Cabergoline and Octreotide

Mechanism

Pharmacological Class and Group

Potent long-acting ergotin dopamine agonist (Cabergoline) and Long-acting synthetic somatostatin analogue (Octreotide).

Mechanism of Action

Both drugs selectively suppress the secretion of trophic pituitary hormones through inhibitory G protein-coupled receptors (G_i):

• Cabergoline: It has a high affinity and selectivity for the dopamine type 2 receptor (D2R) expressed in the cell membrane of the lactotroph cells of the anterior lobe of the pituitary gland. Their union mimics the physiological hypothalamic dopaminergic tone of prolactin inhibition.
• Octreotide: It is an octapeptide analogue of natural somatostatin with markedly higher affinity and pharmacological stability for somatostatin receptor subtypes 2 and 5 (SSTR2, SSTR5), expressed mainly in growth hormone (GH)-producing somatotroph cells.

Inhibitory Intracellular Signaling

1. G_i Protein Coupling: Both the activation of D2R by cabergoline and SSTR2/5 by octreotide recruit inhibitory G proteins:

D₂ / SSTR2 agonists G_i activation Inhibition of adenylate cyclase

2. Reduction of cAMP and Inactivation of PKA: By decreasing the levels of cytoplasmic cAMP, protein kinase A (PKA) is inactivated, stopping the transcription of the genes that code for prolactin and growth hormone.

3. L Type Calcium Channel Blocking and Potassium Channel Opening GIRK: Promotes cellular hyperpolarization through potassium efflux. This dramatically decreases voltage-coupled cellular entry of extracellular calcium, terminally blocking pulsatile exocytosis of prolactin/GH-secreting granules.

4. Antitumor and Antiproliferative Effect: It induces cell cycle arrest in the G1 phase and activates programmed apoptosis mechanisms mediated by cytoplasmic phosphatases, progressively reducing the tumor mass of pituitary macroadenomas and microadenomas.

Pharmacokinetics

High Resolution Pharmacokinetics

• Cabergoline (Oral Route): Variable bioavailability. Its binding to plasma proteins is 41%. Extensive hepatic metabolism by hydrolysis (independent of CYP450). Extremely long elimination half-life of between 63 and 69 hours in healthy volunteers, prolonged in hyperprolactinemic patients, which allows taking 1 or 2 times a week.
• Octreotide (Subcutaneous or IM Depot): Complete SC bioavailability (100%). Maximum plasma concentration reached 30 minutes after SC injection. Short plasma half-life of 1.7 hours for the immediate formulation; LAR (Long-Acting Release) intramuscular depot presentations allow administration intervals every 4 weeks due to their encapsulation in biodegradable polymer microspheres.

Indicators and dose

Clinical Indications and Off-Label Uses

Indications of Cabergoline

• First-line treatment in prolactinomas (microprolactinomas and macroprolactinomas) to restore fertility, correct galactorrhea and normalize secondary hypogonadism.
• Inhibition or suppression of postpartum physiological lactation for medical reasons.
• Advanced Parkinson's disease (as adjuvant therapy at high doses).
• Acromegaly (off-label / adjuvant): Partial efficacy in mixed GH and Prolactin producing tumors.

Indications of Octreotide

• Acromegaly: Control of circulating levels of GH and IGF-1 in patients refractory to pituitary surgery or radiotherapy.
• Gastroenteropancreatic neuroendocrine tumors (GEP-NET): For the symptomatic relief of skin flushing and profuse secretory diarrhea in Carcinoid Syndrome.
• Acute hemorrhage from esophageal varices (due to induction of selective splanchnic vasoconstriction).

Dosage and Clinical Adjustment

Cabergoline (Hyperprolactinemia / Prolactinoma):

• Initial Dose: 0.25 mg to 0.5 mg weekly by mouth, given as a single dose or divided into two weekly doses (e.g., 0.25 mg on Tuesdays and 0.25 mg on Fridays). Preferably ingest at night with dinner to alleviate nausea and orthostatism.
• Dose Adjustment: Assess serum prolactin levels every 4 weeks, increasing the dose in steps of 0.25-0.5 mg weekly according to goals. Most prolactinomas are controlled with doses between 0.5 mg and 1.0 mg weekly (maximum dose of 4.5 mg weekly).

