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Tags: pharmacology, Obstetrics

Uterotonics

vs Tocolytics

First line

Oxytocin and the synthetic analogue carbetocin are the agents of choice for initiating and maintaining uterine tone.
They are defined as first-line uterotonic agents as they mimic the naturally occurring hormone to act on its native receptor.

Carbetocin

Carbetocin is a long-acting synthetic analogue of oxytocin.
Its pharmacological difference to oxytocin comes from a deamination at the N-terminus and replacement of a disulphide bridge to connect a butyric acid functional group
As a result, carbetocin is resistant to aminopeptidase degradation and disulphide cleavage, is more lipophilic and has an altered tissue distribution, providing it with a half-life 4-10x longer than oxytocin of 40 min

this provides carbetocin with an increased in vivo efficacy, with uterine contractions of sustained higher frequency and amplitude compared with oxytocin.
Carbetocin also exerts its effects via stimulation of the oxytocin receptor.

The oxytocin receptor undergoes desensitisation in response to agonist stimulation.
This occurs via a pathway of phosphorylation and the binding of β-arrestin proteins, which cause uncoupling of the receptor from the G-protein, preventing receptor activation and promoting internalisation from the cell membrane.
This desensitisation phenomenon also occurs with exposure to carbetocin. However, the process of receptor internalisation with carbetocin is not thought to occur via the β-arrestin pathway

in vitro studies suggest that when the oxytocin receptor is internalised after oxytocin exposure, it is contained within intracellular vesicles and recycled back to the cell surface after 4 h

with exposure to carbetocin, it appears that the receptors are not recycled back to the cell membrane, suggesting the need for the initial β-arrestin involvement for the cycle to be completed
This key in vitro difference between oxytocin and carbetocin suggests that repeated doses of carbetocin may lead to tolerance, as receptor numbers dwindle without being recycled, which would be of significance in the clinical setting

Administration and pharmacokinetics

Carbetocin can be administered intramuscularly or intravenously as a bolus dose without the need for a follow up intravenous infusion, due to its longer half-life and ability to produce immediate tetanic uterine contractions followed by sustained rhythmic contractions for up to 3 h

It is less potent than oxytocin and so the manufacturer recommended IV or IM 100 mcg dose is equipotent to 5 IU of oxytocin

It is only used for prophylaxis or management of PPH in vaginal delivery or CD. It is not used for labour induction or augmentation like oxytocin due to its long duration of action and lack of titratability in this setting

With regards to storage, carbetocin has advantages over oxytocin in that it can be stored at room temperature and has a shelf life of 3 years

in vitro studies suggest the likelihood that it is partially degraded in the kidneys by carboxypeptidase enzymes that cleave the C-terminal
The resultant metabolites display a similar affinity for the oxytocin receptor as oxytocin, but likely have a much shorter half-life than carbetocin itself or may be excreted at a faster rate

C/I & SE

preeclampsia was originally stated as a contraindication to the use of carbetocin in the EU, due to the relatively unknown effects on blood pressure when it was first introduced

similar safety profile between the two drugs and no association with oliguria or hypertension with carbetocin

haemodynamic changes were more profound with oxytocin, suggesting that carbetocin may be a better choice for women with hypertensive disorders or pregnancy. Furthermore, the lack of a need for a follow up infusion means less fluid co-administration, which will also be of benefit in the preeclamptic patient

potential difference in the side effect profile of carbetocin and oxytocin lies in their different affinities for the vasopressin receptor

in vitro study demonstrated that when carbetocin binds to the vasopressin receptor it is markedly inactive, and likely even acts as a competitive antagonist, whilst oxytocin promotes the receptor activity
a clear difference has not yet been demonstrated in clinical practice.

