Antiparkinsonian drugs

Definition

Anti-Parkinsonian drugs are drugs which slow the progression or otherwise reduce the effects of Parkinson's disease.

Description

Parkinson's disease is a slowly progressive disease in which the nerve cells in the brain that control movement, and which produce the neurohormone dopamine, fail to work properly, degenerate, and die. Because these nerves are responsible for motor coordination, the disease is characterized by involuntary movements, stiffness, and slowness of movement. The disease is seen more frequently in the elderly, affecting only about 1% of people at age 65, but 10% of people by the age of 80.

Treatment is aimed at maintaining function and slowing the disease progression, but at this time there is no single treatment which is applicable to all patients. The decision as to which drugs to use is based on a number of factors, including the age of the patient at presentation, the rate of disease progression, as well as other illnesses and their treatment.

Levodopa or a fixed combination of levodopa and carbidopa is the mainstay of treatment. Dopamine itself cannot pass from the blood into the brain, but levodopa is a precursor of dopamine, and it can pass from the blood into the brain, where it is converted to dopamine. Carbidopa is a dopa decarboxylase inhibitor and blocks the action of this enzyme which commonly degrades levodopa in the brain. Using this combination permits the use of smaller doses of levodopa, and provides a longer duration of action for a single dose. While levodopa is the most important single drug in Parkinson's treatment, it has significant adverse effects, and, depending on the rate of disease progression, will lose effectiveness after 2 to 5 years. This is termed the “on-off phenomenon” in which the drug may stop working for a period of time, and the benefits of each dose last for a shorter period. Because of this limitation, the decision when to initiate levodopa treatment varies with the age of the patient—younger patients with mild disease might be treated with other medications in order to reserve levodopa for later in the course of the disease, while older patients may be treated with levodopa immediately.

While levodopa and levodopa-carbidopa are the key drugs in Parkinson's treatment and have been described as the gold standard, they do not stop the progression of the disease, nor are they effective against loss of balance or “freezing.”

A number of levodopa formulations have been developed which can be of use in dealing with some of the problems associated with levodopa therapy. One example is the dissolvable levodopa-carbidopa, which can be placed on the tongue, for patients who have difficulty swallowing. Although this has the same properties as traditional formulations, it can be of value to patients who are unable to take oral solids. A second approach is demonstrated in a product which contains levodopa, carbidopa and entacapone.

Entacapone and tolcapone are Catechol Omethyltransferase (COMT) inhibitors. COMT is an enzyme which destroys both dopamine and levodopa. Simultaneous use of these drugs improves the effectiveness of levodopa treatment, with increased “on” time and decreased “off” time. In addition, there is some evidence that the adverse effects of levodopa are dose related, so that there is the possibility, not yet proved, that lowering the dose of levodopa might reduce the frequency or severity of the adverse effects of the drug. Although a fixed combination product containing levodopa, carbidopa and entacapone is marketed, and offers the obvious benefit of requiring fewer doses per day, it might be necessary to take the drugs separately. A general rule of drug therapy is to adjust the dose of each drug individually, and then, if there is a combination product that matches the dose regimen, it may be used to replace the individual drugs. At this time, the three-drug levodopa/carbidopa/entacapone combination is not available in a wide enough range of doses to meet the needs of all patients.

Besides levodopa and the enzyme inhibitors which improve its efficacy, there are a number of other classes of drugs which offer some degree of benefit, usually by producing dopamine-like effects. These are dopamine agonists, drugs that act on the dopamine receptor proteins, and that can be used alone in the early stages of Parkinson's Disease. The drugs in this group are Pramipexole, ropinirole, rotigotine and apomorphine. An additional drug, bromcriptine, also has dopamine agonist activity, and has been used as an adjunct to levodopa, but it has largely fallen into disuse because its adverse effects may be more severe than those of the other drugs in this group. When used early in treatment, pramipexole, ropinerole and rotigotine are effective in controlling the symptoms of Parkinson's disease, and if used as adjuncts to levodopa after the patient has shown an “on-off” response, can increase the amount of “on” time, in one study by about 12%. These drugs generally have fewer adverse effects than levodopa.

The three dopamine agonists currently available seem to be roughly equal in efficacy, with a modest advantage to rotigotine because it is available as a transdermal patch, which offers some convenience of administration. What seems more important, however, is that there are some data implying that these drugs might have a slight neuroprotective action, which could slow the progression of the disease. This possible neuroprotective effect may be due to an antioxidant property, or some other mechanism as yet unknown. This has opened an important area for research which could have major implications for future treatment.

Rasagline and selegeline are monoamine oxidase type B inhibitors (MAO-B). Monoamine oxidase is an enzyme which breaks down certain neurohormones, including serotonin, norepinephrine and dopamine. There are two forms of MAO, A and B, and the B form is found primarily in the brain. While the mechanism of action of rasagline and selegeline has not been fully determined, it is believed that they act by helping to maintain the levels of dopamine in the brain. The benefits of these drugs are modest, but they too can be used either as the sole therapy, or as adjuncts to levodopa in later stages of the disease. There have been some claims that the MAO-B inhibitors have a neuroprotective effect, but the evidence for this is limited. Compared with selegiline, rasagiline is more effective in laboratory studies, and because its metabolism is different, it has fewer of the adverse effect seen with selegiline.

