UTERINE DRUGS presentation, moa, uses ,adrs

Uterine drugs

1. UTERINE STIMULANTS AND RELAXANTS

2. CONTENTS INTRODUCTION OXYTOCICS TOCOLYTICS SUMMARY

3. INTRODUCTION OXYTOCICS : Drugs that stimulate the contraction of uterine muscles. Also called uterotonics . Use : in labour; PPH; abortion TOCOLYTICS: Drugs that relax the uterine muscles. Use: to delay preterm labour.

4. OXYTOCICS - Classification Posterior Pituitary hormones Oxytocin Ergot alkaloids Ergometrine/ Ergonovine Methylergometrine Prostaglandins PGE2 PGF2 α Misoprostol

5. OXYTOCIN

6. Oxytocin Sensory stimuli arising from cervix, vagina and breasts, emotional stimuli and nonspecific stimuli like pain, and apprehension, can lead to secretion/release of oxytocin from posterior pituitary.

7. The name is derived from the term OXYS means “quick” and TOKOS m eans “childbirth”. Hence from the term oxytocin should be in parturition (child birth)

8. Oxytocin Mechanism of action : oxytocin receptors of myometrium. Mobilization of bound intracellular calcium from sarcoplasmic reticulum to activate the contractile protein. There is increase in frequency and force of uterine contractions, similar to physiological uterine contractions

9. Pharmacological Actions

10. Oxytocin oxytocin receptors Concentration : Lower in non pregnant state and early pregnancy, but increases markedly as the pregnancy advances (becomes nearly 100 folds at 32 weeks and 300 folds at the onset of labour). Sensitivity : Lower in first and second trimester, but increases tremendously in late pregnancy and labour, due to modulation of the oxytocin receptors by estrogen/prostaglandins, making the uterus highly sensitive to oxytocin ( small doses ) during labour.

11. Oxytocin Contraction of myoepithelial cells surrounding the alveoli of mammary glands resulting in expulsion of milk from alveoli and ducts into the milk sinusoids and cisterns; ‘ milk letdown / milk ejection reflex’. This reflex (naturally) is initiated by the stimulus of suckling, which leads to the release of oxytocin.

12. Oxytocin Duration of action : Non pregnant women - t1/2 is 10-15 minutes and metabolized by kidneys and liver. Pregnant women – t ½ is 3 minutes, due to oxytocinase in placenta, uterine tissue and plasma. Orally - ineffective : inactivated rapidly in the GIT by trypsin. Hence administered by parenteral, nasal or buccal routes. Unitage and Preparation : 1 (i.u.) of oxytocin is equivalent to 2 microgram of pure hormone. Commercially available preparation is produced synthetically. Oxytocin injections are available in concentration of 5 i.u. / ml ( Syntocinon ) , 5 i.u/ 0.5ml. ( pitocin ) or 2 i.u./ 2ml. ( oxytocin ). Oxytocin nasal spray contains 40 units/ ml.

13. Oxytocin INDICATIONS Induction of labour: Given as a slow i.v. infusion (5 i.u . in 500 ml of glucose or normal saline solution ). Started at 0.2 ml/ min and gradually increased, once optimal response ( 3 Conts . in 10 minutes, each lasting 45 seconds), continued at that rate. In active management of third stage of labor: (to reduce the blood loss) 5 I.U., i.m. or slow i.v. for an immediate response where ergometirne is contraindicated.

14. Oxytocin For prevention/control of post partum haemorrhage (PPH); Oxytocin is administered by i.m. (2-5 i.u .) inj./ i. v. infusion (10 i.u./500ml) after the delivery of placenta, to produce a firm contraction of uterus and thus prevent PPH. To accelerate abortion , used along with prostaglandins, especially in second trimester abortion To stop bleeding following evacuation of uterus. In cases of breast engorgement to promote milk ejection . It is given intranasally, 40 i.u., 2-5 minutes before breast feeding.

15. Oxytocin ADVERSE EFFECTS Maternal Uterine hyper stimulation Urine rupture Water intoxication; due to its ADH like antidiuretic action, Foetal Foetal distress, foetal hypoxia or even foetal death may occur due to reduced placental blood flow due to uterine hyper stimulation.

