3. OXYTOCICS
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• The drugs of varying chemical nature that have the
power to stimulate the contraction of uterine
muscles.
• Aka Uterotonics
" one of the enduring achievements of modern
science”.
5. Oxytocic drugs
• Used for :
1.The contraction stress test to evaluate fetal well-being
during the antepartum period
2.Induction of labor
3.Treatment of labor arrest
4.Active management of labor
5.Treatment of uterine atony and postpartum hemorrhage
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6. 1.Oxytocin
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i. Synthesis:
• pituitary hormone secreted by the posterior pituitary gland.
• secretion occurs by sensory stimulation from cervix ,vagina ,
and from suckling at breast.
9. Mechanism of action
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Endogenous or administered oxytocin,
membrane receptor
Promotes the influx of ca++
From extra cellular fluid from S.R
Into the cell
Increase in cytoplasmic ca, stimulates uterine contraction
.
10. UTERUS
•acts through G protein-coupled receptors And the
phosphoinositide -calcium second-messenger system to
contract uterine smooth muscle.
•stimulates the release of prostaglandins &
leukotrienes that augment uterine contraction.
•small doses increases both the frequency & the force
of uterine contractions.
•At higher doses, it produces sustained contraction.
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11. •These contractions resemble the normal physiological
contractions of uterus (contractions followed by relaxation)
• Immature uterus is resistant to oxytocin.
•Contract uterine smooth muscle only at term.
•Sensitivity increases to 8 fold in last 9 weeks and 30
times in early labor.
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13. OXYTOCIN
• first-line agent
• polypeptide structure
• produced in the paraventricular nucleus of the
hypothalamus and released by the posterior pituitary gland
• roles of oxytocin in the obstetric population include
• induction and augmentation of labor, and
• prevention and treatment of postpartum uterine atony.
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14. Structure/Activity
• short polypeptide consisting of 9 peptides
• C46H66N12O12S2 structurally similar to vasopressin
• A disulfide bridge connects 2 cystines in the primary
sequence (Cys1 and Cys 6), forming a ring.
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15. Pharmacokinetics
• absorbed via IV, IM, buccal, or nasal mucosal routes
• IV has an immediate onset of action compared with IM, which
takes ~ 3 to 7 minutes
• The half-life is 10 to 12 minutes
• linear increase in plasma concentration of oxytocin after a
continuous infusion
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16. Clinical Role
• Uterine atony
• DOC for prevention and treatment of uterine atony after
vaginal and operative deliveries.
• It is also widely used to induce and augment the labor
process.
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17. Routes and Dosages
• Repeated exposure of the myometrial cells to oxytocin
• oxytocin receptor desensitization
• significant loss in the capacity to respond to additional oxytocin
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18. • Repeated doses
• ineffective
• 2nd -line uterotonics
• (ergometrine, prostaglandins F2a and E1)
• The recommended dose, timing, and rate of administration for
oxytocin during cesarean delivery remain ambiguous
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19. Intravenous infusion
• 10-40 I/U of oxytocin in 500-1000 mL of 0.9 % NS
• Rate of infusion adjusted according to uterine tone, up to
500mL/hour.
• The rate is then decreased (1-2.5 I/U) as long as uterine tone is
maintained and bleeding is not excessive.
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20. Intramuscular administration
• IM 10 units is an acceptable alternatives to IV Infusion.
• Less effective than IV
• Onset is slower but the clinical effect lasts longer (probably >1hour vs
3-5 min with IV route)
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21. Intravenous blous
• “Rule of Threes” algorithm to minimize the dose-related
and rate-related side effects of oxytocin
Initial 3 units of oxytocin given over 5 sec after delivery of
the fetus, & uterine tone is assessed every 3 min
thereafter
An additional 3 units of oxytocin is given if inadequate tone
is observed after each 3-minute interval.
If a 3rd bolus of oxytocin is given for inadequate tone and
uterine atony continues, then a 2nd -line uterotonic agent is
recommended.
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22. Side Effects and Contraindications
• S/E
• hemodynamic instability
• (hypotension, tachycardia, MI & arrhythmias),
• nausea,
• vomiting,
• headache, and
• flushing
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23. Side Effects and Contraindications
• Transient relaxation of vascular smooth muscle cells via Ca2-
dependent stimulation of the nitric oxide pathway, which leads to
• peripheral vasodilation
• hypotension,
• a compensatory increase in heart rate
stroke volume,
cardiac output.
