Atosiban

Mechanism

Mechanism of Action

Atosiban is a synthetic peptide that acts as a selective competitive antagonist of the oxytocin receptors (OXTR) and the vasopressin receptor type V_1a located in the pregnant myometrial muscle cell.

Molecular Mechanism of Tocolytic Blockade

1. Inhibition of the Calcium cascade: By competitively binding to OXTR, atosiban prevents the coupling of oxytocin. This stops the activation of phospholipase C, completely blocking the generation of IP₃ and the subsequent release of calcium from sarcoplasmic reticulum stores.
2. Myometrial quiescence: The reduction of free cytosolic calcium inactivates the calcium-calmodulin complex, inhibiting the phosphorylation of myosin light chains by MLCK. The uterus recovers a state of dynamic relaxation and quiescence.
3. V_1a blockade: Its moderate antagonist activity on the V_1a receptor additionally inhibits the minor contractile effects mediated by endogenous plasma vasopressin.

Pharmacokinetics

Pharmacokinetics

• Rout of administration: Exclusively intravenous, structured in three consecutive phases (rapid initial bolus, concentrated rapid loading infusion and subsequent prolonged maintenance infusion).
• Distribution: Apparent volume of distribution of approx. 18 to 25 L. It is moderately bound to plasma proteins (46-48%). It crosses the placental barrier in clinically safe amounts (fetal/maternal concentration ratio of 0.12).
• Metabolism: It is cleaved by enzymatic hydrolysis of specific peptide bonds, generating two main inactive metabolites (M1 and M2). It is not a significant substrate of hepatic cytochrome P450.
• Half-life (t_1/2): Short. It presents an initial phase of rapid plasma clearance (13 minutes) and a terminal elimination phase of about 1.7 to 1.8 hours.
• Excretion: Predominant renal excretion in the form of inactive polar metabolites.

Indicators and dose

Indications

• Delay of imminent preterm birth in pregnant women who present:
  - Regular uterine contractions lasting at least 30 seconds, with a frequency of 4 in 30 minutes.
  - Cervical dilation of 1 to 3 cm and 50% effacement.
  - Gestational age between 24 and 33 complete weeks.
  - Normal fetal heart rate.

Dosage and Administration Protocol

The treatment must be carried out continuously and rigorously in three consecutive phases, without exceeding 48 hours of total cumulative infusion:

Pregnancy and Breastfeeding

Only indicated if imminent preterm birth is diagnosed between weeks 24 and 33 of gestation. It is not prescribed during active puerperal breastfeeding.

Security

Contraindications

Absolute

• Gestational age < 24 weeks or > 33 completed weeks.
• Premature rupture of membranes (PROM) with suspected or confirmed active chorioamnionitis (delayed delivery increases the risk of neonatal or maternal sepsis).
• Severe uterine hemorrhage with hemodynamic compromise (placental abruption, placenta prior).
• Intrauterine fetal death or suspected critical fetal compromise.
• Severe preeclampsia or medically indicated eclampsia that ends immediately.

Relative

• Severe intrauterine growth restriction (IUGR).
• Suspected silent placenta prior without active bleeding.
• Multiple pregnancy (higher failure rate of pharmacological tocolysis).

Adverse Effects (ADR)

Atosiban stands out for having the best maternal-fetal tolerability profile of all clinically active tocolytic agents:

• Local reactions: Pain, erythema or inflammation at the intravenous injection site (7-10% of cases).
• Gastrointestinal: Mild nausea or vomiting.
• Vascular: Hot flashes, minor transient hypotension and marginal hyperglycemia.
• Fetal: Does not significantly alter the fetal hemodynamic profile or the variability of the newborn's heart rate.

Interactions

It does not present clinically relevant interactions. It is compatible with the concomitant use of antenatal corticosteroids for fetal lung maturation (betamethasone/dexamethasone) and maintenance micronized progesterone.