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Parkinson's disease

Description

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

Medications

Monoamine Oxidase B (MAO-B) Inhibitors

Selegiline (Eldepryl, Movergan, Zelepar), also known as deprenyl, is an antioxidant drug that blocks monoamine oxidase B (MAO-B), an enzyme that degrades dopamine. Until recently, selegiline was the drug most commonly used in early-onset disease and in combination with levodopa for maintenance. A major 2002 study reported, however, that although selegiline delays the need for L-dopa by a few months, it has no effect on long-term progression.

Rasagiline (Azilect), another MAO-B inhibitor, was approved in May 2006 for the initial treatment of Parkinson’s disease. It is used alone during early-stage PD and in combination with L-dopa for moderate to advanced PD. Unlike selegiline, which is taken twice a day, rasagiline is taken once a day.

Other Adverse Effects. MAO-B inhibitors may have severe side effects:

• One of the most important side effects is orthostatic hypotension, particularly in people taking Sinemet plus selegiline. This condition is a sudden drop in blood pressure that causes dizziness and lightheadedness when a patient stands up. Orthostatic hypotension can also occur with other Parkinson's drugs.
• Can cause high blood pressure (hypertension) if combined with drugs that increase serotonin levels--such drugs include nearly every major antidepressant. Patients suffering from depression and taking selegiline should discuss all treatment options with their doctor.
• Can also cause a dangerous increase in blood pressure if patients eat foods rich in the amino acid tyramine. Patients should avoid the following foods while taking selegiline or rasagiline and for 2 weeks after stopping medication: aged cheeses, air-dried meats, pickled herring, yeast extract, aged red wines, draft beers, sauerkraut, and soy sauce

Debate over Mortality Rates. Some major studies have reported a higher mortality rates in patients with advanced PD. Such findings may be due to adverse effects on the heart and blood vessels. Although other studies have not reported lower survival rates, some experts believe that, given its modest effects, selegiline may be a poorer drug choice than others, particularly in patients with risk factors for heart disease.

Dopamine Agonists

Dopamine agonists stimulate dopamine receptors in the substantia nigra, the part of the brain in which Parkinson's is thought to originate. Dopamine agonists are effective in delaying motor complications during the first 1 or 2 years of treatment.

Newer Dopamine Agonists. The most commonly prescribed dopamine agonists are pramipexole (Mirapex) and ropinirole (Requip). They are used either alone or in combination with L-dopa. Pramipexole appears to work better and have fewer side effects than ropinirole.

Studies still report, however, that L-dopa is superior for improving motor function. In one study, motor function was no difference in disease progression among all of the drugs by the third year of treatment. Recent research suggests that L-dopa is better at improving motor disability and dopamine agonists are better at reducing motor complications. L-dopa has a higher risk for dyskinesia side effects than dopamine agonists, but dyskinesia can also occur with dopamine agonists.

Side Effects. Side effects of pramipexole and ropinirole vary but can be severe and include:

• Gastrointestinal side effects (nausea and constipation). Nausea can be controlled by drugs, such as domperidone.
• Headache
• Orthostatic hypotension (sudden drop in blood pressure upon standing up)
• Nasal congestion
• Nightmares, hallucinations, and psychosis (more severe than with L-dopa for both drugs)
• Sudden sleep attacks. These can be very serious, particularly if patients are driving. (Sleep attacks may occur -- although less commonly -- with other PD drugs.)

Other Dopamine Agonists.

• Specific dopamine agonists that contain ergot alkaloids include pergolide (Permax), bromocriptine (Parlodel), cabergoline (Dostinex), and lisuride (Dopergine). They are effective drugs and some have been available for several decades. In general, they have a good safety record. Uncommon, but serious side effects have been reported with some of these drugs, including scarring on the outside of the lungs or other organs and skin abnormalities. Experts recommend periodic monitoring for these side effects for patients taking any ergot-derived dopamine agonist.
• Apomorphine is a dopamine agonist used as a single daily injection. It is particularly effective when administered as a "rescue" drug in people experiencing on-off effects severe enough to require going off L-dopa for a few days. Apomorphine may also be particularly helpful in alleviating nighttime symptoms, including pain and restless legs syndrome. It is rarely used, however, because it requires the addition of domperidone to control nausea. An injectable apomorphine (Apokyn) was approved by the FDA in 2004.

Catechol-O-Methyl Transferase (COMT) Inhibitors

Catechol-O-methyl transferase (COMT) inhibitors increase concentrations of existing dopamine in the brain. Entacapone (Comtan) is the current standard COMT inhibitor. It improves motor fluctuations related to the wearing-off effect and has shown good results in improving on time and reducing the requirements for L-dopa. If the patient does not respond to the drug within 3 weeks, it should be withdrawn. No one should withdraw abruptly from these drugs.

