Dopaminergic Agonists

DOPAMINERGIC AGONISTS

The DA agonists can act on striatal DA receptors even in advanced patients who have largely lost the capacity to synthesize, store and release DA from levodopa. Moreover, they are longer acting, can exert subtype selective activation of DA receptors involved in parkinsonism and not share the concern expressed about levodopa of contributing to dopaminergic neuronal damage by oxidative metabolism.

Bromocriptine

It is an ergot derivative which acts as potent agonist on D2, but as partial agonist or antagonist on D1 receptors. Improvement in parkinsonian symptoms occurs within ½–1 hr of an oral dose of bromocriptine and lasts for 6–10 hours. If used alone, doses needed in parkinsonism are high, expensive and often produce intolerable side effects—vomiting, hallucinations, hypotension, nasal stuffiness, conjunctival injection. Marked fall in BP with the ‘first dose’ has occurred in some patients, especially those on antihypertensive medication.

In parkinsonism, bromocriptine is used only in late cases as a supplement to levodopa: starting with low doses (1.25 mg once at night) and gradually increasing as needed upto 5–10 mg thrice daily. It serves to improve control and smoothen ‘end of dose’ and ‘onoff’ fluctuations. Dyskinesias are less prominent with bromocriptine compared to levodopa.

PROCTINAL, SICRIPTIN, PARLODEL, 1.25, 2.5 mg tabs, ENCRIPT 2.5, 5 mg tabs.

Ropinirole and Pramipexole

These are two recently developed non-ergoline, selective D2/D3 receptor agonists with negligible affinity for D1 and nondopaminergic receptors. Pramipexole has relatively greater affinity for D3 receptors. Therapeutic effect as supplementary drugs to levodopa in advanced cases of PD as well as side effect profile is similar to bromocriptine, but they are better tolerated with fewer g.i. symptoms. Consequently dose titration for maximum improvement can be achieved in 1–2 weeks, while the same may take several months with bromocriptine.

Ropinirole and pramipexole are now frequently used as monotherapy for early PD as well. Trials have found them to afford symptom relief comparable to levodopa. Fewer cases treated with ropinirole needed supplemental levodopa than those treated with bromocriptine. The Parkinson Study Group and other multicentric trials have noted lower incidence of dyskinesias and motor fluctuations among patients treated with these drugs than those treated with levodopa. There is some indirect evidence that use of these DA agonists may be associated with slower rate of neuronal degeneration. Such encouraging findings indicate that the newer DA agonists are effective alternatives to levodopa and afford longer symptom free life to PD patients.

Ropinirole is rapidly absorbed orally, 40% plasma protein bound, extensively metabolized, mainly by hepatic CYP1A2, to inactive metabolites, and eliminated with a terminal t½ of 6 hrs. It is thus longer acting than levodopa, useful in the management of motor fluctuations and reducing frequency of on off effect.

Side effects are nausea, dizziness, hallucinations, and postural hypotension. Episodes of day time sleep have been noted with ropinirole as well as pramipexole. The higher incidence of hallucinations and sleepiness may disfavour their use in the elderly.

Ropinirole has recently been approved for use in ‘restless leg syndrome’.

Ropinirole: Starting dose is 0.25 mg TDS, titrated to a maximum of 4–8 mg TDS. Early cases generally require 1–2 mg TDS.

ROPITOR 0.25, 0.5, 1.0, 2.0 mg tabs. ROPITOR, ROPARK, ROPEWAY 0.25, 0.5, 1.0, 2.0 mg tabs.

Pramipexole: Starting dose 0.125 mg TDS, titrate to 0.5–1.5 mg TDS.

Pergolide (bromocriptinelike) and Piribedil (apomorphinelike) are other DA agonists used in parkinsonism.