OXYTOCIC DRUGS
Prof.Dr. Zeliha Yazıcı
Stimulate the frequency and force of uterine contractions
I.
II.
III.
IV.
V.
Oxytocin
Ergot Alkaloids
Prostaglandins
Hypertonic solutions
Herbal supplements
Clinical uses
 Cervical ripening and labour induction
 To treat postpartum haemorrhage
 Medical abortus
 To increase the force of uterine contractions during the labour
The motility of uterus
 Uterine smooth muscle contracts rhythmically originating in
the muscle itself
 Myometrial
cells
act
as
pacemakers
and
their
electrophysiological activity is regulated by the sex hormones
Oestrogen depolarises
Progesterone hyperpolarises
 Weak sympathetic inervation
Noradrenaline: - adrenoceptor   stimulate contraction
Adrenaline: 2-adrenoceptor   inhibits contraction
I. OXYTOCIN
 a cylic nonapeptide
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 synthesized in the hypothalamus, the ovary luteal cells, the
endometrium and the placenta
Oxytocin secretion
Increased
Dilation of cervix & vagina
Parturition
Pain
Suckling
Nausea
Be satisfied
Hemorrhage
Hypervolemia
Psychologic stress
Angiotensin
Cholecystokinin
VIP
Noradrenaline
Decreased
Fever
High level noise
Narcotic analgesic
Atrial natriuretic hormone
Relaxin
Met-enkephalin (negative
feedback)
Ethanol
Pharmacodynamics/Kinetics
 inactivated in the liver and kidneys and by circulating
placental oxytocinase, and to a small degree the mammary
gland
 onset of uterine contraction im: 3-5 mins., iv: ~1 min.
 Half-life elimination 1-5 mins.
 acts via G protein-coupled receptors (OT   IP3/DAG/Ca+2 )
 High dose oxytocin activates V1 and V2 receptors
 increases PG and LT production
Actions
On uterus
 contracts uterus
 Both amplitude and frequency of contraction are related to
dose
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 Large doses further increase the frequency of the
contractions, and there is incomplete relaxation between them
 fetal distress, or death, or uterine rupture
 Uterine responsiveness to oxytocin is dependent on estrogen
Mammary gland
 Contracts myoepithelial cells which causes milk let-down
Cardio-vascular system
 Dose-related hypotension arising from its vasodilator action
 Reflex tachycardia
 Large doses: hypotension at the beginning, then hypertension
(vasopressin receptors )
Antidiuretic hormone-like effect
 Weak antidiuretic action can result in water retention which
can be problematic in patient with renal or cardiac disease, or
preeclampsia.
Clinical uses
 Induction of labor
iv, 0.5-1 mIU/min; gradually increase dose 1-2 mIU/min until
desired contraction pattern is establish. 6 mIU/min provide
similar at spontaneous labor, max. 20 mIU/min.
Oxytocin challenge test: iv infusion 0,5 mIU/min, rate is
increased slowly until 3 uterine contractions occur in 10 mins,
concurrent monitoring of the fetal heart rate.
 Augmentation of labor
To augment hypotonic contraction in dysfunctional labor, it
rarely is necessary to exceed an infusion rate of 10 mIU/min.
 Third stage of labor and puerperium
To help maintain uterine contractions and tone 10 mIU/min
im; 20 IU/L, infused iv 10 ml/min until contraction, reduced 1-2
3
ml/min (If this is ineffective ergot alkaloids or misoprostol may
be used).
 Adjunctive treatment of abortion
10-20 mIU/min by iv infusion, max. total dose 30 U/12 hours
 Milk ejection
4-8 U intranasal oxytocin
Adverse reactions
 Mother: arrhytmias, hypertension, premature ventricular
contraction, nausea, vomiting, pelvic hematome, postpartum
hemorrhage, uterine hypertonicity, tetanic contraction, rupture
and spasm in uterus, fatal afibrinogenemia, anaphylactic
reaction, subarachnoid hemorrhage.
 Fetus or neonate: arrhytmias, bradycardia, brain and CNS
damage, neonatal jaundice, retinal hemorrhage, fetal death
 Pregnancy risk factor X
Warning/Precautions
 To be used for medical may produce antidiuretic effect (ie,
water intoxication, excess uterine contractions), high doses or
hypersensitivity to oxytocin may cause uterine hypertonicity,
spasm, titanic contraction, rupture, severe water intoxication
with coma and death is associated with a slow infusion over
24 hours.
