Parkinson's Disease Department of Neurology The University of Chicago Medical Center Hospitals



A variety of drugs have been used to treat the symptoms of Parkinsonís disease with varying results. The gold standard of drug therapy remains treatment with levodopa/carbidopa (Sinemet). This is a combination of two drugs. The active ingredient is levodopa that is broken down by enzymes in the brain and becomes dopamine. Thus, it works to replace the dopamine deficit that is the hallmark of Parkinsonís disease. In principle, this is similar to patients taking insulin to replace the lack of insulin in diabetes. Levodopa can be broken down to dopamine outside the brain as well. This peripheral dopamine can lead to side effects, especially nausea. Carbidopa prevents this peripheral breakdown and allows much higher doses of levodopa to be tolerated. Sinemet is a brand name cleverly derived from Latin roots: sin = without, emet = vomiting (emesis). Thus carbidopa allows higher doses of levodopa to be tolerated without nausea.

In younger patients it may be preferrable to use dopamine agonists (see below) first to reduce the risk of long-term complications.

A group of drugs called anticholinergics was used to treat Parkinsonís disease before levodopa. Drugs in this class include trihexyphenidyl (Artane) and benztropine (Cogentin). These drugs are particularly helpful in treating tremor. However, their side effects tend to limit their use. Older patients, in particular, can have difficulties with short-term memory and confusion that require the drug to be stopped or lowered to a dosage where it is no longer of significant benefit.

Amantidine (Symmetrel) was originally developed for the treatment of influenza. However, it was found to be of benefit in mild Parkinsonís disease. Why it works is unclear. It may cause the release of natural dopamine from brain cells, have mild anticholinergic properties, and block the actions of excitatory neurotransmitters. More recently it has also been found to be useful in reducing dyskinesias.

Dopamine agonists are a class of drugs that mimic the action of dopamine on receptors in the brain. The older agonists are bromocriptine (Parlodel) and pergolide (Permax). The newest agents in this class are pramipexole (Mirapex) and ropinerole (Requip). Others are in the development pipeline, including a dopamine agonist skin patch. (See Clinical Research at The University of Chicago Medical Center Department of Neurology website).

Think of the receptor as a lock and the drug as a key. Every receptor has a specific key that opens it, but duplicate keys may do the trick as well. Levodopa, after its conversion to dopamine, is the specific key for the dopamine receptor. Dopamine agonists act like duplicate keys. However, a poor locksmith makes these duplicates. They are never quite as effective as dopamine in unlocking the dopamine receptor. And yet, they have a growing role to play in the treatment of Parkinsonís disease.

Why should this be so? It certainly goes against intuition to argue that a less effective drug may be preferred over a more effective one. The reasoning in favor of this argument is complex and controversial. When patients on levodopa are followed over a period of 5 years or longer only 25% continue to show a consistent response. Most patients find that the effect of each dose of levodopa becomes less effective. A dose that would last 6 hours is now effective for only 4 hours. Periods between doses may be characterized by a return of the slowness and predominant tremor that was characteristic of the untreated disease. Patients begin to show fluctuations (changes) between an "on" state with good control of symptoms and an "off" state with return of symptoms. Another group begins to have abnormal, involuntary movements called dyskinesias. These may involve the head and neck or the limbs. They may also present as facial twitches or cramping postures.

It has been postulated that fluctuating levels of dopamine, as are seen when dopamine is given from the outside in the form of levodopa, may contribute to the development of fluctuations and dyskinesias. These considerations are even more important in younger patients with Parkinsonís disease. Controversial as these hypotheses are, we do see a growing trend in applying a "dopa-sparing strategy." The principles of this strategy are: delay the use of levodopa as long as is practicable and use as little levodopa as is possible. Balancing this approach against the undoubted efficacy of levodopa in treating symptoms is a delicate issue that must be individualized for each patient. This is a prime example of what makes medicine an art as well as a science. It also illustrates the difficulty of applying a rigid protocol to such diseases.

Sinemet CR is a sustained release form of levodopa/carbidopa. It reduces dose fluctuations and prolongs the duration of action of each dose. It is particularly useful in patients who have a "wearing off" towards the end of their dose. It can be very useful when given at bedtime for patients who wake up from sleep at night feeling profoundly "off" or patients who are having a lot of trouble turning in bed. Using dopamine agonists as adjuncts to levodopa can have similar benefit. Both these strategies can contribute to increasing peak-dose dyskinesias and fine-tuning may be required before an optimal balance is found.

Entacapone (Comtan) was recently approved by the FDA as an adjunct therapy to levodopa/carbidopa. It blocks an enzyme called COMT. By doing so, it prolongs the action of levodopa and helps reduce fluctuations. As would be expected, peak-dose dyskinesias may worsen. This is often a signal for reducing the dose of levodopa. Patients, however, have a smoother response despite the lower levodopa dose, due to the action of Comtan. Tolcapone (Tasmar) is a similar agent which unfortunately caused deaths due to liver failure in a small number of patients. Its use has been superseded by Comtan, which is believed to have no significant risk for liver toxicity.