Definition
Antiparkinson drugs are medicines used to reduce the symptoms of Parkinson's disease.
Purpose
Parkinson's disease (PD) is a neurodegenerative disorder that affects movement. In PD, cells in a part of the brain called the substantia nigra die off. The normal function of these cells is to regulate the action of other cells in other brain regions by releasing a chemical called dopamine. When substantia nigra cells release dopamine, the dopamine attaches to dopamine receptors on the other cells, which influences them in various ways depending on the specific type of cell. The actions of these cells work in concert with other systems that influence movement. When all cells are working properly together, the end result is controlled, fluid movement.
When substantia nigra cells die off, however, as they do in PD, less dopamine is available for release. Consequently, the cells that depend on receiving dopamine are not properly regulated. The result is an imbalance in movement control that causes slowed movements, stiffness, and tremor—the classic signs of PD.
Antiparkinson drugs attempt to restore the balance through one of several mechanisms, depending on drug type. The most effective drugs, called dopaminergic drugs, replace dopamine, or mimic its action in the brain. Another group of drugs delays the breakdown of dopamine, thus increasing the level in the brain. Other drugs act on the other systems that influence movement, preventing them from being too active.
Description
Levodopa
Levodopa, also called L-dopa, is the most widely prescribed antiparkinson medication; almost all PD patients eventually receive levodopa. It is a chemical related to dopamine, and it is converted into dopamine within the brain. Dopamine itself cannot cross the barrier between the bloodstream and the brain, while levodopa can. This chemical form of dopamine works in the place of the natural dopamine that is lost due to the disease process.
Levodopa is chemically similar to amino acids, a type of molecule the body needs and absorbs from foods high in protein. In the digestive system, a carrier picks up the levodopa and transports it into the bloodstream. The same transport process occurs between blood and brain. Meals high in protein may interfere with absorption of levodopa from the digestive tract or from the blood into the brain. Patients may be advised to avoid high-protein meals too close to the time they take levodopa.
Once in the bloodstream, levodopa can be converted to dopamine. This is a problem because, as noted, dopamine cannot be taken into the brain. Additionally, dopamine in the periphery (that is, outside the brain) causes nausea, vomiting, and other adverse effects. To minimize these side effects, levodopa is always given with another drug that inhibits its conversion to dopamine in the periphery. In the United States, this drug is carbidopa. Levodopa and carbidopa are available in a single tablet, with doses adjusted for maximum benefit. However, it should be noted that peripheral dopamine is not always undesirable: it has important metabolic functions, including maintaining blood pressure.
Within the brain, levodopa is taken up by remaining substantia nigra cells, converted to dopamine, and released normally. The extra dopamine provided by the levodopa allows the brain to maintain normal movements, even in the face of dying substantia nigra cells. There are limitations because, as the disease progresses and more cells die, it becomes difficult for the few remaining cells to maintain normal function, even with extra dopamine.
Recommended dosage
Levodopa treatment is usually started when the patient's symptoms begin to interfere with daily living or the ability to work. Initial dosage is typically 200–600 mg of levodopa per day, taken in tablets with carbidopa. This amount of drug is contained in 2–6 tablets, which are taken at regular intervals during the day. The dose is adjusted to the point at which symptoms are well controlled. As the disease progresses, the dose is increased.
Precautions
Levodopa itself is not well tolerated, which is why it is combined with carbidopa. Carbidopa decreases peripheral metabolism of levodopa, which allows for lower doses of levodopa and less-severe side effects. The combination is a safe and well-tolerated medication for patients with Parkinson's disease. Levodopa may cause orthostatic hypotension, or low blood pressure upon standing. Patients with low blood pressure or who are susceptible to ortho-static hypotension should be cautious when starting treatment or increasing the dose.
Levodopa can cause sudden and unexpected extreme drowsiness, which some physicians term "sleep attacks." Currently, no reliable predictive criteria have been developed to determine which patients are susceptible. Patients starting levodopa should be aware of this possibility, and discuss with their physician how best to modify their activities (such as driving) to guard against injury in the event of such an incident.
