Oxytocin antagonists as tocolytics

Oxytocin antagonists as tocolytics:

? What are they: drugs which act as antagonists to the oxytocin receptor.
? What do they do: they bind to OTR preventing the effects of oxytocin.
? How do they act: the patho-physiology of preterm labour is still not understood however women with preterm labour were shown to have a higher sensitivity to oxytocin and a higher OTR concentration compared to women of a similar gestational age but not in labour. By preventing oxytocin binding this stimulation of uterine contractions should be inhibited. Atosiban, an oxytocin derivative is a competitive inhibitor of OTR as well as the vasopressin (V1a) receptor. In vitro, Atosiban was shown to abolish the uterotonic activity of oxytocin in human and animal myometrium and shown in parturient rats to down-regulate OXTRs. Barusiban, has a higher affinity for the OTR and higher potency than Atosiban, and is without side-effects of vasopressin receptor antagonism. In vitro it has been shown to inhibit contraction of human myometrium at least as potently as Atosiban.
? Clinical use: Atosiban was shown to achieve significant prolongation of gestation in a placebo-controlled trial. In the 2005 Cochrane intervention review of OTR antagonists for inhibiting preterm labour, Atosiban was superior neither to ?2-AR agonists or placebo in both tocolysis and neonatal outcome. Furthermore, increased infant death was found. In a recent randomized controlled trial examining the effect of Barusiban on delivery and uterine contractility in women with threatened preterm labour at late gestational age, Barusiban was shown to be ineffective in delaying delivery or reducing uterine contractions. Thus it would seem that the early hope for anti-oxytocics has not been fulfilled.

Carbetocin:
Carbetocin (INN, BAN) (brandnames Duratocin, Pabal, Lonactene, Depotocin, Comoton, Decomoton), or 1-butanoic acid-2-(O-methy-L-tyrosine)-1-carbaoxytocin, is an oxytocic used in obstetrics to control postpartum hemorrhage and bleeding after giving birth, particularly following Cesarean section. It is an eight amino acid long analogue of oxytocin (a nonapeptide) and has a similar mechanism of action. Carbetocin is an agonist at peripherally expressed oxytocin receptors.Carbetocin works as an oxytocic, antihemorrhagic and uterotonic drug in the peripheral nervous system. The most common causes of postpartum hemorrhage are lack of tone in the uterus from overstretching or the use of an anesthetic.7 Carbetocin has been approved for use immediately following an elective Cesarean section when a local or spinal anesthesia has been administered.8 Since the uterus cannot contract on its own following incision during a Cesarean section, exogenous administration of oxytocin or an analog is necessary to restore uterine tone and prevent hemorrhage.
Indications

Accepted: Atony, uterine (treatment) orHemorrhage, postpartum (treatment) Carbetocin is indicated in the management of uterine atony and postpartum bleeding or hemorrhage following elective cesarean section performed under epidural or spinal anesthesia.

Unaccepted: Appropriate studies have not been performed to establish the safety and efficacy of carbetocin following classical or emergency cesarean section or when anesthesia other than epidural or spinal is used. Safety and efficacy also have not been established following vaginal delivery.
Mechanism is actionCarbetocin functions as an agonist at peripheral oxytocin receptors, particularly in the myometrium, with lesser affinity for myopepithelial cells. Oxytocin receptors are G protein-coupled and their mechanism of action involves second messengers and the production of inositol phosphates.Carbetocin mimics this mechanism. Binding for carbetocin and other oxytocin agonists has been shown to be nonselective at the extracellular N-terminus and loops E2 and E3. While the oxytocin receptor shows equal affinity for oxytocin and carbetocin, the biological effect of carbetocin is almost 50% that of endogenous or exogenous oxytocin.Carbetocin has a much longer lasting effect than oxytocin, necessitating only a single dose. Carbetocin inhibits endogenous oxytocin release, interrupting the uterine feedback loop with the hypothalamus and decreasing both central and peripheral release of oxytocin.
During pregnancy, the synthesis of oxytocin receptors in the uterus greatly increases, reaching a peak during labor and delivery. Consequently, the administration of carbetocin or another oxytocin analog during or immediately following birth will have increased uterotonic and contractile effect. The application of carbetocin does not affect a non-pregnant uterus with lower oxytocin receptor expression. Carbetocin also functions to thicken the blood, further preventing post-partum hemorrhage. Carbetocin should not be used to induce or augment labor since it could cause cardiac or respiratory distress to mother or infant.
Carbetocin is a drug used to control postpartum hemorrhage, bleeding after giving birth. It is an analogue of oxytocin, and its action is similar to that of oxytocin — it causes contraction of the uterus.

