Tocolytic drugs
Tocolytics: nifedipine, beta-2 agonists, atosiban, indomethacin and magnesium
Tocolytics for FCPS Part 1: how nifedipine, beta-2 agonists, atosiban, indomethacin and magnesium relax the uterus, and why each has its side effects. Covers why tocolysis is given, contraindications, drug interactions and fetal effects.
Why and when tocolysis is used
- Tocolysis does not by itself improve neonatal outcome; its value is 48 hours for corticosteroids (fetal lung surfactant), magnesium for neuroprotection and in-utero transfer to a unit with neonatal intensive care.
- Contraindications: chorioamnionitis, placental abruption or major bleeding, fetal death or lethal anomaly, fetal compromise, severe pre-eclampsia, and any situation where delivery is in the mother's or baby's interest.
How each drug relaxes the myometrium
- Contraction requires calcium entry through L-type channels and release from stores, calmodulin binding and MLCK activation. Each tocolytic blocks one step.
| Drug | Mechanism | Maternal side effects | Fetal and neonatal effects |
|---|---|---|---|
| Nifedipine | Blocks L-type calcium channels | Hypotension, flushing, headache, reflex tachycardia, ankle oedema | Few; maternal hypotension can reduce placental flow |
| Beta-2 agonists (ritodrine, terbutaline, salbutamol) | Gs, cAMP, PKA inhibits MLCK | Tachycardia, palpitations, tremor, hypokalaemia, hyperglycaemia, pulmonary oedema, myocardial ischaemia | Cross the placenta: fetal tachycardia; neonatal hypoglycaemia |
| Atosiban | Oxytocin and vasopressin V1a receptor antagonist | Fewest: nausea, injection reactions | Minimal |
| Indomethacin | Inhibits COX, less prostaglandin | Gastric irritation, platelet dysfunction | Ductus arteriosus constriction (after 32 weeks), oligohydramnios, neonatal renal impairment, NEC |
| Magnesium sulphate | Competes with calcium at channels and the neuromuscular junction | Flushing, weakness, loss of reflexes, respiratory depression | Neuroprotection before about 30–32 weeks (less cerebral palsy) |
| Glyceryl trinitrate | Nitric oxide, cGMP | Hypotension, headache | Very short acting; for retained placenta or a clamped uterus at caesarean |
Nifedipine and the calcium channel blockers
- Usually the first choice: oral, effective and better tolerated than beta-agonists.
| Group | Examples | Main site | Notes |
|---|---|---|---|
| Dihydropyridines | Nifedipine, amlodipine, nimodipine | Vascular smooth muscle (and myometrium) | Vasodilatation with reflex tachycardia; little effect on the heart |
| Phenylalkylamine | Verapamil | Heart (SA and AV node, myocardium) | Slows heart rate; not used as tocolytic |
| Benzothiazepine | Diltiazem | Heart and vessels | Intermediate |
- Nimodipine is lipid-soluble and acts preferentially on cerebral arteries; it is the calcium channel blocker given in subarachnoid haemorrhage to reduce delayed ischaemia from vasospasm.
- Short-acting capsules can drop pressure abruptly, causing a baroreflex tachycardia; modified-release tablets are smoother.
- Ankle oedema comes from precapillary arteriolar dilatation, not fluid retention.
- Cleared by CYP3A4: clarithromycin or grapefruit raise levels; enzyme inducers such as carbamazepine, phenytoin and rifampicin induce CYP3A4 and increase first-pass metabolism, lowering nifedipine levels and its effect.
- With magnesium sulphate the two reduce calcium entry additively, causing profound hypotension and neuromuscular weakness; calcium gluconate reverses magnesium toxicity.
- Also used for hypertension in pregnancy and Raynaud phenomenon.
Beta-2 agonists
- Terbutaline and salbutamol stimulate beta-2 receptors, but at tocolytic doses they also act on cardiac beta-1 receptors and cause reflex tachycardia from vasodilatation.
- Hypokalaemia: beta-2 stimulation activates Na+/K+-ATPase and raises insulin, shifting potassium into cells; total body potassium is unchanged.
- Hyperglycaemia from glycogenolysis and gluconeogenesis; hazardous in diabetes, especially with steroids; the baby may then become hypoglycaemic after birth from fetal hyperinsulinaemia.
- Pulmonary oedema: sodium and water retention, prolonged tachycardia, IV fluids, steroids and multiple pregnancy combine.
- Tachyphylaxis: receptor phosphorylation, beta-arrestin binding and internalisation, so contractions return in 24–48 hours.
