Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Alliance Pharmaceuticals Limited, Avonbridge House, Bath Road, Chippenham, Wiltshire, SN15 2BB
Pharmacotherapeutic group: Ergot alkaloids and oxytocin incl. analogues, in combination
ATC code: G02AC
Syntometrine combines the known sustained oxytocic action of ergometrine with the more rapid action of oxytocin on the uterus.
Following IM administration, the latent period for the occurrence of the uterine response is considerably shorter with Syntometrine (about 2.5 minutes) than with ergometrine given alone (about 7 minutes), whereas the uterotonic effect of Syntometrine lasts for around 3 hours compared with only 0.5 to 1 hour when oxytocin is given alone.
These properties make Syntometrine IM suitable for the active management of the third stage of labour and for the prevention or treatment of postpartum haemorrhage, particularly in situations where, for any reason, the IV administration of uterotonic agent is impracticable.
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 labour. Oxytocin stimulates the smooth muscle of the uterus, more powerfully towards the end of pregnancy, during labour, and immediately postpartum. At these times, the oxytocin receptors in the myometrium are increased. The oxytocin receptors are G-proteins coupled receptors. Activation of receptor by oxytocin triggers release of calcium from intracellular stores and thus leads to myometrial contraction. Oxytocin elicits rhythmic contractions in the upper segment of the uterus, similar in frequency, force and duration to those observed during labour. Being synthetic, oxytocin in Syntometrine does not contain vasopressin, but even in its pure form oxytocin possesses some weak intrinsic vasopressin-like antidiuretic activity.
Ergometrine produces sustained tonic uterine contraction via agonist or partial agonist effects at myometrial 5-HT2 receptors and alpha-adrenergic receptors. Both upper and lower uterine segments are stimulated to contract in a tetanic manner. Unlike oxytocin ergometrine has an effect on the non-pregnant uterus. Ergometrine inhibits prolactin secretion and in turn can reduce lactation. Compared with other ergot alkaloids, effects of ergometrine on cardiovascular and central nervous system are less pronounced.
Oxytocin is rapidly absorbed from the IM site.
The steady-state volume of distribution determined in 6 healthy men after IV injection is 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 breast milk.
Oxytocinase is a glycoprotein aminopeptidase that is produced during pregnancy. It is capable of degrading oxytocin. It is produced both by the mother and the foetus. The liver and kidney play a major role in metabolising and clearing oxytocin from the plasma. Thus, the liver, kidney and systemic circulation contribute to the biotransformation of oxytocin.
The 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
Ergometrine is absorbed rapidly after IM injection. The latent period for occurrence of the uterine response is about 7 minutes.
The average steady state volume of distribution of ergometrine in healthy man is reported to be 1.04 L/kg. The plasma protein binding of ergometrine is unknown. Ergometrine is known to cross the placenta and its clearance from the foetus is slow. Concentrations of ergometrine achieved in foetus are not known. Ergometrine is also expected to be excreted in the breast milk and to reduce milk secretion.
Ergometrine is mainly metabolised in the liver by hydroxylation and glucuronic acid conjugation and possibly N-demethylation. Like other ergot alkaloids it is a substrate for CYP3A4 enzymes.
The plasma half life of ergometrine is reported to be in the range of 30-120 min. When administered orally, the drug is mainly eliminated with the bile into the faeces as 12-hydroxyergometrine glucuronide. It is eliminated unchanged in the urine and can be detected up to 8 h after injection.
There are no pre-clinical data of relevance to the prescriber which are additional to those already included in other sections of the Summary of Product Characteristics.
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