The final class of drugs includes trihexphenidyl which is an anticholinergic agent (A drug that counteracts the effects of acetylcholine, an important transmitter in the nervous system), and amantidine which was originally developed to prevent influenza , but was subsequently found to offer some use in treatment of Parkinson's Disease. The mechanism of action of amantidine is unknown, but it has been suggested that the drug might either increase the release of dopamine from cells, or block the destruction of the dopamine that has been released. Other anticholinergic drugs have also been used in treatment of Parkinson's Disease, all with approximately equal success. These drugs have limited utility, but may be useful early in the course of the disease since they can minimize tremor. Anticholinergic drugs can also decrease drooling.

QUESTIONS TO ASK YOUR PHARMACIST

• What are the potential interactions for both prescriptons and over-the-counter medication I am taking?
• I have difficulty swallowing pills. Is there an alternative route of administration?

Recommended dosage

See drug specific references

Precautions

The following warnings and precautions are incomplete. See product specific references for complete information.

Tolcapone. Because of the risk of potentially fatal, liver failure, tolcapone should be reserved for patients with Parkinson's disease on levodopa/carbidopa who are experiencing symptom fluctuations and who are not responding satisfactorily to or are not appropriate candidates for other medications. Because of the risk of liver injury and because tolcapone, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial improvement within 3 weeks of initiation of treatment, should discontinue tolcapone. Tolcapone therapy should not be initiated if the patient exhibits clinical evidence of liver disease or if the levels of liver enzymes in the blood are elevated. Patients who develop evidence of liver problem while on tolcapone and who stop the drug for any reason can be at increased risk for liver damage if tolcapone is reintroduced later. Such patients should not ordinarily be considered for retreatment. Cases of severe liver injury, including fulminant liver failure resulting in death, have been reported since the drug went on the market. As of October 1998, 3 cases of fatal liver failure have been reported from amongst 60,000 patients. A prescriber who elects to use tolcapone in the face of the increased risk of liver injury is strongly advised to monitor patients closely for evidence of emergent liver injury. Patients should be advised of the need for self-monitoring for both the classical signs of liver disease (e.g., clay-colored stools, jaundice) and the nonspecific ones (e.g., fatigue, loss of appetite, lethargy). The full FDA warning provides additional details. Consult the official package insert for the complete warning.

Dopamine agonists: Patients treated with dopamine agonists have reported sudden somnolence (falling asleep abruptly), without a warning period of drowsiness. This has occurred to some while driving. Patients treated with dopamine agonists also appear to be prone to hallucinations, and this may increase with age. In one study, 10% of patients being treated with a dopamine agonist and levodopa experienced hallucinations compared with 4% of patients treated with levodopa alone.

Entacapone: In clinical trials, diarrhea has been noted in patients treated with entacapone. The diarrhea was generally mild to moderate but was regarded as severe in some. Diarrhea generally resolved after discontinuation of entacapone. Typically, diarrhea presents within 4 to 12 weeks after entacapone is started, but it can appear as early as the first week and as late as many months after the initiation of treatment.

Amantidine: Suicide attempts, some of which have been fatal, have been reported in patients treated with amantadine hydrochloride, many of whom received short courses for influenza treatment or prophylaxis. The frequency of suicide attempts and why this drug should cause that effect are not understood. Suicide attempts and suicidal thoughts have been reported in patients with and without history of psychiatric illness. Amantadine hydrochloride can worsen mental problems in patients with a history of psychiatric disorders or substance abuse. Patients who attempt suicide may exhibit abnormal mental states which include disorientation, confusion, depression , personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions, and somnolence or insomnia . Because of the possibility of serious adverse effects, caution should be observed when prescribing amantadine hydrochloride to patients being treated with other drugs having central nervous system effects, or for whom the potential risks outweigh the benefit of treatment. Because some patients have attempted suicide by overdosing with amantadine, prescriptions should be written for the smallest quantity consistent with good patient management.

Side effects

These drugs have many side effects and drug specific references should be consulted. The most significant adverse effect of levodopa is involuntary movement or dyskinesia, and this can occur at lower doses when levodopa is administered with carbidopa. One study indicates that this effect might be related to the dose level, and careful dosing should reduce the risk. An Italian report indicates that post-menopausal women might benefit from hormone replacement therapy in reducing dyskinesia.