Side Effects. Side effects include:

• Involuntary muscle movements
• Mental confusion and hallucinations
• Cramps, nausea, and vomiting
• Insomnia
• Headache
• Urine discoloration (a harmless side effect but should be reported to the doctor)
• Diarrhea
• Less commonly, constipation, susceptibility to respiratory infection, sweating, dry mouth

Of major concern are reports of a few deaths from liver damage in patients taking the COMT inhibitor tolcapone (Tasmar). The drug has been taken off the market in many countries and is recommended in the U.S. only for patients who cannot tolerate another other drugs. Entacapone does not appear to have the same effects on the liver and does not require monitoring. A 2003 3-year study suggested that the drug is safe and effective over the long term. Still, patients should watch out for symptoms of liver damage, including jaundice (yellowish skin), fatigue, and loss of appetite.

Anticholinergic Drugs

Anticholinergics were the first drugs used for PD, but have largely been replaced by dopamine drugs. They are generally used only against tremor in the early stages. They are not as effective against bradykinesia and posture problems and may increase the risk for dementia in late stages. Among the many anticholinergics are trihexyphenidyl (Artane, Trihexy), benztropine (Cogentin), biperiden (Akineton), procyclidine (Kemadrin), and ethopropazine (Parisdol). Orphenadrine (Norflex) is a drug with anticholinergic properties, but is also a muscle relaxant and does not cause urinary retention.

Side effects of Anticholinergics. Anticholinergics commonly cause dryness of the mouth (which can actually be an advantage in some people who experience drooling). Other side effects are nausea, urinary retention, blurred vision, and constipation. These drugs can also increase heart rate and worsen constipation. Anticholinergics can sometimes cause significant mental problems, including memory loss, confusion, and even hallucinations. People with glaucoma should use these drugs cautiously.

Amantadine

Amantadine (Symadine, Symmetrel) stimulates the release of dopamine and may be used for patients with early mild symptoms. It has some benefit against muscle rigidity and slowness and may help some patients in advanced stages who are unresponsive to other drugs. It is less powerful than levodopa and may lose its effectiveness after 6 months. It may also reduce motor fluctuations brought on by levodopa, however, and these benefits appear to persist for at least a year. Large, well-conducted studies are still needed to determine its true benefits and safety.

Side Effects. Side effects are similar to those of anticholinergic drugs and also may include swollen ankles and mottled skin. It can also cause visual hallucinations. Overdose can cause serious and even life-threatening toxicity. Patients with Parkinson's should not withdraw from this drug abruptly. In rare instances, it can cause acute delirium or a life-threatening condition called neuroleptic malignant syndrome. Pregnant or nursing women should not use this drug.

Investigative Drugs

Dopamine Agonists. A rotigotine transdermal patch (Neupro) is showing promise in late-stage (Phase III) trials. Piribedil (Trivastal) is also progressing in clinical trials.

Cholinesterase Inhibitors . The Alzheimer’s drug rivastigmine (Exelon) is being investigated for treatment of dementia in Parkinson’s patients. Initial results show moderate improvement but side effects include nausea, vomiting, and tremors.

Coenzyme Q10 (Ubiquinone). Coenzyme Q10 (also called ubiquinone) is an antioxidant that is being studied for Parkinson's disease. This enzyme is important for cellular energy, which may be impaired in PD. In one study, patients who took coenzyme Q10 experienced slower decline in daily activities and mental and motor skills compared to patients on placebo. This is available as a supplement in health food stores, but such products are not necessarily those used in clinical studies. Patients should check with their doctor about taking this supplement.

Budipine and Other Glutamate Blockers. A number of experimental drugs are being investigated for Parkinson's disease because they block the actions of glutamate, an amino acid that is a particularly potent nerve cell killer. Some of these drugs block a receptor group to glutamate called N-methyl-D-aspartate (NMDA). Investigative NMDA antagonists include remacemide, memantine, riluzole, and budipine. Budipine is of particular interest. It not only blocks NMDA, but it increases levels of two enzymes involved in the production of dopamine. Studies suggest that it reduces tremor in PD and it proving to be beneficial in combination with levodopa.

Cannabinoids. Drugs derived from cannabinoids, the active ingredients in marijuana, may have nerve protecting properties. Adverse effects include anxiety and sedation. Investigators are studying cannabinoid derivatives, including cannabidiol and dronabinol, which do not have psychologic side effects.

• 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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