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  1. 1. <ul><li>Venkataramu – OXYTOCICS </li></ul><ul><li>(Oxytocin, Ergot, PGs) </li></ul><ul><li>Vijay Kumar - AntiHTN, Diuretics , </li></ul><ul><li>Tocolytics , TERATOLOGY </li></ul><ul><li>Vishwanath – Anesthesia & Analgesia </li></ul>
  2. 2. OXYTOCICS Venkataramu.B.S 9term, MIMS
  3. 3. “ OXYTOCICS are the drugs of varying chemical nature that have the power to excite contraction of the uterine muscles .” Ergometrine & Methergin E2&F2 ά PGE 2 & PGF 2 ά OXYTOCICS OXYTOCIN ERGOT DERIVATIVES PROSTAGLANDINS
  4. 4. Oxytocin: physiology <ul><li>Human hypothalamus </li></ul>
  5. 5. Diagram depicts a sagittal section through the hypothalamus and pituitary gland. The posterior pituitary consists of axon terminals of magnocellular neurons arising in the supraoptic and paraventricular nuclei of the hypothalamus. ● ● ● ●
  6. 7. During lactation … Axon terminals myoepithelial cells contract STIMULUS RESPONSE oxytocin mechanoreceptors in the nipple/ areola hypothalamic neuronal activity MILK EJECTION Suckling
  7. 8. During parturition… <ul><li>oxytocin is the primary mediator of myometrial contractility during labor. </li></ul><ul><li>During the second half of pregnancy , uterine smooth muscle shows an increase in the expression of oxytocin receptors(100-200fold) and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. </li></ul><ul><li>Stimulates PG synthesis. </li></ul><ul><li>Physiological uterine contraction - fundal contraction; cervical relaxation. (law of polarity maintained) </li></ul><ul><li>Cervical and vaginal dilatation results in an acute release of oxytocin from the posterior pituitary in a process known as the Ferguson reflex . </li></ul>
  8. 9. ABSORPTION, METABOLISM, AND EXCRETION <ul><li>Intravenously (controlled infusion) for initiation and augmentation of labor. </li></ul><ul><li>intramuscularly -control of postpartum bleeding. </li></ul><ul><li>Buccal & nasal spray- Limited use. </li></ul><ul><li>Preparations: </li></ul><ul><ul><li>Synthetic oxytocin (Syntocinon, Pitocin) 5IU/ml amp </li></ul></ul><ul><ul><li>Syntometrine (Sandoz - Syntocinon 5U+Ergometrine 0.5mg) </li></ul></ul><ul><ul><li>Desamino oxytocin - Buccal tablet 50 I.U. </li></ul></ul><ul><ul><li>Oxytocin nasal spray – 40U/ml </li></ul></ul><ul><li>Oxytocin is not bound to plasma proteins and is eliminated by the kidneys and liver . </li></ul><ul><li>Circulating half-life of max. 5 minutes . (avg 3-4min) </li></ul><ul><li>Duration of action-20min </li></ul><ul><li>Stored at 2-8 0 C </li></ul>
  9. 10. Pharmacodynamics <ul><li>UTERUS </li></ul><ul><li>Oxytocin acts through G protein-coupled receptors and the phosphoinositide - calcium second -messenger system to contract uterine smooth muscle . </li></ul><ul><li>Oxytocin also stimulates the release of prostaglandins and leukotrienes that augment uterine contraction . </li></ul><ul><li>Oxytocin in small doses increases both the frequency and the force of uterine contractions . </li></ul><ul><li>At higher doses , it produces sustained contraction . </li></ul>
  10. 12. <ul><li>BREAST </li></ul><ul><li>Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection . </li></ul><ul><li>Without oxytocin-induced contraction, normal lactation cannot occur. </li></ul><ul><li>KIDNEYS </li></ul><ul><li>At high concentrations, oxytocin has weak antidiuretic and pressor activity due to activation of vasopressin receptors. </li></ul>
  11. 13. Toxicity <ul><li>“ serious toxicity is rare ” when oxytocin is used judiciously. </li></ul>fetal distress STIMULATION HYPER Grand multipara, Malpresentation Contracted pelvis Prior uterine scar (hyterotomy) NOTE: These complications can be detected early by means of standard fetal monitoring equipment . excessive uterine stimulation Hypertonia (↑duration) uterine rupture . Polysystole (>6 in 10min) placental abruption
