CABGOLIN

Indications

• Parkinson's disease
• Prolactin-secreting tumors (prolactinomas)
• Suppression of lactation

Dosage

Adults: Initially 1 mg daily, increased in steps of 0.5–1 mg

Mechanism of action

Cabergoline acts primarily as an agonist at dopamine D2 receptors, which are G-protein coupled receptors. Activation of these receptors inhibits adenylyl cyclase activity, leading to decreased intracellular cAMP levels. This results in reduced release of prolactin from lactotrophs in the pituitary gland and improved muscle coordination in individuals with movement disorders. Additionally, cabergoline has a high affinity for D2 receptors and lower affinity for D1, adrenergic, and serotonin receptors, contributing to its therapeutic effects.

Pharmacodynamics

Cabergoline stimulates dopaminergic receptors, particularly D2 and D3 subtypes, which are critical in managing symptoms of Parkinson's disease. The drug enhances motor function by modulating neurotransmitter release in the nigrostriatal pathway. Its effects include reduced prolactin secretion and improved motor control, as well as potential neuroprotective benefits through presynaptic D2 receptor stimulation. Cabergoline is associated with various side effects, including impulse control disorders and fibrotic reactions, necessitating careful monitoring during treatment.

Pharmacokinetics

Cabergoline is administered orally and is well absorbed, with peak plasma concentrations reached within 1 to 4 hours post-dose. It has a long half-life, allowing for once or twice weekly dosing. The drug undergoes hepatic metabolism, mainly via CYP3A4, and is excreted primarily in feces. Dose adjustments may be necessary in patients with hepatic impairment due to increased plasma concentrations. Regular monitoring is required to evaluate for potential cardiac and pulmonary fibrotic complications associated with long-term use.

Contra-indications

• history of puerperal psychosis
• pulmonary fibrotic disorders
• retroperitoneal fibrotic disorders
• severe cardiovascular disease
• history of serious mental disorders, especially psychotic disorders
• pre-eclampsia

Adverse effects

• pulmonary fibrotic reactions
• retroperitoneal fibrotic reactions
• pericardial fibrotic reactions
• hypotensive reactions
• excessive daytime sleepiness
• sudden onset of sleep
• impulse control disorders such as pathological gambling, binge eating, and hypersexuality

Interactions

• dronedarone: increases concentration of cabergoline
• cobicistat: increases concentration of cabergoline
• crizotinib: increases concentration of cabergoline
• idelalisib: increases concentration of cabergoline
• imatinib: increases concentration of cabergoline
• memantine: increases effects of cabergoline
• metoclopramide: decreases effects of cabergoline
• nilotinib: increases concentration of cabergoline

Precautions

• monitor for pituitary enlargement, particularly during pregnancy
• monitor visual field to detect secondary field loss in macroprolactinoma
• monitor blood pressure for a few days after starting treatment and following dosage increase
• caution in patients with a history of peptic ulcer
• caution in patients with Raynaud's syndrome
• monitor for dyspnoea, persistent cough, chest pain, and cardiac failure

Pregnancy

Avoid use during pregnancy due to potential risks; monitoring for fibrotic reactions is advised.

Breast-feeding

Suppresses lactation; avoid breastfeeding for about 5 days if lactation prevention fails.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• tablets
• oral suspension

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 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. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D1, α₁,- and α₂- adrenergic, and 5-HT₁- and 5-HT₂-serotonin receptors.

Pharmacodynamics

Cabergoline 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- and D₃-receptors. It also exhibits: agonist activity (in order of decreasing binding affinities) on 5-hydroxytryptamine (5-HT)_2B, 5-HT_2A, 5-HT_1D, dopamine D₄, 5-HT_1A, dopamine D₁, 5-HT_1B and 5-HT_2C receptors and antagonist activity on α_2B, α_2A, and α_2C 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.