indication

For the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications. Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome.

pharmacology

Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D₁ and D₅ subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D₂, D₃ and D₄ subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D₂ and D₃ receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D₂ stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D₂ stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D₂-receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT)_1D, dopamine D₃, 5-HT_1A, 5-HT_2A, 5-HT_1B, and 5-HT_2C receptors, antagonist activity on α_2A-adrenergic, α_2C, α_2B, and dopamine D₁ receptors, partial agonist activity at receptor 5-HT_2B, and inactivates dopamine D₄ and 5-HT₇ receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT_2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT_1B and 5-HT_2B receptors.

mechanism of action

The dopamine D₂ receptor is a 7-transmembrane G-protein coupled receptor associated with G_i proteins. In lactotrophs, stimulation of dopamine D₂ receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca²⁺ from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D₂ receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders.

toxicity

Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension.

biotransformation

Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion.

absorption

Approximately 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1.5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2.5 mg and decreased growth hormone concentrations persist for at least 4-5 hours.

half life

2-8 hours

route of elimination

Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney.

drug interactions

Acetophenazine: The phenothiazine decreases the effect of bromocriptine

Chlorpromazine: The phenothiazine decreases the effect of bromocriptine

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Erythromycin: Erythromycin increases serum levels of bromocriptine

Ethopropazine: The phenothiazine decreases the effect of bromocriptine

Fluphenazine: The phenothiazine decreases the effect of bromocriptine

Josamycin: Erythromycin increases serum levels of bromocriptine

Mesoridazine: The phenothiazine decreases the effect of bromocriptine

Methdilazine: The phenothiazine decreases the effect of bromocriptine

Methotrimeprazine: The phenothiazine decreases the effect of bromocriptine

Paliperidone: The atypical antipsychotic agent, paliperidone, may decrease the therapeutic effect of the anti-Parkinson's agent, bromocriptine. This interaction may be due to the dopamine antagonist properties of paliperidone. Consider an alternate antipsychotic in those with Parkinson's disease or consider using clozapine or quetiapine if an atypical antipsychotic is necessary.

Perphenazine: The phenothiazine decreases the effect of bromocriptine

Phenylpropanolamine: The sympathomimetic, phenylpropanolamine, increases the toxicity of bromocriptine.

Prochlorperazine: The phenothiazine decreases the effect of bromocriptine

Promazine: The phenothiazine decreases the effect of bromocriptine

Promethazine: The phenothiazine decreases the effect of bromocriptine

Propiomazine: The phenothiazine decreases the effect of bromocriptine

Pseudoephedrine: The sympathomimetic, pseudoephedrine, increases the toxicity of bromocriptine.

Tacrolimus: Bromocriptine may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Bromocriptine therapy is initiated, discontinued or altered.

Telithromycin: Telithromycin may reduce clearance of Bromocriptine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Bromocriptine if Telithromycin is initiated, discontinued or dose changed.

Thiethylperazine: The phenothiazine decreases the effect of bromocriptine

Thioridazine: The phenothiazine decreases the effect of bromocriptine

Thiothixene: Thiothixene may antaonize the effects of the anti-Parkinsonian agent, Bromocriptine. Consider alternate therapy or monitor for decreased effects of both agents.

Tipranavir: Tipranavir may increase the plasma concentration of Bromocriptine. Concomitant therapy should be avoided.

Tramadol: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Tranylcypromine: Increased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trifluoperazine: The phenothiazine decreases the effect of bromocriptine

Triflupromazine: The phenothiazine decreases the effect of bromocriptine

Trimeprazine: The phenothiazine decreases the effect of bromocriptine

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Voriconazole: Voriconazole may increase the serum concentration of bromocriptine likely by decreasing its metabolism. Concomitant therapy is contraindicated.

Ziprasidone: The atypical antipsychotic, ziprasidone, may antagonize the effect of the dopamine agonist, bromocriptine. Consider alternate therapy or monitor for worsening of movement disorder.

Zolmitriptan: Concomitant use of the serotonin 5-HT1D receptor agonist, zolmitriptan, and the ergot derivative, bromocriptine, may result in additive vasoconstrictive effects. Concomitant use within 24 hours is contraindicated. Use of two serotonin modulators, such as zolmitriptan and bromocriptine, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Zuclopenthixol: Antagonism may occur between zuclopenthixol, a dopamine D2 receptor antagonist, and bromocriptine, a dopamine agonist. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of both agents if concurrent therapy is initiated, discontinued or dose(s) changed.