Pharmacological Management of Parkinson's Disease
PHARMACOLOGICAL MANAGEMENT OF PARKINSON'S DISEASE
by Michael Rezak, MD, PhD
The medications available for the treatment of Parkinson's disease (PD) can be extremely effective in relieving the symptoms of the disease for long periods of time. Furthermore, some drugs currently on the market may have a role in slowing the progression of the disease (neuroprotection), although this still remains to be definitively proven. What follows is a brief description of the currently available medications for PD along with some discussion as to their proper role in the course of treatment. It must be emphasized that all treatments for PD must be individualized for each patient. No "textbook" formula can be used, and medications must be evaluated and then titrated to the meet the specific needs and clinical presentation of each patient.
This drug appears to exert benefits for PD by enhancing release of dopamine as well as from its modest anticholinergic effects. Clinically, amantadine is useful in early PD and appears to benefit tremor most. Recent evidence has documented amantadine's benefit in reducing l-dopa-induced dyskinesias. Furthermore, amantadine has been proposed to have possible neuroprotective benefits via its blockade of certain receptors (NMDA receptors) in the brain that are believed to mediate dopamine cell death in PD.
This class of drugs can be helpful in the treatment of tremor in PD. Unfortunately, these drugs are fraught with side effects, which limit their use. The side effects can include dry mucous membranes, blurry vision, urinary retention, hallucinations and memory difficulties. The key to using this class of drugs effectively while minimizing the risk of side effects is to very slowly titrate (increase) the dosage until an appropriate response is achieved. The anticholinergic medications most commonly used include Artane® (trihexyphenidyl), Cogentin® (benztropine), Kemadrin® (procyclidine), and Akinetone® (biperiden).
DOPAMINE RECEPTOR AGONISTS
This class of drugs exerts its influence by mimicking the action of naturally occurring dopamine and thus directly stimulates the dopamine receptors in the basal ganglia. Originally, these drugs were used as an adjunct to l-dopa, however recent data has confirmed their effectiveness when used as monotherapy for up to five years in early PD. This latter fact is extremely important because these drugs have a much lower probability of inducing dyskinesias and motor fluctuations compared to l-dopa, perhaps related to their longer half-life. Thus, whenever possible, beginning symptomatic treatment with a dopamine receptor agonist rather than with l-dopa is now an accepted principal of treatment. In the United States, the currently available dopamine receptor agonists for the treatment of PD include Parlodel® (bromocriptine), Permax® (pergolide), Mirapex® (pramipexole) and Requip® (ropinerole). Furthermore, there is some evidence suggesting a neuroprotective role for dopamine agonists, further underscoring the desirability of this class of medications in early PD. Finally, it should be noted that recent reports suggest that use of the ergot-containing agonist, Permax® may result in a serious side effect, heart valve injury. This side effect is presumably due to the propensity of ergotcontaining drugs (e.g., Permax® and Parlodel®) to result in fibrosis of various organs. Although the likelihood of this side effect appears low, it must be taken seriously and patients remaining on Permax® should have serial echocardiograms as a precautionary measure.
Special mention must be given to Apokyn® (apomorphine), a potent dopamine receptor agonist injectable drug, approved by the FDA for the treatment of acute intermittent "off" episodes that are otherwise difficult to manage. Patients who receive Apokyn® must be pre-treated and receive on-going treatment with the anti-emetic drug Tigan® (trimethobenzamide). The first dose of Apokyn® is given at the physician's office so that an appropriate dose can be titrated and side effects observed. Typically, a caregiver is trained to give the subcutaneous injection since the patient may be too "off" to manipulate the syringe. This drug should be considered a "rescue" medication and used in those patients that manifest the most stubborn and unpredictable "off" episodes.
A new continuous transdermally delivered (a patch) dopamine receptor agonist is soon to be released in the U.S. It is called Neupro® (rotigotine). The patch will be applied once a day. LEVODOPA (SINEMET®, STALEVO®, PARCOPA®) This is the most efficacious drug available to treat the symptoms of PD. Upon its release in 1968 it was thought to be virtually curative. However, as years of experience have shown, despite its significant benefit for symptoms it has been shown to have a propensity to induce dreaded dyskinesias and motor fluctuations. Therefore, delaying its use until it is deemed necessary is the standard of care today.
