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Dopamine Agonists

Dopamine agonists differ from levodopa, since they do not have to be modified by brain enzymes in order to activate dopamine receptors. They may be used in place of levodopa or in combination with it. Although treatment with dopamine agonists causes motor fluctuations less frequently than levodopa, dopamine agonists are more likely to cause a number of other side effects (such as nausea, somnolence, postural hypotension, hallucinations, and lower extremity edema), particularly in patients over 70 and those with baseline cognitive deficits. Thus, in prescribing dopamine agonists, the treating physician must weigh the potential benefits and adverse effects.

There are two commonly prescribed oral dopamine agonists in the United States:

  • Pramipexole
  • Ropinirole

Apomorphine, a subcutaneously administered dopamine agonist, was approved for use in the United States in 2004. The dopamine agonists differ in several respects, including:

  • chemical structure
  • duration of action
  • side effects

Bromocriptine and the recently withdrawn pergolide are ergot derivatives and may rarely cause retroperitoneal, pulmonary, and pericardial fibrosis, and cardiac valvulopathies. Pramipexole and ropinirole have half-lives 6-12 hours and are therefore taken 2-3 times daily.

 

Pramipexole and ropinirole

Pramipexole and ropinirole are not ergot compounds. Large clinical trials comparing these medications to levodopa showed that they can be used in early Parkinson's disease and reduce the severity of symptoms. Over the years, differences in the effects of the dopamine agonists have emerged. One side effect is daytime sleepiness and "sleep attacks." Although this may occur with all of the dopamine agonists (and levodopa), it was first appreciated in people treated with pramipexole.

Apomorphine

Apomorphineis indicated in patients who experience "off states"refractory to modifications of oral medications such as increasing the dose or frequency of dopaminergic medications or introducting a COMT inhibitor. It has a rapid onset of action, usually within 10-20 minutes but the duration of action is short, lasting for only about an hour. Apomorphine is only available from specialty pharmacies. Because nausea occurs in the vast majority of patients, pretreatment with trimethobenzamide (Tygan®) is required. Initial titration and observation for side effects (syncope, hypotension) must occur in the physician's office.

Prescribing dopamine agonists

The response to a particular dopamine agonist is idiosyncratic. If one dopamine agonists does not offer benefit or causes bothersome side effects, another agonist may be tried. Treatment with dopamine agonists should begin at a low dose, which is increased at intervals (depending on the agent) until benefit occurs.

In two recent clinical studies, patients with early Parkinson's disease were randomly assigned to treatment with either a dopamine agonist (pramipexole or ropinirole) or levodopa. In both trials, about half of the participants assigned to dopamine agonist treatment required supplemental levodopa because of worsening symptoms. Dyskinesias developed more frequently with levodopa than the dopamine agonist. However, other side effects were more common in the dopamine agonist group, and patients treated with levodopa alone had slightly better control of movement.

Dopamine agonists and their preparations:

  • Bromocriptine (Parlodel®): 2.5 mg tablet and 5 mg capsule.  Common therapeutic dose: 0.5-1.5mg tid.
  • Pramipexole (ER) (Mirapex®): 0.375mg, 0.75mg, 1.5 mg, 3mg, 4mg, 5 mg.  This extended-release formulation of pramipexole allows for a single daily dose that is chosen to match the total daily dose of  standard-release pramipexole.
  • Ropinirole (Requip®): 0.25 mg, 0.5, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg tablets.  Common therapeutic dose: 3-8 mg tid.  
  • Ropinirole XL (Requip XL®): 2mg, 4mg, 6mg, 8mg, 12mg.  Common therapeutic dose: 4-20mg daily.  The extended-release formulation of ropinirole allows one single daily dose to be taken. The dose of ropinirole XL is chosen to match the total daily dose of standard ropinirole.
  • 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 (0.1-.8 ml). The starter kit includes trimethobenzamide (Tygan®) which patients should start 3 days prior to dose titration.

*Cabergoline (Dostinex®): not approved in the United States for the treatment of PD

*Lisuride (Dopergine®): not currently available in the United States

Side effects

Side effects include drowsiness, nausea, vomiting, dry mouth, dizziness, leg swelling, and orthostatic hypotension. Although these symptoms are common when starting a dopamine agonist, they typically resolve over several days. In some inpiduals, dopamine agonists cause confusion, hallucinations, or psychosis. Sleepiness, drowsiness, or sedation is sometimes a significant side effect of certain dopamine agonists, and may interfere with driving or other activities. 

Behavioral side effects occur in 5-10 percent of patients taking dopamine agonists. The behaviors often reflect a disorder of “impulse control” in which 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, and binge eating, as well as increased sexual behaviors. These behavioral changes typically resolve once the dose of the dopamine agonist is reduced or discontinued.

The nausea associated with apomorphine may be profound. In the United States, pretreatment with trimethobenzamine (Tygan®) 250 mg 3 times daily for 3 days prior to initial apomorphine dosing is required. Some patients are able to discontinue trimethobenzamine after several weeks of treatment with apomorphine.