  12. 14. Seizures & death Inadvertent activation of vasopressin receptors - 30-40mIU/min 40-50IU/min Pul. Edema Heart Failure water Intoxication- hyponatremia Antidiuresis excessive fluid retention activation of vasopressin receptors -
  13. 15. <ul><li>To avoid hypotension, oxytocin is </li></ul><ul><li>administered intravenously as </li></ul><ul><li>dilute solutions at a controlled rate. </li></ul>OXYTOCIN BOLUS HYPOTENSION Transient vasodilation
  14. 16. INDICATIONS -To accelerate Abortion (inevitable, Missed). -Molar preg. -To stop bleeding. -Induction of Abortion. To induce labour. For cervical ripening. Augmentation of labour. Uterine inertia. Active management of 3 rd stage To minimise blood loss. Control PPH DIAGNOSTIC Contraction stress test (CST) Oxytocin sensitivity test (OST) THERAPEUTIC PREGNANCY LABOUR PUERPERIUM EARLY LATE
  15. 17. CST/ oxytocin challenge test <ul><li>During the antepartum period, oxytocin induces uterine contractions that transiently reduce placental blood flow to the fetus . </li></ul><ul><li>The oxytocin challenge test measures the fetal heart rate response to a standardized oxytocin infusion and provides information about placental circulatory reserve . </li></ul><ul><li>An abnormal response (+test) , seen as late decelerations in the fetal heart rate, indicates fetal hypoxia and may warrant immediate cesarean delivery. </li></ul><ul><li>Interpretation- Positive Suspecious </li></ul><ul><li>Negative Unsatisfactory </li></ul><ul><li>Hyperstimulation </li></ul>
  16. 18. Contraction stress test (CST) <ul><li>Assess irritability of uterus to oxytocin </li></ul><ul><li>Procedure – </li></ul><ul><li>0.01U given IV at the end of spontaneous contraction </li></ul><ul><li>Repeated at 1min interval until induced contraction starts (hardening) </li></ul><ul><li>Inference- </li></ul><ul><li>failure of ut.contraction after 4 inj signifies uterus is unlikely to be responsive to induction. </li></ul>
  17. 19. Contraindications <ul><li>PREGNANCY </li></ul><ul><li>Grand multipara </li></ul><ul><li>malpresentation </li></ul><ul><li>contracted pelvis </li></ul><ul><li>cephalopelvic disproportion </li></ul><ul><li>prior uterine scar (hysterotomy) </li></ul><ul><li>LABOUR </li></ul><ul><li>All cont. in preg. </li></ul><ul><li>+ </li></ul><ul><li>Obstructed labour </li></ul><ul><li>Incoordinate uterine contraction </li></ul><ul><li>FETAL DISTRESS </li></ul><ul><li>prematurity </li></ul><ul><li>ANY TIME </li></ul><ul><li>Hypovolemic state </li></ul><ul><li>Cardiac disease </li></ul>
  18. 20. Methods of administration Controlled intravenous Infusion 1-4mU/min (↑gradually) . INTRAMUSCULAR
  19. 21. For induction of labour <ul><li>Principle: </li></ul><ul><li>Start with LOW DOSE, escalate to achieve optimal response </li></ul><ul><li>(3contraction in 10min each lasting 45sec) </li></ul><ul><li>Maintain the dose- oxytocin titration technique. </li></ul><ul><li>OBJECTIVE - Maintain normal pattern of uterine activity till delivery and 30-60min beyond that. </li></ul><ul><li>NOTE: </li></ul><ul><li>Start with 4mU/min & ↑every 20min </li></ul><ul><li>Semi-Fowlers position - avoid venecaval compression. </li></ul>
  20. 22. Calculation of dose delivered in milliunits(mU) & its correlation with drop rate per minute NOTE: In majority of cases, max. response is seen with 16 mU/min i.e 2U in 500ml RL at 60 drops per min Units of oxytocin mixed in 500ml Ringer solution 1unit=1000 miliunits(mU) Drops per minute (15drops=1ml) 15 30 60 In terms of mU/min 1 2 8 2 4 8 4 8 16 16 32 64
  21. 23. Calculation <ul><li>500ml contains 1I.U. i.e 1000mU of oxytocin </li></ul><ul><li>So 1ml contains </li></ul>1000mU X 1ml = 2mU 500ml 1ml = 2mU Also 1ml~15drops
