Oxytocic drugs are used to promote uterine contractions, whereas tocolytic drugs relax the uterus. Both groups of drugs are widely used in obstetric practice.
Oxytocic drugs
These drugs may be given: (1) during labour to augment progress; (2) at delivery and in the puerperium to reduce postpartum haemorrhage and aid expulsion of the placenta; and (3) at earlier stages of pregnancy to help empty the uterus, for example following evacuation of retained products of conception or termination of pregnancy. While uterotonics may be life-saving in postpartum haemorrhage (PPH), they must be used with care as they all have significant side effects.
Although the third stage of labour can be managed without oxytocic drugs (‘physiological management of the third stage’), it is common practice to give an oxytocic to all women at childbirth, usually on delivery of the anterior shoulder (vaginal delivery) or following delivery of the baby (caesarean section) to hasten delivery of the placenta and reduce the risk of PPH. In most units, the drug used is either a mixture of oxytocin analogue and ergometrine or oxytocin analogue alone, according to local protocols.
Oxytocin analogues
The most widely used is Syntocinon, a synthetic oxytocin; its effects resemble those of natural oxytocin, released from the posterior pituitary gland. Oxytocin causes milk ejection from the lactating breast and acts directly on specific oxytocin receptors in the uterine myometrium, increasing the force and frequency of contractions. In early pregnancy, the uterine receptors are present in small numbers and their sensitivity is low; thus there is little value in giving the drug for operative procedures in early pregnancy, although this is commonly requested by the surgeon. Syntocinon may cause vasodilatation and tachycardia; the latter is especially likely if the intravenous route is used, if large doses (> 5 U) are given by bolus injection, and if other drugs causing tachycardia (e.g. ephedrine) are given concurrently. These effects can be disastrous in patients with fixed cardiac output states such as aortic stenosis.
A potential problem with prolonged Syntocinon therapy during labour is related to its antidiuretic effect, due to its similar structure to vasopressin, which may result in excessive water retention, compounded by excessive fluid administration if infused in weak solution over a long period of time. This has resulted in hyponatraemia and convulsions, hence the recommendation that Syntocinon should be diluted in physiological saline rather than dextrose solutions. The half-life of Syntocinon is approximately 10 minutes, another reason for giving it by infusion at caesarean section. Over recent years, dose-finding studies have been done in relation to Syntocinon because of the recent discovery that it may be associated with coronary artery vasospasm, which has been implicated in intraoperative ECG changes. The current ED95 for adequate uterine tone is ~0.3-3 U, with the lower bolus dose being recommended in the elective setting and the higher bolus dose in the emergency setting.
Carbetocin is a longer-acting oxytocin analogue, otherwise similar to Syntocinon. It was introduced as an alternative to Syntocinon in the hope of avoiding the side effects associated with the latter. However, as it is an analogue of oxytocin, the side effects are expected to be similar - though they have not yet been studied in detail. It is more expensive than Syntocinon and not routinely used in most units in the UK. However, its longer duration of action may be advantageous in prophylaxis of PPH, and current evidence suggests it may be more effective at reducing the need for further uterotonics, particularly after caesarean section.
Ergometrine
This acts on smooth muscle generally; thus it may cause vasoconstriction and hypertension (both systemic and pulmonary), coronary artery spasm and increased central venous pressure. It may also cause severe vomiting, and bronchospasm has been reported. It is therefore avoided in women with hypertensive disease. It is commonly given intramuscularly together with oxytocin analogue (Syntometrine; 5 U Syntocinon and 500 µg ergometrine) at vaginal delivery, though Syntocinon 10 U intramuscularly is currently recommended as first-line PPH prophylaxis because of its more favourable side effect profile. Ergometrine may also be given by slow intravenous injection, although side effects are more common so this is usually reserved for major haemorrhage. It increases the force, frequency and duration of uterine contractions.
Prostaglandins
Gemeprost (PGE1) is given vaginally to soften and ripen the cervix before termination of pregnancy or to induce abortion. Dinoprostone (PGE2) has also been used for this purpose but is more commonly used to induce labour. Both may cause nausea, vomiting, pyrexia, diarrhoea, bronchospasm and hypertension (especially dinoprostone, which may also cause uterine hypertonus and fetal distress. The occurrence of bronchospasm and hypertension is despite PGE2’s traditionally ascribed broncho- and vasodilator effects).
Carboprost (PGF2a) is used in PPH associated with uterine atony if standard oxytocics are ineffective. It is given intramuscularly (250 µg, repeated every 15 minutes up to 2 mg if necessary) and has been injected directly into the myometrium (off-licence); following reports of myometrial ischaemia, this mode of administration has now become obsolete in the UK but is still used in other parts of the world. Carboprost is associated with the same side effects listed above.
Misoprostol has been used for medical termination of pregnancy, induction of labour and prevention/treatment of PPH; it is usually given per rectum (600-1000 µg), but may be given sublingually. The main side effects seen are diarrhoea, shivering and pyrexia, although uterine hyperstimulation has been reported when misoprostol is used for induction.
