Tocolytics

Overview

Tocolytics are drugs that relax the myometrium and suppress uterine contractions in threatened preterm labour. None of them prevents preterm birth in the long run, and none improves survival on its own. Their value is in gaining time: enough for a course of antenatal corticosteroids to work on the fetal lungs and, where needed, for transfer to a hospital with neonatal intensive care. Understanding the receptor mechanism of each class, and the one side effect that limits it, answers most exam questions.

Where tocolytics act

Myometrial contraction depends on a rise in intracellular calcium, which activates myosin light chain kinase through calmodulin so that myosin can interact with actin. Oxytocin and prostaglandins raise intracellular calcium. Three facts follow:

• Oxytocin production does not rise at the onset of labour; what rises is myometrial sensitivity, through more oxytocin receptors.
• Prostaglandins ripen the cervix and drive contractility; PGF2 alpha contracts, prostacyclin relaxes, and PGE2 can do either depending on the receptor subtype.
• Anything that reduces calcium entry, blocks the oxytocin receptor, or blocks prostaglandin synthesis will reduce contractions.

The classes

Calcium channel blockers (nifedipine)

• Mechanism: binds L-type calcium channels, reducing transmembrane calcium entry and intracellular calcium.
• Current guidance names a calcium channel blocker as a first choice.
• Oral, cheap and widely available, which matters in Pakistani practice.
• Side effects: flushing, headache, palpitations, low blood pressure.
• Compared with other classes, its rates of adverse drug reactions and neonatal problems sit between atosiban (best) and beta agonists (worst).
• Nifedipine is also used with external cephalic version to improve success.

Oxytocin receptor antagonists (atosiban)

• Mechanism: competitive antagonist at the oxytocin receptor and at the vasopressin V1a receptor in myometrium, so contractility and oxytocin-driven prostaglandin release both fall in a dose-dependent way.
• Given by intravenous infusion; only a small amount crosses to the fetus.
• As effective as beta agonists but far better tolerated: the lowest rates of adverse reactions, discontinuation, neonatal respiratory distress, necrotising enterocolitis, intraventricular haemorrhage and neonatal jaundice.
• The other first choice alongside nifedipine; cost and availability limit its use.

Prostaglandin synthesis inhibitors (indometacin)

• Mechanism: reversible non-selective cyclooxygenase inhibitor, so prostaglandin synthesis falls.
• Genuinely effective: delays delivery at 48 hours, at 7-10 days and even beyond 37 weeks, so fewer babies weigh under 2,500 g.
• Fetal hazards decide its use:
  • Premature closure of the ductus arteriosus, because prostaglandin keeps the duct open. Possible from the late second trimester and the risk climbs sharply from 32 weeks. It can cause persistent pulmonary hypertension in the newborn, and is reversible if caught early and the drug stopped.
  • Reduced renal perfusion and fetal urine output, giving oligohydramnios (reversible on stopping).
  • Association with necrotising enterocolitis and neonatal renal dysfunction.
• The same drug is used to reduce fetal urine output in severe polyhydramnios, with the duct watched closely.

Beta sympathomimetics (ritodrine, salbutamol, terbutaline)

• Mechanism: beta-2 adrenoceptor agonists that relax the myometrium by raising cyclic AMP.
• Effective at delaying delivery, but they do not improve neonatal outcome or the final preterm birth rate.
• Maternal side effects are serious and have made them rare in UK practice although they remain widely used elsewhere: tremor, palpitations, tachycardia, headache, hyperglycaemia, low potassium, and above all pulmonary oedema, with an estimated incidence of about 1 in 350 to 1 in 400 treated women. Deaths from acute cardiopulmonary collapse are described.
• Risk is higher with large fluid volumes, multiple pregnancy and maternal cardiac disease.
• Fetal effect to remember: ritodrine and other adrenoceptor agonists cause fetal tachycardia on the cardiotocograph.
• Subcutaneous terbutaline is the standard treatment for uterine hyperstimulation during induction or augmentation, after the oxytocin has been turned off.

Magnesium sulphate

• Mechanism: alters how smooth muscle cells take up, bind and distribute calcium, and lowers the frequency of depolarisation, so contractions are inhibited.
• As a tocolytic it has not been shown to work: comparison with placebo did not demonstrate a useful effect on the length of pregnancy, and systematic review found no benefit over controls. It is still widely used for this purpose in the USA.
• It is, however, given for fetal neuroprotection: it lowers the chance of cerebral palsy among babies who survive, although the absolute effect is not large.
• Toxicity matters: it has a narrow therapeutic range, and excess causes loss of reflexes, respiratory depression and cardiac arrest. The antidote is 10 ml of 10% calcium gluconate given slowly intravenously. Monitor urine output, since the drug is excreted by the kidney.

Comparison table

Using tocolysis in practice

• Who is treated: a woman in threatened preterm labour where delay is useful. A negative fetal fibronectin test has a high negative predictive value, so most of these women can be sent home; a positive test means admission for tocolysis and steroids.
• Corticosteroids matter more than any tocolytic. A single course reduces neonatal death, respiratory distress syndrome and intraventricular haemorrhage. Betamethasone or dexamethasone are used; both cross the placenta in active form, and dexamethasone preparations containing a sulphite preservative should be avoided. Repeated courses are discouraged.
• Who should not be treated: where delay is dangerous rather than helpful, for instance significant antepartum haemorrhage, chorioamnionitis, severe fetal compromise or a condition needing delivery now. Beta agonists in particular are avoided in cardiac disease.
• Preterm prelabour rupture of membranes: erythromycin improved neonatal outcomes in singleton pregnancies, and a 10-day course has been adopted in many units; antibiotics did not help women with intact membranes. Conservative management is usual before 34 weeks and induction after 37 weeks.
• Local guidance in Pakistan may differ in which agent is stocked and used; keep to the current national guideline, as recommendations change.

Quick revision

• Tocolysis buys about 48 hours for steroids and in utero transfer.
• First-line: nifedipine (L-type calcium channel block) or atosiban (oxytocin and V1a antagonist).
• Indometacin works but closes the fetal duct and reduces amniotic fluid.
• Beta-2 agonists raise cyclic AMP; pulmonary oedema is the danger, fetal tachycardia the trace finding.
• Magnesium sulphate is a poor tocolytic but reduces cerebral palsy; antidote calcium gluconate.
• Terbutaline subcutaneously treats hyperstimulation once oxytocin is stopped.
• Antenatal corticosteroids do more good than any tocolytic.
• Negative fetal fibronectin means most women can go home.
• Do not use tocolysis where delivery is the safer option.

Written by The House Job from standard references (Obstetrics by Ten Teachers; Basic and Clinical Pharmacology by Katzung).

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