This drug is always combined with carbidopa to prevent the systemic side effects related to the peripheral metabolism of l-dopa (nausea, vomiting, blood pressure changes and sweating). Carbidopa/levodopa (Sinemet®) is available in an immediate release form and in a long acting form, Sinemet CR®. Sinemet CR® is most appropriate in the earlier stages of PD and allows for a reduction in dosing frequency. Sinemet CR® should be replaced with the immediate release drug when motor fluctuations are present in order to achieve more reliable drug levels. PARCOPA® is a newer orally disintegrating formulation of carbidopa/levodopa and is available in the same dosage strengths as the immediate release carbidopa/levodopa i.e., 10/100, 25/100 and 25/250. PARCOPA® is absorbed in the small bowel as are all the other formulations of l-dopa. Stalevo®, a combination drug consisting of carbidopa, entacapone (Comtan®, see section below) and levodopa was recently released onto the market. Stalevo® is available in three levodopa dosage forms, 50 mg., 100 mg. and 150 mg. By combining carbidopa and entacapone with levodopa, the metabolism of levodopa in the GI tract is limited and thus more levodopa is allowed to enter the brain where it can be converted to dopamine. Combining levodopa with entacapone also extends the half-life of levodopa, allowing fewer fluctuations in blood levels. The fluctuations in blood levels are thought to be related to the development of motor fluctuations and dyskinesias.
Motor fluctuations are a challenging complication related to the use of l-dopa that occurs in some patients. Motor fluctuations can sometimes result in severe oscillations in motor functioning such that a patient may rapidly alternate from having severe parkinsonism ("off " state) to manifesting marked involuntary movements (dyskinetic state). The development of motor fluctuations has been well documented to be related to the dose and duration of use of l-dopa in the setting of the progressive loss of dopamine neurons. Nevertheless, it must be emphasized that although it is appropriate to delay l-dopa use for as long as possible, this drug (in the forms noted above) remains the "gold standard" medication for the treatment of PD.
CATECHOL-O-METHYLTRANSFERASE INHIBITORS (COMTI)
This is the newest class of medications added to the drugs used to treat PD. Tasmar® (tolcapone) and Comtan® (entacapone) inhibit the enzyme catechol-O-methyltransferase in the gastrointestinal tract. By doing this, more l-dopa is allowed to enter the brain instead of being metabolized before getting to the brain. It is estimated that approximately 20% more l-dopa can reach the brain when one of these drugs is added. It should be noted that Comtan® and Tasmar® will have no benefit unless you are taking l-dopa concurrently (see Stalevo® above). These drugs are most useful in treating "wearing off" phenomenon (an early motor complication of l-dopa therapy). Side effects of the COMTI drugs include diarrhea, urinary discoloration and dyskinesias. It should be noted that the use of Tasmar® has been greatly restricted by the FDA because of several deaths due to liver damage in patients not being properly monitored for liver enzyme elevation. The FDA has mandated strict monitoring criteria as well as requiring a signed informed consent when prescribing Tasmar®. Thus, Comtan® is the more widely used COMTI because of ease of use and the absence of any reported liver problems. Comtan® is available as a separate drug or in a combined form, Stalevo®.
This drug is the only monoamine oxidase inhibitor (MAOI) approved in the treatment of PD. By inhibiting MAO, the major breakdown enzyme of dopamine, levels of dopamine are increased in the brain and thus can improve symptoms. Additionally, a number of studies have documented a small but definite neuroprotective benefit when used in the early stages of PD. Although the issue of neuroprotection is controversial for Eldepryl®, its use in early PD can certainly be well justified by existing research. Even though it is an MAO inhibitor, no special diet needs to be maintained if one follows the recommended dosing, i.e., 5 mg twice a day. This drug should not be taken late in the day as it may cause insomnia.
Rasagaline (Agilect®), a new MAO inhibitor is soon to be released in the U.S and promises to be more effective for symptoms and perhaps a more potent neuroprotective agent. Finally, it must be emphasized to the patient with PD that adjusting medications to meet your specific need is the "art" in treating your PD. In order to avoid serious side effects this must be done in conjunction with your physician. By carefully reporting your response to medication changes, you and your physician form a team whereby your medications can be optimized.
Dr. Rezak is the Medical Director of the APDA National Young Onset Center as well as the Director of the Movement Disorders Center and Co-Director of the Deep Brain Stimulation Program of the Neurosciences Institute at Central DuPage Hospital in Winfield, IL. Dr. Rezak is also on the Speaker's Bureau for Allergan, Novartis, Medtronic, Teva, and GlaxoSmithKline.