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24. •caution must be taken to patients with
•abnormal ventricular function,
•valvular stenosis, or
•hypovolemia
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25. •Due to its structural similarity to vasopressin, oxytocin
administered in high dosages may lead to
•water intoxication,
•Hyponatremia
•seizures, and
•coma.
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27. Introduction
• semisynthetic amide ergot derivative
• ACOG recommends a 2nd-line uterotonic for refractory
uterine atony
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28. Structure/Activity
• Methylergonovine should be administered only if it is clear and colorless.
• Storage = refrigerated.
• Stability is compromised when exposed to higher temperatures, light, or
humidity
• Ergot alkaloids are serotonergic receptor agonist in the smooth muscles ,
weak antagonist of dopaminergic receptors and partial agonist of alpha-
adrenergic receptors
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29. • Methylergonovine causes uterine contractions and relaxation at low
doses, but causes sustained contractions and increased basal tone at
high doses
• Uterine contraction = methylergonovine agonist effects on the 5-HT2
receptor found in uterine smooth muscle
• uterine contraction through direct stimulation of the a-adrenergic
receptors in the uterus
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30. Pharmacokinetics
• O/A of IV methylergonovine is 2- 5 min & after oral administration is
5-10 min
• The half-life of methylergonovine after IV is 2.3 hours and after oral
administration is 2.7 hours
• Ergot alkaloids are mainly eliminated by hepatic metabolism.
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31. Clinical Role
• Treatment for postpartum hemorrhage due to uterine atony or
subinvolution
• At high doses, it creates sustained contractions in the uterus
• When compared with carboprost, methylergonovine has been
associated with reduced risk of hemorrhage related morbidity in
women with uterine atony refractory to oxytocin
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32. Route and Dosage
• ACOG recommends methylergonovine at a dosage of 0.2 mg
administered IM at a frequency of 2 to 4 hours as needed
• IM directly into the uterine corpus has been reported that
inappropriate myometrial absorption was a suspected cause of
MI , likely because the highly vascularized myometrial tissue
increased the rate of systemic uptake
• Due to hypertensive or cerebrovascular events, intravenous
injection is not recommended
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33. Side Effects and Contraindications
• hypertension due to vasoconstriction
• associated with headaches or seizures
• Nausea and vomiting
• Rare s/e include bradycardia, tachycardia, dyspnea,
thrombophlebitis, dizziness, and diarrhea
• coronary vasospasm, myocardial ischemia
• CAD or R/F for CAD are at increased risk of developing acute
coronary syndrome or infarction
• R/F include smoking, obesity, diabetes, and high cholesterol
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34. • Methylergonovine goes through CYP3A4 metabolism
• Potent CYP3A4 inhibitors should be avoided.
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36. CARBOPROST
• an analog of 15-methyl prostaglandin F2a.
• One cause of uterine atony may be a deficiency of prostaglandin F2a
concentration increase during the third stage of labor.
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37. Pharmacokinetics
• Carboprost is injected IM for the treatment of postpartum
hemorrhage
• Plasma levels peak 20 minutes after injection, and decline by
approximately half after 2 hours.
• Urinary excretion is the major route of elimination of carboprost
• Excretion of metabolites is almost complete 24 hours after
subcutaneous administration in women.
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38. Clinical Role
• 2nd -line treatment for uterine atony
• For refractory uterine atony , both methylergonovine and
carboprost are used in an effort to avoid surgical interventions
such as
• ligation of the uterine or hypogastric arteries or peripartum
hysterectomy.
• Carboprost is a treatment alternative for patients with
hypertensive disorders, such as preeclampsia (a relative
contraindication to methylergonovine), and for patients with
atonic bleeding refractory to methylergonovine
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39. Routes and Dosage
• Route : IM
• Dose : 250 mcg
• The dosage may be repeated every 15 to 30 minutes.
• Total dose should not exceed 2 mg (8 dosages).
• The need for repeated doses should be evaluated based on
clinical effect.
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40. Side Effects and Contraindications
• Nausea, vomiting, and diarrhea.
• Flushing, pyrexia, and myalgia
• The cause of these adverse effects is likely the stimulation of
smooth muscle in the gastrointestinal tract.
• Moderate increases in blood pressure are often seen, caused by
vascular smooth muscle contraction
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41. • Carboprost can precipitate
• bronchospasm,
• increased intrapulmonary shunt fraction
• abnormal ventilation-perfusion ratio, and
• hypoxemia.