KEY TERMS

Agonist —A drug which can bind to a receptor protein and produce the same effects as the natural substance that ordinarily binds to that receptor

Enzyme —A substance produced by the body that breaks down another chemical

Fulminant —Starting suddenly with great severity

Neurohormone —A chemical which goes from one nerve cell to another, causing an action by the second cell

Transdermal —Through the skin, as a drug which can be applied to the skin but is absorbed and produces an effect in the entire body

Tremor —Shaking or trembling

Dopamine agonists: these drugs have been reported to increase gambling behavior.

Interactions

These drugs have a large number of interactions. Consult product specific references. Rasagline requires special diet restrictions.

Caregiver concerns

Scheduling doses may be a problem, since many patients are on a large number of medications, with potential interactions.

Consider the reports of sudden sleepiness associated with the dopamine agonists, particularly if these drugs are used early in the course of the disease.

Consider the safety of having the patient drive or perform other tasks requiring alertness.

Resources

BOOKS

Ebadi, M., Pfeiffer, R. Parkinson's Disease. Honolulu: CRC Press, 2005.

Weiner, W., Shulman, L. et al. Parkinson's Disease: A Complete Guide for Patients and Families. Baltimore: Johns Hopkins, 2001.

Lieberman A, William F. Parkinson's Disease: The Complete Guide for Patients and Caregivers. New York: Simon'schuster, 1993.

PERIODICALS

Fedorova, NV, Chigir' IP. “Use of the dopamine receptor agonist Mirapex in the treatment of Parkinson's disease.” Neurosci Behav Physiol. (July 2007) 37(6):539-46

Hauser, RA, Rascol O, Korczyn AD, “Ten-year follow-up of Parkinson's disease patients randomized to initial therapy with ropinirole or levodopa.” Mov Disord. (December 2007) 22(16):2409-17.

Joyce, JN, Millan MJ. “Dopamine D3 receptor agonists for protection and repair in Parkinson's disease.” Curr Opin Pharmacol. (February 2007) 7(1):100-5.

Kitamura, Y, Taniguchi T, Shimohama S et al “Neuroprotective mechanisms of antiparkinsonian dopamine D2-receptor subfamily agonists.” Neurochem Res. (July 2003) 28(7):1035-40

Le, WD, Jankovic J. “Are dopamine receptor agonists neuroprotective in Parkinson's disease?” Drugs Aging. (2001) 18(6):389–96.

Mercier, F, Lefèvre G, Huang HL, Schmidli H, Amzal B, Appel-Dingemanse S. “Rivastigmine exposure provided by a transdermal patch versus capsules.” Curr Med Res Opin. (December 2007) 23(12):3199-204

Nicoletti, A, Arabia G, Pugliese P et al. “Hormonal replacement therapy in women with Parkinson disease and levodopa-induced dyskinesia: a crossover trial.” Clin Neuropharmacol. (Sep-Oct 2007) 30(5):276–80.

Noyes, K, Dick AW, Holloway RG “Pramipexole and levodopa in early Parkinson's disease: dynamic changes in cost effectiveness.” Pharmacoeconomics. (2005) 23(12):1257-70

Pinter, MM, Pogarell O, Oertel WH. “Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study.” J Neurol Neurosurg Psychiatry. (April 1999) 66(4):436-41.

Radad, K, Gille G, Rausch WD. “Short review on dopamine agonists: insight into clinical and research studies relevant to Parkinson's disease.” Pharmacol Rep. (Nov-Dec 2005) 57(6):701-12.

Sharma, JC, Ross IN, Rascol O, Brooks D. “Relationship between weight, levodopa and dyskinesia: the significance of levodopa dose per kilogram body weight.” Eur J Neurol. (March 18, 2008).

Sharma, JC, Ross IN, Rascol O, “Relationship between weight, levodopa and dyskinesia: the significance of levodopa dose per kilogram body weight.” Eur J Neurol. (March 18, 2008).

Tse, W. “Optimizing pharmacotherapy: strategies to manage the wearing-off phenomenon.” J Am Med Dir Assoc. (September 2006) 7(7 Suppl 2):12-7.

OTHER

http://www.levodopa.com/levodopa_information/

http://online.factsandcomparisons.com/

http://www.cenes.com/COMT.htm

http://www.merck.com/mmpe/sec16/ch221/ch221g.html#sec16-ch221-ch221g-75

http://www.nlm.nih.gov/medlineplus/parkinsonsdisease.html

http://www.ninds.nih.gov/funding/research/parkinsonsweb/

http://www.pdf.org/AboutPD/

http://www.mayoclinic.com/health/parkinsons-disease/DS00295

http://www.michaeljfox.org/

ORGANIZATIONS

National Parkinson Foundation, 1501 N.W. 9th Avenue / Bob Hope Road, Miami, Florida, 33136-1494, (305) 243-6666, 1-800-327-4545, (305) 243-5595, [email protected], http://www.parkinson.org.

NIH Neurological Institute, P.O. Box 5801, Bethesda, MD, 20824, (301) 496-5751, (800) 352-9424, http://www.ninds.nih.gov/contact_us.htm, http://www.ninds.nih.gov/index.htm.

Sam Uretsky PharmD