DA agonists - Ergot derivaties: Bromocriptine

Abstract

Bromocriptine is a tetracyclic ergoline compound derived from plant alkaloids. 6 It is the first DA agonist marketed for the treatment of PD. Bromocriptine is a D2-like receptor agonist and a partial D1-like receptor agonist (which means that it has some weak D1 antagonistic effects on normosensitive receptors). Like most ergot derivatives, bromocriptine has also 5-HT2 antagonist effects and mild adrenergic effects.Bromocriptine improves the symptoms of all available rodent and primate models of PD. Bromocriptine lowers prolactine plasma levels, induces nausea and lowers blood pressure. Some authors speculate that bromocriptine might have neuroprotective properties because it can act in vitro as a free radical scavenger, and it can reduce DA turnover in vivo and therefore, may minimize damage caused by oxidative stress. 7,8 PHARMACOKINETICSAfter oral administration, bromocriptine is not completely absorbed (in humans), and maximal plasma levels are reached after 70 to 100 minutes with high variations among individuals.9,10 The absolute oral bioavailability is less than 10 % since 90% of it undergoes first-pass hepatic metabolism. Bromocriptine plasma elimination half-life is about 6-8 hours. Ninety percent is bound to plasma proteins. Only a small amount is excreted unchanged in the urine (5%). The high level of metabolism that occurs increases the risk of drug interaction. Macrolides, acting as enzyme inhibitors and displacing bromocriptine from the binding protein, may lead to increased plasma bromocriptine concentrations and toxicity. REVIEW OF CLINICAL STUDIESThis paragraph is limited to clinical trials involving standard formulations of bromocriptine. A slow release formulation of bromocriptine has also been developed, but is excluded from this review because it has not been marketed in most countries. 11,12 PREVENTION OF DISEASE PROGRESSIONLevel-I Studies Olanow et al. (1995) 13 : Olanow and colleagues performed a randomized, parallel groups, double-blind, placebo-controlled study (also known as the SINDEPAR trial), which assessed the effect of selegiline and bromocriptine on the progression of PD. In this study, 101 untreated patients with PD (mean age = 66 years) were randomly assigned to one of the following four treatment groups (Deprenyl(r) plus Sinemet(r); placebo-Deprenyl(r) plus Sinemet(r); Deprenyl(r) plus bromocriptine; placebo-Deprenyl(r) plus bromocriptine). The final visit was performed at 14 months, 2 months after withdrawal of Deprenyl (or its placebo) and 7 days after withdrawal of Sinemet or bromocriptine. Deterioration of UPDRS total score between baseline and final visit was used as an index of PD progression. Deterioration in UPDRS score was not significantly different in patients randomized to treatment with Sinemet (1.7 ±1.6) or bromocriptine (4.5±1.2), suggesting that the disease probably progressed at the same rate in the L-dopa-and bromocriptine-treated patients. This result does not support a "neuroprotective" effect of bromocriptine. However, in the absence of placebo only-treated...