Ergot alkaloids:
Ergot, derived from the fungus Clavicepspurpurea, was the first effective oxytocic drug. Since 600 BC the fungus has been known as ”the noxious pustule in the ear of grain”, owing to epidemics of ergotism, characterized by either central nervous complications or peripheral gangrene. These agents were used in obstetrics from 1582 to 1822, when the view on their role changed from ”pulvis ad partum” (the powder of birth), to ”pulvis ad mortem” (the powder of death), due to the associated titanic uterine contractions, leading to fetal asphyxia, stillbirth and uterine rupture.Ergometrine is a naturally occurring alkaloid, first isolated in 1932 by Dudley and Moir. Currently this agent, although appropriately banned from intrapartum use, remains the second line intervention in the absence of contraindications, if uterine atony persists after oxytocin administration during caesarean delivery. Ergometrinemaleate or methylergometrine cause a rapid and sustained contraction of the pregnant and non-pregnant uterus. The half-life of ergometrine is 120 min. Little is known about the mechanism of action, which may be via a calcium channel, or an a-receptor in the inner myometriallayer. Ergometrine is also a partial agonist at aadrenergic, 5HT-1, and dopamine receptors.Although ergometrine and methylergometrine have the least vasoconstrictor effects of all the ergot alkaloids, the use of
ergometrine has been associated with a mean arterial pressure increase of 11% after intravenous injection of0.2 mg, and pulmonary wedge and pulmonary artery pressures increase by 30%.10 There are also reported cases of renal and coronary artery spasm, and there are eight recorded cases of myocardial infarction associated with their use. In several of these cases the use of ergot alkaloids was inappropriate. One patient had familial hypercholesterolaemia and ergometrine precipitated a requirement for stenting of the left anterior descending coronary artery.In another case a fatal myocardial infarction followed the administration of ergometrineto a hypertensive patient with preeclampsia.Despite these rare complications, ergot alkaloids still have an important role as a second-line agent at CS when administered with due care, but are contraindicated in preeclampsia. The RCOG guideline recommends an intravenous injection of 0.5 mg slowly for the management of uterine atony,while the World Health Organisation (WHO) stipulates 0.2 mg intravenously or intramuscularly, to be repeated as necessary every 15 min to a maximum of 1 mg.The high incidence of nausea and vomiting after the recommended
0.5 mg dose47 has discouraged its use as a first-line agent at CS. There are no published dose response curves for its use during CS, and it may be that doses smaller than those currently recommended work well enough, as in the case of oxytocin. One early publication described a dose-response curve during the first 4 days postpartum, employing a strain gaugetocograph positioned upon the abdomen. This study, employing 15, 30 and 60 lg intravenous boluses of ergometrine, showed dose-related increases in uterine contraction.

Syntometrine:

Syntometrine is a combination preparation, seldom used during CS, containing 5 IU oxytocin and 0.5 mg ergometrine. Following intramuscular administration, the time to onset of the uterine response is considerably shorter than after ergometrine alone, and the duration of action is several hours.

Prostaglandins:
Like oxytocin, prostaglandins increase intramyometrialcalcium concentrations and enhance uterine contraction. Their effects are mediated via G-proteins and the activation of calcium channels. Side effects after pharmacological administration include fever, diarrhoea, nausea and vomiting. The use of intramyometrial prostaglandin F2a (dinoprost) for atonic PPH was first described by Takagi in 1976subsequently, 15-methyl prostaglandin F2a (carboprost) was shown to have an extended half-life, fewer gastrointestinal and vasopressor side effects, and good uterotonic activity. Since 15-methyl prostaglandin F2a may be associated with bronchospasm, ventilation–perfusion mismatch and hypoxaemia, it is best used not as a first-line agent and not as prophylaxis. There is very limited experience with intravenous administration. Infusion at 100 lg/min during early pregnancy has been shown to cause systemic and pulmonary hypertension, and administration via the intravenous route is contraindicated. By contrast, prostaglandin E2 is associated with a marked decrease in systemic vascular resistance and hypotension. The recommended dose is 250?g intramuscularly, repeated every 15 min to a maximum of eight doses. Carboprost 500?g may be administered intramyometrially, but this remains the responsibility of the clinician. Prostaglandin E1 (misoprostol) is a cheap and widely available oxytocic, which has been little studied during CS. It is less effective than oxytocin and ergometrine, but has a role as a first line agent where the former are unavailable, and is under extensive investigation as a second-line agent. The sublingual route is probably the most reliable, since misoprostol is a methyl ester and undergoes first pass elimination. Misoprostol is frequently used off-label via the sublingual or rectal route for the management of uterine atony. Studies of its use during CS are few. One concluded that buccal misoprostol may reduce the need for additional uterotonic agents at CS. In a further small randomised comparison, oral misoprostol was concluded to be as effective as intravenous oxytocin in reducing intra-operative blood loss during elective CS under regional anesthesia. Importantly, 600?g misoprostol via the vaginal route in the midtrimester did not alter maternal haemodynamics as assessed by transthoracicbioimpedance measurements. The knownbenefits and risks of various doses and routes of administration of misoprostol in the prevention and treatment of PPH following vaginal and caesarean delivery, are summarized in excellent recent reviews and guidelines. Following vaginal delivery and prophylactic oxytocin, sublingual misoprostol 800?g has been found to be clinically equivalent to the rapid intravenous administration of a high dose of oxytocin in the management of PPH. There was a higher incidence of shivering and fever in the misoprostol group. A recent editorial highlighted the dose dependent nature of side effects, and cautions that the administration of a therapeutic dose of misoprostol after an initial prophylactic dose may be harmful. A recent systematic review reports 11 maternal deaths during five trials. Eight of these women received 600?g or more of misoprostol and three were controls. Further research will elucidate whether a dose of 400?g is safer than 600?g as prophylaxis, and whether doses as high as 800?g are required for treatment of PPH. Unlike most other uterotonics misoprostol does not need to be kept refrigerated to maintain its pharmacological activity.
Recommendation:
Uterotonic drugs remain an important intervention in the prevention of uterine atony. In addition,these agents are essential adjuncts to aggressive resuscitation and surgical management of PPH during CS. Current evidence is that oxytocin remains the uterotonic of the first choice. There are few definitive studies upon which to base a protocol for recommendation for dosing of oxytocin and second line uterotonics. Recommendations vary considerably from country to country
Prophylaxis against uterine atony:
In healthy parturients at low risk for uterine atony, aninfusion of oxytocin of no more than 3 IU over 3–5 min,22,25,26 or a bolus dose of up to 3 IU intravenouslyover 30 s in combination with phenylephrine,12 is recommended.This dose of oxytocin may be repeated after 3-5min should the initial response be inadequate. Optimalsubsequent infusion rates require further investigation.Carbetocin requires further investigation; current evidencesuggests an intravenous or intramuscular dose of100?g. In patients with preeclampsia, the slow administrationof up to 3 IU oxytocin is a reasonable first-lineintervention, followed by infusion at the lowest requiredrate, to avoid fluid retention. Administration of oxytocinin advanced cardiac disease requires further investigation.Slow infusion of small doses would seem prudent,24with special care in patients with pulmonaryhypertension

