355306758-Oxytosscics-and-Tocolytics.pptx

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1. DRUGS AFFECTING UTERINE MUSCLE CONTRACTILITY Oxytocics Tocolytics Drugs 1

2. Objectives At the end of this session, you will be able to: 1.Describe drugs used to induce & augment labor. 2.List drugs used to control post partum hemorrhage. 3.Describe drugs used to induce abortion. 4.Explain types of drugs used to arrest premature labor. 2

3. DRUGS PRODUCING UTERINE CONTRACTIONS( Oxytocic Drugs ) OXYTOCIN, DESAMINO OXYTOCIN ERGOT ALKALOIDS Ergometrine ( Ergonovine ) Methyl ergometrine PROSTAGLANDINS a) PGE2 b) PGF2 α c) 15-methyl PGF2a, d) Misoprostol 3

4. OXYTOCIN Synthesis Is a posterior pituitary hormone secreted by the posterior pituitary gland. Oxytocin secretion occurs by sensory stimulation from cervix ,vagina , and from suckling at breast. released by stimuli e.g -coitus, parturition, suckling 4

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6. ACTIONS 1 . Uterus Oxytocin increases the force and frequency of uterine contractions. The increased contractility is restricted to the fundus and body; lower segment is not contracted, may even be relaxed at term With low doses, full relaxation occurs in between contractions; These contractions resemble the normal physiological contractions of uterus (contractions followed by relaxation) basal tone increases only with high doses 6

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8. Immature uterus is resistant to oxytocin. Contract uterine smooth muscle only at term. Sensitivity increases to 8 fold in last 9 weeks and 30 times in early labor . Clinically oxytocin is given only when uterine cervix is soft and dilated. 8

9. Mechanism of action The interaction of endogenous or administered oxytocin , with myometrial cell membrane receptor promotes the influx of ca ++ from extra cellular fluid and from S.R in to the cell , this increase in cytoplasmic calcium ,stimulates uterine contraction . 9

10. 2. Breast ★ Stimulation of milk ejection (milk letdown) mammary alveoli Oxytocin contracts myoepithelium of mammary alveoli and forces milk into the bigger milk sinusoids-'milk ejection reflex' (milk letdown in cattle) is initiated by suckling so that it may be easily sucked by the infant. It has been used in milch cattle to facilitate milking 10

11. Pharmacokinetics of oxytocin Absorption ,Metabolism and Excretion Not effective orally---- peptide Administered intravenously, or IM Also as nasal spray Not bound to plasma proteins Catabolized by liver & kidneys Half life = 5 minutes 11

12. Therapeutic Uses of Oxytocin Induction & augmentation of labor (slow I.V infusion) Post partum uterine hemorrhage (I.V drip) It acts by forcefully contracting the uterine muscle which compresses the blood vessels passing through it to arrest haemorrhage Impaired milk ejection (breast engorgement) One puff in each nostril 2-3 min before nursing It increase milk ejection, not milk production 12

13. Side Effects: a) Hypertension b) Uterine rupture c) Fetal death(over contraction) d) Water intoxication e) Neonatal jaundice 13

14. Contraindications a) Hypersensitivity b) Prematurity c) Abnormal fetal position d) Evidence of fetal distress e) Cephalopelvic disproportion Precautions a) Multiple pregnancy b) Previous c- section c) Hypertension 14

15. Effects on the Uterus Alkaloid derivatives induce TETANIC CONTRACTION of uterus without relaxation in between (not like normal physiological contractions) It causes contractions of uterus as a whole i.e. fundus and cervix(tend to compress rather than to expel the fetus) Difference between oxytocin & ergots?? Ergot Alkaloids 15

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17. Ergot alkaloids( pharmacokinetics) Absorption ,fate and excretion Absorbed orally from GIT(tablets) Usually given I.M Extensively metabolized in liver. 90% of metabolites are excreted in bile 17

18. Clinical uses Post partum hemorrhage (3 rd stage of labor) ** Hastens involution of the uterus Preparations Syntometrine ( ergometrine 0.5 mg + oxytocin 5.0 I.U), I.M. 18

19. Side effects a) Nausea, vomiting, diarrhea b) Hypertension b) Vasoconstriction of peripheral blood vessels ( toes & fingers) c) Gangrene 19

20. Contraindications: Induction of labor 1 st and 2 nd stage of labor vascular disease Severe hepatic and renal impairment Severe hypertension 20

21. PROSTAGLANDINS (PGE2 & PGF2 α ) MECHANISM OF ACTION: Contract uterine smooth muscle Difference between PGS and Oxytocin : PGS contract uterine smooth muscle not only at term(as with oxytocin ), but throughout pregnancy. Receptors are present throughout the pregnancy PGS soften the cervix; whereas oxytocin does not. PGS have longer duration of action than oxytocin . 21

22. Therapeutic uses 1. Induction of abortion 2. Induction of labor 3. Postpartum hemorrhage 22

23. Side Effects a) Nausea , vomiting b) Abdominal pain c) Diarrhea d) Bronchospasm (PGF2 α ) e) Flushing (PGE2) 23

24. Contraindications: a) Mechanical obstruction of delivery b) Fetal distress c) Predisposition to uterine rupture Precautions: a) Asthma b) Multiple pregnancy c) Glaucoma d) Uterine rupture 24

25. Difference B/w Oxytocin and Prostaglandins Prostaglandins Oxytocin Character Contraction through out pregnancy Only at term Contraction soften the cervix Does not soften the cervix Cervix 25

26. Difference (cont’d) Prostaglandins Oxytocin Character Longer Shorter Duration of action Used for abortion in 2 nd trimester of pregnancy. Used as vaginal suppository for induction of labor Not used for abortion Used for induction and augmentation of labor and post partum hemorrhage uses 26