Contrendications
 Significant cephalopelvic disproportion, unfavorable fetal
position, fetal distress, hypertonic or hyperactive uterus,
contrendicated vaginal delivery (ie, invasive cervical cancer,
active genital herpes)
Prep: Postuitrin-N, Synpitan
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II. ERGOT ALKALOIDS
Ergonovine (Ergometrine) & Methylergonovine




Contract uterus
Partial agonist and antagonist actions at 5-HT1
Weak agonist at α- adrenoceptors
Agonist or partial agonist actions at CNS dopamine receptors
Advantages of ergonovine
 has a very rapid onset of action.
 Its effect last for 3-6 hours.
 can be given orally, im or iv.
 Ergonovine is the most active and less toxic then ergotamine
 has a moderate degree of vasoconstrictor action per se.
Actions on uterus
 in very small doses, can evoke rhythmic contraction and
relaxation of uterus
 initiate strong contraction on relaxed uterus, reduses bleeding
from placental bed
 at higher concentrations, induce powerful and prolonged
contracture
Pharmacokinetic aspects and unwanted effects
 They are rapidly absorb and reach peak concentration within
60 to 90 mins
 Uterojenic effect can be observed within 10 mins, half-life 0.52 hours.
Clinical Use
 Used for the management of the thirt stage of labour
 to control bleeding due to incomplete abourtion
 to treat postpartum heamorrhage
Contraindications
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 pregnancy, treatened spontaneous abortion, induction of
labor, with CYP3A4 inhibitors, hypersensitivity
 used with caution in sepsis, heart disease, hypertention,
hepatic or renal impairment
 avoid prolong use (pleural & peritoneal & cardiac valvular
fibrosis)
 discontinue if ergotism develop
Advers reactions
 Nausea, vomiting, bradycardia, cerebrovascular accidents,
diapdoresis, dizziness, dyspnea, ergotism, headache,
hypertension, myocardial infarction, palpitation, seizures,
shock, thrombophlebitis, tinnitus, transient chest pain
Prep: Methergin, Metiler, Uterjin
 0,125 mg tablet, 0,25 mg/ml oral solution, 0,2 mg/ml
parenteral solution.
 3x0,2-0,25 mg/day, oral, im, sk, iv.
III. PROSTAGLANDINS




PGE2, PGF2 and analogs
contract the pregnant and nonpregnant uterus
uterine muscle sensitivity to PGs increases during gestation
promote coordinated contraction of the pregnant uterus, while
relaxing the cervix
reliably cause abortion in early and middle pregnancy unlike
oxytocin
Advantages of PGs
 Relax the cervix
 Do not increase the incident of neonatal jaundice
 Do not cause H2O and NaCl retantion
Prep:
 Dinoprost (PGF2), carboprost
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 Dinoprostane (PGE2), meteneprost, sulprostan
 Gemeprost (PGE1)
Clinical uses
Dinoprostane
 Given by the extra-amniotic route is used for late (2. trimester)
therapeutic abortion; given as vaginal gel, it is used for
cervical ripening and induction of labour
Gemeprost
 Given as vaginal pessary following mifepristone, is used as
medical alternative to surgical termination of pregnancy
Carboprost
 Used to treat postpartum heamorrhage as a alternative to
ergometrine
Advers reactions
 Uterine pain, nausea, vomiting, cardiovascular collaps,
phlebitis at the iv infusion site, bradycardia, fever, back pain,
broncospasm, chills, dyspne, flushing, pain, hypotention,
syncope
Contraindications
 Vaginal insert: hypersensitity, fetal distress, unexplained
vaginal bleeding, cephalopelvic disproportion, prolong
contraction of the uterus
 Gel: hypersensitity, history of asthma, contracted pelvis,
malpresentation of the fetus, prior uterine surgery, breech
presentation, multiple gestation
 Suppository: hypersensitity, acute pelvic inflammatory disease
uterine fibroids, servical stenosis
 Should be used by only by medically trained personnel
IV. HIPERTONIC SOLUTIONS
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Used for medical abortion
 Hipertonic saline solution (20% NaCl)
Latency time 36 h.
