Dopaminergic Agonists

Mechanism

Mechanism of Action

Cabergoline and Bromocriptine are alkaloid derivatives of ergot that act as highly selective agonists of dopamine type 2 (D₂) receptors located in the membranes of the lactotroph cells of the adenohypophysis.

Physiology of Prolactin Suppression

1. Inhibition of Adenylate Cyclase (Gi pathway): The binding of the drug to the D₂ receptor activates the Gi inhibitory subunit of the G protein, suppressing the intracellular activity of adenylate cyclase and decreasing intracellular levels of cAMP.
2. Blocking Prolactin synthesis: The reduction of cAMP inactivates calcium-dependent transcriptional kinase, blocking the transcription of the genes that encode prolactin. The exocytosis of circulating preformed prolactin granules is inhibited immediately and sustainably.
3. Effect on the gonadotropic axis: The therapeutic decrease in prolactin restores the normal and pulsatile secretion of hypothalamic GnRH, allowing the physiological resumption of the release of pituitary FSH and LH, reestablishing ovarian folliculogenesis and correcting the chronic anovulation of hyperprolactinemia.

Pharmacokinetics

Pharmacokinetics

• Route of administration: Oral; Cabergoline can also be administered vaginally in patients with severe gastrointestinal intolerance.
• Bromocriptine: Rapid absorption but undergoes massive hepatic first-pass metabolism (bioavailability of only 6%). It requires daily dosing in multiple doses due to its short elimination half-life of approx. 12 to 15 hours.
• Cabergoline: Rapid absorption. It stands out for having an extremely long affinity of very slow dissociation of pituitary D2 receptors. It has an ultra-long plasma elimination half-life of approx. 63 to 68 hours in healthy subjects, allowing convenient dosing regimens of one or two weekly doses.
• Excretion: Mainly fecal-biliary after inactive hepatic conjugation.

Indicators and dose

Indications

• Treatment of disorders associated with hyperprolactinemia, including secondary amenorrhea, oligomenorrhea, chronic anovulation, infertility and galactorrhea of any etiology.
• Primary medical treatment of prolactin-secreting pituitary adenomas (micro- and macroprolactinomas) due to their ability to induce apoptosis and reduction in tumor size.
• Physiological inhibition or suppression of postpartum breastfeeding for strict medical indication (e.g., fetal death, perinatal loss, or severe maternal breast infection).

Dosing and Precision Adjustment

• Treatment of Hyperprolactinemia (Cabergoline): Start with very low doses of 0.25 to 0.5 mg orally per week, divided into one or two weekly doses (e.g., taken with dinner on Mondays and Thursdays to mitigate dizziness). It can be adjusted monthly by increasing by 0.25-0.5 mg until plasma prolactin levels are normalized (average therapeutic dose of 1 mg/week).
• Postpartum lactation inhibition (Cabergoline): 1 mg administered as a single dose orally in the first 24 hours after delivery.
• Established lactation suppression (Cabergoline): 0.25 mg orally every 12 hours for 2 consecutive days to prevent congestive rebound.

Pregnancy and Breastfeeding

FDA category B for cabergoline. In women treated for infertility associated with microprolactinoma, it is recommended to discontinue cabergoline as soon as a positive pregnancy test is confirmed to avoid fetal exposure in utero, except in exceptional cases of macroprolactinomas with imminent risk of compression of the maternal optic chiasm due to gestational tumor growth. Its use is contraindicated if you wish to maintain active breastfeeding.

Security

Contraindications

• Hypersensitivity to ergot alkaloids.
• History or suspicion of underlying fibrotic heart valve pathologies (serious complication associated with stimulation of serotonin 5-HT_2B receptors at continuous high doses).
• Preeclampsia or eclampsia in the immediate postpartum.
• Active uncontrolled arterial hypertension.
• Severe active psychotic disorders or history of induced psychosis.

Adverse Effects (ADR)

• Gastrointestinal: Very frequent nausea (30% of patients), reflex vomiting and constipation due to slowing of gastrointestinal smooth motility.
• Cardiovascular: Severe orthostatic hypotension with dizziness and transient syncope after initial doses (due to peripheral vasodilation mediated by peripheral dopamine receptors).
• CNS: Headache, daytime drowsiness and sudden drowsiness (caution when driving).