  22. 24. Table showing convenient regime Dose of oxytocin Solution used Escalating Drop rate at intervals of 20-30min To start with 1unit If no response-2units If still no response-8units 500ml Ringer solution -do- -do- 15-30-60 15-30-60 15-30-60
  23. 25. OBSERVATION DURING OXYTOCIN INFUSION <ul><li>RATE of flow – calculating drops/min </li></ul><ul><li>Uterine contraction - Finger tip palpation (hardening) </li></ul><ul><li>Intra uterine pressure:-peak 50to60mmHg resting 10to15mmHg </li></ul><ul><li>FHR </li></ul><ul><li>Assessment of progress of labour. </li></ul>
  24. 26. Indications for stopping the oxytocin infusion <ul><li>Nature of uterine contractions- </li></ul><ul><ul><li>abnormal uterine contractions occurring frequently (every 2 min or less ) </li></ul></ul><ul><ul><li>lasting more than 60sec(hyperstimulation) </li></ul></ul><ul><ul><li>↑ tonus in between contractions </li></ul></ul><ul><li>Fetal distress </li></ul><ul><li>Maternal complications </li></ul><ul><li>~•~•~•~ </li></ul>
  25. 27. Ergot Alkaloids <ul><li>Ergot is the natural alkaloid of Claviceps purpurea that grows on rye, wheat and other grains. </li></ul><ul><li>Chemistry </li></ul><ul><li>The ergot alkaloids are derivatives of the tetracyclic compound 6-methylergoline. </li></ul><ul><li>The first pure ergot alkaloid ergotamine was obtained in 1920, followed by the isolation of ergometrine/ergonovine in 1932. </li></ul><ul><li>The therapeutically useful natural alkaloids are </li></ul><ul><li>amide derivatives of d -lysergic acid. </li></ul><ul><li>Semi-synthetic derivatives are obtained from </li></ul><ul><li>catalytic hydrogenation of the natural alkaloids . </li></ul><ul><li>e.g.- Methergin (methylergonovine) </li></ul>
  26. 28. PHARMACOKINETICS of Ergometrine & methergin -:Composition of ergot preparations:- Absorption ORAL PARENTERAL(IM,IV) rapidly absorbed peak concentrations (plasma) -60 to 90min PREFERED ROUTE Preparation ampoules tablets Ergometrine 0.25mg/ 0.5mg 0.5-1.0mg methergin 0.2mg 0.5-1.0mg Syntometrine (sandoz) 0.5mg Ergometrine+ 5U-syntocinon
  27. 29. METABOLISM, EXCRETION <ul><li>Ergotamine is metabolized in the liver by largely </li></ul><ul><li>undefined pathways . </li></ul><ul><li>90% of the metabolites are excreted in the bile . </li></ul><ul><li>Only traces of unmetabolized drug are found in urine and feces. </li></ul><ul><li>Ergometrine (Ergonovine) and methergin ( methylergonovine)- </li></ul><ul><li>Ergometrine (Ergonovine) is metabolized and/or eliminated more rapidly than is ergotamine. </li></ul><ul><li>The half-life (plasma) - 0.5 and 2 hours. </li></ul><ul><li>Duration of action - 3hrs </li></ul>Onset of action Route Ergometrine Methergin IV 45-60sec 95sec IM 6-7min 7min Oral 10min 10min
  28. 30. Pharmacodynamics: <ul><li>MECHANISM OF ACTION- </li></ul><ul><li>Serotonin Receptor (5-HT 2 )+++ Mixed partial agonist Adrenoceptor++ effects </li></ul><ul><li>DIRECTLY ON MYOMETRIUM (Uterine Smooth Muscle) </li></ul><ul><li>Sensitivity of the uterus to the stimulant effects of ergot increases dramatically during pregnancy - increasing dominance of receptors as pregnancy progresses. </li></ul><ul><li>Non-physiological action i.e uniform contraction of uterus (loss of polarity). </li></ul><ul><li>In very small doses, ergot preparations can evoke rhythmic contraction and relaxation of the uterus. </li></ul><ul><li>At higher concentrations, these drugs induce powerful and prolonged contracture - STATE OF SPASM </li></ul><ul><li>Ergonovine is more selective than other ergot alkaloids in affecting the uterus and is the agent of choice in obstetric applications of these drugs. (Onset of action - 55sec by i.v.) </li></ul>
  29. 31. The uterine smooth muscle fibers when contracted compress traversing blood vessels –Principle for its clinical use.
