Pharmacology of Uterotonics

Uterotonics Oxytocin Tocolytics Prostaglandin Ergot alkaloid Progesterone antagonist Tocolytics -adrenergist agonist Ca2+-channel blocker PG-synthase inhibitors Magnesium Sulfate Ethanol

Oxytocin Biosynthesis a cyclic non peptic, structurally similar to vasopressin synthesized as a larger precursor molecul rapidly broken down to the active hormone packaged into secretory granules as and oxytocin-neurophysin complexs secreted from nerve ending primarily in the posterior pituitary gland (neurohypophyses)

Physiologycal Roles Uterus Stimulates contraction : frequency and force highly dependent on estrogen immature uterus : resistance Responsiveness : paralel to spontaneous activity Exogenous oxytocin : enhance rythmic contraction high dose for early pregnancy Breast milk ejection

MOA Oxytocin 1,4,5 triphosphate • mobilization Ca2+ intracellular • activation voltage-sensitive Ca2+ channels Local prostaglandin production

Clinical Use Induction of labor (selected) risk of continued pregnancy isoimmunization intrauterine growth retardation placental insufficiency

Augmentation of labor should not be used : progressing normally hypotonic contraction in disfunctional labor complication : trauma of the mother / fetoes uterine rupture compromized fetal oxygenation very prolong latent phase of cervical dilation arrest / descent of dilation epidural anesthesia

Third stage of labor and puerperium after delivery or following therapeutic abortion Oxytocin challenge test pregnancy hold increased risk for maternal or fectal complication Oxytocin receptor antagonists competitively inhibit the interaction of oxytocin with its membran receptor potential use in the treatment of preterm labor

Prostaglandin HPETEs

Inhibitors of Eicosanoid Biosynthesis Calcium reducer Glucocorticoids NSAIDs Analogs of the natural fatty acid precursores

Pharmacological Properties Cardiovascular system prostaglandin tromboxan A2 leukotriens Blood Smooth muscle bronchial and tracheal uterus

Non pregnant : contractile > before menstruation continued PGFs TXA PGEs : relaxes Non pregnant : contractile > before menstruation relaxation > midcycle Pregnant : low concentration PGE2 high concentration PGE2 PGI2 iv PGE2 PGF2 contracted contracted relaxed Tone, frequency & intensity of rhytmic contraction >

Gastric and intestinal secretion Kidney and Urine Formation continued Gastric and intestinal secretion Kidney and Urine Formation Central Nervous System Endocrine Metabolic effects

Therapeutic uses Therapeutic abortion abortifacients when given early in pregnancy dinoprostone (PGE2) misoprostol (PGE1) + mifepristone or methotrexate Gastric Cytoprotection Impotence Maintenance of Patent Ductus Arteriosus

The Ergot Alkaloids Pharmacokinetic Absorption : variably from GI tract Oral dose of ergotamine 10x > im dose speed of absorption and peak blood level can be improved with caffeine Also absorbed from buccal cavity, rectum and after aerosol inhaler Metabolism : extensive

Pharmacodynamics A MOA : agonist partial agonist antagonist agonist at dopamine CNS receptor uterus : agonist / partial agonist at 5-HT2R B Organ system effects CNS Vascular smooth muscle Uterine smooth muscle Other smooth muscle at -adrenoceptor & serotonin receptor

Clinical Uses : A. Migraine B. Hyperprolactinemia C. Postpartum hemorrhage D. Diagnosis of Variant Angina E. Senile Cerebral Insufficiency

* periodic drug holidays (methysergide) Contraindication : Toxicity : - gastrointestinal - medullary vomiting centre - prolong vasospasm * large doses of nitroprusside - fibroblastic changes * periodic drug holidays (methysergide) Contraindication : - obstructive vascular diseases - collagen disease - (pregnancy)

Antiprogestins Mifepristone (RU486) derivate of the 19-norprogestin norethindrone competitive antagonist of glucocorticoid and progesterone Pharmacological actions : - antagonist progesterone - mifepristone - antagonist invivo - agonist invitro - onapristone - antagonist invivo & invitro

MOA : Mifepristone Early stage of pregnancy Decidual breakdown Detachment of the blastocyst h CG < Progesterone < PG > Contraction

Pharmacokinetics : - orally active - good bioavailability - peak plasma : several hours - H.L. : 20-40 hours - Binding 1 – acid glycoprotein - Liver metabolism & enterohepatic circulation - Excretion : > faeces

Therapeutic Uses : + misoprostol + prostaglandin - Mifepristone termination early pregnancy + misoprostol - Mifepristone (48 hours) medical abortion T 1 + prostaglandin - Postcoital contraceptive

TOCOLYTICS treatment of Preterm Labor * bedrest * hydration * sedation (+ tocolytics)

 - Adrenergic Agonists Ritodrine Terbutaline Tachycardia Hypotension Pulmonary edema Hypo kalemia Palpitation, tremor, Hyperglycemia angina

Therapeutic Uses iv. to arrest premature labor can prolong pregnancy

ETHANOL Inhibit preterm labor Overt inebriation iv : impaired gag reflex Carbohydrate metabolism more serious in diabetic Crosses placenta Overt:lahir inebrition :pemabuk impaired : merusak

Prostaglandin Synthase Inhibitor Inhibit labor Oral / rectal endomethacin effective in the treatment of preterm labor Serious potential ADR in the fetoes

Calcium Channel Blockers Verapamil and nifedipine Inhibition of premature labor Nifedipine : - decreasing uterine contraction - severe dysmenorrhea - PG – induced abortion

Magnesium Sulfate Inhibiting premature labor antagonizes Ca 2+ Agent of choice in diabetic patients Crosses placenta // maternal level Respiratory depression in the mother : 10 ml of 10% calcium gluconate

Suggested for the Treatment of Preterm Labor Diazoxide Aminophylline Progesterone

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