Carbetocin vs oxytocin

Much argument around the benefit of carbetocin lies with its relatively easy storage, bolus administration and similar side effect profile to oxytocin
RCTs and meta-analyses over the years have also demonstrated the superiority of carbetocin with regards to outcomes in PPH

A 2019 meta-analysis and trial sequential analysis (TSA) comparing oxytocin to carbetocin in elective CD, found that carbetocin reduced the need for additional uterotonics by 53% compared to oxytocin

An initial factor favouring oxytocin in clinical practice was the relatively expensive cost of carbetocin

cost effectiveness from long-term savings
The largest cost savings related to a reduction in PPH incidence and postoperative recovery duration. Such data suggest that, in spite of the upfront costs, carbetocin may be a financially better choice than oxytocin.

Second line uterotonics

Second-line uterotonics are composed of the ergot alkaloids (methylergometrine, ergometrine) and prostaglandin analogues (misoprostol, sulprostone, and carboprost), and are so called as they do not act at the oxytocin receptor.
This is valuable when oxytocin or carbetocin alone fail to achieve appropriate uterine tone, or indeed when the desensitisation phenomenon of the oxytocin receptor impedes their efficiency.
They are administered either at the same time or following the first-line uterotonic if a patient is considered to be at increased risk of PPH, the uterine tone is assessed to be inadequate by the obstetrician subsequent to the administration of the first-line uterotonic, the extent of intraoperative blood loss is greater than anticipated or a PPH has occurred

Ergometrine

Structure and mechanism of action

Ergometrine is a semisynthetic derivative of d-lysergic acid and an amine

Its mechanism of action has not been fully elucidated.
Ergometrine does not have a specific ergometrine receptor in the uterus, but has been demonstrated to have agonist or partial agonist activity at α1, dopaminergic and 5-HT2 receptors and on the inner layer of the uterine myometrium, leading to uterine contraction

ergometrine has a direct vasoconstrictive action, mainly affecting the arteriolar vasculature, and stimulates the central dopaminergic receptors

The uterotonic effects of ergometrine are not influenced by the phenomenon of desensitisation

Administration and PK

Ergometrine is not stable and becomes less effective when stored unrefrigerated and exposed to light. It should therefore be stored in a refrigerator at a temperature of 2–8°C and protected from light

It can be administered at a dose of 200–500 mcg via the IM route and may be repeated following a 2 h interval

The IV route of administration is not advised as standard clinical practice, in the opinion of the authors, due to the potential for coronary vasoconstriction and myocardial infarction, and should only hence be considered in the exceptional circumstances of severe and life threatening PPH as a slow injection diluted to 5 ml with normal saline and administered over at least 1 min

The uterotonic effects subsequent to the intramuscular administration of ergometrine can be observed within 7 min and it has a plasma half-life of 30–120 min. It is metabolised under the influence of CYP3A4 enzymes in the liver by glucuronic acid conjugation, hydroxylation and possibly demethylation, and eliminated with bile into the faeces and unchanged in the urine.

C/I & SE

Contraindications to the use of ergometrine encompass the presence of cardiovascular disease, hypertension and pre-eclampsia. Coronary artery spasm, chest pain, palpitations, significantly increased hypertensive effects and pulmonary vasoconstriction may occur with its use

Given its pharmacokinetics, it is contraindicated in severe hepatic and renal impairment. Ergometrine is not recommended to be used in occlusive vascular disease and sepsis

Inhibitors of CYP3A4 enzymes, such as macrolide antibiotics, HIV protease or reverse transcriptase inhibitors and azole inhibitors, should be avoided as severe vasoconstriction and its sequelae may otherwise result

Side effects of ergometrine include the occurrence of

• dyspnoea,
• cardiac arrhythmias,
• bradycardia,
• nausea and vomiting,
• abdominal pain,
• dizziness
• headache.

