Rozaimah Zain-Hamid & Yazanul Anwar Department of Pharmacology and Therapeutics Faculty of Medicine, Universitas Sumatera Utara

OXYTOCIC / UTEROTONIC AGENTS Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

OXYTOCIC / UTEROTONIC AGENTS UTERINE CONTRACTION  Induction/augment dysfunctional labor  Control of post partum hemorhage  Incomplete abortion/abortion therapeutic Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Stimulation

OXYTOCIC / UTEROTONIC AGENTS  Oxytocin  Derivate of Ergot Alkaloids  Derivate of Prostaglandin Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

Oxytocin Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

OXYTOCIC / UTEROTONIC AGENTS Stimulation of prostaglandin synthesis Uterine contraction Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Direct action on uterus smooth muscle At terminal stage of pregnancy (  oxytocin receptor in myometrium) Cervix dilatation & stretching of vagina

Uterine contraction Cervix dilatation & stretching of vagina Stimulation of cervix & vagina  oxytocin secretion Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

Pharmacokinetic : * RoA : i.v & buccal absorption * Swallowed  inactive * Not bound to plasma protein * Catabolized by the kidneys & liver * Circulating t 1/2 : 5 minutes OXYTOCIN (Posterior pituitary hormone) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

Pharmacodynamic : Alters transmembrane ionic currents in myometrial smooth muscle cells & myoepithelial cells of mammary alveoli Uterine contraction & leads to milk ejection UTEROTONIC (OXYTOCIN) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

Clinical pharmacology :  Diagnostic : placental circulatory condition = Preparation available : Syntocinon & pitocin Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara UTEROTONIC (OXYTOCIN)

 Therapeutic :  Induce labor  Augment dysfunctional labor for : 1.Conditions requiring early vaginal delivery: Rh problem, maternal DM, preeclampsia 2. Uterine inertia 3. Incomplete abortion Clinical pharmacology : Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara UTEROTONIC (OXYTOCIN)

Adverse reaction : * Maternal death  hypertensive episodes * Uterine rupture * Water intoxication * Fetal death * Afibrinogenemia Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara UTEROTONIC (OXYTOCIN)

Contraindication :  Fetal distress  Prematurity  Abnormal fetal presentation  Cephalo-pelvic disproportion  Other predispositions for uterine rupture  Using sympathomimetic agents Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara UTEROTONIC (OXYTOCIN)

Derivate of Ergot Alkaloids Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

ERGOT ALKALOIDS  Adrenoceptors Dopamine receptors 5-HT receptors Produced by Claviceps purpurea Histamine Acetylcholine Tyramine UTEROTONIC (ERGOT ALKALOIDS) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

PHARMACOKINETICS: Variably absorbed from g.i.t  Amino acid alkaloids (ergotamine):  oral dose > i.m  Speed of absorption & peak blood level improved by caffeine UTEROTONIC (ERGOT ALKALOIDS) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

PHARMACOKINETICS:  Amine alkaloids (ergonovine / ergometrine) :  Also absorbed from rectum, buccal cavity, aerosol inhaler  After i.m : slow absorption (reliable)  Metabolism : liver Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara UTEROTONIC (ERGOT ALKALOIDS)

PHARMACODYNAMICS: STIMULANT EFFECTS ON THE UTERUS:  Combine  agonist, 5-HT receptors  Changes dramatically  pregnancy (  dominance  1 receptors as pregn.progresses)  Sensitivity: uterus aterm > earlier pregn. > non pregn. Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara UTEROTONIC (ERGOT ALKALOIDS)

 Small doses: rhytmic contr. & relaxation  Higher doses: powerful & prolonged contr.  Ergonovine : more selective  uterus (drug of choice : obstetric application) PHARMACODYNAMICS: STIMULANT EFFECTS ON THE UTERUS: Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara UTEROTONIC (ERGOT ALKALOIDS)

CLINICAL APPLICATION:  For control of late uterine bleeding (Post-partum hemorrhage)  Should never be given before delivery  Given at the time of delivery of placenta or immediately afterward if bleeding is significant Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara UTEROTONIC (ERGOT ALKALOIDS)

SIDE EFFECTS : Nausea, vomiting,  Blood Pressure Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara UTEROTONIC (ERGOT ALKALOIDS)

 Gastrointestinal disturbancies: diarrhea, nausea, vomiting  activation of medullary vomiting center & gastrointestinal serotonin receptors  prolonged vasospasm (gangrene  amputation) Therapy: infusion of large doses of nitroprusid or nitroglycerin Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara TOXICITY: UTEROTONIC (ERGOT ALKALOIDS)

CONTRA INDICATION : Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Obstructive vascular disease & collagen disease UTEROTONIC (ERGOT ALKALOIDS)

Derivate of Prostaglandin Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

UTEROTONIC ( PGE2 & PGF2  ) Contractile effects Release of calcium ions  the frequency & strength of uterine contraction Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

A. ABORTION  PGE 2 & PGF 2   1 st & 2 nd trimester abortion    proteoglycan & changing biophysical properties of collagen  soften the cervix UTEROTONIC ( PGE2 & PGF2  ) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

