Each mL of sterile nonpyrogenic solution prepared by synthesis contains: oxytocin activity 10 IU (10 USP Posterior Pituitary Units), sodium acetate 2 mg, sodium chloride 5.1 mg and chlorobutanol 5 mg (as preservative) in water for injection. pH adjusted with acetic acid to approximately 3.9. Single-dose ampuls of 0.5, 1 and 5 mL. Sleeves of 5 or 10. Use only if solution is clear. Discard unused portion. Store at room temperature (15 to 30°C). Protect from freezing.
Amino acid alkaloids – partial agonist and antagonist of alpha receptor, serotonergic and dopeminergic, Amine alkaloides – no alpha blocking action, hydrogenation – produces more alpha blocking but no vasoconstriction
Drugs acting on UterusDr. D. K. BrahmaDepartment of PharmacologyNEIGRIHMS, Shillong
Oxytocin secretion Sensory stimuli from cervix, vagina andbreast suckling Expulsive phase is triggered by sustaineddistension of uterine cervix and vagina Oestrogen increases its secretion Ovarian polypeptide relaxin inhibits itsrelease ADH: Pain, haemorrhage and dehydrationincreases secretion
Actions of Oxytocin –Uterus Increase in force and frequency of contractions Low doses: Full relaxation occurs between the contractions, buthigh doses – basal tone increases Mechanism - High electrical activity of myometrium cellmembrane – burst of discharges Very low level of motor activity in the first two trimesters - 3rdtrimester onwards – spontaneous motor activity progressivelyincreases and sharp rise initiates labor Uterine sensitivity - 8 fold increase in in last 9 weeks and 30 fold increasein number of oxytocin receptors between early pregnancy and early labour –estrogen No. of receptors and myometrium sensitivity increases late in pregnancy –labour initiation and postpartum involution Increase in contraction is restricted to fundus and the body Non pregnant uterus are resistant to its action Oxytocin antagonist ATOSIBAN suppresses preterm labor
… Actions – contd.Breast Role in milk ejection Breast suckling and manipulation induces oxytocin release Mechanism: Contractions of myoepithelial surrounding alveolarchannels in mammary gland forces milk into large collectingsinuses – milk ejection reflex
Oxytocin – other effectsCVS No effect in low dose but at higher dosesfall in BP, reflex tachycardia and flushingKidney ADH like effect in high doses – decreasedurine output, pulmonary oedema etc.
Oxytocin – Mechanism ofaction (OXTR) Specific G protein-coupled membrane receptorsrelated to Vasopressin (V1 and V2) receptors Depolarization of muscle fibres and Ca++ influx Human myometrium – receptors coupled to Gqactivation leads to generation of IP3 – release of Ca++ ions Increase in local prostaglandin concentration –uterine contraction Kinetics: Being a peptide not effective orally Short half life – 3 to 6 minutes Available as injections for IM and IV use – 0.5 ml, 1 ml and 5ml etc.
Clinical uses ofoxytocin1. Induction of labour To induce or augment labor inpregnant women Indications:Premature rupture of membranesPre and post maturityIntra uterine growth retardation (IUGR)Placental insufficiency – diabetes, preeclampsia or eclampsia Before induction, rule out:Abnormal fetal positionCephalopelvic disproportionEvidence of fetal distressPlacental abnormalitiesPrevious uterine surgeryOxytocin is the drug of choice for induction of labor
Clinical uses of oxytocin (Pitocinor syntocinon) – contd. 5 IU is diluted in 500 ml of5% glucose or 0.9% saline– 5 milli IU/ml Start at low doseprogressively increase0.2 – 2 ml/min Induces labour within 2 – 4IU If no induction after givingupto 30 – 40 mU/min –higher doses areunsuccessful If labour – reduce the doseprogressively Unitage: 1 IU of Oxytocin= 2 mcg of pure hormone
Oxytocin infusion Monitoring Presence of Physician Mother and fetus monitoring – fetal andmaternal heart rate, maternal BP and strengthof contractions If uterine hyper stimulation – discontinueinfusion Higher dose (more than 20 mu/min) mayreduce water clearance – leading to waterintoxication, coma and death
Clinical uses of oxytocin – contd.2. Augmentation of labour In hypotonic contractions in dysfunctional labour(nulliparous) – administer as above But be careful, normal progression of labor shouldnever be tried to hasten, because over stimulationmay cause Uterine rupture Trauma of mother Trauma of fetus Compromised fetal oxygenation Useful in prolong latent phase of cervical dilation or arrest ofdilation
