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

Journal: back to pharmacology

The last two weeks were the mid-term break for the university, and I was happy to take a break from study.  However, it wasn't a restful time for me, as several babies needed to make their entry into this world of ours, and they all needed me to be on the job through the night.  The early postnatal days are very demanding for the new mother, even after an uncomplicated birth, and the midwife needs to stay focused as we watch and support and at times guide.

We are now in Week 9 of the pharmacology course.  The focus is on writing prescriptions, and working on the second case study.

Today I have listened to the recording of an online tutorial of a session that one of the tutors has put up for students to access.  This is the first 'live' opportunity that any of the students have had to interact with the faculty.  Unfortunately it was attended by only 3 students, who were able to put questions and discussion.

The tutor gave information about the course expectations for the assignments.  I found the tutor's comments useful - would have preferred having this prior to submission of the first case study. The tutor stressed the importance of referencing scholarly articles, and going into depth about the pharmacology of the medications that are being discussed. This is the field that I would like more teaching on. I have read the articles, but find there is a lot of new knowledge to acquire, and I think it's a good learning strategy to hear and discuss a topic as well as to read about it.

For example, when considering the pharmacology of metoclopramide, used to treat nausea, we need to discuss the general pharmacokinetic and pharmacodynamic actions of the drug, together with the changes that occur as a result of pregnancy.  In addition to the physiological changes in a pregnant woman's digestive system, metoclopramide has an effect on the dopamine receptors in the GI tract, inhibiting some receptors, and activating cholinergic effects leading to increased motility of the GI tract, in addition to the effect of metoclopramide on the central nervous system.  Reference to scholarly papers is needed for each point made.

Much of this language is new to me, and to the midwifery profession as I know it.  I recognise the importance of a strong foundation when establishing a new body of knowledge.  I have written to the tutor requesting more opportunities for live teaching as well as discussion, so that I can hear as well as read and discuss these aspects of the course. 


Thankyou for your comments

Journal: Case Studies

Assessment for this topic consists of an exam (50%), two case studies (each 20%) and a personal portfolio (10%).

I think the work required is mainly reading and writing.

• Reading the subject notes, text and the e-readings, which are papers published in professional journals, or parts of other books
• Writing reflections about the issues raised in the provided material, as well as the portfolio, and case studies.  I don't know what the exam will look like - multiple choice, short answer, or essay. 

Today I had intended to get started on preparing the first case study, which is due for submission in a few weeks.  Another student has kindly posted a university 'guide' to answering case study assignments on the group facebook site.  It's not rocket science: there's nothing surprising in the guide, but I appreciate having it so that I approach the work systematically.

The case study question is about a 25 year old woman who is 7 weeks pregnant and suffering with nausea. 

It's an interesting scenario.  The assignment will require discussion about investigations and advice, possible treatments (over the counter, 'alternative', and on prescription), and follow-up.  The issue of teratogenic drugs is very pertinent.

My mind immediately returned to a Saturday afternoon some years ago (in the early 1990s I think) when I listened to the ABC Science program that exposed Dr William McBride for his scientific fraud relating to the anti-nausea medication, Debendox.  McBride was the highly respected obstetrician who had 'discovered' thalidomide as the cause of dreadful limb abnormalities in children in the 1960s. 

Debendox contained vitamin B6 (pyridoxine) and doxylamine.  My understanding is that pyridoxine has anti-nausea properties, and is excreted in urine.  There are no concerns about drug toxicity in the mother or the baby.  I don't know about doxylamine.  I will plan to follow up on that as part of my case study.  Debendox was withdrawn from the market, even though the data used to discredit it was shown to be manipulated, and Dr McBride was struck off the medical register for a few years.  I remember in the early 1980s, comments by colleagues that without Debendox many women with hyperemesis have no reasonable treatment.  I used vitamin B6 in my pregnancies to manage morning sickness, and in late pregnancy as a mild diuretic.

Some women experience mild nausea in the first trimester without vomiting - the sort of nausea that feels better if you have something to eat.  Others vomit almost every day of their pregnancy, without experiencing dehydration, and without any medical intervention.  Others have had multiple admissions to hospital emergency rooms for rehydration.

I have worked with women who have experienced a high level of nausea and vomiting, and managed to avoid medication.  Even in labour they have managed to keep enough fluid down, and avoided needing IV fluids or an injection of Maxolon (Metoclopramide).  Within minutes of the birth of the placenta these mothers have announced that they are no longer nauseated!

I'll leave it there for now.  The case study raises interesting professional and ethical questions.  I have some reading to do, some thinking, and then some writing.

Your comments are welcome.

ps - Another student posted a paper by Nulman et al (2009), Long-term Neurodevelopment of Children Exposed to Maternal Nausea and Vomiting of Pregnancy and Diclectin, published in the Journal of Pediatrics. 
The study showed that nausea and vomiting of pregnancy (NVP) has "an enhancing effect on later child outcome" and that "Diclectin® does not appear to adversely affect fetal brain development and can be used to control NVP when clinically indicated." (J Pediatr 2009;155:45-50)
My next question was, What is Diclectin, and is it available in Australia??
Answer: http://diclectin.com/ 

Diclectin®, the only pharmacological solution specifically indicated, prescribed and labelled for the management of NVP. Diclectin® consists of a combination of 10 mg of doxylamine succinate and 10 mg of pyridoxine hydrochloride (vitamin B₆) in a delayed-released formulation. This combination has been prescribed for over 50 years to more than 33 million pregnant women. 

It appears that Diclectin® is very similar to Debendox.

I am pleased with this piece of information.  I don't have the opportunity to get medicines from Canada, but pyridoxine is readily available, and as I wrote earlier, I have always found it a useful treatment for NVP.