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 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 , PGF2 Drugs inhibiting uterine contractions 2 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 2 Ischaemic necrosis of the myometrium preceding menstrual flow. Has a little vasoconstrictor effect.
Vasodilators PGE2, PGF2 Dysmenorrhea increased production of PGE2 and PGF2 increased production. Menorrhagia increased vasodilation and reduced haemostasis. Due to PGE2 and PGI2 increase compared to PGF2. COX INHIBITORS- useful in managing these conditions.
EXOGENOUG PGS Dinoprostone Carboprost PGE2 15-Methyl PGF2
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.