  30. 32. INDICATION - THERAPEUTIC <ul><li>POSTPARTUM HEMORRHAGE- </li></ul><ul><li>The uterus at term is extremely sensitive to the stimulant action of ergot and even moderate doses produce a prolonged and powerful spasm of the muscle quite unlike natural labor . </li></ul><ul><li>Therefore, ergot derivatives should be used only for control of late uterine bleeding and should never be given before delivery . </li></ul><ul><li>Oxytocin is the preferred agent for control of postpartum hemorrhage but if this is ineffective, ERGOMETRINE (0.2 mg ) is given intramuscularly. </li></ul><ul><li>It is usually effective within 1–5 minutes and is less toxic than other ergot derivatives for this application. </li></ul>
  31. 33. PROPHYLACTIC : AFTER DELIVERY OF ANT. SHOULDER / FOLLOWING DELIVERY OF BABY at the time of delivery of the placenta.
  32. 34. CAUTIONS
  33. 35. Toxicity <ul><li>Most common - gastrointestinal disturbances: diarrhea, nausea, and vomiting . (Activation of the medullary vomiting center and of the gastrointestinal serotonin receptors ) </li></ul><ul><li>Precipitate MI, STROKE, BRONCHOSPASM & raise in BP (Vasoconstrictive action) </li></ul><ul><li>More dangerous toxic effect of overdosage is prolonged vasospasm -> gangrene of toes and requires amputation. </li></ul><ul><li>Bowel infarction has also been reported and may require resection. </li></ul><ul><li>Interferes with LACTATION (↓prolactin) </li></ul>
  34. 36. Contraindications <ul><li>PROPHYLACTIC </li></ul><ul><li>Suspected multiple gestation </li></ul><ul><li>Organic cardiac disease </li></ul><ul><li>Severe pre-eclampsia, eclampsia </li></ul><ul><li>Rh-negative mother </li></ul><ul><li>THERAPEUTIC </li></ul><ul><li>Heart disease or severe hypertensive disorders </li></ul>~•~•~•~
  35. 37. <ul><li>20-Carbon carboxylic acids with Cyclopentane ring </li></ul><ul><li>Formed by PUFA </li></ul>Prostaglandins Prostanoic acid 2 4 6 8 10 12 14 16 18 20 PGE 2 PGF 2 ά COOH PGE 1
  36. 38. SYNTHESIS & ACTION Lungs & liver Lungs & liver
  37. 39. <ul><li>PGF 2 ά - acts predominantly on myometrium </li></ul><ul><li>PGE 2- on the cervix due to collagenolytic property </li></ul>LOCAL HARMONES
  38. 40. <ul><li>The amnion synthesizes PGE 2 and decidua – PGF 2 ά </li></ul><ul><li>During pregnancy, the transport of prostaglandins from the amnion to maternal tissues is limited by expression of the inactivating enzymes, prostaglandin dehydrogenase (PGDH) in the chorion. </li></ul><ul><li>Late in pregnancy synthesis is increased by increased phospholipase-A2 and prostaglandin -H-synthase-type 2 (PGHS-2) activity. </li></ul><ul><li>During labor, PGDH levels decline and amnion-derived prostaglandins can influence membrane rupture and uterine contractility. </li></ul><ul><li>“ PGs action is independend of the period of gestation”. </li></ul>-ve PGDH -ve phospholipase-A2 PGHS-2 +
