Journal: the pharmacology of uterotonics

Today I have reflected on bleeding after birth.


In preparation for this study I accessed MIMS online, to revise the pharmacology of the uterotonics that midwives and doctors use in the third stage of labour.  These drugs are Syntocinon, Syntometrine, and Misoprostol. A site linked to MIMS, with consumer information about medicines, is myDr.com.au . Readers may search for other information online, but I have linked each of these drugs to the myDr site to allow easy access to consumer information.

My study method when reading copious pages of information is to look for flashing red lights, which are anything that I didn't know, didn't expect, or am surprised about.  Today's study has provided me with a few flashing red lights.



Before revising the pharmacology of these drugs, I have reviewed the evidence around bleeding and the management of the third stage.  The unavoidable issue that arises for me is that I do not agree with national and international experts who recommend routine active management of third stage for all women.  My disagreement relates to women in my world: women who are well, and who intend to give birth within unmedicated normal physiological processes, and for whom there is a very low risk of morbidity as a result of post partum haemorrhage.  This is an informed position, which I have been studying since I began private midwifery practice in 1993, and realised that there is something unique and protective about protecting, promoting and supporting natural processes in birth and the nurture of the infant.  The principle I follow was set down by World Health Organisation:

"In normal birth there should be a valid reason to interfere with the natural process."

WHO (1996) Care in Normal Birth: A practical guide. 

When I attend a birth at home I carry an ampoule of Syntocinon®10 units, and an ampoule of Syntometrine®.  I use an intramuscular injection of one or both of these drugs if indicated.  A more recent development in preventing obstetric haemorrhage, developed for use particularly in resource-poor countries, is Misoprostol.  I have used this drug in hospital births, but do not carry it.

A few selected facts:

Syntocinon® is a synthetic oxytocin.  Oxytocin is that wonderful love hormone that causes the uterus to contract, and the breast to yield its milk in abundance. 

Pharmacodynamics:

... stimulates the smooth muscle of the uterus, producing rhythmic contractions, particularly towards the end of pregnancy, during labour, after delivery and in the puerperium, i.e. at times when the number of specific oxytocin receptors in the myometrium is increased.... being a polypeptide, is largely inactivated in the alimentary tract and therefore virtually ineffective when ingested. (MIMS)

Pharmacokinetics: 
Plasma levels and onset/ duration of effect. Intravenous injection and intramuscular injection. When administered by intravenous or intramuscular injection for prevention or treatment of postpartum haemorrhage, Syntocinon acts rapidly, with a latency period of less than one minute by intravenous injection and of two to four minutes by intramuscular injection. The oxytocic response lasts for 30 to 60 minutes after intramuscular administration and possibly less after intravenous injection. Distribution. Oxytocin distributes throughout the extracellular fluid, with minimal amounts reaching the fetus. ... Plasma protein binding is very low. Oxytocin may be found in small quantities in mothers' breast milk.
Biotransformation. A glycoprotein aminopeptidase, oxytocinase, is produced during pregnancy and appears in the plasma. It is capable of degrading oxytocin. Enzyme activity increases gradually until term approaches, at which time it rises steeply to high levels. Enzyme activity then declines after delivery. Enzyme activity in the placenta and in the uterine tissue is also high during this period. There is little or no degradation of oxytocin by plasma in men, nonpregnant women or cord blood.
Excretion. The relative ease with which the rate and force of uterine contractions can be regulated by the intravenous infusion of Syntocinon is due to the short half-life of oxytocin. Values reported by various investigators range from 3 to 20 minutes. Removal of oxytocin from plasma is accomplished mainly by the liver and the kidneys. The metabolic clearance rate amounts to about 20 mL/kg/minute in men as well as in pregnant women. Less than 1% of a given dose is excreted unchanged in the urine.(MIMS)

Precautions: ...
Third stage of labour and puerperium. When Syntocinon is used for prevention or treatment of uterine haemorrhage, rapid intravenous bolus injection of oxytocin at high doses should be avoided, as it may cause acute short lasting hypotension accompanied by flushing and reflex tachycardia. These rapid haemodynamic changes may result in myocardial ischemia, particularly in patients with pre-existing cardiovascular disease. Rapid i.v. bolus injection of oxytocin at doses amounting to several IU may also lead to QTc prolongation. When Syntocinon is used for the management of the third stage of labour, multiple pregnancy must be excluded before the drug is injected.(MIMS)

Use in pregnancy. (Category A) Use of oxytocin has contributed significantly to the safety of parturition. However, there have been instances of idiosyncratic sensitivity of the uterus resulting in fetal anoxia.(MIMS)

NOTE: I have asked a question in a tutorial about Syntocinon's inability to cross the blood-brain barrier, while endogenous oxytocin, from the posterior lobe of the pituitary, does.  This topic is not addressed in the MIMS information.  The tutor said she would check the specific pharmacokinetics of synthetic oxytocin.


Syntometrine® synthetic oxytocin/ergometrine maleate

... Syntometrine combines the rapid uterine action of oxytocin, a nonapeptide hormone released by the posterior lobe of the pituitary, with the sustained uterotonic effect of ergometrine [an ergot alkaloid].

Following intramuscular administration, the latent period for the occurrence of the uterine response is considerably shorter with Syntometrine (about 2 1/2 minutes) than with ergometrine given alone (about 7 minutes), whereas the uterotonic effect of Syntometrine lasts for several hours, compared with only 1/2 to 1 hour when oxytocin is given alone. These properties make Syntometrine intramuscular suitable for the active management of the third stage of labour (see Dosage and Administration) and for the prevention or treatment of postpartum haemorrhage, particularly in situations where for any reason the intravenous administration of a uterotonic agent is impracticable. ...

Indications: Active management of the third stage of labour. Prevention and treatment of postpartum haemorrhage associated with uterine atony.

Contraindications: Hypersensitivity to oxytocin, ergometrine or to any of the components in the formulation. Pregnancy, ... Severe hypertension, pre-eclampsia or eclampsia. Severe cardiac disorders. Severe hepatic or renal impairment. Occlusive vascular disease. Sepsis.

Syntometrine has the potential to cause serious adverse drug reactions in breastfed newborns/ infants. Postpartum women receiving Syntometrine should avoid breastfeeding for at least 12 hours after the administration. Milk secreted during this period should be expressed and discarded. (MIMS)

NOTE: I have highlighted this paragraph in red, because I need to follow up on it.  I have never heard this information before, despite many years of working and using it in hospitals, as well as private practice.

Misoprostol is a synthetic prostaglandin E₁ analogue.is used in tablet form, given either orally, PR or PV.  Its use has been promoted for use in resource-poor settings - see FIGO initiative. 
I will not go into the pharmacology of this drug here, as I do not use it.  As with Syntometrine above, it comes with a warning about breast feeding:

Use in lactation. Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. Misoprostol should not be administered to breastfeeding mothers because the excretion of misoprostol acid could cause undesirable effects such as diarrhoea in breastfeeding infants.  (MIMS)

COMMENT:
This study has given me information which confirms my commitment to protecting, promoting and supporting unmedicated, physiological birth, except in clinical situations where there is a valid reason to intervene.  The benefit of synthetic oxytocic treatment in preventing excessive blood loss after birth is undeniable.  My reluctance to use these drugs routinely rather than as indicated is related to the majority of women for whom the treatment is not required, and who are thereby exposed to unnecessary medication with attendant risks.

I am also concerned about the extent of possible adverse effects in newborn babies, particularly any sick babies who may need to receive drug treatments, and who may experience adverse drug reactions to syntometrine in mother's milk.  

Thankyou for your comments