16. Contraindications Cephalo-pelvic disproportion Breech presentation Placenta previa Fetal distress

17. ERGOT ALKALOIDS Ergometrine Methyl ergometrine (Methergine) Ergometrine, an alkaloid , isolated from Ergot, derived from a fungus, Claviceps purpurea , growing on rye, wheat etc. Methergine is semi synthetic, derived from lysergic acid. Increases myometrial contractions, involving fundus, body cervical segments of uterus. In therapeutic doses: contractions tend to be sustained with intervening relaxations. In higher doses; no relaxations in between contractions.

18. ERGOT ALKALOIDS Act directly on myometrium. Gravid uterus is more sensitive, esp. at term & early peurperium. Very effective for haemostasis , to stop bleeding from uterine sinuses following delivery/abortion. CVS effects: adrenergic agonists, cause contractions of smooth muscles, both arterial and venous vasoconstriction, increased PVR, CVP and MAP . Partly metabolized in liver and excreted in urine. Can be given by oral, intramuscular and i.v. routes.

19. ERGOT ALKALOIDS Indications Used for prevention/control of PPH (delivery/LSCS) bleeding after abortion. In the dose of 0.2 – 0.5 mg IM. & to ensure normal involution of uterus Management of third stage of labour Ergometrine – 0.2 – 0.5 mg IM after the appearance of anterior shoulder of foetus. Contractions appear in 2 – 3 mins. Not to be used to induce labour as cervical segment is also contracted, there might be a risk of foetal distress, asphyxia and death.

20. ERGOT ALKALOIDS Adverse effects Nausea, vomiting , headache, pruritus, hypertension, blurring of vision, dizziness, seizures, retinal detachment, suppression of lactation and gangrene of toes after prolonged use. Contraindicated in hypertensive patients and those with pre-eclampsia Also contra-indicated during pregnancy or before the third stage of labor.

21. Prostaglandins (PGs) C 20 fatty acid compounds containing cyclopentane ring, derivatives of Prostanoic acid. Act as local hormones. PGE2; Dinoprostone. PGF2α; Carboprost. And recently PGE1; Misoprostol Potent uterine stimulants; specially later part of pregnancy and to cause ripening of cervix.

22. Prostaglandins (PGs) Abortion : Dinoprostone( PG E2) : vaginally adm for sec trimester pregnancy. Ripening cervix at full term . Misoprostol( PG E1): orally adm. Used with Mifepristone to induce first trimester pregnancy. Carboprost( PG F2alpha): intra amniotic inj for sec trimester pregnancy

23. Facilitation of labour, cervical priming and PPH Oral PGE2 superior to oral oxytocin in augmenting labour and PPH treatment and equal to IV oxytocin. Vaginal administration softens the cervix. Preferred to oxytocin for inducing labour in women with pre eclampsia, eclampsia or cardiac or renal disease as they have diuretic effects. PGF2 alpha –Carboprost used for PPH.

24. Prostaglandins (PGs) Pharmacokinetics: Rapidly metabolized in lungs and liver. Given by intra vaginal, oral, rectal, intra muscular or intra myometrial routes. Prostin 15m ( carboprost ) has longer duration of action. Side effects: Nausea, vomiting, diarrhea, fever, flushing and bronchospasm. Use caution in hypertension, diabetes, angina epilepsy and raised intra-ocular pressure. Contraindicated in bronchial asthma, uterine rupture ( used with oxytocin), cardiac renal or hepatic diseases.

25. Pharmacology of oxytocic agents Drug Regimen Side-effects Contra-indications/ cautions Oxytocin 10 unit i.m. /or 10units/hr infusion Vasodilatation Hypotension, Tachycardia Hypovolemia Do not give undiluted as an i.v. bolus Methyl ergometrine 250µgm i.m./ slow i.v. repeat every 5-15 min. as needed (max 5 doses) Vasoconstriction Hypertension, bradycardia Hypertension, cardiac disease 15 methyl PGF2α (Carboprost) 250 µgm i.m./intra myometrial Repeat every 15 min. as needed (max 8 doses) Bronchospasm, pulmonary edema, Cardiac, renal, hepatic and pulmonary disorders Misoprostol 200- 400 µgm sublingual, 800- 1000 µgm per rectally Uterine scar

26. Tocolytics : Uterine Relaxants Decrease uterine contractility. Used to delay/postpone labour , arrest threatened abortion & treatment of dysmenorrhea. Suppression of labour Allow the foetus to mature Initiate glucocorticoid therapy for foetal lung maturation Transfer the woman in labour to proper health care centre.

