Oxytocics

Venkataramu – OXYTOCICS (Oxytocin, Ergot, PGs) Vijay Kumar - AntiHTN, Diuretics , Tocolytics , TERATOLOGY Vishwanath – Anesthesia & Analgesia

OXYTOCICS Venkataramu.B.S 9term, MIMS

“ 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

Oxytocin: physiology Human hypothalamus

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. ● ● ● ●

During lactation … Axon terminals myoepithelial cells contract STIMULUS RESPONSE oxytocin mechanoreceptors in the nipple/ areola hypothalamic neuronal activity MILK EJECTION Suckling

During parturition… oxytocin is the primary mediator of myometrial contractility during labor. 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. Stimulates PG synthesis. Physiological uterine contraction - fundal contraction; cervical relaxation. (law of polarity maintained) Cervical and vaginal dilatation results in an acute release of oxytocin from the posterior pituitary in a process known as the Ferguson reflex .

ABSORPTION, METABOLISM, AND EXCRETION Intravenously (controlled infusion) for initiation and augmentation of labor. intramuscularly -control of postpartum bleeding. Buccal & nasal spray- Limited use. Preparations: Synthetic oxytocin (Syntocinon, Pitocin) 5IU/ml amp Syntometrine (Sandoz - Syntocinon 5U+Ergometrine 0.5mg) Desamino oxytocin - Buccal tablet 50 I.U. Oxytocin nasal spray – 40U/ml Oxytocin is not bound to plasma proteins and is eliminated by the kidneys and liver . Circulating half-life of max. 5 minutes . (avg 3-4min) Duration of action-20min Stored at 2-8 0 C

Pharmacodynamics UTERUS Oxytocin acts through G protein-coupled receptors and the phosphoinositide - calcium second -messenger system to contract uterine smooth muscle . Oxytocin also stimulates the release of prostaglandins and leukotrienes that augment uterine contraction . Oxytocin in small doses increases both the frequency and the force of uterine contractions . At higher doses , it produces sustained contraction .

BREAST Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection . Without oxytocin-induced contraction, normal lactation cannot occur. KIDNEYS At high concentrations, oxytocin has weak antidiuretic and pressor activity due to activation of vasopressin receptors.

Toxicity “ serious toxicity is rare ” when oxytocin is used judiciously. 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

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 -

To avoid hypotension, oxytocin is administered intravenously as dilute solutions at a controlled rate. OXYTOCIN BOLUS HYPOTENSION Transient vasodilation

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

CST/ oxytocin challenge test During the antepartum period, oxytocin induces uterine contractions that transiently reduce placental blood flow to the fetus . The oxytocin challenge test measures the fetal heart rate response to a standardized oxytocin infusion and provides information about placental circulatory reserve . An abnormal response (+test) , seen as late decelerations in the fetal heart rate, indicates fetal hypoxia and may warrant immediate cesarean delivery. Interpretation- Positive Suspecious Negative Unsatisfactory Hyperstimulation

Contraction stress test (CST) Assess irritability of uterus to oxytocin Procedure – 0.01U given IV at the end of spontaneous contraction Repeated at 1min interval until induced contraction starts (hardening) Inference- failure of ut.contraction after 4 inj signifies uterus is unlikely to be responsive to induction.

Contraindications PREGNANCY Grand multipara malpresentation contracted pelvis cephalopelvic disproportion prior uterine scar (hysterotomy) LABOUR All cont. in preg. + Obstructed labour Incoordinate uterine contraction FETAL DISTRESS prematurity ANY TIME Hypovolemic state Cardiac disease

Methods of administration Controlled intravenous Infusion 1-4mU/min (↑gradually) . INTRAMUSCULAR

For induction of labour Principle: Start with LOW DOSE, escalate to achieve optimal response (3contraction in 10min each lasting 45sec) Maintain the dose- oxytocin titration technique. OBJECTIVE - Maintain normal pattern of uterine activity till delivery and 30-60min beyond that. NOTE: Start with 4mU/min & ↑every 20min Semi-Fowlers position - avoid venecaval compression.

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

Calculation 500ml contains 1I.U. i.e 1000mU of oxytocin So 1ml contains 1000mU X 1ml = 2mU 500ml 1ml = 2mU Also 1ml~15drops

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

OBSERVATION DURING OXYTOCIN INFUSION RATE of flow – calculating drops/min Uterine contraction - Finger tip palpation (hardening) Intra uterine pressure:-peak 50to60mmHg resting 10to15mmHg FHR Assessment of progress of labour.

