Oxytocics and prostaglandins

The common final pathway

• Myometrial contraction needs a rise in cytosolic calcium, which binds calmodulin and activates myosin light chain kinase (MLCK); phosphorylated myosin binds actin.
• Oxytocin and PGF2-alpha act on Gq-coupled receptors: phospholipase C makes IP3 (calcium release from the sarcoplasmic reticulum) and DAG, and calcium enters through L-type channels. So oxytocin stimulates contraction primarily by raising intracellular calcium through the IP3 pathway; it also stimulates local prostaglandin production.
• Oxytocin receptors multiply many-fold in late pregnancy under oestrogen, so the uterus is most sensitive at term. Prolonged infusion desensitises the receptors.
• Relaxation is the reverse: a beta-2 agonist such as terbutaline raises cAMP; protein kinase A phosphorylates and inhibits MLCK and lowers calcium. This is the rescue for hyperstimulation, after first removing the prostaglandin pessary or stopping oxytocin.

Oxytocin

• A nonapeptide synthesised in the supraoptic and paraventricular nuclei of the hypothalamus, carried down axons bound to neurophysin and released from the posterior pituitary (a neurosecretory hormone, like ADH).
• Its two physiological actions are contraction of the uterus in labour and milk ejection (myoepithelial cells); it does not make milk or maintain pregnancy.
• Being a peptide it is digested in the gut, so it is given IV or IM. Half-life is a few minutes, shortened by placental oxytocinase, so it is given by infusion. It produces rhythmic contractions.
• Hyperstimulation: more than five contractions in 10 minutes causes fetal hypoxia and risks uterine rupture.
• Water intoxication: weak ADH-like (V2) action; high doses in large volumes of dextrose cause hyponatraemia and fits.
• Hypotension and tachycardia after a rapid IV bolus.
• First-line drug for prevention and treatment of PPH; heat-stable carbetocin is a long-acting analogue.

Ergometrine

• An ergot alkaloid acting on alpha-adrenergic, 5-HT2 and dopamine receptors: sustained tonic contraction lasting 2–3 hours, and vasoconstriction.
• Syntometrine (oxytocin 5 units with ergometrine 0.5 mg IM) combines fast onset with sustained action.
• Side effects: hypertension, coronary and peripheral vasospasm, nausea and vomiting.
• Contraindicated in hypertension and pre-eclampsia, heart disease, peripheral vascular disease, and before the last baby is delivered.
• Cleared by CYP3A4: ritonavir (a strong inhibitor in boosted HIV regimens) or clarithromycin raise ergot levels, causing ergotism with cold, white, painful fingers and weak pulses. Check the drug list first.

Prostaglandin biology

• Phospholipase A2 releases arachidonic acid from membrane phospholipids (blocked by corticosteroids). Cyclo-oxygenase (COX-1, COX-2) makes prostaglandins and thromboxane; lipoxygenase makes leukotrienes.

• Aspirin and NSAIDs relieve pain and inflammation by decreasing prostaglandin synthesis (COX inhibition); bradykinin and histamine themselves are not blocked.
• Gastric prostaglandins (PGE2, PGI2) reduce acid and increase mucus and bicarbonate, protecting against ulcers; NSAIDs remove this protection.

Uterotonic prostaglandins

• Cervical ripening: prostaglandins increase collagenase and matrix metalloproteinase activity, break collagen cross-links and raise hyaluronic acid and water, so the cervix softens and effaces.

• Carboprost diarrhoea and cramps: PGF2-alpha contracts gut smooth muscle as well as the uterus; vomiting and fever are common too. It may be repeated every 15 minutes up to 8 doses.
• Misoprostol routes:

• Misoprostol is a prodrug (de-esterified to misoprostol acid), cheap and stable at room temperature.
• Fever and shivering come from PGE1 raising the hypothalamic set point; they settle within hours.
• In a scarred uterus its strong prolonged contractions risk scar rupture. A failed abortion can cause facial and abducent palsy and limb defects.

Antiprogestogen and other drugs

• Mifepristone blocks progesterone receptors, softening the cervix and sensitising the myometrium to prostaglandins; misoprostol follows 24–48 hours later.
• Tranexamic acid blocks plasminogen binding to fibrin and reduces PPH bleeding.
• Volatile anaesthetics above 1 MAC relax the uterus.
• Primary dysmenorrhoea: PGF2-alpha from secretory endometrium; NSAIDs such as mefenamic acid relieve it.

When uterotonics fail

• Order: bimanual compression and uterotonics, then intrauterine balloon tamponade, then surgery: compression (B-Lynch) sutures and stepwise devascularisation, in which the uterine arteries are ligated first (they carry most uterine flow), then the utero-ovarian anastomoses, then internal iliac (anterior division) ligation, then hysterectomy. Interventional radiology embolisation is an alternative.

Remember Ergometrine fails the hypertensive woman, carboprost fails the asthmatic woman, and oxytocin is safe for both.

Exam trap Carboprost is PGF2-alpha and constricts bronchi; dinoprostone and misoprostol are PGE analogues and are safe in asthma.

Exam trap Ergometrine causes tonic, not rhythmic, contraction, so it is never given before the last baby is delivered.

How FCPS asks about this

• Actions of oxytocin: uterine contraction and milk ejection; synthesised in supraoptic and paraventricular nuclei.
• How oxytocin contracts the uterus: Gq, IP3 and calcium activating myosin light chain kinase.
• Ergometrine contraindication: hypertension and pre-eclampsia; ergotism with ritonavir (CYP3A4).
• Carboprost avoided in: asthma (PGF2-alpha bronchospasm); never IV.
• Misoprostol for PPH versus ripening: sublingual peaks fast; vaginal lasts longer.
• Aspirin relieves pain by decreasing: prostaglandin synthesis.
• First artery ligated for uncontrolled PPH: the uterine artery.