Prostaglandins

Prostaglandins are lipids that are derived from the enzymatic modification of arachidonic acid by cyclooxygenase and prostaglandin or thromboxane synthase
Those which are endogenous, however, are subject to rapid metabolism and deactivation, and hence have limited therapeutic effect once administered

Carboprost, sulprostone and misoprostol were developed in response to this as synthetic analogues of prostaglandin F2α, E2 and E1, respectively, and are relatively resistant to inactivation

Over the course of labour, the concentration of endogenous prostaglandins increases,

• gradually in the first stage,
• rapidly in the second stage
• with a peak following the delivery of the placenta
  It is possible that the presence of insufficient naturally occurring prostaglandins in the third stage of labour may explain, at least in part, the occurrence of uterine atony

Carboprost activates the prostaglandin F receptors (FP)
sulprostone interacts with the EP1 and EP3 receptors
misoprostol stimulates the EP3 receptors.
These receptors are part of the G protein coupled family, which have seven transmembrane domains.
Stimulation of the FP and EP1 receptors leads to the activation of phospholipase C, which then hydrolyses the membrane phospholipid to inositol triphosphate and diacylglycerol.
Inositol triphosphate formation results in the release of calcium from the sarcoplasmic reticulum and subsequent uterine contraction.
Stimulation of EP3 receptors leads to the inhibition of cyclic AMP activation and the increase of intracellular calcium with subsequent uterotonic effects
Moreover, prostaglandins result in the production of oxytocin receptors. The uterotonic effects of carboprost and misoprostol are not influenced by the phenomenon of desensitisation

Administration & PK

Carboprost and sulprostone are not stable and become less effective when stored at room temperature.
Carboprost should be stored in a refrigerator at a temperature of 2–8°C
sulprostone should be stored in a freezer at −20 °C
Misoprostol may be stored at room temperature.

Carboprost

• 250 mcg IM
• may be repeated at Q15min
  • up to 8 times
  • to a maximum cumulative dose of 2 mg
    The IV route of administration is not advised due to the potential for significant side effects, such as
• ↓ PaO2
• bronchospasm
• ↑ PVR,
• hypertension,
• nausea & vomiting
  Carboprost is also recommended for administration via the intramyometrial route, particularly as this leads to a shorter time to peak plasma concentration. However, this is an off-label route and life threatening complications such as hypertension, pulmonary oedema and cardiovascular collapse have been reported, possibly owing to inadvertent IV injection in the vascular uterus
  The peak plasma concentration following IM administration of carboprost can be observed at 20–30 min
  It is metabolised by omega oxidation and eliminated mainly as metabolites in the urine.

Sulprostone

• 100 mcg/h IV
• if required, infusion rate may be ↑ to 500 mcg/h
  • to a maximum cumulative dose of 1.5 mg in 24 h
    In vitro animal studies suggest that sulprostone has a plasma half-life of 0.45 h, is metabolised by hydrolysis and β-oxidation to metabolites that are excreted in the urine

misoprostol

• use as a uterotonic remains unlicensed worldwide
• 400–600 mcg
• oral, rectal, sublingual or vaginal routes
• may be repeated Q15min
  • to a maximum cumulative dose of 800 mcg

The pharmacokinetics of misoprostol are dependent on the route of administration and it has a plasma half-life of 20–40 min.
Oral and sublingual administration lead to a shorter time to peak plasma concentration of 14.2–27.5 and 26 min, respectively, compared to 72 min for the rectal route and 65–72 min if used vaginally, giving rise to their faster time to onset of uterotonic effect.

Sublingual use results in a greater peak plasma concentration relative to the oral, rectal and vaginal routes.
Subsequent to rectal and vaginal administration, the characteristics of absorption and reduction in plasma concentration are responsible for their longer duration of uterotonic effect.
It is metabolised to misoprostol acid, which then undergoes oxidation, and eliminated mainly in the urine

C/I & SE

Contraindications to the use of carboprost encompass the presence of active respiratory disease, including asthma, due to the potential for bronchospasm, decreased pulmonary blood flow, ventilation-perfusion mismatch and intrapulmonary shunting, right ventricular dysfunction or pulmonary hypertension, owing to its effects on pulmonary vascular resistance, and hepatic and renal impairment.
Importantly, bronchospasm has been reported to occur even in patients without asthma