- Fetal tachycardia with normal variability and no decelerations during a salbutamol infusion is caused by transplacental passage of the drug, not hypoxia; still check maternal temperature, because chorioamnionitis also causes fetal tachycardia.
- Now rarely used for preterm labour, but a single subcutaneous terbutaline dose treats uterine hyperstimulation.
Atosiban
- Blocks myometrial oxytocin receptors (and V1a), so it targets the uterus with few systemic effects; it is the choice when the cardiovascular effects of nifedipine or beta-agonists are unwanted (cardiac disease, multiple pregnancy). It is expensive and given IV.
Indomethacin
- The fetal ductus is kept open by PGE2; COX inhibition constricts it, causing tricuspid regurgitation and fetal pulmonary hypertension, with risk highest after 32 weeks; use is limited to under 32 weeks and 48 hours.
- It reduces fetal urine output, which treats polyhydramnios but causes oligohydramnios if prolonged.
- The same action closes a patent ductus in preterm newborns.
Other agents
- Ethanol once given IV inhibited release of oxytocin and ADH; abandoned.
- Vaginal progesterone prevents preterm birth in women with a short cervix; it is not acute tocolysis.
- Corticosteroids (betamethasone or dexamethasone) are not tocolytics; they prepare the baby for delivery.
Remember Match the drug to the step: nifedipine blocks calcium entry, beta-agonists raise cAMP, atosiban blocks the oxytocin receptor, indomethacin stops prostaglandin synthesis.
Exam trap Indomethacin after 32 weeks risks premature closure of the ductus arteriosus and oligohydramnios.
Exam trap Hypokalaemia with beta-agonists is a shift into cells, not potassium loss.
How FCPS asks about this
- Terbutaline as tocolytic causes: maternal tachycardia, tremor, hypokalaemia, hyperglycaemia and pulmonary oedema.
- Fetal tachycardia with normal variability on salbutamol: transplacental passage of the beta-agonist.
- Why carbamazepine reduces nifedipine's effect: induction of CYP3A4 increases its metabolism.
- Calcium channel blocker for subarachnoid haemorrhage: nimodipine.
- Tocolytic with fewest maternal side effects: atosiban, an oxytocin receptor antagonist.
- Indomethacin fetal risks: ductal constriction after 32 weeks and oligohydramnios.
Test yourself on this topic
5 of the 14 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
At caesarean section, the uterus clamps down on the baby's head before it can be delivered. The anaesthetist gives sublingual glyceryl trinitrate, and within a minute the uterus relaxes. How does this drug relax the myometrium?
Answer: Nitric oxide raises cGMP in smooth muscle
Glyceryl trinitrate releases nitric oxide, which activates soluble guanylate cyclase in smooth muscle. The rise in cGMP activates protein kinase G, which lowers intracellular calcium and dephosphorylates myosin light chains, relaxing the muscle within seconds to a minute. Its very short action makes it useful for brief uterine relaxation, such as a trapped fetal head or retained placenta. Hypotension is the main side effect.
GTN for uterine relaxation
- Releases nitric oxide
- Activates guanylate cyclase, cGMP up
- Rapid, short-lived relaxation
- Main side effect: hypotension
Remember Need the uterus to relax for a minute: GTN.
Exam trap GTN is for seconds-to-minutes relaxation, not for prolonged tocolysis in preterm labour.
Why the other options are wrong
- It blocks L-type calcium channels Calcium channel block is the action of nifedipine.
- It antagonises oxytocin receptors Oxytocin receptor antagonism is the action of atosiban.
- It stimulates beta-2 adrenoceptors Beta-2 stimulation is the action of terbutaline, which acts more slowly by injection.
- It inhibits prostaglandin synthesis COX inhibition is the action of indomethacin.
In preterm labour, a salbutamol infusion first stops the contractions, but despite a constant dose they return within about 24 to 48 hours. What is the main pharmacological reason?
Answer: Beta-2 receptor desensitisation
Continuous stimulation of beta-2 receptors leads to phosphorylation of the receptor by G protein–coupled receptor kinases, binding of beta-arrestin, uncoupling from Gs and internalisation, followed by reduced receptor numbers. The cAMP response to the same dose wanes (tachyphylaxis), so contractions return. This, with the side effects, limits beta-agonists to short-term use.
Beta-receptor tachyphylaxis
- Continuous agonist exposure
- Receptor phosphorylation, beta-arrestin
- Uncoupling and internalisation
- Effect wanes in 24–48 h
Remember Keep pressing the receptor and it stops answering.
Exam trap Increasing the dose to overcome tolerance mainly increases maternal side effects.
Why the other options are wrong
- Increased hepatic metabolism of salbutamol Salbutamol metabolism does not increase enough to explain this.
