Uterine Stimulants & Tocolytics

Drugs that act on the myometrium fall into two opposing camps: uterotonics (oxytocics) that increase uterine tone and contractility, and tocolytics that suppress contractions to delay preterm labour. NEET PG loves the "drug of choice" angles here — for primary PPH, for cervical ripening, for second-trimester abortion, and for arresting preterm labour — so commit the indications, contraindications, and receptor mechanisms to memory.

Classification

Uterine pharmacology is best organised by direction of effect and by chemical class.

Class	Drugs	Net myometrial effect
Oxytocics (uterine stimulants)	Oxytocin, carbetocin	Stimulate (rhythmic, physiological)
Ergot alkaloids	Ergometrine (ergonovine), methylergometrine	Stimulate (sustained tonic contraction)
Prostaglandins	Dinoprostone (PGE₂), misoprostol (PGE₁), carboprost (15-methyl PGF₂α)	Stimulate + ripen cervix
Tocolytics	Nifedipine (CCB), atosiban (oxytocin antagonist), ritodrine/salbutamol/terbutaline (β₂-agonists), magnesium sulphate, indomethacin (NSAID), nitroglycerin (NO donor)	Relax / suppress contractions

High-yield: The three uterotonic groups used after delivery are oxytocin, ergometrine and prostaglandins. Oxytocin is the WHO and FIGO drug of choice for prevention and treatment of primary PPH.

Oxytocin — receptor pharmacology

Oxytocin is a nonapeptide synthesised in the supraoptic and paraventricular nuclei of the hypothalamus and released from the posterior pituitary (neurohypophysis). It acts on oxytocin receptors, which are Gq-protein coupled receptors → activate phospholipase C → IP₃/DAG → rise in intracellular Ca²⁺ → myometrial contraction.

Key pharmacodynamic points tested:

• Oxytocin receptor density on the myometrium rises markedly near term (and with oestrogen priming), explaining why a near-term uterus is exquisitely sensitive while an early-pregnancy uterus is relatively resistant.
• It produces rhythmic contractions with relaxation in between at therapeutic doses — physiological, unlike ergot.
• It also contracts myoepithelial cells of the breast → milk ejection (let-down reflex).
• Plasma half-life is very short (3–5 min), so it is given as a controlled IV infusion for induction/augmentation.

High-yield: Oxytocin has structural similarity to vasopressin (ADH); at high doses it has an antidiuretic effect. Prolonged high-dose infusion in dextrose/water → water intoxication, hyponatraemia, convulsions, coma. Always infuse oxytocin in saline-based fluid, not plain dextrose, and monitor fluid balance.

Other oxytocin adverse effects: rapid IV bolus → hypotension, reflex tachycardia, flushing (transient vasodilatation); uterine hyperstimulation/tetany → fetal distress or rupture; neonatal jaundice.

Carbetocin is a long-acting oxytocin analogue (single IM/IV dose) increasingly used for PPH prophylaxis, especially after caesarean section, and is heat-stable (WHO-relevant for low-resource settings).

Uses of oxytocin

1. Induction and augmentation of labour (titrated IV infusion).
2. Prevention and treatment of postpartum haemorrhage — active management of third stage.
3. Promote milk ejection (rare clinical use).
4. Oxytocin challenge / contraction stress test (historical).

Ergot alkaloids — ergometrine & methylergometrine

Ergometrine acts on α-adrenergic, 5-HT and dopamine receptors and produces a powerful, sustained, tonic contraction of the uterus (no relaxation phase). This is excellent for controlling atonic bleeding but dangerous before delivery because tonic contraction can cause fetal hypoxia and uterine rupture.

• Onset is rapid; given IM or slow IV after delivery of the anterior shoulder / baby.
• It is a vasoconstrictor → can raise blood pressure.

High-yield: Ergometrine is contraindicated in hypertension, pre-eclampsia/eclampsia, and cardiac disease (vasoconstriction → BP spike). It is also contraindicated for induction of labour and in malpresentation/undelivered second twin because the sustained tetanic contraction is unsafe for the fetus.

Adverse effects: nausea/vomiting (prominent), hypertension, coronary vasospasm (angina), gangrene with chronic ergotism. Methylergometrine is the commonly used agent and is part of many "active management of third stage" protocols (often combined as oxytocin + ergometrine = Syntometrine).

Prostaglandins

Prostaglandins both contract myometrium and soften/ripen the cervix (collagen remodelling), so they uniquely act when oxytocin would fail — e.g. an unripe cervix or early/mid pregnancy when oxytocin receptors are sparse.

Drug	Type	Main obstetric uses	Caution
Dinoprostone (PGE₂)	Gel / pessary / vaginal insert	Cervical ripening & induction at/near term	Asthma; uterine hyperstimulation
Misoprostol (PGE₁)	Oral/sublingual/vaginal tablet	Medical abortion, cervical ripening, PPH (heat-stable, cheap), induction	Avoid in prior uterine scar/CS for induction
Carboprost (15-methyl PGF₂α)	IM (or intramyometrial)	Refractory atonic PPH	Asthma — contraindicated (bronchospasm)
Gemeprost (PGE₁ analogue)	Vaginal pessary	Second-trimester termination	—

High-yield: Misoprostol + mifepristone is the regimen for medical abortion. Mifepristone (an antiprogestin / progesterone-receptor antagonist) is given first, then misoprostol 24–48 h later. Misoprostol is a stable, inexpensive PGE₁ and is the alternative uterotonic for PPH where oxytocin/cold chain is unavailable.

