SYNTOMETRINE COMBINATION PRODUCT AMPOULE

Indications

• Postpartum hemorrhage caused by uterine atony
• Active management of the third stage of labor

Dosage

Children: Refer to the BNF for Children for paediatric dosing information.

Adults: For postpartum hemorrhage, 0.5 mg (500 micrograms) can be administered intramuscularly or intravenously, followed by 0.5-1 mg after 6 hours if required, with a maximum of 4 mg per course.

Mechanism of action

Ergometrine maleate primarily acts as an agonist at alpha-adrenergic receptors, and to a lesser extent at serotonin receptors. This leads to increased uterine smooth muscle contraction. The contraction of the uterus helps to reduce blood loss by compressing the blood vessels supplying the uterus, thus minimizing postpartum hemorrhage.

Pharmacodynamics

The pharmacodynamic effects of ergometrine maleate include powerful uterotonic activity, which enhances the frequency and intensity of uterine contractions. This is essential in managing the third stage of labor and in preventing excessive blood loss. The effects are dose-dependent, and the drug also has vasoconstrictive properties that may influence blood pressure.

Pharmacokinetics

Ergometrine maleate is rapidly absorbed after intramuscular or intravenous administration. It has a relatively short half-life, approximately 2-3 hours, and is primarily metabolized in the liver. The elimination of ergometrine occurs through urine, and the drug's efficacy can be influenced by hepatic function.

Contra-indications

• Active cardiac disease
• Severe hypertension
• Vascular disease
• Severe renal impairment
• Severe hepatic impairment
• Active pelvic infection
• History of uterine rupture
• History of severe asthma
• History of epilepsy
• History of glaucoma and raised intraocular pressure

Adverse effects

• Headache
• Nausea
• Vomiting
• Abdominal pain
• Diarrhoea
• Pruritus
• Vaginal burning
• Genital oedema
• Hyperbilirubinaemia
• Neonatal hypotension
• Uterine atony
• Fever
• Amniotic cavity infection
• Disseminated intravascular coagulation
• Uterine rupture

Interactions

• Oxytocin (effect enhanced)
• Caution advised with other drugs that may affect uterine activity

Precautions

• Monitor uterine activity when used after oxytocin
• Caution in patients with mild to moderate renal impairment
• Caution in patients with mild to moderate hepatic impairment
• Monitor for disseminated intravascular coagulation after use

Pregnancy

Ergometrine maleate is used in the management of postpartum hemorrhage and during the active management of the third stage of labour.

Breast-feeding

Caution is advised as ergometrine maleate may pass into breast milk; monitor infants for adverse effects.

Storage

Store in a cool, dry place, protected from light. Do not freeze.

Formulations

• 500 micrograms/1 ml solution for injection ampoules

Indications

• Induction of labor
• Management of postpartum hemorrhage
• Facilitation of uterine contraction during labor

Dosage

Children: Dosing information for pediatric use of oxytocin is not provided in the BNF. Consult the BNF for Children for appropriate guidance.

Adults: For induction of labor, oxytocin is typically administered intravenously, starting with a low dose and adjusted based on uterine response. Refer to the BNF for specific dosing guidelines.

Mechanism of action

Oxytocin induces uterine contractions by binding to oxytocin receptors on the myometrium, which are significantly upregulated during pregnancy. This binding triggers a cascade that increases intracellular calcium in uterine myofibrils, leading to enhanced contraction strength and frequency. The hormone's secretion is regulated by a positive feedback mechanism, where the pressure of the fetus against the cervix stimulates further release of oxytocin, thus facilitating labor.

Pharmacodynamics

As a pleiotropic hormone, oxytocin influences numerous physiological processes beyond childbirth, including lactation, metabolism, cardiovascular function, and social behaviors. Its receptors are widely distributed, including in the central nervous system, where they affect emotional and social functions. Oxytocin's action is characterized by its ability to modulate both reproductive and non-reproductive behaviors, suggesting its broad physiological impact.

Pharmacokinetics

Oxytocin is administered either intravenously or intramuscularly, with rapid absorption and onset of action. Its half-life is relatively short, generally around 3 to 5 minutes, necessitating continuous infusion or repeated dosing to maintain effective levels during labor. The distribution volume is extensive, and it is metabolized in the liver and kidneys. Exogenous oxytocin exhibits similar pharmacokinetics to the endogenous form, ensuring effective therapeutic outcomes.

