Oxytocin

Mechanism

Mechanism of Action

Oxytocin is a synthetic octapeptide identical to the natural neurohypophysial hormone. It acts as a selective agonist of the oxytocin receptor (OXTR), a G protein-coupled receptor of the Gq/11 subfamily, located in the cells of the uterine myometrium and the myoepithelial cells of the mammary glands.

Intracellular Signaling and Contraction Dynamics

1. Activation of Phospholipase C beta (PLCβ): Oxytocin binding to OXTR activates the α subunit of Gq/11, which stimulates PLCβ to cleave phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG).
2. Release of Intracellular Calcium: IP₃ binds to its specific receptors in the sarcoplasmic reticulum, releasing calcium ions (Ca²⁺) to the cellular cytosol. Simultaneously, DAG activates L-type voltage-gated calcium channels, promoting the influx of extracellular calcium.
3. Calcium-Calmodulin Complex: The increase in cytosolic Ca²⁺ favors its binding to calmodulin. This complex activates myosin light chain kinase (MLCK).
4. Myosin phosphorylation: MLCK phosphorylates the 20 kDa myosin light chains, allowing their interaction with actin and triggering rhythmic uterine contractions, the frequency and amplitude of which emulate spontaneous labor.

Pharmacokinetics

Key Pharmacokinetics

• Routes of administration: Intravenous (continuous infusion dosed by pump for induction) and intramuscular (exclusively for management of PPH in the absence of venous access).
• Bioavailability (F): None orally due to its proteolytic degradation in the stomach by digestive peptidases.
• Distribution: Reduced apparent volume of distribution (approx. 0.2 to 0.3 L/kg). Negligible binding to plasma proteins. Crosses the placental barrier in non-significant trace amounts.
• Metabolism: Extremely rapid purification by enzymatic means. It is hydrolyzed by circulating oxytokinase (a glycoprotein aminopeptidase produced by the placenta that increases exponentially throughout pregnancy) and by tissue peptidases in the liver and kidney.
• Half-life (t_1/2): Very short, from 3 to 5 minutes, which allows minute-by-minute control of uterine dynamics by varying the infusion flow. The steady state is reached 30-40 minutes after starting the infusion.
• Excretion: Renal and biliary, with total plasma clearance of approximately 20 mL/kg/min in the pregnant woman.

Indicators and dose

Indications

• Medical induction or active management of labor for maternal or fetal indication.
• Active prevention and treatment of postpartum hemorrhage (PPH) associated with uterine atony.
• Support treatment in incomplete, delayed or induced abortion.
• Oxytocin tolerance test (contraction stress test) to evaluate placental reserve.

Dosing and Precision Adjustment

Induction and conduction of labor: It is prepared by dissolving 10 IU of oxytocin in 1000 mL of 0.9% normal saline (concentration: 10 mIU/mL). It is recommended to start with a low dose regimen: 1 to 2 mIU/min (6 to 12 mL/hour), increasing at intervals of 15 to 30 minutes by 1 to 2 mIU/min until a pattern of 3 to 4 contractions in 10 minutes is achieved. The maximum safe dose rarely exceeds 20 mIU/min.

Postpartum hemorrhage (Active management of the third period): 10 IU IM after delivery from the anterior shoulder of the fetus, or 20 to 40 IU in 1000 mL of crystalloids infused at a rate of 250 mL/hour immediately after delivery.

Pregnancy and Breastfeeding

FDA Category C. Indicated exclusively for therapeutic use at or near term. During lactation, it is not excreted significantly in breast milk and has no toxicity in the newborn, since it is inactivated orally in the gastrointestinal tract.

Security

Contraindications

Absolute

• Obvious cephalopelvic disproportion (CPD).
• Anomalous fetal presentation or situation (transverse, oblique).
• Acute fetal distress or suspicion of fetal compromise prior to induction.
• Opponent placenta prior or vasa prior.
• History of uterine rupture or more than two previous cesarean sections (or transmural myometrial surgeries).
• Umbilical cord prolapse.

Relative

• Single previous segmental uterine scar.
• Great multiparity (more than 5 births).
• Uterine overdistention (multiple pregnancy, polyhydramnios).
• Severe arterial hypertension or maternal cardiovascular disease.
• Breech presentation.

Adverse Effects (ADR)

• Uterine hyperstimulation (Tachysystole): Defined as > 5 contractions in 10 minutes in two successive periods. It can compromise uteroplacental blood flow, inducing hypoxia and acute fetal acidosis.
• Water intoxication (Dilutional Hyponatremia): Oxytocin shares structural homology with the antidiuretic hormone (vasopressin). At high doses (> 20 mIU/min) and administered with massive volumes of hypotonic solutions (e.g. 5% dextrose), it activates V2 receptors in the renal collecting duct, causing water retention, cerebral edema, seizures and coma.
• Acute arterial hypotension with reflex tachycardia: Especially if administered as a rapid intravenous bolus (contraindicated). Oxytocin relaxes vascular smooth muscle by induction of endothelial nitric oxide.

Interactions

Extreme pharmacodynamic synergy with other prostaglandins (misoprostol, dinoprostone). Their joint administration drastically increases the risk of uterine rupture and tachysystole; Therefore, a minimum interval of 4 to 6 hours should be waited after the last dose of prostaglandins before starting the oxytocin infusion.