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Levodopa

(carbidopa/levodopa; Sinemet®, Atamet®, and Parcopa®)

The introduction of levodopa (L-dopa) more than 40 years ago revolutionized the treatment of Parkinson's disease. Although Parkinson's disease is characterized by a loss of neurons that contain and release dopamine, oral or intravenous dopamine is not effective because like other charged amino acids, it does not pass the blood/brain barrier. However, levodopa (a precursor of dopamine) is transported to the brain and is then metabolized to dopamine.

For most individuals, treatment with levodopa reduces the symptoms of slowness, stiffness, and tremor. To prevent blood amino acid decarboxylases from metabolizing most of an administered does of levodopa before it reaches the brain, levodopa is always combined with an inhibitor of this enzyme. In the US, the dopa decarboxylase inhibitor is carbidopa, whereas in Europe benserazide is used. Many patients need a minimum of 75 mg/d of carbidopa to avoid the nausea that occurs if levodopa is converted to dopamine systemically.

Although levodopa remains the single most effective treatment for Parkinson's disease, treatment over a number of years may lead to variability in an individual's response to treatment—so-called “motor fluctuations.”

The fluctuating response to levodopa can be broadly pided into "on" and "off" periods. During an "on" period, a person can move with relative ease often with reduced tremor and stiffness. “Off” periods describe those times when a person has greater difficulty with movement. A common time for a person with Parkinson's disease to experience an "off period" is just prior to taking the next dose of levodopa, and this experience is called "wearing off." The “off periods” may also occur unpredicatably without a consistent relation to the timing of medication. Another form of motor fluctuation is uncontrolled abnormal movements, called “dyskinesias.” These may take a variety of forms and may be localized or generalized. About 40% of patients treated with levodopa will develop motor fluctuations within six years of treatment.

Levodopa is rapidly absorbed from the small intestine. Most patients experience improvement in symptoms about 30 minutes after a dose, and the benefit lasts for about 3-5 hours. However, the duration of benefit may range from as long as a day to as short as an hour. Food (in particular, protein-rich food) delays absorption of levodopa by the gastrointestinal tract and delivery into the bloodstream and diminishes transport across the blood-brain barrier. Thus, patients should be instructed to take levodopa 30-45 minutes before meals or 2 hours after meals to maximize the benefit of an individual dose.

Over the past decade, there has been increasing concern that treatment with levodopa might hasten the rate of neurodegeneration. The Early versus later Levodopa Study was designed to address this concern. About 360 patients with early Parkinson's disease were assigned to receive carbidopa/levodopa at daily doses of 37.5/150, 75/300 , 150/600 versus placebo over a period of 40 weeks and then undergo a withdrawal of treatment for 2 weeks. After the 2-week withdrawal, the severity of parkinsonism was greater in the placebo group than in those undergoing treatment. These data were interpreted as suggesting that levodopa either slows the progression of PD or has a prolonged effect on the symptoms of the disease (Fahn et al, 2004).

Levodopa preparations

Levodopa is available in a standard and a "controlled-release" (CR or SR) formulation. Controlled-release levodopa has a longer duration of action because the time taken for the gastrointestinal tract to absorb levodopa is increased. However, because the controlled-release formulation only allows 70% of the levodopa to be absorbed by the gastrointestinal tract, it is often necessary to increase the amount of levodopa taken when a person is switched from standard (or immediate-release) levodopa to controlled-release levodopa, in order to obtain the same benefit.

 

Standard release preparations

  • carbidopa/levodopa (Sinemet® or Atamet®) available in 10/100, 25/100, or 25/250 tablets
  • Parcopa® is an accelerated-release preparation available in 10/100, 25/100, or 25/250 tablets

Controlled-release preparations

  • levodopa/carbiopa (Sinemet CR®) 25/100 or 50/200 tablets

Side effects include nausea, vomiting, dry mouth, dyskinesias, and dizziness. In some individuals, levodopa may cause confusion, hallucinations, or psychosis. Motor fluctuations develop in about 40% of individuals treated for 4-6 years.