A dopamine antagonist is a drug, such as Compazine, Haldol, or Thorazine, that blocks dopamine receptors in the brain. These drugs cause a form of Parkinson disease that is reversible when the drug is stopped. A dopamine agonist is the opposite of an antagonist.
Agonists, like dopamine itself, excite or stimulate dopamine receptors in the brain. Unlike levodopa, agonists work directly and do not have to be changed to dopamine by a decreasing number of inefficient neurons in the substantia nigra.
There are at least five types of dopamine receptors in the brain: D-1, D-2, D-3, D-4, and D-5. The D-1 and D-2 receptors are located on neurons in the puta-men, and are the targets of the neurons in the substantia nigra. The D-1 and D-2 neurons are important in PD. The D-3, D-4, and D-5 receptors are on neurons in other regions of the brain: the mesolimbic and mesocortical regions.
These neurons may be important in regulating anxiety, depression, and compulsive behav-ior. Dopamine formed from levodopa stimulates both the D-1 and the D-2 receptors, which is why it is so effective. But this may also be why levodopa causes dyskinesias. The dopamine agonists stimulate a differ-ent combination of receptors. Mirapex (pramipexole) and Requip (ropinirole) stimulate the D-2, D-3, and D-4 receptors.
They tend to be less effective than Sinemet, but don’t cause dyskinesia. Mirapex also has an anti-depressant effect in some people. Unfortu-nately, because they stimulate the neurons regulating compulsive behavior, Mirapex, Requip, and Neupro (rotigotine) may cause compulsive eating, gambling,shopping, or sexual behavior in a small number of patients (perhaps 5%).
The agonists Mirapex, Requip, and Neupro have been shown through clinical research to be so effective in treating people with early PD that the need for lev-odopa/carbidopa may be delayed for several years. There is less risk of developing wearing off, “on-off,” dystonia, and dyskinesias with the agonists than with levodopa/carbidopa. This is primarily due to the short half-life of levodopa, which is approximately 90 minutes.
A half-life of 90 minutes means that after that time, the peak dose level of the drug has decreased by half (or 50%). After another 90 minutes the dose level will have decreased by another 50%. Most drugs are elimi-nated from the body and their effectiveness is gone, after five half-lives.
The half-life gives you an idea as to how frequently you must take a drug to maintain effective circulating levels of the drug. However, drugs that enter the brain (such as levodopa and the dopamine agonists) are stored there and may continue to be active even after they have been eliminated from the body on the basis of their half-lives.
The short half-life of levodopa results in alternating high and low blood and brain levels of, first levodopa, then dopamine. It’s this alternation of high and low levels of dopamine that’s thought to lead to wearing-off, dystonia, and dyskinesia. It’s as though you keep hitting the dopamine receptors with a “jack-hammer” until you finally change their sensitivity. Dopamine agonists have a much longer half-life, thus prolonging the stimulation of the receptors and delaying the development of wearing-off, dystonia, and dyskinesia.
Mirapex, one of the dopamine agonists, is usually started at a dose of 0.25 mg three times a day. Talk to your doctor about what dose will be most effective for you. The half-life of Mirapex is 8 hours, so if you take doses too closely together you’re more likely to have side effects: drowsiness, dizziness on standing (ortho-static hypotension), and nausea. Discuss any side effects you have with your doctor. In some patients, Mirapex has a specific anti-tremor effect.
I led a large, multi-centered, double-blind, placebo-controlled study of patients with advanced PD that showed Mirapex, at a mean dose of 3.0 mg per day, could lower the dose of levodopa/carbidopa by almost two tablets (200 mg of levodopa) while maintaining a comparable anti-Parkinson effect, increasing the number of hours patients were “on” or mobile, and decreasing the preva-lence and severity of dyskinesias. The study was pub-lished in Neurology in 1997.
Another dopamine agonist, Requip, is also usually started at a dose of 0.25 mg three times a day. Side effects may be similar to those of Mirapex. Again, discuss proper dosing and side effects with your doc-tor. A new preparation of Requip, Requip-XL (Requip extended release) has recently become available.
Requip XL is administered once a day and appears more helpful. On a mg per mg basis, Requip XL is at least as effective as regular Requip in patients with early, newly diagnosed PD, as well as those with advanced PD. Patients can easily be switched from regular Requip to Requip XL.
Mirapex’s main route of elimination is the kidneys, while Requip’s main route of elimination is the liver. Drugs like Mirapex that are eliminated through the kidney are less likely to lead to drug-drug interactions.
Drug-drug interactions are always a consideration in older patients who are on multiple drugs for disorders other than PD, such as heart disease, hypertension,hypercholesterolemia, diabetes, and overactive bladder. Drugs like Requip, which are eliminated through the liver, are more likely to have a larger “spread” in their dosing level. In patients who will be treated for several years, the availability of a larger dosing spread is invaluable in managing them.
Neupro, or rotigotine, can be characterized as a dopamine receptor agonist with a preference for the D3 receptor over D2 and D1 receptors. In addition, it exhibits interaction with D4 and D5 receptors, the role of the D4 and D5 receptors is, as yet, unclear in PD.
Neupro is fat soluble, which allows it to be administered through a patch applied to the skin. The patch, applied once per day, releases rotigotine at a constant rate over 24 hours. The drug bypasses the gut and is metabolized in the liver. The patch has been shown to be effective in newly diagnosed patients with early PD, as well as in patients with advanced PD who are already on levodopa/ carbidopa.
The Neupro patch increases the amount of time spent in “on” or mobile periods, and decreases the prevalence of dyskinesias.