• Patients with asthma are particularly susceptible to these
complications
• Based on plasma clearance rates, the manufacturer recommends that
breastfeeding be delayed for at least 6 hours after administration
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43. MISOPROSTOL
•Synthetic analog of prostaglandin E1(PGE1)
•The list of clinical applications include
• medically induced abortion
• medically assisted evacuation after
miscarriage,
•Cervical ripening, induction of labor, and
•treatment of uterine atony
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44. Structure/Activity
• PGE1 is rapidly metabolized, which hinders its utility via oral and
parenteral routes, and it also produces more side effects while being less
chemically stable.
• PGE1 has a carboxyl group at carbon 1 and a hydroxyl group at carbon
15.
• Misoprostol improves on the characteristics of PGE1 by having a methyl
ester at carbon 1 (imparting greater duration of action), a carbon 16 methyl
group, and hydroxyl group at carbon 16 rather than carbon 15.
• The modifications at carbon 16 increase oral activity, duration of action,
and safety
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45. Pharmacokinetics
• Clinically useful routes include the following:
• oral, buccal, sublingual, vaginal, and rectal
• Sublingual administration yields the highest peak
plasma concentrations of any route, and peak plasma
concentrations are seen in approximately 30 minutes.
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46. • Vaginal administrations of misoprostol produce slower onset and
a longer time to peak effect than routes involving the mouth.
• Buccal misoprostol exhibits a time to peak concentration and a
gradual fall in concentration comparable to the kinetics of vaginal
misoprostol
• Rectal misoprostol generates the slowest onset, with a long
offset time comparable to that of vaginal misoprostol.
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47. • Misoprostol exhibits extensive renal clearance.
• Renal impairment may extend its half-life as well as increase
bioavailability and maximum plasma concentrations.
• However, there is no recommended dose adjustment for
patients in renal failure
• Misoprostol acid is found in breast milk for several hours after
oral administration
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48. Clinical Role
• 2nd -line agent for treatment of uterine atony.
• Where the supply and storage of expensive, or light-
sensitive or temperature sensitive medications is limited,
misoprostol tablets offer an inexpensive and easy to-store
uterotonic option
• In a meta-analysis of recent large randomized controlled
trials involving misoprostol versus placebo, misoprostol
effectively prevented postpartum hemorrhage and severe
postpartum hemorrhage by 24% and 41%, respectively
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49. Routes and Dosage
• As a 1st -line treatment in situations in which active
management of the third stage of labor is not possible
• FIGO & WHO recommends 600mcg orally when injectable
uterotonics are not available.
• Repeat doses of misoprostol are not recommended for at
least 2 hours, or 6 hours in patients exhibiting shivering and
pyrexia .
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50. Side Effects and Contraindications
• S/E are self-limited and may be more common with
sublingual misoprostol administration due to its
pharmacokinetics, notably the high peak serum
concentrations that correspond to that route.
• FDA warning related to misoprostol applies to pregnant or
potentially pregnant women due to its abortifacient and
possible teratogenic effects
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54. Difference B/w Oxytocin and Prostaglandins
Prostaglandins
Oxytocin
Character
Contraction
through out
pregnancy
Only at term
Contraction
soften the cervix
Does not soften the
cervix
Cervix
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56. Difference b/w Oxytocin and Ergometrine
Ergometrine
Oxytocin
Character
Tetanic contraction ;
doesn't resemble
normal physiological
contractions
Resembles normal
physiological
contractions
Contractions
Only in P.partum
hemorrhage
*To induce &augment
labor.
*Post partum
hemorrhage
Uses
Moderate onset
Long duration of
action
Rapid onset
Shorter duration of
action
Onset and
Duration
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68. References
• Vallera, Cristianna et al. “Uterotonic Medications: Oxytocin,
Methylergonovine, Carboprost, Misoprostol.” Anesthesiology clinics
vol. 35,2 (2017): 207-219. doi:10.1016/j.anclin.2017.01.007
• (Heesen et al. 2019)Heesen, M. et al. 2019. “International Consensus
Statement on the Use of Uterotonic Agents during Caesarean
Section.” Anaesthesia 74(10): 1305–19.
• Uptodate
• 6th Edition Morgan & Mikhail's Clinical Anesthesiology
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Editor's Notes
An anesthesiologist is most likely to give an oxytocic drug for the indication of uterine atony and postpartum hemorrhage.
In case of uterine atony bimanual massage is first attempted before administration of an oxytocic agent. Oxytocic drugs are also given routinely following C-section to prevent development of uterine atony.
polypeptide structure
produced in the paraventricular nucleus of the hypothalamus and released by the posterior pituitary gland
roles of oxytocin in the obstetric population include
induction and augmentation of labor, and
prevention and treatment of postpartum uterine atony.
