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Understanding Pharmacology of Uterotonics: Oxytocin & More

Explore the pharmacology of uterotonics including oxytocin, prostaglandin, ergot alkaloids, and progesterone antagonist tocolytics. Discover their physiological roles, clinical uses, and pharmacokinetic properties. Learn about antiprogestins and tocolytics in managing preterm labor.

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Understanding Pharmacology of Uterotonics: Oxytocin & More

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  1. Pharmacology of Uterotonics

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

  3. 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) Oxytocin

  4. 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

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

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

  7. 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

  8. 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

  9. HPETEs Prostaglandin

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

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

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

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

  14. 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

  15. 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

  16. 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

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

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

  19. 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

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

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

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

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

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

  25. Therapeutic Uses • iv. to arrest premature labor • can prolong pregnancy

  26. ETHANOL • Inhibit preterm labor • Overt inebriation • iv : impaired gag reflex • Carbohydrate metabolism more serious in diabetic • Crosses placenta

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

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

  29. 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

  30. Suggested for the Treatment of Preterm Labor • Diazoxide • Aminophylline • Progesterone

  31. Terimakasih

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