Over the years, a number of substitutes for levodopa have been developed. Unlike levodopa, these medications do not have to be modified by brain enzymes in order to activate dopamine receptors. As a class, these medications are called dopamine agonists and they act like dopamine. They may be used in place of levodopa or in combination with it. Although treatment with dopamine agonists appear to cause motor fluctuations less frequently than levodopa, dopamine agonists are more likely to cause certain other side effects than levodopa, so doctors must consider a number of factors in deciding whether to prescribe dopamine agonist or levodopa.
There are two commonly prescribed dopamine agonists in the United States which are taken by mouth:
A third dopamine agonist, apomorphine, is an injectable drug that is used to treat “off periods.” The dopamine agonists differ in several respects, including:
- chemical structure
- duration of action
- side effects
Bromocriptine, originally popular, is now rarely used. Bromocriptine (and the recently withdrawn pergolide) are similar in chemical structure to a chemical called "ergot." Like other ergot medications, bromocriptine may rarely cause fibrosis (or scarring) of the tissues that surrounds the lung, heart, and kidney. Bromocriptine, pramipexole, and ropinirole provide benefit for 6-12 hours so they are usually given 2-4 times daily.
Pramipexole and ropinirole
Pramipexole and ropinirole were developed more recently than bromocriptine. They are not ergot compounds. Large trials comparing use of these medications show that they can be used in early or advanced Parkinson's disease and can reduce the severity of symptoms. One side effect which occurs with all dopamine agonists is daytime sleepiness and "sleep attacks." Some patients manage this symptom by taking the dopamine agonist once they have arrived at a destination instead of just before beginning a monotonous activity like highway driving.
Apomorphine is not an ergot compound. It is given as an injection into the skin, and for this reason has a rapid effect, usually within 10-20 minutes. Its effects last for only about an hour. Because of these properties, apomorphine is frequently used as a rescue treatment (given occasionally or several times a day) for those individuals who experience a profound "off state," that does not respond to other medication adjustments. Apomorphine is only available from specialty pharmacies. Because nausea occurs in the vast majority of patients, pretreatment with an antinausea medication (trimethobenzamide (Tygan®) is required. Moreover, because use of this medication is more complex and side effects (such as a drop in blood pressure) are more profound, patient training and the initial dosing of apomorphine must occur in the physician's office.
Starting treatment with dopamine agonists
The response to a particular dopamine agonist varies considerably between individuals, so that if one dopamine agonist does not help or causes bothersome side effects, another agonist may be tried. Most dopamine agonists are given 2-4 times a day. Treatment with dopamine agonists often begins at a very low dose. The dose is increased every 5-7 days until benefit is appreciated.
Two recent clinical studies observed patients with early Parkinson's disease randomly assigned to treatment either with a dopamine agonist (pramipexole or ropinirole) or with levodopa. Over the course of both trials, about half of the participants assigned to dopamine agonist treatment received supplemental levodopa because of worsening symptoms. In the final analysis of these studies, dyskinesias developed at a higher rate in the levodopa groups than the dopamine agonist groups. These findings are balanced by two other findings: those patients treated with levodopa alone had slightly better control of movement and other side effects were more common in the dopamine agonist group than the levodopa groups.
The ropinirole study followed participants for 5 years. In that study, dyskinesias developed in about 20% of people initially treated with ropinirole compared to about 45% of participants treated with levodopa alone. Drowsiness, hallucinations and swelling of the legs were more common in the ropinirole group than the levodopa group.
The pramipexole study followed participants for 2 years. Dyskinesias developed in about 10% of participants in the pramipexole group compared to 31% of the levodopa group. Wearing off occurred in 24% of the pramipexole group and 38% of the levodopa group. Drowsiness, hallucinations, generalized swelling and leg swelling occurred more frequently in the pramipexole group.
Preliminary controlled trials with pramipexole and ropinirole, although encouraging, did not provide conclusive proof that either agent slowed the progression of PD.
Preparations of Dopamine Agonists
- Bromocriptine (Parlodel®): 2.5 mg tablet and 5 mg capsule
- Pramipexole (Mirapex®): 0.125 mg, 0.25 mg, 0.5 mg, .75mg, 1 mg, and 1.5 mg tablets
- Pramipexole (ER) (Mirapex®): 0.375mg, 0.75mg, 1.5 mg, 3mg, 4mg, 5 mg
- Ropinirole (Requip®): 0.25 mg, 0.5, 1 mg, 2mg, 3,mg 4 mg, 5 mg tablets
- Ropinirole XL (Requip XL®): 2mg, 4mg, 6mg, 8mg, 12mg
- Apomorphine (Apokyn®): 2 ml vials or 3 ml cartridges. The cartridges are used with a reusable, multiple dose injector. Typical doses vary from 1-8 mg (.1-.8ml).
Side effects for all the dopamine agonists include drowsiness, nausea, vomiting, dry mouth, dizziness, leg swelling, and feeling faint upon standing. Although these symptoms are common when starting a dopamine agonist, they typically resolve over several days. In some individuals, dopamine agonists may cause confusion, hallucinations, or psychosis. Sleepiness, drowsiness, or sedation may be a significant side effect of some dopamine agonists in some people, and may interfere with driving or other activities.
A number of behavioral side effects also occur. These behavioral changes are often called “impulse control disorders” because the patient fails to resist the behavior even when it may be distressing or may impair function socially or occupationally. These behavioral changes are often compulsive and include gambling, shopping, binge eating, as well as increased sexual behaviors. They occur in 5-10 percent of patients on these medications and may occur more frequently in patients with depression. These behavioral changes typically resolve once the dose of the dopamine agonist is reduced or discontinued.
The nausea associated with apomorphine may be profound. For this reason, in the United States, pretreatment with the antinausea agent, trimethobenzamine hydrochloride (Tygan®), 250 mg 3 times daily for 3 days prior to initial apomorphine dosing is required. Some patients are able to discontinue trimethobenzamine hydrochloride after several weeks of treatment with apomorphine.
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