化合物信息

Drug Groups

approved; investigational

Description

Bromocriptine mesylate is a semisynthetic ergot alkaloid derivative with potent dopaminergic activity. It is indicated for the management of signs and symptoms of Parkinsonian Syndrome. Bromocriptine also inhibits prolactin secretion and may be used to treat dysfunctions associated with hyperprolactinemia. It also causes sustained suppression of somatotropin (growth hormone) secretion in some patients with acromegaly. Bromocriptine has been associated with pulmonary fibrosis.

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.

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.

Affected Organisms

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

Protein Binding

90-96% bound to serum albumin

Elimination

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

References

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