The Role of Dopamine Receptor Agonists in PD

THE ROLE OF DOPAMINE RECEPTOR AGONISTS IN PD

by Michael Rezak, MD, PhD

WHAT ARE DOPAMINE RECEPTOR AGONISTS? These medicines constitute a class of drugs used to treat Parkinson's disease symptoms that mimic the action of naturally occurring dopamine. They stimulate dopamine receptors directly without being metabolized to another compound as is the case with levodopa. Although this class of medication is less potent than levodopa, they can be very beneficial in treating symptoms for long periods of time.

WHAT ARE THE CURRENTLY AVAILABLE DOPAMINE RECEPTOR AGONISTS IN THE UNITED STATES? Five drugs are now FDA approved and available for use in the United States to treat PD. The first agonist released was Parlodel® (bromocriptine) in the 1970's. Parlodel® firmly established the beneficial role that this class of drugs can play in the treatment of PD. Subsequently, Permax® (pergolide), Mirapex® (pramipexole) and Requip® (ropinirole) were released in that order. Most recently, Apokyn® (apomorphine) was approved for the treatment of acute and unpredictable episodes of hypomobility, i.e., "off" episodes. Apokyn® can be thought of as a "rescue" medication, with onset of action within 10 minutes. Apokyn® is the first Parkinson's drug that can be delivered by injection.

HOW DO THE DOPAMINE RECEPTOR AGONISTS DIFFER FROM ONE ANOTHER? At least five subtypes of dopamine receptors (D1-D5) have been identified in the brain. It appears that the D1, D2 and D3 receptors are located in the striatum, a major target of dopamine neurons projecting from the substantia nigra. The role of the D3-D5 receptors is not fully known, but have been suggested to play roles in neuroprotection, psychosis and mood changes. The dopamine receptor agonists differ in their affinities to bind to these different receptor subtypes. Mirapex® and Requip® bind moderately to the D2 receptor and more strongly to the D3 receptors, while Permax® binds strongly to the D2 and D3 receptors and mildly to the D1 receptor. Interestingly, Apokyn®, binds strongly to the D4 receptor and has a moderate affinity for the D2, D3 and D5 receptors. It is unclear as to how significant these differences in binding affinities are clinically. However, there is no doubt that some patients respond better to one agonist as opposed to another. Furthermore, it is clear that the D2 and D1 receptors play critical roles in producing smooth voluntary movement.

WHAT ARE THE ADVANTAGES OF THE DOPAMINE RECEPTOR AGONISTS? This class of medications acts directly on the dopamine receptors without the need for metabolic conversion, transport, storage and then release, as is the case for l-dopa. Furthermore, because of the longer half-life of these drugs (compared to l-dopa), there is less fluctuation of blood levels which appears to be a significant factor in reducing the probability of the future development of motor fluctuations (e.g., "onoff" and "wearing off" phenomenon) and dyskinesias. Thus, the concept of more continuous dopaminergic stimulation should remain a guiding principle in the treatment strategies in PD.

WHERE DO THE DOPAMINE RECEPTOR AGONISTS FIT IN THE OVERALL STRATEGY FOR OPTIMIZING THE TREATMENT OF PARKINSON'S DISEASE? The dopamine receptor agonists were originally employed as adjunctive or "add on" medications to supplement the use of l-dopa when further dopaminergic effect was desired or when complications of treatment were encountered such as dyskinesias, "wearing off," and motor fluctuations. Dopamine receptor agonists continue to be used in this way today. However, recent data has confirmed the effectiveness of using agonists as monotherapy in early PD. The use of Mirapex® and Requip® as monotherapy has been documented to provide clinical effectiveness for a number of years in some individuals, thus allowing a significant delay in the use of levodopa. This latter point is very important for all individuals with PD, but especially in the young-onset PD group, as this group is at greater risk for the development of motor fluctuations and dyskinesias after relatively short term use of levodopa. Levodopa sparing strategies should be taken advantage of whenever possible, especially in the young-onset PD group.

WHAT ARE SOME POSSIBLE SIDE EFFECTS OF THE DOPAMINE RECEPTOR AGONISTS? As a group, the dopamine receptor agonists have a significantly increased safety margin with regard to the production of dopaminergic side effects such as dyskinesias and motor fluctuations compared to l-dopa. In general, the newer agonists (Mirapex® and Requip®) are less likely to generate side effects. Nevertheless, dyskinesias, confusion and hallucinations are certainly possible with all of these drugs. Furthermore, leg swelling (edema) and orthostatic hypotension (causing fainting or dizziness) have been reported. Of note, Mirapex® and Requip® can induce sleepiness and sleep attacks (sudden falling asleep) and must be used with great caution in those patients who are driving. Permax® has not been reported to cause these sleep attacks. Most recently, Mirapex® and Requip® have been shown to result in a heretofore unknown side effect called dopamine dysregulation syndrome, i.e. compulsive behavior. This problem can occur in up to 5% of patients taking these drugs and can be quite serious. The compulsive behavior can take many forms, but most commonly involves gambling, shopping and sexual behavior. Recent reports suggest that use of the ergot containing agonist, Permax® (cabergoline in Europe) may result in a serious side effect, i.e. heart valve injury. This side effect is presumably due to the propensity of ergot containing drugs to result in fibrosis (stiffening) of various organs. Although few patients remain on Permax®, this problem must be taken seriously and patients remaining on this drug should undergo serial echocardiograms. Cardiac valvular fibrosis has never been reported with Mirapex® or Requip®.

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.

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