1.1.1

Structure and mechanism of action

Oxytocin is an endogenous neuropeptide hormone, with a nonapeptide structure, released by the posterior pituitary gland. It exerts its main effects on uterine smooth muscle to cause contraction in labour and on the mammary glands to cause lactation [ ]. The mechanisms of action of uterotonics are shown in Fig. 1 .

Mechanism of action of first- and second-line uterotonics.

Oxytocin exerts its uterine effects by stimulation of oxytocin receptors in the myometrium. This causes direct myometrial contraction via phospholipase C activation and inositol triphosphate release, leading to the release of intracellular calcium [ ]. It also stimulates the production of prostaglandin PGF _2α and PGE ₂ in the endometrium, which help to initiate labour [ ].

1.1.2

The oxytocin receptor

The oxytocin receptor is a G-protein-coupled receptor. These receptors are known to exhibit receptor downregulation within a short time frame of exposure to the receptor agonist. The receptors undergo rapid internalisation from the cell membrane due to this homologous stimulation [ ]. This phenomenon has been demonstrated with the oxytocin receptor, in both in vitro and in vivo studies, in relation to endogenous as well as exogenously administered oxytocin [ ]. There is a decrease in the expression of oxytocin receptor messenger RNA (mRNA) and the binding sites of oxytocin, leading to reduced myometrial cell response and reduced contractions [ ]. The time frame within which this occurs may be relatively short, with unpublished data by Gimpl & Fahr suggesting that greater than 60% of human oxytocin receptors are internalised into the myometrial cell within 5–10 min of agonist stimulation [ ]. However, more in-depth research and focus on this phenomenon within clinical practice only gained momentum in the late 2000s. The majority of this research was undertaken by Balki and colleagues in Canada, who demonstrated that oxytocin receptor desensitisation occurs in both a concentration and time-dependent manner [ ]. As a result of this, oxytocin dose requirements in clinical practice vary depending on prior exposure.

1.1.3

Administration and pharmacokinetics

Synthetic oxytocin first came about in the 1950s and has since been exogenously administered for labour induction and labour augmentation, as well as for the prophylaxis and management of postpartum haemorrhage (PPH) in both vaginal and caesarean deliveries [ ]. It is typically presented as a clear colourless solution for intramuscular or intravenous administration, either concentrated or diluted with saline, respectively. The drug is stored in the fridge at a temperature of 2–8 °C and has a mean half-life of distribution of 2 min and an elimination half-life of 12 min [ ]. Both the liver and kidneys are involved in its rapid elimination, with very little being excreted in the urine. Additionally, to further metabolise oxytocin, the placenta produces the enzyme oxytocinase which is released into the plasma, levels of which increase in pregnancy and peak at term [ ]. This enzyme metabolises both endogenous and synthetic oxytocin, therefore bolus doses need to be followed up with intravenous infusions to maintain the desired uterine contractile effects. Typical intravenous bolus doses in clinical practice have been 5 IU followed by infusions of 10 IU/hr for two to 4 h. However, recent evidence has challenged traditional dosing strategies ( see section 3.2 ).

1.1.4

Contraindications and side effects

The main side effects of concern with oxytocin are predominantly cardiovascular. Oxytocin causes transient hypotension, reflex tachycardia and an increase in cardiac output [ , ]. In anaesthetised women in their first trimester of pregnancy, an intravenous bolus of oxytocin 10 IU was associated with rapid (within 30 s) decreases in systemic vascular resistance (59%), vascular pulmonary resistance (44%) and femoral arterial pressure (40%) [ ]. Compensatory increases in heart rate (31%) and stroke volume (17%) yielded an improvement in cardiac output (54%), whilst pulmonary arterial pressure and wedge pressure increased by 33% and 35%, respectively (150 s) [ ]. Such changes are known to occur in fit and healthy women and are more prominent with rapid intravenous boluses [ ].

For PPH prophylaxis in caesarean delivery (CD), traditionally the intravenous bolus dose of oxytocin administered has been 10 IU. In healthy women undergoing CD, electrocardiography changes of ST depression and T-wave inversion were commonly seen [ ]. However, these effects were not attributed to the oxytocin bolus, but rather the sympathetic block of subarachnoid anaesthesia, surgery, pregnancy or delivery [ ]. A randomised controlled trial (RCT) comparing intravenous bolus doses of 10 IU oxytocin with 200 mcg ergometrine in healthy women undergoing CD demonstrated that the negative cardiovascular effects were indeed a result of 10 IU oxytocin [ ]. A further RCT published the following year compared intravenous bolus doses of 5 or 10 IU of oxytocin, finding that ST depression was more common with the 10 IU bolus [ ]. In addition, the Confidential Enquiries into Maternal Deaths in the UK (1997–1999) reported maternal cardiac arrests without the ability to resuscitate from an intravenous bolus of oxytocin 10 IU in the setting of spinal anaesthesia with associated hypotension [ ].

The main absolute contraindication to oxytocin is true allergy. Relative contraindications relate to its negative cardiovascular side effects, however modifications to the dosing regime allow it to be used even in women with severe cardiovascular disease.

