Dopamine Receptor Agonists

DOPAMINE RECEPTOR AGONISTS

Drugs acting directly on dopamine receptors may have a benefi-cial effect in addition to that of levodopa (Figure 28–5). Unlike levodopa, they do not require enzymatic conversion to an active metabolite, have no potentially toxic metabolites, and do not compete with other substances for active transport into the blood and across the blood-brain barrier. Moreover, drugs selec-tively affecting certain (but not all) dopamine receptors may have more limited adverse effects than levodopa. A number of dopamine agonists have antiparkinsonism activity. The older dopamine agonists (bromocriptine and pergolide) are ergot (ergoline) derivatives , and are rarely—if ever— used to treat parkinsonism. Their side effects are of more con-cern than those of the newer agents (pramipexole and ropinirole).

There is no evidence that one agonist is superior to another; individual patients, however, may respond to one but not another of these agents. Apomorphine is a potent dopamine agonist but is discussed separately in a later section because it is used primarily as a rescue drug for patients with disabling response fluctuations to levodopa.

Dopamine agonists have an important role as first-line therapy for Parkinson’s disease, and their use is associated with a lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy. In consequence, dopaminergic therapy may best be initiated with a dopamine agonist. Alternatively, a low dose of carbidopa plus levodopa (eg, Sinemet-25/100 three times daily) is introduced, and a dopamine agonist is then added. In either case, the dose of the dopamine agonist is built up gradu-ally depending on response and tolerance. Dopamine agonists may also be given to patients with parkinsonism who are taking levodopa and who have end-of-dose akinesia or on-off phenome-non or are becoming resistant to treatment with levodopa. In such circumstances, it is generally necessary to lower the dose of levodopa to prevent intolerable adverse effects. The response to a dopamine agonist is generally disappointing in patients who have never responded to levodopa.

Bromocriptine

Bromocriptine is a D₂ agonist; its structure is shown in Table 16–6. This drug has been widely used to treat Parkinson’s disease in the past but is now rarely used for this purpose, having been super-seded by the newer dopamine agonists. The usual daily dose of bromocriptine for parkinsonism varies between 7.5 and 30 mg. To minimize adverse effects, the dose is built up slowly over 2 or 3 months depending on response or the development of adverse reactions.

Pergolide

Pergolide, another ergot derivative, directly stimulates both D₁ and D₂ receptors. It too has been widely used for parkinsonism but is no longer available in the United States because its use has been associated with the development of valvular heart disease.

Pramipexole

Pramipexole is not an ergot derivative, but it has preferential affin-ity for the D₃ family of receptors. It is effective as monotherapy for mild parkinsonism and is also helpful in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations. Pramipexole may ameliorate affective symptoms. A possible neuroprotective effect has been suggested by its ability to scavenge hydrogen peroxide and enhance neurotrophic activity in mesencephalic dopaminergic cell cultures.

Pramipexole is rapidly absorbed after oral administration, reach-ing peak plasma concentrations in approximately 2 hours, and is excreted largely unchanged in the urine. It is started at a dosage of 0.125 mg three times daily, doubled after 1 week, and again after another week. Further increments in the daily dose are by 0.75 mg at weekly intervals, depending on response and tolerance. Most patients require between 0.5 and 1.5 mg three times daily. Renal insufficiency may necessitate dosage adjustment. An extended-re-lease preparation is now available and is taken once daily at a dose equivalent to the total daily dose of standard pramipexole. The extended-release preparation is generally more convenient for patients and avoids swings in blood levels of the drug over the day.

Ropinirole

Another nonergoline derivative, ropinirole (now available in a generic preparation) is a relatively pure D₂ receptor agonist that is effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations. It is introduced at 0.25 mg three times daily, and the total daily dose is then increased by 0.75 mg at weekly intervals until the fourth week and by 1.5 mg thereafter. In most instances, a dosage between 2 and 8 mg three times daily is necessary. Ropinirole is metabolized by CYP1A2; other drugs metabolized by this isoform may signifi-cantly reduce its clearance. A prolonged-release preparation taken once daily is now available.

Rotigotine

The dopamine agonist rotigotine, delivered daily through a skin patch, was approved in 2007 by the Food and Drug Administration (FDA) for treatment of early Parkinson’s disease. It supposedly pro-vides more continuous dopaminergic stimulation than oral medica-tion in early disease; its efficacy in more advanced disease is less clear. Benefits and side effects are similar to those of other dopamine ago-nists but reactions may also occur at the application site and are sometimes serious. The product was recalled in the United States in 2008 because of crystal formation on the patches, affecting the avail-ability and efficacy of the agonist. It is still available in Europe.

Adverse Effects of Dopamine Agonists

A. Gastrointestinal Effects

Anorexia and nausea and vomiting may occur when a dopamine agonist is introduced and can be minimized by taking the medica-tion with meals. Constipation, dyspepsia, and symptoms of reflux esophagitis may also occur. Bleeding from peptic ulceration has been reported.

B. Cardiovascular Effects

Postural hypotension may occur, particularly at the initiation of therapy. Painless digital vasospasm is a dose-related complication of long-term treatment with the ergot derivatives (bromocriptine or pergolide). When cardiac arrhythmias occur, they are an indica-tion for discontinuing treatment. Peripheral edema is sometimes problematic. Cardiac valvulopathy may occur with pergolide.

C. Dyskinesias

Abnormal movements similar to those introduced by levodopa may occur and are reversed by reducing the total dose of dopamin-ergic drugs being taken.

D. Mental Disturbances

Confusion, hallucinations, delusions, and other psychiatric reac-tions are potential complications of dopaminergic treatment and are more common and severe with dopamine receptor agonists than with levodopa. Disorders of impulse control may lead to compulsive gambling, shopping, betting, sexual activity, and other behaviors . They clear on withdrawal of the offending medication.

E. Miscellaneous

Headache, nasal congestion, increased arousal, pulmonary infil-trates, pleural and retroperitoneal fibrosis, and erythromelalgia are other reported adverse effects of the ergot-derived dopamine ago-nists. Cardiac valvulopathies have occurred with pergolide. Erythromelalgia consists of red, tender, painful, swollen feet and, occasionally, hands, at times associated with arthralgia; symptoms and signs clear within a few days of withdrawal of the causal drug. In rare instances, an uncontrollable tendency to fall asleep at inap-propriate times has occurred, particularly in patients receiving pramipexole or ropinirole; this requires discontinuation of the medication.

Contraindications

Dopamine agonists are contraindicated in patients with a history of psychotic illness or recent myocardial infarction, or with active peptic ulceration. The ergot-derived agonists are best avoided in patients with peripheral vascular disease.