Pharmacology: Pharmacodynamics: Mechanism of Action: Oxytocin is a cyclic nonapeptide that is obtained by chemical synthesis. This synthetic form is identical to the natural hormone that is stored in the posterior pituitary and released into the systemic circulation in response to suckling and labor. Oxytocin stimulates the smooth muscle of the uterus, more powerfully towards the end of pregnancy, during labor, and immediately postpartum. At these times, the oxytocin receptors in the myometrium are increased. The oxytocin receptors are G-proteins couple receptors. Activation of receptor by oxytocin triggers release of calcium from intracellular stores and thus leads to myometrial contraction. Oxytocin elicits rhythmic contractions in upper segment of uterus, similar in frequency, force and duration to those observed during labor. Being synthetic, it does not contain vasopressin, but even in its pure form oxytocin possesses some weak intrinsic vasopressin-like antidiuretic activity.
Based on in vitro studies, prolonged exposure of oxytocin had been reported to cause desensitization of oxytocin receptors probably due to down-regulation of oxytocin-binding sites, destabilization of oxytocin receptors mRNA and internalization of oxytocin receptors.
Plasma levels and onset/duration of effect: Intravenous infusion: When oxytocin (Oxyla) is given by continuous I.V. infusion at doses appropriate for induction or enhancement of labor, the uterine response sets in gradually and usually reaches a steady state within 20 to 40 minutes. The corresponding plasma levels of oxytocin are comparable to those measured during spontaneous first-stage labor. For example, oxytocin plasma levels in 10 pregnant women at term receiving a 4 milliunits per minute intravenous infusion were 2 to 5 microunits/mL. Upon discontinuation of the infusion, or following a substantial reduction in the infusion rate, e.g. in the event of overstimulation, uterine activity declines rapidly but may continue at an adequate lower level.
Intravenous injection and intramuscular injection: When administered by I.V. or I.M. injection for prevention or treatment of postpartum hemorrhage, oxytocin (Oxyla) acts rapidly with a latency period of less than 1 minute by I.V. injection, and of 2 to 4 minutes by I.M. injection. The oxytocic response lasts for 30 to 60 minutes after I.M. administration, possibly less after I.V. injection.
Pharmacokinetics: Absorption: Oxytocin is rapidly absorbed from the I.M. site. Plasma levels of oxytocin following intravenous infusion at a rate of 4 milliunits/minute in pregnant women at term were 2 to 5 microunits/mL.
Distribution: The steady-state volume of distribution determined in 6 healthy men after I.V. injection was 12.2 L or 0.17 L/kg. Plasma protein binding is negligible for oxytocin. It crosses the placenta in both directions. Oxytocin may be found in small quantities in mother's breast milk.
Biotransformation/Metabolism: Oxytocinase is a glycoprotein aminopeptidase that is produced during pregnancy and appears in the plasma. It is capable of degrading oxytocin. It is produced from both the mother and the fetus. Liver and kidney plays a major role in metabolizing and clearing oxytocin from the plasma. Thus, liver, kidney and systemic circulation contribute to the biotransformation of oxytocin.
Elimination: Plasma half-life of oxytocin ranges from 3 to 20 min. The metabolites are excreted in urine whereas less than 1% of the oxytocin is excreted unchanged in urine. The metabolic clearance rate amounts to 20 mL/kg/min in the pregnant woman.
Renal impairment: No studies have been performed in renally impaired patients. However, considering the excretion of oxytocin and its reduced urinary excretion because of anti-diuretic properties, the possible accumulation of oxytocin can result in prolonged action.
Hepatic impairment: No studies have been performed in hepatically impaired patients. Pharmacokinetic alteration in patients with impaired hepatic function is unlikely since metabolizing enzyme, oxytocinase, is not confined to liver alone and the oxytocinase levels in placenta during the term has significantly increased. Therefore, biotransformation of oxytocin in impaired hepatic function may not result in substantial changes in metabolic clearance of oxytocin (see Precautions).