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• Levadopa (L-dopa)
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Parkinson's disease

Description

An in-depth report on the causes, diagnosis, and treatment of Parkinson's Disease

Levadopa (L-dopa)

Levodopa, also called L-dopa, which is converted to dopamine in the brain, remains the gold standard for treating Parkinson's disease. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, which improves the action of levodopa and reduces some of its side effects, particularly nausea. Levodopa can also be combined with benserazide (Madopar) with similar results, but Sinemet is almost always used in America. Dosages vary, although the preparation is usually taken in three or four divided doses per day. In 2004, the FDA approved a new oral form of carbidopa-levodopa (Parcopa) that dissolves on the tongue.

Indications of Early Treatment Success or Failures

In general L-dopa has the following effects on Parkinson's disease:

• It is most effective against rigidity and slowness
• It produces less benefit for tremor, balance, and gait

In many patients, levodopa significantly improves the quality of life for many years. If symptoms do not improve after 2 or 3 months, one of the following reasons may account for the failure:

• Other neurologic problems may be causing the symptoms.
• Some patients have abnormalities in other brain sites that do not respond to L-dopa.
• Sometimes patients are so depressed they cannot tell if the drug is beneficial or not. Only a series of physical examinations by the doctor will indicate that the drug is actually helping.

Studies suggest that levodopa may help slow disease progression and protect against brain cell degeneration.

Toxic Effects

The toxic effects of levodopa with or without carbidopa are considerable.

Physical Side Effects. The physical side effects are as follows:

• Low blood pressure. Low blood pressure is a common problem during the first few weeks, particularly if the initial dose is too high. The addition of extra supplements of carbidopa reduces this effect to some degree. The patient should drink lots of fluids and possibly increase salt intake to maintain normal blood pressure.
• Arrhythmia. In some cases the drug may cause abnormal heart rhythms.
• Gastrointestinal effects. Stomach and intestinal side effects are common even with carbidopa. Taking the drug with food can alleviate the nausea. However, proteins interfere with intestinal absorption of levodopa, and some doctors recommend not eating any protein until nighttime in order to avoid this interference. The drug can also cause gastrointestinal bleeding.
• Effects in the lung. Levodopa can cause disturbances in breathing function, although it may benefit patients who have upper airway obstruction.
• Hair loss.

Psychiatric and Mental Side Effects. The major adverse effects of the drug are psychiatric. Patients taking levodopa, especially in combination with other drugs, can experience:

• Confusion.
• Extreme emotional states, particularly anxiety.
• Vivid dreams.
• Visual and possibly auditory hallucinations. The drug may even unmask dementia that had not been previously noticed.
• Effects on learning. L-dopa appears to have mixed effects on learning. It may improve working memory. However, some evidence suggests that it impairs areas of the brain related to other learning functions and social behavior.  
• Sleepiness and sleep attacks.

Levodopa causes fewer psychiatric side effects than other drugs used for Parkinson's disease, including anticholinergics, selegiline, amantadine, and dopamine agonists. Because psychiatric side effects often occur at night, if they are severe some doctors recommend reducing or stopping the evening dose.

The Wearing-Off Effect and Dyskinesia (Inability to Control Muscles)

Within 4 to 6 years of treatment with levodopa, the effects of the drug in many patients begin to last for shorter periods of time (called the wearing-off effect ) and the following pattern may occur:

• Patients may first notice slowness ( bradykinesia ) or tremor in the morning before the next dose is due.
• Less commonly, some experience painful dystonia, muscle spasms that can cause sustained contortions of various parts of the body, particularly the neck, jaw, trunk, and eyes and possibly the feet.
• Patients must increase the frequency of levodopa doses. This puts them at risk for dyskinesia (the inability to control muscles), which usually occurs when the drug level peaks. Dyskinesia can take many forms, most often uncontrolled flailing of the arms and legs or chorea , rapid and repetitive motions that can affect the limbs, face, tongue, mouth, and neck. Dyskinesia is not painful, but it is very distressing.
• In some people, eventually L-dopa is effective only for 1 to 2 hours and most patients start to experience motor fluctuations. In about 15 - 20% of patients such fluctuations become extreme, a phenomenon known as the on-off effect , which consists of unpredictable, alternating periods of dyskinesia and immobility. Sometimes the symptoms switch back in forth within minutes or even seconds. (The transition may follow such symptoms as intense anxiety, sweating, and rapid heartbeats.)

Reasons for the Wearing-Off Effect. Debate is ongoing about the cause of the wearing-off effect and dyskinesia. Some theories suggested for these effects are:

• The disease progresses beyond the ability of levodopa to control it
• Some patients become tolerant to prolonged exposure to dopamine and, at the same time, the disease is progressing
• The brain's own dopamine neurons become incapable of storing dopamine and when the levodopa wears off, little or no natural dopamine remains
• Levodopa itself accelerates the disease by producing oxygen free radicals, unstable particles that increase injuries to the brain and dopamine degradation

Preventing the Wearing-Off Effect. To reduce the effects of fluctuation and the wearing-off effect, it is important to maintain as consistent a level of dopamine as possible. Unfortunately, levodopa is poorly absorbed and may remain in the stomach a long time. A number of strategies are being developed to take care of these problems:

• Some patients take multiple small doses on an empty stomach, crushing the pills and mixing them with a lot of liquid.
• A liquid form of Sinemet may produce fewer fluctuations and a prolonged "on" time compared with the tablet.
• A prolonged release version of levodopa and carbidopa (Sinemet CR) is also available to control fluctuations for some people. (Some evidence suggests that there is no actual difference in symptom control between the sustained and immediate release forms, but patients on Sinemet CR tend to experience a better quality of life.)

• Review Date: 3/30/2007
• Reviewed By: A.D.A.M. Editorial Team: Greg Juhn, M.T.P.W., David R. Eltz, Kelli A. Stacy. Previously reviewed by Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (5/22/2006).

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