Patients who have had myocardial infarction (heart attack) or other heart abnormalities should be monitored carefully when beginning levodopa treatment.
Side effects
Early on in the disease, levodopa can cause nausea, vomiting, orthostatic hypotension, and drowsiness. Nausea and vomiting typically stop being problems within several months of treatment.
Long-term use of levodopa in PD often leads to dyskinesias, or unwanted and uncontrolled movements. Dyskinesias appear as writhing, shaking, or twitching movements that may involve a small or large part of the body. Early in the disease, lowering the dose of levopoda can help control dyskinesias, but later on, the lower dose leads to significant loss of movement. Balancing the control of symptoms with the control of dyskinesias is a difficult and frustrating challenge for both patient and physician.
Long-term levodopa use can also lead to psychotic symptoms, including hallucinations, vivid and disturbing dreams, paranoia, and confusion.
Interactions
Patients who are taking drugs called nonselective MAO (monoamine oxidase) inhibitors should discontinue these drugs at least two weeks before beginning levodopa. MAO inhibitors are used to treat depression. A selective MAO-B inhibitor, such as selegiline, may be taken, and indeed is often prescribed for use in Parkinson's disease.
Description
Dopamine agonists
Dopamine agonists are drugs that mimic the effect of dopamine by stimulating the same cells as dopamine. They have several theoretical advantages over levodopa in the treatment of PD: dopamine agonists do not require uptake and release by substantia nigra cells; they do not compete with amino acids for transport, and so high-protein meals are not a problem; and the effect of an individual dose lasts longer.
One of the most significant advantages of the dopamine agonists is their ability to delay the onset of dyskinesias when used instead of levodopa at the start of disease. Patients who take a dopamine agonist instead of levodopa for the first 1–2 years tend to develop dyskinesias many months later than those who begin on levodopa. On the other hand, dopamine agonists are not quite as effective as levodopa at controlling other PD symptoms, and may cause more confusion in elderly patients. For this reason, common advice for elderly patients is to begin on levodopa, with the expectation that dyskinesias are less likely to be a serious problem within the treatment timeframe, while younger patients should begin on a dopamine agonist to delay dyskinesias within a much longer timeframe of treatment.
Dopamine agonists prescribed for PD in the United States include pramipexole, ropinirole, pergolide, and bromocriptine. Approval of another, apomorphine, was expected in early 2004. Unlike the others, apomorphine is injected and has a very short duration of action. It is intended for intermittent (not continuous) use as a treatment for emergent symptoms while waiting for the effect of other medications to begin.
Recommended dosage
There are half a dozen dopamine agonists available in oral forms for treatment of PD. The individual dosage and schedule for each vary. In each case, a low dose is used to begin with, with a gradual adjustment over several weeks to achieve the optimum level of symptomatic benefit.
Precautions
Like levodopa, the dopamine agonists may cause sudden and unpredictable episodes of extreme drowsiness.
Side effects
Long-term use of dopamine agonists can cause nausea, vomiting, orthostatic hypotension, and psychotic symptoms, including hallucinations, vivid and disturbing dreams, paranoia, and confusion. While the risk for developing dyskinesias is lower with dopamine agonists, their long-term use does lead to this complication in many patients.
Description
COMT inhibitors
COMT (Catechol-O-Methyl Transferase) inhibitors restrict the action of an enzyme that converts levodopa to dopamine in the periphery (outside the brain). This allows more of the levodopa to reach the brain. In this way, a COMT inhibitor increases the effectiveness of a dose of levodopa. A COMT inhibitor cannot be used by itself, but must be administered with levodopa.
Recommended dosage
There are two COMT inhibitors approved for use in PD. Entacapone is dosed at 200 mg with each dose of levodopa. Tolcapone is dosed at either 100 or 200 mg three times per day.