Management of uterine atony:
Before Delivery
If you are at risk for uterine atony, your doctor or nurse should make the following preparations in case excessive bleeding occurs during or after delivery:
• at least one large intravenous line should be established;
• medication to induce contractions of the uterus–oxytocin (Pitocin), methylergonovine (Methergine), and/or prostaglandins–should be on hand; and
• appropriate nursing and anesthesia personnel should be available.
In addition, the blood bank should be notified of the possible need for a blood transfusion for certain high-risk patients.
After Delivery
Uterine atony is diagnosed after delivery when there is excessive bleeding and a large, relaxed uterus. The doctor first rules out other potential causes of the bleeding (tears in the vagina or cervix and fragments of the placenta remaining in the uterus); these problems should be resolved if they are present. If the bleeding continues, the uterus may be stimulated to contract with use of massage and intravenous oxytocin. Many studies show this technique reduces postpartum hemorrhage and the need for blood transfusions. If heavy bleeding from atony occurs despite the use of oxytocin after delivery, then two additional medications may be used to help control hemorrhage:
• Methylergonovine, a strong vasoconstrictor derived from ergot, is injected into a muscle. It is not given to patients with preeclampsia or a history of high blood pressure because it can cause high blood pressure.
• Prostaglandin F-2-alpha (Hemabate) is injected under the skin and also directly into the uterus. Frequent side effects include diarrhea and vomiting. It can cause bronchial constriction and is usually avoided in patients with asthma.
Emergency surgery should be performed if atony persists despite these measures to control the bleeding. This may be accomplished by tying off the blood vessels that supply the uterus. If successful, this procedure should not affect future pregnancies. In a more involved procedure, the doctor uses x-rays to guide a small catheter through blood vessels in the mother’s leg and into the blood vessels supplying the uterus. These blood vessels are then injected with gelatin sponge particles or spring coils to obstruct blood flow to the uterus. Although successful control of hemorrhage has been reported with this technique, the equipment necessary to perform it may not be available in most emergency situations.If bleeding persists in spite of all conservative measures to control it, a hysterectomy (removal of the uterus) may be necessary.Twenty patients with severe postpartum hemorrhage due to uterine atony who were unresponsive to conventional therapy were treated with 0.25-mg intramuscular injections of (15-S)-15-methyl prostaglandin F2 alpha-tromethamine. A rapid and successful response was obtained in 18 patients. Two patients required surgical procedures to control bleeding. Both patients with treatment failure had chorioamnionitis. Side effects of the prostaglandin therapy included nausea, vomiting and diarrhea, a transient mild temperature elevation, and a transient moderate blood pressure elevation. Those subjects with preeclampsia did not demonstrate a serious elevation of blood pressure. The prostaglandin F2 alpha analogue appears to be very effective in the treatment of postpartum hemorrhage due to uterine atony.