Slower administration of oxytocin, co-administered with intravenous boluses or infusions of phenylephrine has been shown to mitigate the negative haemodynamic effects [ ]. Patients with pre-eclampsia and cardiac disease are at heightened risk for unpredictable and potentially severe cardiovascular and haemodynamic responses to oxytocin, mediated possibly by an inability to increase stroke volume in the setting of diastolic dysfunction. A 2011 review indicated that small oxytocin doses (0.1–0.5 IU) during CD resulted in transient blood pressure and cardiac output changes, with acceptable hemodynamic stability in parturients with advanced cardiac disease that included cardiomyopathy, congenital and valvular heart disease [ ].

Other side effects of oxytocin include nausea, vomiting, headache and flushing. As a result of structural similarities with vasopressin, large doses of oxytocin may cause water retention, hyponatremia, seizures and coma [ ]; however, the antidiuretic effects may be minimised with an infusion rate of less than 45 mIU/min [ ]. Consequently, in patients at higher risk of pulmonary oedema, such as those with severe cardiac conditions or preeclampsia, a lower rate of oxytocin infusions should be utilised.

1.2.1

Structure and mechanism of action

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 [ , ]. Furthermore, 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.

1.2.2

Carbetocin and 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 [ ]. Furthermore, 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 [ ]. However, 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 [ ].

1.2.3

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 intravenous or intramuscular 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. The lack of a requirement for cold chain storage, transportation, and distribution of carbetocin make it favorable for use in low-resource settings.

The process of elimination for carbetocin has not been fully elucidated, however 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 [ ].

1.2.4

Contraindications and side effects

The side effect profile of carbetocin is similar to that of oxytocin, in that mainly cardiovascular effects are seen, which are more profound with higher, rapid bolus doses.

Interestingly, 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 [ ]. However, a 2011 RCT comparing an oxytocin 125 ml/h infusion to a slow intravenous bolus of carbetocin 100 mcg in vaginal delivery in women with severe preeclampsia, demonstrated a similar safety profile between the two drugs and no association with oliguria or hypertension with carbetocin [ ]. Similarly, an RCT comparing intravenous boluses of oxytocin 5 IU with carbetocin 100 mcg in elective CD showed an increase in heart rate and decrease in blood pressure with both drugs [ ]. However, the 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.

Another potential difference in the side effect profile of carbetocin and oxytocin lies in their different affinities for the vasopressin receptor. An 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 [ ]. If such a characteristic also occurs in vivo , this may have clinical benefits over oxytocin, which is known to cause water retention. However, a clear difference has not yet been demonstrated in clinical practice.

2.1.1

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 α ₁ , dopaminergic and 5-HT ₂ receptors and on the inner layer of the uterine myometrium, leading to uterine contraction [ , ]. Further, 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 [ ].

2.1.2

Administration and pharmacokinetics

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 ^o C and protected from light [ , ]. It can be administered at a dose of 200–500 mcg via the intramuscular route and may be repeated following a 2 h interval [ ]. The intravenous 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.

2.1.3

Contraindications and side effects

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 and headache.

2.2.1

Structure and mechanism of action

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 F _2α , E ₂ and E ₁ , 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 and 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 EP ₁ and EP ₃ receptors and misoprostol stimulates the EP ₃ receptors. These receptors are part of the G protein coupled family, which have seven transmembrane domains. Stimulation of the FP and EP ₁ 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 EP ₃ 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 [ , ].

2.2.2

Administration and pharmacokinetics

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 ^o C [ ], whilst sulprostone should be stored in a freezer at −20 °C [ ]. Misoprostol may be stored at room temperature.

Carboprost can be administered at a dose of 250 mcg intramuscularly and, if needed, may be repeated at a minimum interval of 15 min up to eight times, to a maximum cumulative dose of 2 mg [ ]. Even though it can be administered more than once, 73% of patients respond to one dose. The intravenous route of administration is not advised due to the potential for significant side effects, such as a decrease in the partial pressure of arterial oxygen, bronchospasm, increase in pulmonary vascular resistance, hypertension, as well as the occurrence of nausea and 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 intravenous injection in the vascular uterus [ ]. The peak plasma concentration following intramuscular 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 can be administered at a dose of 100 mcg per hour through the intravenous route and, if required, the rate of infusion may be increased to 500 mcg per hour 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 [ , ].

The use of misoprostol as a uterotonic remains unlicensed worldwide. It can be administered at a dose of 400–600 mcg through the oral, rectal, sublingual or vaginal routes and, if needed, may be repeated at a minimum interval of 15 min 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 [ ].

2.2.3

Contraindications and side effects

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 [ , ]. 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 [ ]. Similarly, sulprostone is contraindicated in cardiovascular disease, as well as liver or kidney disease and 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 [ ]. 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 [ , , ]. Side effects of misoprostol include nausea and vomiting, abdominal pain, diarrhoea, constipation, dizziness, headache, rash, shivering and pyrexia [ , , ].