High-yield: Carboprost is contraindicated in bronchial asthma; the safe uterotonic choice for atonic PPH in an asthmatic is oxytocin (and misoprostol). Conversely, ergometrine is the one to avoid in hypertension. These two "avoid" pairs are classic single-best-answer questions.

Drug of choice — obstetric flow

Postpartum haemorrhage (atonic, primary): Oxytocin (first line) → if inadequate, add methylergometrine (if no hypertension) → carboprost IM (if no asthma) / misoprostol → tranexamic acid (give early, within 3 h) → mechanical/surgical (balloon tamponade, B-Lynch, ligation, hysterectomy).

Second-trimester (mid-trimester) termination: Prostaglandins are the drug of choice — misoprostol ± mifepristone, or dinoprostone/gemeprost. Oxytocin is relatively ineffective here due to low receptor density.

Cervical ripening before induction (unfavourable Bishop score): Dinoprostone (PGE₂) or misoprostol; oxytocin works best once the cervix is favourable.

Tocolytics — suppressing preterm labour

Tocolytics are used to delay preterm delivery by 48 hours, the window needed to (a) administer antenatal corticosteroids for fetal lung maturity and (b) arrange in-utero transfer to a unit with NICU. They do not improve perinatal mortality on their own — the benefit comes from buying time for steroids.

High-yield: The single most important reason to give a tocolytic is to gain 48 h for betamethasone/dexamethasone to mature fetal lungs. Magnesium sulphate given to mothers in preterm labour (<32 weeks) provides fetal neuroprotection (reduces cerebral palsy) — a frequently tested fact, distinct from its tocolytic role.

Tocolytic	Mechanism	Key adverse effects	Notable contraindication
Nifedipine	L-type Ca²⁺ channel blocker → ↓ Ca²⁺ entry	Maternal hypotension, flushing, headache	Hypotension; avoid with MgSO₄ (additive)
Atosiban	Oxytocin receptor antagonist	Very few; well tolerated	Costly
Ritodrine / salbutamol / terbutaline	β₂-agonists → ↑ cAMP → relaxation	Maternal tachycardia, hyperglycaemia, hypokalaemia, pulmonary oedema, arrhythmia; fetal tachycardia	Maternal cardiac disease, diabetes (hyperglycaemia)
Magnesium sulphate	Ca²⁺ antagonism at myometrium	Flushing, respiratory depression, loss of reflexes	Myasthenia gravis; renal failure
Indomethacin (NSAID)	↓ prostaglandin synthesis (COX inhibition)	Premature closure of ductus arteriosus, oligohydramnios	Use only <32 weeks, short course
Nitroglycerin	NO donor → ↑ cGMP	Headache, hypotension	—

High-yield: Nifedipine is widely regarded as the preferred first-line tocolytic in many guidelines — oral, cheap, effective, fewer maternal/fetal side effects than β-agonists. Atosiban has the best maternal safety profile (fewest side effects) but is expensive.

High-yield: Indomethacin is restricted to gestation <32 weeks and short courses because, beyond this, prostaglandin inhibition causes premature closure of the fetal ductus arteriosus and oligohydramnios (reduced fetal renal blood flow). This is a favourite "why not after 32 weeks" question.

β₂-agonist toxicity — the classic warning

Ritodrine and salbutamol stimulate β₂ receptors → ↑ cAMP → smooth muscle (including myometrial) relaxation. But β-spillover causes maternal pulmonary oedema (especially with fluid overload or co-administration of steroids and MgSO₄), hyperglycaemia (avoid in diabetics), and hypokalaemia. Maternal cardiac monitoring is mandatory; these agents have fallen out of favour.

Magnesium sulphate — two roles, do not confuse

1. Eclampsia / severe pre-eclampsia: MgSO₄ is the drug of choice for prevention and control of eclamptic seizures (Pritchard or Zuspan regimen). Antidote for toxicity = IV calcium gluconate. Toxicity sequence: loss of deep tendon reflexes → respiratory depression → cardiac arrest.
2. Preterm labour: weak tocolytic, but valued for fetal neuroprotection at <32 weeks.

Mechanisms in one glance

• Contract uterus: oxytocin (Gq → ↑Ca²⁺), ergometrine (sustained tonic), prostaglandins (contract + ripen cervix).
• Relax uterus: β₂-agonists (↑cAMP), nifedipine (↓Ca²⁺ entry), atosiban (block oxytocin receptor), MgSO₄ (Ca²⁺ antagonism), NO donors (↑cGMP), NSAIDs (↓PG).

A neat unifying theme: anything that raises intracellular Ca²⁺ contracts the uterus; anything that lowers it relaxes it.