Octreotide (LAR - Acromegaly):

• Initial Dose (Depot Formulation): 20 mg by deep intramuscular route in the gluteal region every 4 weeks for a period of 3 months. Subsequently, adjust the dose to 10 mg or 30 mg every 4 weeks according to the normalized serum growth hormone (GH < 1 µg/L) and IGF-1 values.

Adjustment in Renal/Hepatic Failure: No adjustment is required in renal dysfunction. Reduce doses in advanced liver cirrhosis Child-Pugh C due to a net decrease in the metabolic clearance of thionamides and peptides.

Security

Absolute and Relative Contraindications

Cabergoline contraindications

• Known hypersensitivity to ergot derivatives (ergotins).
• Personal history of fibrous valvular heart disease: Evidence of valvular thickening or retraction of any of the four heart valves (risk induced at high doses by stimulation of serotonin 5-HT2B receptors).
• Uncontrolled high blood pressure or preeclampsia in pregnancy.

Contraindications of Octreotide

• Hypersensitivity to the peptide.
• Severe symptomatic pre-existing cholelithiasis or refractory choledocholithiasis.

Adverse Effects (ADR) and Specific Toxicity

• Cabergoline (Common 1%-10%): Postural dizziness, headaches, nausea, vomiting, symptomatic orthostatic hypotension (due to peripheral dopaminergic stimulation), nasal congestion, transient fatigue, impulse control disorders (hypersexuality, gambling, compulsive shopping due to overstimulation of the mesolimbic dopaminergic reward system).
• Cabergoline (Rare): Refractory Fibrosing Heart Valve Disease and retroperitoneal/pleural fibrosis (ADR linked to high cumulative doses > 2-3 mg weekly).
• Octreotide (Very common >10%): Acute gastrointestinal disturbances: steatorrheic diarrhea with floating greasy stools (due to potent blockage of the secretion of pancreatic exocrine enzymes), crampy abdominal pain, nausea, flatulence.
• Octreotide (Common 1%-10%): Cholelithiasis and biliary sludge (in up to 25% of patients due to suppression of motility and cholecystokinin-mediated gallbladder emptying), hypoglycemia or hyperglycemia (simultaneously and variably blocks the secretion of insulin and pancreatic glucagon), mild hypothyroidism (suppression TSH transient).

Class Alert: Valvulopathy due to Cabergoline and 5-HT2B Receptors

At high doses (common in the treatment of Parkinson's, but exceptional in standard endocrine prolactinoma dosing), cabergoline acts as a potent agonist of serotonin 5-HT2B receptors expressed on heart valve fibroblasts. Stimulation of these receptors induces fibroblast proliferation and massive collagen deposition:

Stimulation of the 5-HT_{2B receptor} Mitral/Aortic Valve Fibrogenesis Restrictive valve regurgitation

It is recommended to perform a baseline transthoracic echocardiogram before starting treatment with cabergoline and periodically if weekly doses greater than 2 mg are used cumulatively.

Drug Interactions of Clinical Relevance

• Dopaminergic antagonists (antipsychotics such as Haloperidol, Risperidone, or antiemetics such as Metoclopramide, Sulpiride): They completely annul the inhibitory therapeutic effect of cabergoline on lactotroph cells, rapidly worsening hyperprolactinemia.
• Macrolide antibiotics (Erythromycin, Clarithromycin): Clearance inhibitors, increasing the bioavailability and systemic levels of cabergoline with an increase in severe orthostatic hypotension.
• Ciclosporine (with Octreotide): Drastically decreases intestinal absorption of cyclosporine, with risk of acute graft rejection in transplant patients. Requires strict monitoring of serum cyclosporine levels.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Cabergoline should be discontinued once pregnancy is confirmed in patients with stable microprolactinomas or macroprolactinomas, to avoid unnecessary exposure to the fetus (although retrospective studies in >1000 pregnancies have not shown increased rates of spontaneous abortion or congenital malformations). If the tumor is a macroadenoma with risk of optical volumetric expansion during pregnancy, cabergoline can be continued under strict ophthalmological monitoring. Octreotide should be avoided due to the theoretical risk of restricting uteroplacental perfusion.
• Breastfeeding: Absolutely contraindicated for cabergoline because it physiologically cancels milk production by suppressing prolactin. It is unknown whether octreotide passes into milk, but its use is not advised during this period.