Parkinson’s disease is a progressive neurodegenerative disorder that primarily affects dopamine-producing nerve cells in the brain. Dopamine is a neurotransmitter, or cell-signaling molecule, that relays information between nerve cells and between the brain and the rest of the body. It exerts its action by binding to cell surface proteins called dopamine receptors. Dopamine-producing nerve cells control multiple functions including voluntary body movements and an array of behavioral processes including mood, reward, addiction, and stress.
In Parkinson’s disease, the dopamine-producing nerve cells degenerate and die, leading to reduced dopamine levels in the brain. Thus, body movements cannot be property regulated and motor function becomes impaired. This leads to the characteristic symptoms of Parkinson’s disease, such as tremors of hands, feet, or the entire body; slowness of movement (bradykinesia), rigidity, and gait and balance problems.
There are several treatments and management strategies for Parkinson’s disease, including medications that increase dopamine levels in the brain such as levodopa — a precursor of dopamine that crosses the blood-brain barrier and is converted to dopamine, and dopamine agonists.
Dopamine agonists mimic the effect of dopamine by binding to the dopamine receptors. Dopamine agonists are less potent than levodopa but are useful in treating Parkinson’s disease because they can overcome or delay a levodopa-induced side effect called dyskinesia (involuntary movement of the arms, legs, and other body parts), which can severely affect patients’ quality of life.
How dopamine agonists work
Dopamine agonists work by mimicking the action of dopamine. They bind to dopamine receptors found on the nerve cells that regulate motor function and body movement. There are five types of dopamine receptors (D1, D2, D3, D4, and D5) belonging to two dopaminergic subfamilies (D1 and D2). The dopaminergic receptor subfamily D1 consists of D1 and D5 receptors, generally associated with dyskinesia. The dopaminergic receptor subfamily D2 includes D2, D3, and D4 receptors, which are related to symptoms of movement disorders. Dopamine agonists primarily target agonist activity specific to D2 subfamily receptors.
Types of dopamine agonists
Dopamine agonists can be subdivided into ergoline (derivatives of an alkaloid called ergot) and non-ergoline agonists. Ergoline agonists such as bromocriptine, cabergoline, and pergolide are first-generation agents, whereas non-ergoline derivatives such as pramipexole, ropinirole, rotigotine, and apomorphine are second-generation medications.
Currently, ergoline derivatives are not preferred for first-line treatment because they are associated with a higher risk of heart problems such as fibrotic cardiac valvulopathy (where the valve of the heart does not open or close properly).
The U.S. Food and Drug Administration (FDA) approved four non-ergoline dopamine agonists to treat Parkinson’s disease. These are Mirapex (pramipexole), Requip (ropinirole), Neupro (rotigotine), and Apokyn (apomorphine).
Pramipexole and ropinirole are available in both regular and long-acting slow-release formulations. Rotigotine is available as a skin patch to be used once daily. Apomorphine is delivered by injection and thought of as a rescue medication, with an onset of action within 10 minutes. It is also under FDA review in the form of a sublingual film to be used as a rescue medication.
Advantages of dopamine agonists
Dopamine agonists have several benefits:
- They can cross the blood-brain barrier on their own and do not need any carriers to reach the brain;
- They act directly on the dopamine receptors found on the nerve cells and do not require any metabolic modification, release, or storage;
- They have longer half-lives than levodopa and therefore produce more persistent dopamine receptor stimulation than levodopa;
- The metabolism of levodopa produces free radicals that are toxic to nerve cells and especially dopamine-producing nerve cells. However, the metabolism of dopamine agonists does not generate any toxic byproducts;
- Patients with early Parkinson’s disease can be treated with dopamine agonists for several years before they require levodopa treatment. This reduces exposure to levodopa and therefore minimizes the impact of side effects such as levodopa-induced dyskinesia;
- When dopamine agonists are taken alongside levodopa, they lower the dosage of levodopa required and smoothen out the on-off effects of levodopa that are responsible for dyskinesia;
- Dopamine agonists can also have a positive effect on non-motor symptoms of Parkinson’s disease, such as sleep problems, mood changes, and pain.
Side effects of dopamine agonists
The side effects of using dopamine agonists include nausea, headaches, constipation, hallucinations, orthostatic hypotension (a drop in blood pressure when standing), swelling of legs, sleepiness, dizziness, fainting, sleep attacks, and impulsive-compulsive behaviors such as over-shopping, over-eating, gambling, or hypersexuality.
When the dopamine agonist dose is lowered or stopped, some patients experience symptoms of withdrawal such as anxiety, pain, depression, and suicidal tendencies. Therefore, caution is necessary during the use as well as discontinuation of dopamine agonists.
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