Contraindications & precautions to memorise

Scenario	Avoid	Prefer
Hypertension / pre-eclampsia (need uterotonic)	Ergometrine	Oxytocin
Bronchial asthma (need uterotonic for PPH)	Carboprost	Oxytocin / misoprostol
Diabetes (need tocolysis)	β₂-agonists (hyperglycaemia)	Nifedipine / atosiban
Gestation >32 weeks (need tocolysis)	Indomethacin (ductus closure)	Nifedipine
Induction of labour	Ergometrine (tonic contraction)	Oxytocin ± dinoprostone

Complications of uterotonic therapy

• Uterine hyperstimulation/tetany → fetal distress, abruption, rupture (oxytocin, prostaglandins).
• Water intoxication / hyponatraemia with high-dose oxytocin (ADH-like).
• Hypertensive crisis, coronary vasospasm with ergometrine.
• Bronchospasm with carboprost; diarrhoea, pyrexia with prostaglandins.
• Pulmonary oedema, arrhythmia with β₂-agonist tocolytics.

Key differentials / comparisons

Oxytocin vs Ergometrine: oxytocin gives rhythmic contractions with a relaxation phase (physiological, safe before delivery for induction); ergometrine gives a sustained tonic contraction (used only after delivery; contraindicated in hypertension). Carbetocin vs oxytocin: carbetocin is long-acting and heat-stable, single dose, useful post-CS. Atosiban vs ritodrine: both tocolytics, but atosiban (oxytocin-receptor antagonist) has far fewer maternal side effects than the β₂-agonist ritodrine.

Mnemonics & eponyms

• "ASTHMA → no PG-F (carboPROST)" and "HYPERTENSION → no ERGOT." Two avoidance pairs that map cleanly onto each other.
• Tocolytic side-effect recall for β-agonists — "THE PAH": Tachycardia, Hyperglycaemia, (h)Eypokalaemia, Pulmonary oedema, Arrhythmia, Headache/tremor.
• Syntometrine = oxytocin + ergometrine (third-stage prophylaxis).
• Pritchard / Zuspan regimens — magnesium sulphate for eclampsia.
• Bishop score — assesses cervical favourability before induction; low score → ripen with prostaglandins first.

Recently asked / exam angle

• "Drug of choice for prevention of primary PPH" → Oxytocin (carbetocin acceptable; misoprostol if no cold chain).
• "Uterotonic contraindicated in asthma" → Carboprost (PGF₂α).
• "Uterotonic contraindicated in hypertension" → Ergometrine / methylergometrine.
• "Drug of choice for second-trimester abortion / mid-trimester termination" → Prostaglandins (misoprostol ± mifepristone).
• "Oxytocin receptor antagonist used as tocolytic" → Atosiban.
• "Tocolytic causing premature closure of ductus arteriosus" → Indomethacin.
• "Tocolytic of choice / preferred first line in preterm labour" → Nifedipine (or atosiban for safety).
• "Mechanism of oxytocin receptor" → Gq → PLC → IP₃ → ↑intracellular Ca²⁺.
• "Why oxytocin causes water intoxication" → structural similarity to ADH (antidiuretic effect).
• "Drug used for cervical ripening" → Dinoprostone (PGE₂) / misoprostol.
• "MgSO₄ in preterm labour purpose" → fetal neuroprotection (reduces cerebral palsy) <32 weeks.
• "Antidote for magnesium toxicity" → calcium gluconate IV.
• "First step / earliest sign of magnesium toxicity" → loss of deep tendon (patellar) reflex.

Rapid revision

1. Oxytocin = DOC for prevention & treatment of primary PPH; Gq-coupled receptor → ↑intracellular Ca²⁺; t½ 3–5 min, give as titrated IV infusion.
2. High-dose oxytocin → antidiuretic (ADH-like) → water intoxication, hyponatraemia, seizures; never run in plain dextrose alone.
3. Ergometrine → contraindicated in hypertension/pre-eclampsia, cardiac disease, and before delivery (sustained tonic contraction).
4. Carboprost (PGF₂α) → contraindicated in bronchial asthma; use oxytocin/misoprostol instead.
5. Misoprostol (PGE₁) — cheap, heat-stable; used for PPH and, with mifepristone (antiprogestin), for medical abortion.
6. Prostaglandins are DOC for second-trimester termination (oxytocin ineffective — low receptor density early).
7. Dinoprostone (PGE₂) = cervical ripening agent before induction when Bishop score is low.
8. Tocolytics buy ~48 h for antenatal corticosteroids (lung maturity); they don't improve mortality alone.
9. Nifedipine is preferred first-line tocolytic; atosiban (oxytocin antagonist) has the fewest side effects but is costly.
10. β₂-agonist tocolytics (ritodrine, salbutamol) → tachycardia, hyperglycaemia (avoid in diabetics), hypokalaemia, pulmonary oedema.
11. Indomethacin tocolysis only <32 weeks — risk of premature ductus arteriosus closure and oligohydramnios.
12. MgSO₄ = DOC for eclamptic seizures (antidote calcium gluconate) and gives fetal neuroprotection in preterm labour <32 weeks.