Bromocriptine Other names: Bromocriptine mesylate 2-Bromoergocriptine

Bromocriptine is an inhibitor of prolactin secretion and a stimulator of dopamine receptors. The areas of application of bromocriptine are divided into endocrinological and neurological indications. The pharmacological particulars will be discussed under each indication.

Endocrinological indications

Bromocriptine inhibits the secretion of the anterior pituitary hormone prolactin without affecting normal levels of other pituitary hormones. However, bromocriptine is capable of reducing elevated levels of growth hormone (GH) in patients with acromegaly. These effects are due to stimulation of dopamine receptors.

In the puerperium prolactin is necessary for the initiation and maintenance of puerperal lactation. At other times increased prolactin secretion gives rise to pathological lactation (galactorrhoea) and/or disorders of ovulation and menstruation.

As a specific inhibitor of prolactin secretion, bromocriptine can be used to prevent or suppress physiological lactation as well as to treat prolactin-induced pathological states. In amenorrhoea and/or anovulation (with or without galactorrhoea), bromocriptine can be used to restore menstrual cycles and ovulation.

The customary measures taken during lactation suppression, such as the restriction of fluid intake are not necessary with bromocriptine. In addition, bromocriptine does not impair the puerperal involution of the uterus and does not increase the risk of thromboembolism.

Bromocriptine has been shown to arrest the growth or to reduce the size of prolactin-secreting pituitary adenomas (prolactinomas).

In acromegalic patients – apart from lowering the plasma levels of growth hormone and prolactin – bromocriptine has a beneficial effect on clinical symptoms and on glucose tolerance.

Bromocriptine improves the clinical symptoms of the polycystic ovary syndrome by restoring a normal pattern of LH secretion.

Neurological Indications

Because of its dopaminergic activity, bromocriptine, in doses usually higher than those for endocrinological indications, is effective in the treatment of Parkinson’s Disease, which is characterised by a specific nigrostriatal dopamine deficiency. The stimulation of dopamine receptors by PARLODEL can in this condition restore the neurochemical balance within the striatum.

Clinically, bromocriptine improves tremor, rigidity, bradykinesia and other Parkinsonian symptoms at all stages of the disease. Usually the therapeutic effect lasts over years (so far, good results have been reported in patients treated up to eight years). Bromocriptine can be given either alone or – at early as well as advanced stages – combined with other anti-Parkinsonian drugs. Combination with Levodopa treatment results in enhanced anti-Parkinsonian effects, often making possible a reduction of the Levodopa dose. Bromocriptine offers particular benefit to patients on Levodopa treatment exhibiting a deteriorating therapeutic response or complications such as abnormal involuntary movements (choreoatoid dykinesia and/or painful dystonia), end-of-dose failure, and ‘on-off’ phenomenon.

Bromocriptine improves the depressive symptomatology often observed in parkinsonian patients. This is due to its inherent antidepressant properties as substantiated by controlled studies in non-Parkinsonian patients with endogenous or psychogenic depression.

Following oral administration, bromocriptine is rapidly and well absorbed. Peak plasma levels are reached within 1-3 hours. An oral dose of 5mg of bromocriptine results in a C_max of 0.465ng/ml. The prolactin-lowering effect occurs 1-2 hours after ingestion, reaches its maximum within about 5 hours and lasts for 8-12 hours.

Bromocriptine is extensively metabolised. In plasma the elimination half life is 3-4 hours for the parent drug and 50 hours for the inactive metabolites. The parent drug and its metabolites are also completely excreted via the liver with only 6% being eliminated via the kidney. Bromocriptine is 96% bound to plasma proteins.

There is no evidence that the pharmacokinetic properties and tolerability of bromocriptine are directly affected by advanced age. However, in patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may increase, requiring dose adjustment.

Biotransformation

Bromocriptine undergoes extensive first-pass biotransformation in the liver, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and faeces. It shows a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constitute a main metabolic pathway. Inhibitors and/or potent substrates for CYP3A4 might therefore be expected to inhibit the clearance of bromocriptine and lead to increased levels. Bromocriptine is also a potent inhibitor of CYP3A4 with a calculated IC50 value of 1.69 µM. However, given the low therapeutic concentrations of free bromocriptine in patients, a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected.

Pre-clinical data for bromocriptine reveal no special hazard for humans based on conventional studies of single and repeat dose toxicity, genotoxicity, mutagenicity, carcinogenic potential or toxicity to reproduction.

Endometrial carcinomas were observed in pre-clinical rat studies at high dosages only. They are considered to be due to the species-specific sensitivity of the test animals to the pharmacological activity of bromocriptine.

Other effects in pre-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.