Drugs acting on the uterus Dr A.W Olusanya

Objective Understand the pharmacologic basis of drugs causing uterine contraction and relaxations

Physiology of muscle contraction MLCK – myosin light chain kinase, PLC- phospholipase c, and remember myosin light phosphatase , sequestration into sarcoplasmic reticulum, and ca extrusion calcium ATPase, cAMP causes phosphorylation of MLCK thus decreasing its activity.

Uterine contraction Uterine contraction occurs when myosin and actin due to the action of myosin light chain kinase This is brought about by calcium calmodulin complex when there is an increase in intracellular calcium

Increase in intracellular calcium Brought about by Movement of calcium into the intracellular space via voltage gated calcium channels Activation of G-protein coupled receptors which eventually activates sarcoplasmic reticulum to release calcium

B2 adrenoceptor stimulates adenylate cyclase leading to increased levels of cAMP. CYCLIC AMP is inhibitory to myosin light chain kinase thus inhibiting muscle contractions. Alpha adrenoceptor inhibits adenylate cyclase leading to reduced levels of cAMP. This removes the inhibitory effect of cyclic AMP, thus favouring muscle contractions.

Therapeutic targets Drugs that stimulate G protein coupled receptors increases uterine contraction for example oxytocin and prostaglandins. Drugs stimulating alpha receptors – stimulates uterine contractions – ergometrine, methylergometrine. Drugs stimulating beta receptors – blocks uterine contractions ie. salbutamol, terbutaline, ritodrine Drugs blocking calcium entry into the cell – calcium channel blockers (Nifedipine) Drugs blocking prostaglandin production( PGs not available to act at receptors) – Cyclooxygenase inhibitors Drugs blocking oxytocin receptors – e.g atibosan

Uterine contraction Alpha adre

Drugs stimulating uterine contractions Oxytocin Ergot alkaloids – ergometrine, methylergometrine Prostaglandins – PGE2 , PGF2α

Drugs inhibiting uterine contractions β2 receptor agonist – Salbutamol, Ritodrine and terbutaline Oxytocin competitive antagonist-atosiban Prostaglandin synthesis inhibitors- indomethacin, meloxicam Calcium channel blockers - Nifedipine Magnesium sulphate Progesterone

Oxytocin Endogenous form produced by the hypothalamus A nonapeptide Stimulus – cervical dilatation and suckling MOA – activates G protein – coupled receptor – IP3 – increase intracellular calcium, increases local prostaglandin production Action - stimulates uterine contraction, dose related High level of oestrogen induces synthesis of oxytocin receptors during pregnancy

Oxytocin Iv or Im Inactivated in the liver and kidneys circulating oxytocinase Adverse effects Dose related hypotension – reflex taccyhcardia Fetal distress Water retention and dilutional hyponatraemia

Other action Stimulates myoepithelial cells in the mammary gland to contract – milk let down Vasodilator Antidiuretic – large doses Clinical use – labour induction or augmentation, 3rd stage of labour and post partum haemorrhage , abortifacient in incomplete abortion

Ergometrine Derived from ergot –Claviceps purpurea – a fungus Initiates strong contraction on the flaccid/uncontracted uterus Little effect on contracted uterus MOA – Alpha adrenoceptor agonist Vasoconstrictor – moderate

Uses- post partum haemorrhage, 3rd stage of labour Route of administration – oral, im. Iv Side effects – vomiting, nausea Hypertension, headaches Angina Ergotism - cramps, spasm, hallucination, severe GI upset, dry gangrene and burning pains.

Question Choice of drug to use in the 3rd stage of labour for uterine contraction in a patient with hypertension.

PROSTAGLANDINS Endogenous produced from the endo and myometrium in the proliferative stage of menstrual cycle PGE and PGF – contracts the non pregnant and pregnant uterus, relaxes cervix Uterine muscles more sensitive to progesterone during pregnancy PGF 2α – Ischaemic necrosis of the myometrium preceding menstrual flow. Has a little vasoconstrictor effect. Vasodilators – PGE2, PGF2

Dysmenorrhea – increased production of PGE2 and PGF2α – increased production. Menorrhagia – increased vasodilation and reduced haemostasis. Due to PGE2 and PGI2 increase compared to PGF2α. COX INHIBITORS- useful in managing these conditions.

EXOGENOUG PGS Dinoprostone PGE2 Carboprost 15-Methyl PGF2α Misoprostol PGE1 analogue

UNWANTED EFFECts Uterine pain Nausea and vomiting

Clinical uses Abortifacient Induction of labour Post-partum haemorrhage

Clinical uses of tocolytics (drugs inhibiting uterine contraction). Clinical uses – preterm labour to GA- 22-33weeks Caution indomethacin inhibits labour causes premature closure of ductus arteriosus – avoid in late pregnancy.