- Rising maternal plasma volume diluting it Dilution does not explain loss of effect at a constant infusion.
- Antibodies forming against the drug Salbutamol does not provoke antibodies.
- Placental breakdown of salbutamol The placenta does not break down salbutamol significantly.
A woman at 33 weeks with polyhydramnios and preterm contractions is given indomethacin for five days. A fetal echocardiogram now shows narrowing of the ductus arteriosus with tricuspid regurgitation. What is the mechanism?
Answer: Loss of the PGE2 that keeps it open
In the fetus, the ductus arteriosus is held open mainly by prostaglandin E2 from the placenta and the ductal wall, together with low oxygen tension. Indomethacin crosses the placenta and inhibits cyclo-oxygenase, so prostaglandin levels fall and the ductus constricts. Ductal sensitivity rises with gestation, so the risk is greatest after about 32 weeks, and courses are kept short with ductal monitoring.
Indomethacin and the ductus
- Fetal ductus kept open by PGE2
- Indomethacin inhibits COX
- Ductal constriction, tricuspid regurgitation
- Risk greatest after 32 weeks
Remember No prostaglandin, no patent ductus.
Exam trap The same action is used deliberately to close a patent ductus in preterm newborns.
Why the other options are wrong
- Direct toxicity of the drug to ductal muscle The effect is through prostaglandin inhibition, not direct toxicity.
- Fetal hypoxia from reduced uterine flow Indomethacin does not cause fetal hypoxia in this way.
- Raised fetal pulmonary blood flow Pulmonary flow is low in the fetus and does not close the ductus.
- Excess fetal angiotensin II activity Angiotensin II is not the main ductal regulator.
A woman at 29 weeks in preterm labour is taking oral nifedipine, and intravenous magnesium sulphate is started for fetal neuroprotection. She soon becomes weak, cannot lift her head and her BP falls to 85/45 mmHg. What explains the interaction?
Answer: Both cut calcium entry into muscle and nerve
Magnesium competes with calcium at voltage-gated channels in nerve terminals and smooth muscle, reducing acetylcholine release and vascular tone. Nifedipine blocks L-type calcium channels. Together they cause additive vasodilatation and hypotension, and neuromuscular weakness from reduced calcium-dependent transmitter release. The combination can be used with care, but needs close monitoring of BP, reflexes and breathing.
Nifedipine plus magnesium
- Both reduce calcium entry
- Additive hypotension
- Neuromuscular weakness
- Monitor BP, reflexes, breathing
Remember Two calcium blockers together: watch BP and muscle power.
Exam trap Calcium gluconate reverses magnesium toxicity if weakness or breathing problems become severe.
Why the other options are wrong
- Magnesium inhibits nifedipine breakdown Magnesium does not inhibit nifedipine metabolism.
- Nifedipine raises magnesium reabsorption Nifedipine does not change renal handling of magnesium.
- Both block nicotinic receptors directly Neither drug blocks nicotinic receptors directly.
- Magnesium causes hypokalaemia Magnesium does not cause hypokalaemia.
A woman on regular oral nifedipine for threatened preterm labour is started on clarithromycin for a chest infection. Next day her BP is 80/45 mmHg, with a pulse of 125/min and flushing. What is the mechanism?
Answer: CYP3A4 inhibition raising nifedipine levels
Nifedipine is metabolised mainly by CYP3A4 in the gut wall and liver. Clarithromycin is a strong CYP3A4 inhibitor, so nifedipine levels rise and exaggerated vasodilatation causes hypotension, flushing and reflex tachycardia. Grapefruit juice has a similar effect by inhibiting intestinal CYP3A4. Maternal hypotension also threatens uteroplacental perfusion, so another antibiotic should be chosen.
Nifedipine and CYP3A4
- Nifedipine cleared by CYP3A4
- Inhibitors: clarithromycin, grapefruit
- Higher levels: hypotension, flushing
- Risk to placental perfusion
Remember Macrolide plus nifedipine: watch the BP.
Exam trap Rifampicin does the opposite and can make nifedipine ineffective.
Why the other options are wrong
- Clarithromycin blocking alpha receptors Clarithromycin has no alpha-blocking action.
- Additive calcium channel block Clarithromycin does not block calcium channels.
- Clarithromycin-induced QT prolongation QT prolongation causes arrhythmia, not this vasodilated picture.
- Allergic reaction to clarithromycin There is no rash, wheeze or angioedema.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Drugs in obstetrics and gynaecology, Tocolytics: calcium channel blockers, beta-2 agonists, atosiban, indomethacin
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