Oxytocin binds to a G-protein on the surface of the uterine myocyte, resulting in the generation of DAG and IP3 via phospholipase C on PIP2.
diacylglycerol (DAG) and inositol triphosphate (IP3)
phosphatidyl-inositol bisphosphate PIP2.
DAG stimulates prostaglandin synthesis, which also contributes to uterine contractions.
IP3 stimulates the release of calcium from the sarcoplasmic reticulum and increases the concentration of cytoplasmic calcium.
oxytocin–G-protein complex, which causes a conformational change in voltage-gated calcium channels allowing the influx of extracellular calcium.
oxytocin receptor is absent in a nonpregnant uterus. Once a woman becomes pregnant, oxytocin receptors appear in myometrial cells at approximately 13 weeks’ gestation and increase in concentration until term. The distribution of oxytocin receptors in the uterus is not uniform throughout. There is a higher concentration of receptors in the fundus of the uterus, and the concentration decreases closer to the lower uterine segment and cervix.5 This uneven receptor distribution may explain the less prominent uterine contraction seen in the lower third of the uterus after administration of oxytocin
uterus has α and β receptors
α-receptor stimulation resulting in contraction and
β2-receptor stimulation resulting in uterine relaxation.
Oxytocin binds to a G-protein on the surface of the uterine myocyte, resulting in the generation of DAG and IP3 via phospholipase C on PIP2.
diacylglycerol (DAG) and inositol triphosphate (IP3)
phosphatidyl-inositol bisphosphate PIP2.
DAG stimulates prostaglandin synthesis, which also contributes to uterine contractions.
IP3 stimulates the release of calcium from the sarcoplasmic reticulum and increases the concentration of cytoplasmic calcium.
oxytocin–G-protein complex, which causes a conformational change in voltage-gated calcium channels allowing the influx of extracellular calcium.
oxytocin receptor is absent in a nonpregnant uterus. Once a woman becomes pregnant, oxytocin receptors appear in myometrial cells at approximately 13 weeks’ gestation and increase in concentration until term. The distribution of oxytocin receptors in the uterus is not uniform throughout. There is a higher concentration of receptors in the fundus of the uterus, and the concentration decreases closer to the lower uterine segment and cervix.5 This uneven receptor distribution may explain the less prominent uterine contraction seen in the lower third of the uterus after administration of oxytocin
Oxytocin, the first-line agent in the prevention and treatment of( postpartum hemorrhage) uterine atony after vaginal and operative delivery.
Oxytocin binds to a G-protein on the surface of the uterine myocyte, resulting in the generation of DAG and IP3 via phospholipase C on PIP2.
diacylglycerol (DAG) and inositol triphosphate (IP3)
phosphatidyl-inositol bisphosphate PIP2.
DAG stimulates prostaglandin synthesis, which also contributes to uterine contractions.
IP3 stimulates the release of calcium from the sarcoplasmic reticulum and increases the concentration of cytoplasmic calcium.
oxytocin–G-protein complex, which causes a conformational change in voltage-gated calcium channels allowing the influx of extracellular calcium.
oxytocin receptor is absent in a nonpregnant uterus. Once a woman becomes pregnant, oxytocin receptors appear in myometrial cells at approximately 13 weeks’ gestation and increase in concentration until term. The distribution of oxytocin receptors in the uterus is not uniform throughout. There is a higher concentration of receptors in the fundus of the uterus, and the concentration decreases closer to the lower uterine segment and cervix.5 This uneven receptor distribution may explain the less prominent uterine contraction seen in the lower third of the uterus after administration of oxytocin
Iv is preferred bcoz it is more effective, dosing is likely more precise , onset of action is more rapid
It takes approximately 20 to 30 minutes to reach a steady-state in plasma, and a maximum concentration is reached in approximately 40 minutes.
Uterine atony - m/c cause of severe postpartum hemorrhage.
Oxytocin is the drug of choice for prevention and treatment of uterine atony after vaginal and operative deliveries.
It is also widely used to induce and augment the labor process.
Repeated doses of oxytocin may become increasingly ineffective and 2nd -line uterotonics (ergometrine, prostaglandins F2a and E1) should be considered earlier for laboring patients, especially in those who have received oxytocin.
Dose and duration of IV oxytocin infusion as a prophylactic agent vary widely.
rate of infusion adjusted according to uterine tone, up to 500mL/hour.
Iv is preferred bcoz it is more effective, dosing is likely more precise , onset of action is more rapid
It takes approximately 20 to 30 minutes to reach a steady-state in plasma, and a maximum concentration is reached in approximately 40 minutes.
