BROMODEL

Indications

• Parkinson's disease
• Hyperprolactinemia
• Acromegaly
• Type 2 diabetes mellitus (as an adjunct treatment)

Dosage

Adults: The usual adult dose for Parkinson's disease is 1.25 mg to 2.5 mg taken once or twice daily, which may be increased

Mechanism of action

Bromocriptine stimulates dopamine D2 receptors, which are G-protein coupled receptors. This leads to the inhibition of adenylyl cyclase activity, resulting in decreased levels of intracellular cAMP and reduced release of intracellular calcium through voltage-gated calcium channels. The inhibition of calcium influx contributes to the drug's effects in treating movement disorders and hormonal imbalances. Additionally, bromocriptine's action on these receptors mediates neuroprotective effects and influences hormone secretion in the pituitary gland.

Pharmacodynamics

Bromocriptine exhibits potent agonist activity at dopamine D2 and D3 receptors, which are crucial for the management of Parkinson's disease and other dopaminergic disorders. The stimulation of postsynaptic D2 receptors primarily accounts for the antiparkinsonian effects, while presynaptic D2 receptor stimulation may confer neuroprotective benefits. The drug also interacts with serotonin receptors, including 5-HT1D and 5-HT1A, contributing to its pharmacological profile.

Pharmacokinetics

Bromocriptine is well absorbed following oral administration, with peak plasma concentrations typically reached within 1 to 3 hours. The drug undergoes extensive first-pass metabolism in the liver, leading to a variable bioavailability. It is primarily metabolized via CYP3A4 and has a half-life of approximately 3 to 6 hours. The drug is excreted mainly in the bile, with a minor portion eliminated in urine. Renal and hepatic impairment may affect the drug’s clearance and necessitate dose adjustments.

Contra-indications

• Hypersensitivity to bromocriptine or any of its components
• Severe cardiovascular disorders
• Pregnancy (in the context of certain conditions such as uncontrolled hypertension or pre-eclampsia)

Adverse effects

• Nausea
• Headache
• Dizziness
• Fatigue
• Orthostatic hypotension
• Somnolence
• Constipation
• Dry mouth
• Abdominal cramps

Interactions

• Antihypertensive agents (may enhance hypotensive effects)
• Dopamine antagonists (may reduce the effectiveness of bromocriptine)
• Ergot alkaloids (increased risk of vasospastic reactions)
• Other medications acting on the central nervous system (may increase sedative effects)

Precautions

• Use with caution in patients with a history of severe mental illness
• Monitor blood pressure regularly, especially in patients with cardiovascular disease
• Caution in patients with hepatic impairment
• Discontinue if new or worsening psychiatric symptoms occur

Pregnancy

Bromocriptine is contraindicated during pregnancy when used for conditions such as hyperprolactinemia or acromegaly, due to potential risks to the fetus. However, it may be used in special cases under strict medical supervision.

Breast-feeding

Bromocriptine may inhibit lactation. Caution is advised when used by breastfeeding mothers, and it is generally not recommended.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 2.5 mg, 5 mg

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.

Pharmacodynamics

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.