Clinical uses of oxytocin –contd3. Post partum haemorrhage, cesarean section: 5 IU IM or slow IV for immediate response Especially useful in hypertensive women whereergometrine cannot be used Also to maintain normal tone of uterine muscle4. Breast engorgement: Inefficient milk ejection reflex Intranasal spray before suckling
Pharmacological Actions -ergometrine Uterus: Increases force, frequency and duration of contractions At low dose contraction is phasic in nature with normal relaxation inbetween But moderate increase in dose – sustained contraction occurs More sensitive - Gravid uterus and at puerperium Contractions involve lower segment also CVS: Weaker vasoconstrictors than their amino acid counterparts - less chance ofdeveloping endothelial damage No significant rise in BP CNS: Interacts partially with dopaminergic, adrenergic and serotonergic receptors No significant effect in usual doses GIT: High doses cause increased peristalsis
Ergometrine – contd. Methylergometrine is preferred over ergometrine - higherpotency and less marked other effects Pharmacokinetics: Near complete absorption form GIT Immediate onset of action with IV route Metabolized in liver and excreted in urine Half life – 1 to 2 hrs Adverse effects: No complication in usual doses - Nausea, vomiting and rise in BPmay occur Decrease in milk secretion (dopaminergic) Contraindications: Pregnancy before 3rdstage of labour, vasculardisease, hypertension, liver and kidney diseases
Ergometrine - Uses Postpartum haemorrhage: to prevent Used the dose of 0.2 to 0.3 mg IM immediatelyafter delivery Continued for 4 - 7 days post partum If already PPH, use higher dose 0.5 mg IV Cesarean section and instrumental delivery –to prevent uterine atony For normal involution: 0.125 mg orally tds for4 – 7 days postpartum
Prostaglandins PGE2 and PGF2α – tocolytics Uses: AbortionIn early termination with antiprogesterone (Mifepristone)Midtrimester abortion – extra-amniotic injection followed byoxytocin (1o mg/ml available) Induction/augmentation of labour – intravaginalroute is preferred Cervical priming – intravaginal gel (cerviprime) Post-partum haemorrhage
Tocolytics - drugs These are drugs that inhibit uterinecontractions Beta-sympathomimetics (beta-2)Ritodrine, isoxsuprine, terbutaline and salbutamol Calcium channel blockers: Nifedepine Magnesium sulfate Prostaglandin inhibiting agents: Indomethacin Oxytocin antagonist: Atosiban Ethyl alcohol
Tocolytics Therapeutic uses: Delay or postpone labor – to allow fetus tomature and transfer of mother to ahealthcare centre Threatened abortion Dysmenorrhoea
Ritodrine MOA: Relaxation of uterine smooth muscle bystimulation of beta-2 receptors Doses: 50 mg of ritodrine in 500 ml of 5% glucosesolution. Start by 10 drops per minute and increaseby 5 drops every 10 minutes until uterine contractionscease Infusion should be continued for 12-48 Hrs after cessation ofcontractions Oral therapy should be continued every 8 Hrs after food Monitor maternal pulse, BP and FHS Adverse effects: CVS effects like hypertension, tachycardia,arrhythmia etc. & metabolic effects like hyperglycemia,hyperinsulinemia and hypokalaemia – also foetalhypoglycaemia and paralytic ileus
Ritodrine – contd. Contraindications: Heart disease - Hypertension or hypotension Hyperthyroidism and diabetes Antepartum haemorrhage (dilatation of the uterinearteries may increase the bleeding) Rupture of membrane Preparations: available as Ritodie/yutopar Tablet 10 mg / tablet or injections 10 mg/ml – 1mlor 5 ml Isoxsuprine (duvadilan) is available asoral and injections (10, 20, 40 mg tablets)
Magnesium sulfate andCalcium channel blockers Magsulf: Action: The intracellular calcium is displaced by magnesiumion leading to inhibition of the uterine activity Dosage: The initial dose is 40 cc of 10% solution givenslowly IV. The subsequent doses depend upon the responseand the development of MgSO4 toxicity so reflexes andrespiratory rate should be observed Uses: Used for prevention of seizures in eclampsia, notused for arrest of preterm labor for its toxicites Nifedepine: equal efficacy with beta-2 agonists Dose: 10 mg every 30 minutes and followed by 10 mg every6 hrly Problems: tachycardia, hypotension and foetal hypoxia
Summary – must know Drugs used as uterine stimulants -Classification Oxytocin – Mechanism of action o uterus andits therapeutic uses Ergometrine – Pharmacological actions inuterus and therapeutic uses Drugs used as Tocolytics – role of ritodrine(beta-2 agonists) in arrest of labor