Pergolide

Abstract

Synopsis

The semisynthetic ergotine dopamine agonist pergolide has demonstrated activity at pre- and postsynaptic dopamine D₂ receptors in vitro and in vivo animal studies. However, unlike other dopamine agonists such as bromocriptine, pergolide also has agonist activity at dopamine D₁ receptors. Certain other pharmacological effects of pergolide, such as reduction of dopamine turnover and effects on free radical scavenging enzymes, may be relevant in the early treatment of Parkinson’s disease but this has not been conclusively determined.

Short and long term noncomparative studies show that pergolide is an effective adjunct to levodopa therapy in patients with advancing Parkinson’s disease, reducing the adverse effects of long term levodopa monotherapy and often enabling a reduction in levodopa dosage. In placebo comparisons pergolide was generally more effective than placebo and was associated with benefits similar to those seen in noncomparative studies.

Longitudinal comparisons in individual patients indicate that the antiparkinsonian efficacy of pergolide is similar to that of mesulergine, lergotrile and lisuride, and may be superior to that of bromocriptine. Controlled comparisons with bromocriptine tend to support this latter finding.

Studies evaluating the efficacy of pergolide as monotherapy early in the course of Parkinson’s disease have shown the drug to be effective, but opinion is divided as to the value of early treatment with dopamine agonists (as opposed to levodopa monotherapy).

Thus, pergolide is an effective adjunct to levodopa therapy in patients with advanced Parkinson’s disease and may have a role in the treatment of early disease if its postulated beneficial effects on disease progression are proven.

Pharmacodynamic Properties

Pergolide is a semisynthetic ergoline dopamine agonist used in the treatment of Parkinson’s disease. It has potent activity at presynaptic dopamine D2 receptors but is also active at postsynaptic D2 and dopamine D1 receptors.

In vitro, pergolide suppressed D₂-mediated prolactin release from rat anterior pituitary fragments and inhibited potassium-mediated dopamine or acetylcholine release from rat caudate slices. Pergolide-induced activation of rat striatal D₁ receptors has been shown to stimulate adenylate cyclase activity which, in turn, increased production of cyclic AMP.

The majority of receptor binding studies indicate that pergolide is considerably more selective for D₂ than for D₁ receptors.

In vivo, pergolide has been shown to induce contralateral turning in rats with right-side nigrostriatal lesions; it also induced climbing in rats selected on the basis of a climbing response to apomorphine.

Pergolide had similar actions to those of selective D₂ agonists in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced hemiparkinsonian monkeys but was more potent than selective D₁ agonists. Pergolide improved parkinsonian symptoms in another study in this model. Its effects were more marked, but of shorter duration, than those of bromocriptine or cabergoline.

One theory regarding the cause of Parkinson’s disease is that metabolism of dopamine produces free radicals which damage nigral neurons. Its effects on oxygen radical scavenging enzymes are unclear; the drug induced Superoxide dismutase in one in vivo animal study but had no effect in another (but did induce catalase and glutathione peroxidase).

Pharmacokinetic Properties

Single 1, 2, 5 and 10mg doses of pergolide produced mean peak plasma concentrations (Cmax) of 2.09, 4.57, 20.3 and 26 μg/L, respectively, in rhesus monkeys (administration of therapeutic doses to volunteers was considered unethical). The time to Cmax ranged between 2.4 and 2.7 hours at all dose levels.

Mean steady-state pergolide plasma concentrations of 0.0275 to 1.167 μg/L were recorded during treatment with pergolide 2.25 to 9 mg/day in patients with Parkinson’s disease; extensive interpatient variability was noted.

55% of a 0.138mg radiolabelled oral dose of pergolide was excreted in the urine of volunteers; a further 40 to 50% of radioactivity appeared in the faeces and approximately 3% appeared in expired air.

Analysis of urine and faecal extracts indicated the formation of 10 or more metabolites.

Therapeutic Use

A large noncomparative Japanese study has evaluated the short term efficacy of pergolide in combination with levodopa ± carbidopa (n = 314) or as monotherapy (n = 86). Addition of pergolide allowed a significant reduction in levodopa dosage and about 65% of patients experienced at least a mild improvement in wearing off and on-off phenomena. 45.3% of monotherapy recipients experienced at least moderate improvement according to a final global rating scale (vs 52.9% of combination therapy recipients).

Additional noncomparative studies in Australian, Thai, Chinese and Italian patients also reported adjunctive pergolide therapy to be effective.

Early noncomparative long term studies reported an initial response to pergolide but the rate of clinical improvement tended to peak after 2 to 12 months, then decline. However, it does appear that the efficacy of pergolide, despite waning, can be maintained at a satisfactory level for several years.

A long term continuation of the Japanese study discussed above reported a final global improvement rate that was at least moderate in 51.4% of adjunctive pergolide therapy recipients treated for at least 1 year, although the drug tended to become less effective after this time. 62 monotherapy recipients were included in this long term continuation; final global improvement rates were similar (moderate or greater in 61.3% of monotherapy recipients vs 51.4% in the combination therapy group).

Results from a large 6-month multicentre double-blind placebo comparison have confirmed the result of earlier, smaller placebo comparisons. Pergolide recipients (n = 189) experienced a significantly greater improvement in many subjective measures of disease severity than placebo recipients. Pergolide allowed a 24.7% reduction in levodopa dosage compared with an approximate 5% reduction with placebo.

On the basis of longitudinal sequential comparisons in individual patients, pergolide was considered to have similar utility to mesulergine, lergotrile and lisuride and appeared to be more effective than bromocriptine. In addition, a number of controlled studies reported that although both drugs were useful, pergolide tended to allow a greater reduction in levodopa dosage than bromocriptine. The sole available comparison of pergolide and bromocriptine as monotherapy reported the 2 drugs to be similarly effective.

Tolerability

Postural hypotension occurs quite frequently in patients starting pergolide therapy but usually diminishes over time.

In a recent placebo comparison, adverse events occurring significantly more frequently in pergolide recipients included dyskinesia (62% in the pergolide group vs 25% in placebo recipients), nausea (24 vs 13%), hallucinations (14 vs 3%), drowsiness (10 vs 3%), insomnia (8 vs 3%), nasal congestion (7 vs 1%), dyspepsia (6 vs 2%) and dyspnoea (5 vs 1%).

ECG changes and palpitations have been noted in some patients receiving pergolide during clinical trials and close observation may be needed in patients with concomitant heart disease; limited data indicate that addition of domperidone attenuates these cardiac adverse events.

Rarely, abrupt withdrawal of pergolide therapy can cause confusion or hallucinations; thus, when required, cessation of pergolide therapy should be gradual.

Dosage and Administration

To avoid first dose hypotension and other adverse effects such as nausea and vomiting, pergolide therapy must be initiated at a low dosage (often 0.05 mg/day for 2 days). The dose should be slowly increased until maximum clinical benefit is achieved with no or minimal adverse effects.

The drug is administered in divided doses, usually 3 or 4 times per day, and the most frequent effective total daily dose is 3 to 4mg; however, mean effective dosages were somewhat lower in Japanese studies.