1. Drugs acting on the uterus
Dr A.W Olusanya

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

3. 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.

4. 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

5. 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

6. 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.

7. 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

8. Uterine contraction
Alpha adre

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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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.

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

17. 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

18. 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.

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

20. UNWANTED EFFECts
Uterine pain
Nausea and vomiting

21. Clinical uses Abortifacient Induction of labour
Post-partum haemorrhage

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