All the prostaglandins are more effective in late pregnancy, although this is thought to be related to increased sensitivity rather than increased number of receptors.
Tocolytic drugs
Tocolytic drugs may be used to reduce uterine contractions in preterm labour or uterine hyperstimulation during labour, or to relax the uterus in situations such as shoulder dystocia or external cephalic version. There are several different groups of drugs that have been used or studied as tocolytics. As with many areas of obstetric practice, their value (and even efficacy in some cases) is controversial.
e2-Adrenergic agonists
These act on uterine β-receptors, causing relaxation of myometrium. Although these are the most commonly prescribed tocolytics for premature labour, improvement in outcome has not been conclusively proven. The emphasis of therapy has shifted away from long-term prolongation of pregnancy towards allowing enough time for steroids to promote fetal lung maturity before delivery. The most commonly used drugs are terbutaline, salbutamol and ritodrine, and these may be given orally, subcutaneously or by intravenous infusion. They may cause tremor, restlessness, hypotension, tachycardia and pulmonary oedema. The last is thought to arise from fluid overload during the infusion, together with increased pulmonary blood flow resulting from β-receptor -mediated pulmonary vasodilatation, often compounded by maternal steroid administration. Careful monitoring of blood pressure, pulse and arterial oxygen saturation is required during therapy. Metabolic effects include hypokalaemia and hyperglycaemia (thus they should be used with caution in women with diabetes). Salbutamol is no longer licensed for tocolysis in the UK for oral use, or for intravenous infusions lasting more than 48 hours.
Both regional and general anaesthesia may be used following β2-agonist therapy; excessive fluid administration (e.g. during regional anaesthesia) should be avoided and drugs that may cause tachycardia (e.g. ephedrine) used with caution. The drugs may also be given by intravenous bolus (salbutamol or terbutaline 100-250 µg) as part of intrauterine resuscitation of the fetus, for example in severe fetal distress.
Oxytocin antagonists
Oxytocin antagonists (e.g. atosiban) bind competitively to uterine oxytocin receptors, causing dose-dependent reduction in contractions. Atosiban does not affect uterine sensitivity to oxytocin subsequently, and thus does not increase the risk of uterine atony and PPH. It has been shown to be comparable with p2-agonists in preterm labour and to have fewer side effects (although it may cause nausea, vomiting, tachycardia and hypotension), but it is more expensive. It is usually given as a bolus injection followed by a continuous infusion.
Calcium channel antagonists
Oral calcium antagonists (e.g. nifedipine) are commonly used as tocolytics in preterm labour as they are associated with superior efficacy and fewer side effects than other drugs. However, the safety of calcium channel antagonists has not been rigorously tested and nifedipine is still unlicensed for use as a tocolytic.
Glyceryl trinitrate (GTN)
This acts directly on uterine smooth muscle and has been given intravenously (50 µg boluses) or sublingually (200-400 µg) to produce acute but relatively brief uterine relaxation, for example in cases of uterine hypertonicity, retained placenta and uterine inversion and for external cephalic version. Similar doses have been used in severe fetal distress. Hypotension and headache are the main side effects. The use of GTN delivered by dermal patch has been studied as a means of preventing premature labour following preterm rupture of membranes.
Magnesium sulfate
This acts directly on smooth muscle via calcium ion antagonism; it is rarely used as a tocolytic in the UK, although it is more commonly given for this purpose elsewhere, for example in the USA. (Anaesthetic considerations of magnesium therapy are discussed in Chapter 87, Magnesium sulfate.) It is however used for fetal neuroprotection in preterm labour between 24 and 30 weeks’ gestation, where its tocolytic action maybe a desirable side effect.
Key points
• Oxytocic drugs are used routinely during labour, following delivery, in early pregnancy and in the emergency management of postpartum haemorrhage.
• Tocolytic drugs are used in premature labour and for intrauterine resuscitation of the fetus.
• Drugs of both groups may have implications for the anaesthetist because of their side effects.
Further reading
Mavrides E, Allard S, Chandraharan E, et al.; Royal College of Obstetricians and Gynaecologists. Prevention and management of postpartum haemorrhage. BJOG 2016; 124: e106-49.
Meshykhi LS, Nel MR, Lucas DN. The role of carbetocin in the prevention and management of postpartum haemorrhage. Int J Obstet Anesth. 2016; 28: 61-9.
National Institute for Health and Care Excellence. Preterm Labour and Birth. NICE Guideline NG 25. London: NICE, 2015. www.nice.org.uk/guidance/ng25 (accessed December 2018).
Vallera C, Choi LO, Cha CM, Hong RW. Uterotonic medications: oxytocin, methylergonovine, carboprost, misoprostol. Anesthesiol Clin 2017; 35: 207-19.
Vercauteren M, Palit S, Soetens F, Jacquemyn Y, Alahuhta S. Anaesthesiological considerations on tocolytic and uterotonic therapy in obstetrics. Acta Anaesthesiol Scand 2009; 53: 701-9.