Indications for stopping the oxytocin infusion Nature of uterine contractions- abnormal uterine contractions occurring frequently (every 2 min or less ) lasting more than 60sec(hyperstimulation) ↑ tonus in between contractions Fetal distress Maternal complications ~•~•~•~

Ergot Alkaloids Ergot is the natural alkaloid of Claviceps purpurea that grows on rye, wheat and other grains. Chemistry The ergot alkaloids are derivatives of the tetracyclic compound 6-methylergoline. The first pure ergot alkaloid ergotamine was obtained in 1920, followed by the isolation of ergometrine/ergonovine in 1932. The therapeutically useful natural alkaloids are amide derivatives of d -lysergic acid. Semi-synthetic derivatives are obtained from catalytic hydrogenation of the natural alkaloids . e.g.- Methergin (methylergonovine)

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

METABOLISM, EXCRETION Ergotamine is metabolized in the liver by largely undefined pathways . 90% of the metabolites are excreted in the bile . Only traces of unmetabolized drug are found in urine and feces. Ergometrine (Ergonovine) and methergin ( methylergonovine)- Ergometrine (Ergonovine) is metabolized and/or eliminated more rapidly than is ergotamine. The half-life (plasma) - 0.5 and 2 hours. Duration of action - 3hrs Onset of action Route Ergometrine Methergin IV 45-60sec 95sec IM 6-7min 7min Oral 10min 10min

Pharmacodynamics: MECHANISM OF ACTION- Serotonin Receptor (5-HT 2 )+++ Mixed partial agonist Adrenoceptor++ effects DIRECTLY ON MYOMETRIUM (Uterine Smooth Muscle) Sensitivity of the uterus to the stimulant effects of ergot increases dramatically during pregnancy - increasing dominance of receptors as pregnancy progresses. Non-physiological action i.e uniform contraction of uterus (loss of polarity). In very small doses, ergot preparations can evoke rhythmic contraction and relaxation of the uterus. At higher concentrations, these drugs induce powerful and prolonged contracture - STATE OF SPASM 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.)

The uterine smooth muscle fibers when contracted compress traversing blood vessels –Principle for its clinical use.

INDICATION - THERAPEUTIC POSTPARTUM HEMORRHAGE- 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 . Therefore, ergot derivatives should be used only for control of late uterine bleeding and should never be given before delivery . Oxytocin is the preferred agent for control of postpartum hemorrhage but if this is ineffective, ERGOMETRINE (0.2 mg ) is given intramuscularly. It is usually effective within 1–5 minutes and is less toxic than other ergot derivatives for this application.

PROPHYLACTIC : AFTER DELIVERY OF ANT. SHOULDER / FOLLOWING DELIVERY OF BABY at the time of delivery of the placenta.

Toxicity Most common - gastrointestinal disturbances: diarrhea, nausea, and vomiting . (Activation of the medullary vomiting center and of the gastrointestinal serotonin receptors ) Precipitate MI, STROKE, BRONCHOSPASM & raise in BP (Vasoconstrictive action) More dangerous toxic effect of overdosage is prolonged vasospasm -> gangrene of toes and requires amputation. Bowel infarction has also been reported and may require resection. Interferes with LACTATION (↓prolactin)

Contraindications PROPHYLACTIC Suspected multiple gestation Organic cardiac disease Severe pre-eclampsia, eclampsia Rh-negative mother THERAPEUTIC Heart disease or severe hypertensive disorders ~•~•~•~

20-Carbon carboxylic acids with Cyclopentane ring Formed by PUFA Prostaglandins Prostanoic acid 2 4 6 8 10 12 14 16 18 20 PGE 2 PGF 2 ά COOH PGE 1

SYNTHESIS & ACTION Lungs & liver Lungs & liver

PGF 2 ά - acts predominantly on myometrium PGE 2- on the cervix due to collagenolytic property LOCAL HARMONES

The amnion synthesizes PGE 2 and decidua – PGF 2 ά 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. Late in pregnancy synthesis is increased by increased phospholipase-A2 and prostaglandin -H-synthase-type 2 (PGHS-2) activity. During labor, PGDH levels decline and amnion-derived prostaglandins can influence membrane rupture and uterine contractility. “ PGs action is independend of the period of gestation”. -ve PGDH -ve phospholipase-A2 PGHS-2 +

USES IN OBSTETRICS INDUCTION OF ABORTION – MTP / Missed abortion. 1 st trimester - misoprostol vaginally with the other drugs; mid-trimesters:- all analogues are useful Terminate MOLAR PREGNANCY (vaginal misoprostol 400 μ g, 3hr before evacuation) INDUCTION / ACCELERATION OF LABOUR prefered in IUD, shorter period of gestation, elderly primigravida Cervical ripening / dilatation – abortion, labour, diagnostic Atonic PPH (refractory cases - step2)- carboprost 250 μ g i.m/ Misoprostal 1000 μ g PR Tubal-ectopic pregnancy (carboprost for salpingocentesis)

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

Side effects SYSTEMIC NVD Bronchospasm Fall in BP, tachycardia, chest pain Shivering, fever, malaise LOCAL Unduly forceful uterine contractions Uterine cramps Tachysystole (uterine hyperstimulation) Uterine rupture (rare but use is avoided in previous LSCS) Meconium passage. Cervical laceration (when used as an abortifacient) Vaginal bleeding

CONTRAINDICATION Hypersensitivity to the drug Uterine scar Bronchial asthma Heart diseases

Misoprostol ( PGE 1 ) - Important points “ Used for cervical ripening.” It is rapidly absorbed and more effective than oxytocin or dinoprostone for induction of labour. Transvaginal – induction of labour 50 μ g every 3hrs to a max. of 6 doses or 25 μ g every 3hrs to a max of 8 doses. Orally - 50 μ g every 4hrs No evidence of teratogenicity / carcinogenic effects. 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.

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