“Rule of Threes” algorithm minimizes the total dose of oxytocin administered and may represent an optimal regimen for elective cesarean deliveries.
Iv is preferred bcoz it is more effective, dosing is likely more precise , onset of action is more rapid
It takes approximately 20 to 30 minutes to reach a steady-state in plasma, and a maximum concentration is reached in approximately 40 minutes.
Oxytocin used for prophylaxis or treatment of postpartum hemorrhage during cesarean delivery may result in several side effects.
The most common side effects are hypotension and tachycardia and are related to the dose and rate of administration.
Oxytocin used for prophylaxis or treatment of postpartum hemorrhage during cesarean delivery may result in several side effects.
The most common side effects are hypotension and tachycardia and are related to the dose and rate of administration.
Cardiovascular effects may be well tolerated in a healthy patient but
Cardiovascular effects may be well tolerated in a healthy patient but
ERGOT DERIVATIVE
Exposure to water or light leads to the formation of 6-hydroxy derivatives, which will be expedited in an acidic environment. It is easily oxidized, and the oxidation produces a color change.
2012 FDA raised potential safety concerns about methylergonovine-induced vasoconstriction causing MI and infarction, which led to a revision of the methylergonovine label
Exposure to water or light leads to the formation of 6-hydroxy derivatives, which will be expedited in an acidic environment. It is easily oxidized, and the oxidation produces a color change. M
If administered intravenously, methylergonovine is distributed from plasma to peripheral tissue in 2 to 3 minutes. Peak plasma concentration following intramuscular injection occurs in approximately 0.4 hour, and occurs approximately 1 hour after oral administration
Recently, methylergonovine has also been used to treat migraines and cluster headaches and to produce diagnostic coronary vasospasm in patients with variant angina
Due to hypertensive or cerebrovascular events, intravenous injection is not recommended.
If intravenous administration of methylergonovine is necessary as a lifesaving measure, it should be given slowly over a period of more than 60 seconds with close blood pressure monitoring.
Potent CYP3A4 inhibitors (such as protease inhibitors, erythromycin, quinolones, ketoconazole) should be avoided.
For a patient with no history or risk factors for coronary disease, methylergonovine is an extremely effective agent to correct refractory uterine atony and mitigate the postpartum hemorrhage.
Maternal concentrations of endogenous prostaglandins increase during labor, with peak concentrations occurring at the time of placental separation.
This prostaglandin surge likely contributes to uterine contractions and placental delivery. One cause of uterine atony may be a deficiency of prostaglandin F2a concentration increase during the third stage of labor.
Approximately 80% of the dose is excreted within the first 5 to 10 hours, with an additional 5% of the dose excreted over the next 20 hours. Three major metabolites of carboprost have been identified in human urine
Most cases of uterine atony respond to manual uterine massage and oxytocin
Carboprost for uterine atony route: IM
For women with severe postpartum hemorrhage who had already failed conventional therapy with intravenous oxytocin, intramuscular methylergonovine and manual uterine massage, studies showed a rescue rate of 86% overall, with 88% of subjects responding after 2 intramuscular doses.34 The need for repeated doses should be evaluated based on clinical effect.
Naturally occurring prostaglandin E1 (PGE1) protects gastric mucosa through reduction in gastric acid secretion and stimulation of mucus and bicarbonate secretion .Originally developed as a treatment for peptic ulcers, misoprostol found a vital role in obstetric and gynecologic patients thanks to its effects on uterine smooth muscle and the cervix
Misoprostol has differing pharmacokinetic profiles depending on the route of administration
Concomitant food intake and antacid use will measurably reduce the availability of oral misoprostol, but it is not clear whether the effect is clinically significant.
The FDA warns that nursing mothers may cause significant diarrhea in their infants by breast feeding under these circumstances
In situations in which oxytocin is not immediately available, or when oxytocin fails to produce a desired result, methylergonovine has advantages of speed and efficacy over misoprostol. However, in patients with a contraindication to methylergonovine therapy, or in environments in which skilled attendants and supplies are not available to deliver injectable medications, or if methylergonovine is not immediately available, misoprostol can be used.
INTERNATIONAL FEDRATION OF OBS & GYNECOLOGY & WHO
Misoprostol has no serious side effects in doses and durations of therapy that are clinically appropriate for the treatment of uterine atony. If misoprostol is effective in eliciting uterine contractions, patients may complain of cramping. Gastrointestinal upset may occur. With increasing doses, misoprostol has been described to cause shivering and corresponding hyperthermia
Although it cross placenta no fetal harm has been reported