No longer used because of maternal complications
(hypernatremia, coagulopathy, hemorrhage, infection, cervical
injuries)
 Urea solution (40-50%)
Latency time 43 h.
Dehydratasyon, hyponatremia, hypercalemia
 Rivanol solution (0,1%)
10 ml per week, max. 240 ml
V. HERBAL SUPPLEMENTS
 Evenin primrose oil, black haw, black and blue cohosh and
raspberry leaves have been used to induce labor by
midwives
 No evidence to support their safety and efficacy
Myometrial relaxants
Used to delay preterm labour
 B-adrenoceptor agonists (e.g. ritodrine)
 Atosiban (oxytocin antagonist)
Tocolytic agents
 Medications that can stop labor by slowing down or halting
the contractions.
 Agents commonly used as tocolytics magnesium sulfate,
terbutaline, indomethacin, and nifidepine. Systemic review
concludes that tocolytic therapy with the calcium channel
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blockers offers the best benefit-to-risk ratio. However, few
head-to-head comparisons have been made between
agents.
Guidelines recommend:
 selecting an agent based on maternal status and potential
adverse drug reactions
 Do not recommend combination tocolytic therapy
 Do not recommend maintenance tocolytic therapy
 Do not recommend repeated courses of acute tocolytic
therapy owing to increased fetal risk and lack of efficacy
Corticosteroids
 Administration of antenatal corticosteroids during preterm
labor having an onset prior to 34 weeks’ gestation has
been proven to decrease the risk of neonatal respiratory
distress, intraventricular hemorrhage, necrotizing
enterocolitis, and death.
 No benefit from antenatal corticosteroids is gained if labor
starts after 34 weeks’ gestation.
 In order to allow for administration of antenatal steroids,
tocolytic therapy often is used to prolong time to delivery
by 2 to 7 days.
Magnesium sulfate
 Data proving that magnesium sulfate prolongs pregnancy
is lacking.
 It is contraindicated for use in women with myasthenia
gravis, and serious complications such as maternal
pulmonary edema and cardiac arrest have been reported.
 More benign side effects such as flushing, headache, and
nausea often cause discontinuation of therapy.
 Dose: 4–6 mg intravenous bolus over 20 minutes, then 2–
3 g per hour intravenous drip.
Terbutaline
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 Terbutaline has been shown to prolong pregnancy but has
not been associated with decreased neonatal morbidity.
 It is contraindicated for use in women with preexisting
cardiac arrhythmia.
 Potentially serious adverse effects include pulmonary
edema, cardiac arrhythmia, or myocardial ischemia in the
mother.
 Reported fetal and neonatal adverse effects include
tachycardia, hyperglycemia, and hyperinsulinemia.
 Dose: 0.25 mg subcutaneously every 20 minutes to 3
hours
 Antidote: Beta-sympatholytics
Indomethacin
 Indomethacin prolongs pregnancy but has not been
independently associated with decreased neonatal
morbidity.
 It may be of particular benefit in women with hydramnios.
 Avoid use in women with a history of severe renal or
hepatic impairment, aspirin allergy, or a history of peptic
ulcer disease or other bleeding disorders.
 Although typically well tolerated by the mother, reports of
increased risk of postpartum hemorrhage and patent
ductus arteriosus is worrisome.
 Dose: 50–100 mg oral load, then 25–50 mg orally every 6
hours × 48 hours
Calcium channel blockers (Nifedipine)
 The calcium channel blockers have been associated with
both prolonged pregnancy and decreased neonatal
morbidity.
 First-line agent
 When compared with β-mimetics (e.g., terbutaline) and
magnesium, they show better neonatal outcome and a
lower incidence of serious maternal side effects.
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 Potential minor maternal adverse effects include
headache, flushing, dizziness, and transient hypotension.
 Dose: 30 mg oral load, then 10–20 mg every 4–6 hours
Atosiban
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



Oxytocin antagonist
Inhibites uncomplicated premature labor
Decreases the frequency of uterine contractions
The incidence of side effects is lower than beta agonists
IV initial 6.75 mg over 1 min. followed by 18mg/hour for up
to 45 hours, max. duration of treatment 48 hours
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