27. Difference b/w Oxytocin and Ergometrine Ergometrine Oxytocin Character Tetanic contraction ; doesn't resemble normal physiological contractions Resembles normal physiological contractions Contractions Only in postpartum hemorrhage To induce &augment labor. *Post partum hemorrhage Uses Moderate onset Long duration of action Rapid onset Shorter duration of action Onset and Duration 27

28. Abortifacient agents Prostaglandins & their analogues Both PGE and PGF analogues are widely used (PGE preferred) PGE --- selective specificity for the myometrium and fewer GI side effects. PG analogues are Carboprost , Sulprostone , Gemeprost and Misoprostol . 28

29. Abortifacients Cont’d 1. Carboprost A 15(S)-15-methyl PGF2α Limited value as a primary method for abortion (high GI side effect) Used when other methods have failed 2 . Gemeprost PGE1 analogue (16, 16-dimethyl-trans-d2- PGE1 methyl ester) Used as a vaginal pessary . More efficacious when compared with intra-amniotic PGF2α or extra-amniotic PGE2 and dinoprostone intracervically . 29

30. Abortifacients Cont’d 3. Misoprostol A synthetic PGE1 analogue (15-deoxy-16-hydroxy-16-methyl PGE1). Prevention and treatment of peptic ulcer and later used as an abortifacient . Advantages over other PGs; cheap, stable at room temperature and can be stored for a long time. Limited effect on the bronchi or blood vessels. Effective in different routes of administration. Few and dose-dependent side effects. Available in many countries The misoprostol-only regimen used in countries where mifepristone is not available 30

31. Abortifacients Cont’d Antiprogesterone agents Progesterone is a key hormone in maintaining the pregnancy by keeping the uterus in a quiescent state. It prevents softening and dilatation of the cervix, reduces PG output from the decidua, and suppresses uterine contractions. Mifepristone is the only anti-progestin approved for the induction of abortion. Binds with high affinity to the progesterone receptor, inhibiting the effect of Progesterone hormone. 31

32. Mifepristone : soften the cervix, increase the sensitivity to PGs Convert the quiet pregnant uterus into an organ of spontaneous activity The sensitivity of the myometrium is increased by 5 times with maximal effect on uterine contractility and cervical ripening at 36–48 h following treatment. The benefits of pretreatment with mifepristone in comparison with placebo is well evidenced. Mechanism of Mifepristone-induced Abortion: Mifepristone, an anti-progestin, interferes with early pregnancy by competing with progesterone Abortifacients Cont’d 32

33. Abortifacients Cont’d Methotrexate It is an anti-metabolite. MoA: blocking the enzyme dihydrofolate reductase & inhibits the production of thymidine, a requirement for DNA synthesis. It interferes with cell growth & specifically interferes with rapidly dividing cells . It primarily affects the cytotrophoblast and inhibits, rather than weakens, the implantation process. Conditions that produce rapid cell division include neoplastic disease, autoimmune diseases, and pregnancy. 33

34. Combination of agents Mifepristone and Gemeprost Gemeprost was considered as the standard PG analogue in medical abortion until misoprostol emerged and was made available. Gemeprost has several disadvantages compared with misoprostol i.e. cost, need for refrigeration limits, its usage in developing countries and it is only available as vaginal pessary 34

35. Combination Cont’d Mifepristone and Misoprostol Vaginal misoprostol is more effective than oral misoprostol after pretreatment with mifepristone women preferred oral administration considering it more convenient . Incidence of diarrhoea was higher with oral misoprostol. Dose:Mifepristone 100mg - 600mg orally followed by misoprostol 400μg orally or 800μg vaginally in 6 - 72 hrs 35

36. TOCOLYTIC DRUGS Drugs relax uterine muscles & inhibit uterine contractions 36

37. Tocolytic Drugs Uses To arrest premature labor Delay delivery for 48 hrs , this time can be used to administer glucocorticoids ( Injection betamethasone ) to mother for maturation of the fetal lung 37

38. Classification of tocolytic drugs B 2 selective stimulants ( Ritodrine , salbutamol ) Oxytocic Antagonist Atosiban Other dugs Magnesium sulphate Calcium channel blockers ( nifedipine ) COX inhibitors ( indomethacin ) 38

39. DRUGS PRODUCING UTERINE RELAXATION( Tocolytic Drugs ). Action and Uses Relax the uterus and arrest threatened abortion or delay premature labor. 1. β -ADRENOCEPTOR AGONISTS ** Ritodrine, i.v. drip Selective β 2 receptor agonist used specifically as a uterine relaxant. 39

40. β - adrenoceptor agonists Mechanism of action Bind to β -adrenoceptors , activate enzyme Adenylate cyclase , increase in the level of cAMP reducing intracellular calcium level and decreasing the sensitivity of actin myosin contractile unit. 40

41. Side effects: Tremor Nausea , vomiting Flushing Sweating Tachycardia (high dose) Hypotension Hyperglycemia Hypokalaemia 41

42. ( Atosiban ) Oxytocic Antagonist Antagonizes the effects of oxytocin at its receptors Used as tocolytic in premature labor Given by IV infusion for 48 hrs 42

43. 2.CALCIUM CHANNEL BLOCKERS e.g., Nifedipine Causes relaxation of myometrium Markedly inhibits the amplitude of spontaneous and oxytocin-induced contractions 43

44. Unwanted effects Headache, dizziness Hypotension Flushing Constipation Ankle edema Coughing Wheezing Tachycardia 44

45. 3. Prostaglandin synthetase inhibitors cox -inhibitors The depletion of prostaglandins prevents stimulation of uterus NSAID , s e.g. Aspirin Indomethacin Ibuprofen 45

46. Adverse effects ulceration premature closure of ductus arterious . 47