A. ABORTION  PGE 2 & PGF 2  (i.v ) produced abortion in ± 80 % of cases rate  PGF2  (intra-amniotic): success rate ± 100 %  Adverse effects < i.v  Other road of administration : i.m, intravaginal UTEROTONIC ( PGE2 & PGF2  ) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 Success rate  dose, duration of infusion & parity of the woman  Dose-limiting side effects  vomiting, diarrhea, hyperthermia & bronchoconstriction UTEROTONIC ( PGE2 & PGF2  ) A. ABORTION Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 Dinoprost tromethamine ( der. PGF 2  ) : single 40 mg intra-amniotic injection  complete abortion  20 hours Side Effects: cardiovascular collaps/anaphylactic shock, pulmonary hypertension  ultrasonic guidance UTEROTONIC ( PGE2 & PGF2  ) A. ABORTION Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 Carboprost tromethamine (i.m) & multiple dose  Synthetic PGE 2 analogue : vaginal suppositoria direct affects the collagenase UTEROTONIC ( PGE2 & PGF2  ) A. ABORTION Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

B. FACILITATION OF LABOR  PGE 2 & PGF 2   PGF 2  > potent than PGE 2  PGF 2  has more g.i.t toxicity than PGE 2  Success rate = oxytocin  G.i.t side effect > oxytocin UTEROTONIC ( PGE2 & PGF2  ) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

B. FACILITATION OF LABOR  PGE 2 & PGF 2   pass fetoplacental barrier  fetal toxicity uncommon  Oral PGE 2 superior than oral oxytocin, but = oxytocin i.v UTEROTONIC ( PGE2 & PGF2  ) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

B. FACILITATION OF LABOR  PGE 2 & PGF 2  have no antidiuretic effect  induction labor in woman : preeclampsia, cardiac & renal disease  Uterine fetal death  prostglandine alone or + oxytocin UTEROTONIC ( PGE2 & PGF2  ) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

TOCOLYTIC AGENTS Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

TOCOLYTIC AGENTS Suppress UTERINE CONTRACTION Inhibition, delaying or halting labor Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

TOCOLYTIC AGENTS   Adrenergic agents (terbutaline, ritodrine)  Calcium Channel blockers (verapamil, nifedipine)  Prostaglandin synthetase inhibitor (indomethacin) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara  Magnesium sulphate (MgSO 4 )

Magnesium sulphate (MgSO 4 ) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

Magnesium sulphate (MgSO 4 ) Acts as a calcium antagonist & membrane stabilizer (  the force of contraction)  Prophylaxis for preeclampsia (1 st line therapy)  Prevent seizures continued for hours after delivery Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 Route of Administration: oral & i.v  SIDE EFFECTS: Feeling of extreme warmth, perspiration, flushing, nausea, vomiting, blurred vision, lightheadedness, lethargy, nasal stiffness, constipation, affects the reflexes, and slow breathing, chest pain (taking together with other tocolytic) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Magnesium sulphate (MgSO 4 )

 CONTRA INDICATION: Heart block, myocardial infarction, myasthenia gravis, renal impairment Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Magnesium sulphate (MgSO 4 )  TOXICITY: Hypoxia, respiratory depression, cardiac arrest

Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Magnesium sulphate (MgSO 4 )  EFFECTS TO THE NEWBORN:  Baseline heart rate, drowsy, weak cry,  sucking rate in the early postpartum period  Strict monitoring for mother & newborn

 Adrenergic agents (terbutaline, ritodrine) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 Adrenergic agents (terbutaline, ritodrine)  Level of cAMP via adenylate cyclase Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara smooth muscle relaxation  level of free calcium ions

Terbutaline & ritodrine  or stop uterine contraction Preterm labor Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 Route of Administration: oral & i.v, subcutaneus controlled infusion pump (to give continuous low dose of terbutaline) Terbutaline & ritodrine Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

Terbutaline & ritodrine SIDE EFFECTS: Nervousness, restlessness, insomnia headache, rapid heart rate, nausea, hyperglycemia, hypokalemia, and pulmonary edema, shortness of breath, chest pain Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

Terbutaline & ritodrine WARNING: Cardiac dysrhythmia, cardiac disease, hypertension or thyrotoxicosis, shortness of breath, chest pain or contraction still exist during administration of terbutaline & ritodrine Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 EFFECTS TO THE NEWBORN: Fast heart rate, high or low blood sugar after birth Terbutaline  Strict monitoring for mother & newborn Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

Calcium Channel blockers (verapamil, nifedipine) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 the force of smooth muscle contraction Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Calcium Channel blockers (verapamil, nifedipine) Calcium ions Entering smooth muscle cells

Calcium Channel blockers (verapamil, nifedipine)  or stop contraction of uterus Delay labor (used for occasional uterus irritability) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

Calcium Channel blockers (verapamil, nifedipine)  Route of Administration: oral  SIDE EFFECTS: Facial flushing, headache, nausea, palpitation, lightheadedness Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 EFFECTS TO THE NEWBORN: No serious side effects have been note Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Calcium Channel blockers (verapamil, nifedipine)

Prostaglandin synthetase inhibitor (indomethacin) Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara

 the frequency & strength of uterine contraction Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Prostaglandin synthetase inhibitor (indomethacin) Synthesis of prostaglandin

Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Recommended as a tocolytic in preterm labor at << 32 weeks of gestation Indomethacin

 Route of Administration: oral, suppository  SIDE EFFECTS: Abdominal discomfort, nausea, vomiting, depression & dizziness Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Indomethacin

WARNING: Pregnant woman who has a story of bleeding disorders, aspirin sensitivity & kidney problems Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Indomethacin

 EFFECTS TO THE NEWBORN: Have serious side effects on the foetus Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara Indomethacin

Zain-Hamid R & Anwar Y, Faculty of Medicine, Universitas Sumatera Utara