27. Classification of Tocolytics β2 adrenergic receptor agonists Terbutaline , Retodrine , Isoxsuprine Magnesium Sulphate Calcium channel blockers Nifedipine & Nicardipine Oxytocin receptor antagonist Atosiban Prostaglandin synthetase inhibitors Indomethacin Nitric oxide donors Nitroglycerine

28. TOCOLYTICS (MOA) Decrease intracellular concentration of ca. Reducing the effect of ca on muscular contraction. Indirectly by inhibiting synthesis/ release/ receptor actions of PG and oxytocin .

29. β 2 adrenergic receptor agonists Terbutaline Ritodrine Isoxsuprine Mechanism of action is through beta 2 receptor stimulation, causing smooth muscle relaxation . Used in uncomplicated premature labour between 24 th to 33 rd weeks of gestation. Given as i.v. infusions. Terbutaline by i.v., oral or S.C. Isoxsuprin by oral or i.m. Continued for 12 hours after the contractions cease. Should not be administered for more than 48 hours, as it can lead to increased risk to the mother.

30. β 2 adrenergic receptor agonists Side effects : Nausea, vomiting, tachycardia, palpitations, headache, tremors, hypertension, etc. Neonates may develop hypoglycemia and ileus. Contraindications: pregnancy induced diabetic patients, cardiac disease , patients on steroids, beta blockers, digitalis, severe anaemia, hyperthyroidism and hypertension.

31. Magnesium sulphate Acts by competitive inhibition of calcium ions at motor endplates/cell membrane, reducing calcium influx. Direct depressant action on uterine smooth muscle Given by i.v. infusion, loading dose: 4-6 gm. i.v. over 15 to 20 minutes, titrated infusion: 1-2 gm/ hour. For effective relaxant: 6 – 7.5 mEq /L. Infusion continued for 12 hours after cessation of contractions. Preferred to beta agonists in DM, HTN, Hyperthyroidism.

32. Magnesium sulphate Side effects : Nausea, vomiting, flushing, headache, drowsiness, respiratory depression, muscle weakness, blurred vision and cardiac arrhythmias. Foetal / neonatal: Lethargy, hypotonia and respiratory depression Contraindications: Myasthenia gravis, heart blocks and renal disease.

33. Calcium Channel Blockers Nifedipine & Nicardipine Block the influx of calcium ions, thereby reducing the intra cellular calcium, reduces the tone of myometrium & opposes the contraction. Oral nifedipine 10 mg every 20-30 minutes, till uterine contractions subside, followed by 10 mg every 6 hourly. Tachycardia, hypotension, headache, flushing, nausea and peripheral oedema are some of the important side effects. Reduced placental perfusion may cause foetal hypoxia.

34. Oxytocin Receptor antagonists Atosiban is a peptide analogue of oxytocin, acts as an antagonist at oxytocin receptors. Administered i . v.6.75 mg as a bolus over 1 minute followed by infusion at 18 mg/hour for 3 hours & 6mg/ hour for up to 45 hours. Total duration of treatment not to exceed 48 hours and total dose not to exceed 330 mg. Side effects: nausea, vomiting, dyspnoea, chest pain.  

35. Prostaglandin Synthetase inhibitors Indomethacin Based on the effect of action of PGs on uterine contn . Found to reduce preterm birth. Maternal side effects: Headache, dizziness, nausea, vomitting, diarrhea, haematemesis, and malena. Foetal side effects: Oligohydramnios , premature closure of Ductus arteriosus and necrotizing enterocolitits Contraindications: Thrombocytopenia, bronchial asthma and renal disease.

36. OTHER AGENTS Nitric Oxide Donors: Nitroglycerine patches, not very reliable. Side effects: tachycardia, hypotension and methaemoglobinemia .

37. Tocolytics Contraindications : Rupture of membranes Placenta previa, abruption placenta Severe toxemia of pregnancy Intra uterine infection Intra uterine death of the foetus.

38. SUMMARY Clinical significance of Oxytocics . Tocolytics . Side effects of Oxytocics . Tocolytics .

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