Precautions
Tolcapone has been associated with liver damage in a small number of patients, which has led to death in three patients. Tolcapone is only approved for use by patients for whom other therapies are not providing adequate relief of symptoms.
COMT inhibitors increase the effectiveness of levodopa, as well as levodopa's side effects. Consequently, the same precautions apply for use of COMT inhibitors as for levodopa.
Side effects
COMT inhibitors can cause diarrhea. They also can increase the severity of levodopa's side effects, including orthostatic hypotension, hallucinations, and dyskinesias.
Description
MAO-B inhibitors
MAO-B inhibitors restrict the action of monoamine oxidase B, an enzyme that breaks down levodopa in the brain. Thus, an MAO-B inhibitor prolongs the effectiveness of dopamine, as well as a dose of levodopa. The only MAO-B inhibitor in widespread use for Parkinson's disease is selegiline, also called deprenyl.
Selegiline is often used in the early stages of PD, before other drugs, based on its mild symptomatic benefit. It is also often prescribed based on the possibility it may be neuroprotective—that is, it may help slow the death of neurons (brain cells) in the substantia nigra. While some experiments have suggested this may be true, others have shown no effect, and as of late 2003, there was no widespread consensus that selegiline had any effect in PD other than on symptoms.
Recommended dosage
Selegiline is usually prescribed at 5 mg twice daily.
Precautions
At doses higher than those used in PD, selegiline in combination with certain foods can lead to dangerously high blood pressure. These foods include aged cheeses, fermented beverages such as beer or wine, and smoked or pickled meats. This effect is also seen very rarely in patients taking the recommended dose for PD.
Selegiline should not be used with meperidine. Use with other narcotics should only be with the express approval of the patient's physician.
Side effects
Selegiline can cause side effects similar to levodopa, and when taken with levodopa, may worsen those effects. No reports of sudden drowsiness have been published for PD patients on selegiline alone.
Interactions
Interaction between selegiline and certain kinds of antidepressants is possible, and patients should consult with their physician before combining these two types of medications.
Description
Amantadine
Amantadine is prescribed for two different purposes in PD. It has a mild symptomatic effect in early PD, and is often prescribed before levodopa for that reason. It also reduces dyskinesias, and may be prescribed late in the disease once this symptom develops.
Recommended dosage
Amantadine is dosed at 200–300 mg per day.
Precautions
Patients with kidney disease or reduced kidney function require a much lower dose of amantadine.
Side effects
Amantadine can cause side effects similar to levodopa, including hallucinations, confusion, and orthostatic hypotension. Amantadine can also cause mottled skin and swelling in the peripheral tissues such as the legs.
Description
Anticholinergics
Anticholinergics were the first class of antiparkinson medications developed, but are used much less now than in the past, due to the availability of improved drugs. Anticholinergics suppress activity of the acetylcholine system in the brain, which is relatively overactive in PD. They are mainly effective against tremor and rigidity, and less so against slowed movements.
Recommended dosage
Different anticholinergics are dosed at different levels and frequencies. A dose is chosen that maximizes benefits and minimizes side effects. The dose is gradually increased to avoid worsening side effects.
Side effects
Anticholinergics can cause significant confusion, delirium, and hallucinations, especially in older patients. For this reason, they are seldom used in this group. They can also cause constipation and urinary retention.
Resources
PERIODICAL
Olanow, C. W., R. L. Watts, and W. C. Koller, eds. "An Algorithm (Decision Tree) for the Management of Parkinson's Disease (2001): Treatment Guidelines." Neurology 56, Supplement 5 (June 12, 2001): S1–S88.
WEBSITE
Parkinson's Disease: Etiology, Diagnosis and Management—Version 2.2. November 6, 2003 (March 2, 2004). http://www.mdvu.org/multimedia/slides/parv2.2/.
ORGANIZATIONS
National Parkinson Foundation. 1501 N.W. 9th Avenue, Miami, FL 33136-1494. (800) 327-4545. mailbox@parkinson.org. http://www.parkinson.org.
Richard Robinson