Side effects of carboprost include cough and hypertension, nausea and vomiting, abdominal pain and diarrhoea, secondary to the stimulation of smooth muscle in the gastrointestinal tract, and headache, myalgia, flushing and pyrexia.
Hypertension is uncommon, moderate in nature and not clinically significant

Misoprostol has no absolute contraindications apart from true allergy, however, in view of its propensity to lead to cardiac arrhythmias and coronary vasospasm, it should be used with caution in women with cardiovascular disease
Side effects of misoprostol include nausea and vomiting, abdominal pain, diarrhoea, constipation, dizziness, headache, rash, shivering and pyrexia

sulprostone is contraindicated in cardiovascular disease, as well as liver or kidney disease and asthma
Severe cardiovascular and respiratory side effects can occur with sulprostone, as well as side effects common to all prostaglandins, which include diarrhoea, nausea and hyperthermia. Sulprostone has been withdrawn by many manufacturers in several countries following the occurrences of cardiac arrest associated with its use

Calcium = 3rd line

As a third-line agent, calcium augments uterine tone, haemodynamics, and, as coagulation factor IV, haemostatic responses. Its use is particularly valuable in the setting of aggressive fluid repletion or transfusion of four to six units of citrated blood products.

Dosage

The density and binding kinetics of the oxytocin receptor are augmented by alterations in oestrogen and prostaglandins
Oxytocin receptors undergo progressive rise and plateau cycles until parturition, when a 300-fold increase in mRNA for the receptor exists with an accompanying increase in myometrial gap junctions; together, these potentiate myometrial cell conductivity. Consequently, small amounts of oxytocin that are ineffective in the non-pregnant state can establish adequate uterine tone in low risk, non-labouring women undergoing elective CD

adequate uterine tone was established in term, non-labouring parturients with oxytocin 0.5–3 IU

With spontaneous and induced labour of >10 h duration, mRNA levels for the oxytocin receptor decrease by 60- and 300-fold, respectively, in comparison to non-labouring women. Although additional oxytocin receptors continue to be expressed, the overall desensitisation effect increases oxytocin dose requirements for effective uterine tone over time

initial and repeated doses of first-line uterotonics should be administered slowly (over 30 s) to minimise hypotension, particularly in high-risk women (e.g. sepsis, impaired venous return).

After parturition, the density of oxytocin receptors rapidly declines. Coupled with the short half-life of oxytocin, a postpartum intravenous infusion is necessary.

Since low bolus doses of oxytocin administered slowly and low dose postpartum infusions have been shown to have good effects on uterine contractility, this can be exploited in patients with pre-existing cardiac disease

Prophylaxis vs treatment

Initiation of oxytocic agents considers their use in prophylaxis or treatment, relative to placental delivery, as well as in the progression to second- and third-line agents.

Prophylaxis is the active management of the third stage of labour involving administration of a first-line uterotonic before delivery of the placenta

Cochrane review supporting prophylaxis:

• ↓ risk of 500ml blood loss & 1000ml blood loss
• probably ↓ need for additional uterotonics

The progression to second- and third-line agents should occur, typically, when up to a maximum of three doses of oxytocin proves inadequate

recent anaesthetic international consensus guidelines suggest moving on to second-line agents after two bolus doses of oxytocin (maximum 6 IU), or after a maximum carbetocin dose of 100 mcg
Evidence for this relates to oxytocin receptor desensitisation and the need for a different receptor pathway for adequate uterine contraction.

A nuance in timing is whether to administer uterotonic agents with umbilical cord clamping upon fetal delivery or following the completion of blood collection. As the blood collection is relatively rapid, and the uterotonic response to uterotonic agents is not immediate, it is likely acceptable to initiate these agents at the time of umbilical cord clamping so that restoration of uterine tone can commence.

References

International consensus statement on the use of uterotonic agents during caesarean section - Heesen - 2019 - Anaesthesia - Wiley Online Library

Uterotonics Update