation of levodopa to treat Parkinson’s disease as an additional therapy to levodopa/carbidopa. Inhaled levodopa avoids the need for the drug to be absorbed through the intestines and processed by the liver like when taken orally.³

What side effects are associated with levodopa?

The common adverse effects of Levodopa treatment are nausea, dizziness, headache, and drowsiness. To reduce nausea, it's advised to increase the dosage of carbidopa. If nausea persists despite this adjustment, domperidone can be considered as an alternative treatment option. Special precautions are essential for elderly patients because they may be more sensitive to the central nervous system effects. The common side effects in older patients taking levodopa can be confusion, hallucinations, delusions, psychosis, and agitation. The risk of hip fractures might be higher in older patients since levodopa mildly increases homocysteine levels.
People with Parkinson's disease of unknown cause who take levodopa might also have low vitamin B12 levels, high methylmalonic acid levels, and a higher risk of sensorimotor peripheral neuropathy.³

Suddenly stopping or decreasing the dosage of levodopa can raise the chances of experiencing neuroleptic malignant syndrome, also known as parkinsonism hyperpyrexia syndrome. In severe cases, symptoms such as high fever, involuntary movements, and muscle stiffness may occur. Management typically involves reinstating levodopa at previous doses and providing intensive supportive care.³

Common cardiovascular effects include dizziness and postural hypotension, often necessitating the reduction or cessation of hypertension medications for certain patients. Heart arrhythmias have also been documented in research studies.³

Another notable adverse effect is sleepiness, which can onset rapidly and unexpectedly, requiring caution when operating vehicles. Clinicians should discontinue levodopa in patients experiencing excessive daytime sleepiness.³

Long-term use of levodopa can negatively impact patients' quality of life due to lasting changes in movement caused by the drug. These movement problems impact around 50% of patients who have been using levodopa for 5 to 10 years. The probability of encountering these problems is greater among individuals who develop Parkinson's disease at a younger age.³

When should levodopa be avoided?

Levodopa should not be taken at the same time as monoamine oxidase inhibitors because it can lead to a hypertensive crisis. When transitioning from levodopa to monoamine oxidase inhibitor or vice versa, a 14-day washout period is necessary. Patients taking dopamine D2 antagonists may notice a reduction in the effects of levodopa. Individuals with narrow-angle glaucoma should be cautious while using levodopa as it can increase the pressure inside the eye. Special care is necessary when prescribing levodopa to patients with atrial nodal or ventricular arrhythmias, and it's advisable to administer it in a cardiac care unit. Additionally, individuals with pre-existing neuropathy should steer clear of levodopa since it could exacerbate their symptoms. Patients with a history of peptic ulcer disease are at a higher risk of experiencing gastrointestinal bleeding. Similarly, individuals diagnosed with a major psychotic disorder face an increased risk of developing psychosis when treated with levodopa.³

Levodopa should be avoided in patients who have a past of malignant melanoma because it could potentially trigger melanoma. Some studies suggest that the higher risk of melanoma may not be caused by levodopa usage, but rather by the association between Parkinson's disease and melanoma. Hence, further studies are needed to confirm the link between levodopa and any skin-related effects.³

Monitoring requirements for patients on levodopa

The following parameters and conditions should be monitored while being on levodopa treatment ³:

• Blood Urea Nitrogen levels
• Creatinine levels
• Liver function
• Intraocular pressure (especially in patients with glaucoma)
• Peripheral neuropathy (testing before and during levodopa treatment is necessary)
• Dyskinesia
• Psychotic behaviour and hallucinations
• Melanoma

Is it safe for pregnant and breastfeeding women to use levodopa?

Levodopa can cross the placenta in pregnant women and may be metabolised by the foetus. However, due to limited data, it's unclear whether it's safe to use levodopa during pregnancy. Additionally, levodopa is excreted in breast milk, so caution is recommended when giving it to nursing mothers.³

Summary

Parkinson's disease is a condition affecting the nervous system, often observed in older individuals, characterised by symptoms like tremors, slowed movements, and muscle stiffness. Although the cause is mostly unknown, it's linked to the loss of specific brain cells. Treatment typically involves managing symptoms, with levodopa being a key medication.

Levodopa works by replenishing dopamine levels in the brain, which are reduced in Parkinson's patients. It's usually taken orally, often combined with other medications to enhance its effectiveness and minimise side effects. The dosage should be carefully adjusted, starting low and increasing gradually. Levodopa is also available in an inhaled form, offering an alternative route of administration.

Common side effects of levodopa include nausea, dizziness, and drowsiness. Elderly patients may experience additional effects like confusion or hallucinations. Abruptly stopping levodopa can lead to severe complications, necessitating careful management. Cardiovascular effects and sleepiness are also noted concerns.

Certain individuals should avoid levodopa or use it with caution, such as those taking specific medications or with certain medical conditions like glaucoma or neuropathy. Monitoring parameters like liver function and intraocular pressure is essential during treatment. Pregnant and breastfeeding women should approach levodopa with caution due to limited safety data.

In essence, while levodopa offers significant relief for Parkinson's symptoms, its administration and management require careful consideration of potential side effects and individual patient factors.