  40. 43. USES IN OBSTETRICS <ul><li>INDUCTION OF ABORTION – MTP / Missed abortion. </li></ul><ul><li>1 st trimester - misoprostol vaginally with the other drugs; </li></ul><ul><li>mid-trimesters:- all analogues are useful </li></ul><ul><li>Terminate MOLAR PREGNANCY (vaginal misoprostol 400 μ g, 3hr before evacuation) </li></ul><ul><li>INDUCTION / ACCELERATION OF LABOUR prefered in IUD, shorter period of gestation, elderly primigravida </li></ul><ul><li>Cervical ripening / dilatation – abortion, labour, diagnostic </li></ul><ul><li>Atonic PPH (refractory cases - step2)- </li></ul><ul><li>carboprost 250 μ g i.m/ Misoprostal 1000 μ g PR </li></ul><ul><li>Tubal-ectopic pregnancy (carboprost for salpingocentesis) </li></ul>
  41. 44. PG analogues & Common ROA PGE 1 (methyl ester) – MISOPROSTOL (vaginal, oral, rectal) PGE 2 – DINOPROSTONE (vaginal, extra amniotic) (NOTE: less toxic, more effective so widely used.) PGF 2 ά - DINOPROSTONE TROMETHAMINE PGF 2 ά (methyl analogue) – CARBOPROST (i.m., intra/extra-amniotic) -:Preparations:- Tablet -0.5mg dinoprostone (prostinE 2 ) Vaginal suppository- 20mg PGE 2 /50mg PGF 2 ά lipid base Vaginal pessary- 3mg PGE 2 ProstinE 2 gel- 500 μ g into cervical canal, below internal OS/1-2mg in the posterior fornix. -:Parenteral :- PGE 2 - ProstineE 2 1mg/ml PGF 2 ά -ProstinF 2 ά (Dinoprost tromethamine) 5mg/ml Methyl analogue of PGF2 ά - Carboprost 2.5mg/10ml vial
  42. 45. Side effects <ul><li>SYSTEMIC </li></ul><ul><li>NVD </li></ul><ul><li>Bronchospasm </li></ul><ul><li>Fall in BP, tachycardia, chest pain </li></ul><ul><li>Shivering, fever, malaise </li></ul><ul><li>LOCAL </li></ul><ul><li>Unduly forceful uterine contractions </li></ul><ul><li>Uterine cramps </li></ul><ul><li>Tachysystole (uterine hyperstimulation) </li></ul><ul><li>Uterine rupture (rare but use is avoided in previous LSCS) </li></ul><ul><li>Meconium passage. </li></ul><ul><li>Cervical laceration (when used as an abortifacient) </li></ul><ul><li>Vaginal bleeding </li></ul>
  43. 46. CONTRAINDICATION <ul><li>Hypersensitivity to the drug </li></ul><ul><li>Uterine scar </li></ul><ul><li>Bronchial asthma </li></ul><ul><li>Heart diseases </li></ul>
  44. 47. Misoprostol ( PGE 1 ) - Important points <ul><li>“ Used for cervical ripening.” </li></ul><ul><li>It is rapidly absorbed and more effective than oxytocin or dinoprostone for induction of labour. </li></ul><ul><li>Transvaginal – induction of labour </li></ul><ul><li>50 μ g every 3hrs to a max. of 6 doses </li></ul><ul><li>or </li></ul><ul><li>25 μ g every 3hrs to a max of 8 doses. </li></ul><ul><li>Orally - 50 μ g every 4hrs </li></ul><ul><li>No evidence of teratogenicity / carcinogenic effects. </li></ul><ul><li>Advantages over PGE 2 - cheap, stable at room temp., long shelf life, easy to administer, less side effects. Induction delivery interval is short. Need of oxytocin augmentation is less. Failure of induction is less. </li></ul>
  45. 48. T H A N K Y O U ☻