Contra-indications

• Severe fetal distress
• Hypersensitivity to oxytocin
• Uterine hypertonicity
• Certain cardiovascular disorders
• Active genital herpes infection
• Placenta previa

Adverse effects

• Nausea
• Vomiting
• Uterine hypertonicity
• Water retention
• Hypotension
• Tachycardia
• Allergic reactions

Interactions

• Misoprostol may have an additive effect when used with oxytocin

Precautions

• Use with caution in patients with pre-existing cardiovascular conditions
• Monitor for excessive uterine contractions
• Caution in patients with a history of uterine surgery
• Consider the risk of water intoxication with large doses

Pregnancy

Oxytocin is used during pregnancy for induction of labor and to prevent postpartum hemorrhage.

Breast-feeding

Oxytocin is excreted in breast milk, but its effects on a nursing infant are not well established. Monitor for potential effects.

Storage

Store in a refrigerator at 2-8 degrees Celsius. Protect from light and keep out of reach of children.

Formulations

• Injection solution

Indications

• Postpartum hemorrhage
• Uterine atony
• Management of uterine contractions
• Diagnostic aid for coronary vasospasm

Dosage

Adults: For the prevention of postpartum hemorrhage, ergometrine is typically administered as 0.5 mg intramuscularly after the delivery of the placenta. In cases of treatment, doses may be repeated based on clinical judgment and response.

Mechanism of action

Ergometrine directly stimulates the uterine muscle, enhancing the force and frequency of contractions. It causes contraction of the uterine wall around bleeding vessels, promoting hemostasis. At lower doses, contractions are followed by relaxation periods, while higher doses elevate basal uterine tone and reduce relaxation periods. Ergometrine also induces cervical contractions and exhibits arterial vasoconstriction by stimulating alpha-adrenergic and serotonin receptors, while inhibiting the release of endothelial-derived relaxation factors.

Pharmacodynamics

As an ergot alkaloid, ergometrine is primarily indicated for the prevention and treatment of excessive bleeding after childbirth. It increases uterine muscle contraction and is also utilized for its vasoconstrictive effects. The drug is more effective in stimulating uterine contractions, especially towards the end of pregnancy, compared to its vascular effects.

Pharmacokinetics

Ergometrine is absorbed following parenteral administration, with a variable onset of action. It is metabolized in the liver, and its pharmacokinetic profile indicates a half-life that allows for frequent dosing to achieve therapeutic effects. The exact pharmacokinetic parameters may vary based on individual patient factors and the mode of administration.

Adverse effects

• Nausea
• Vomiting
• Hypertension
• Headache
• Abdominal pain
• Diarrhea
• Uterine cramping
• Ergotism

Interactions

• miconazole (severe - increases exposure)
• esketamine (severe - increases risk of elevated blood pressure)
• hiv-protease inhibitors (severe - increases risk of ergotism)
• macrolides (severe - increases risk of ergotism)
• ergometrine + sympathomimetics (inotropic) (severe - increases risk of peripheral vasoconstriction)
• ergometrine + dopamine (severe - increases risk of peripheral vasoconstriction)
• clarithromycin (severe - increases risk of ergotism)
• antifungals, azoles (unknown - increases risk of ergotism)
• beta blockers, selective (unknown - increases risk of peripheral vasoconstriction)
• grapefruit juice (unknown - increases exposure)

Pregnancy

Ergometrine is used in the management of uterine atony and to prevent or treat postpartum hemorrhage. Caution is advised, and it should only be used when the benefits outweigh potential risks.

Breast-feeding

Ergometrine is excreted in breast milk; caution is advised when administering to breastfeeding mothers.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Tablets
• Injectable solution

Mechanism of action

Ergonovine directly stimulates the uterine muscle to increase force and frequency of contractions. With usual doses, these contractions precede periods of relaxation; with larger doses, basal uterine tone is elevated and these relaxation periods will be decreased. Contraction of the uterine wall around bleeding vessels at the placental site produces hemostasis. Ergonovine also induces cervical contractions. The sensitivity of the uterus to the oxytocic effect is much greater toward the end of pregnancy. The oxytocic actions of ergonovine are greater than its vascular effects. Ergonovine, like other ergot alkaloids, produces arterial vasoconstriction by stimulation of alpha-adrenergic and serotonin receptors and inhibition of endothelial-derived relaxation factor release. It is a less potent vasoconstrictor than ergotamine. As a diagnostic aid (coronary vasospasm), ergonovine causes vasoconstriction of coronary arteries. Ergonovine maleate and methylergonovine maleate are pharmacologically similar. Both drugs directly stimulate contractions of uterine and vascular smooth muscle. Following administration of usual therapeutic doses of ergonovine or methylergonovine, intense contractions of the uterus are produced and are usually followed by periods of relaxation. Larger doses of the drugs, however, produce sustained, forceful contractions followed by only short or no periods of relaxation. The drugs increase the amplitude and frequency of uterine contractions and uterine tone which in turn impede uterine blood flow. Ergonovine and methylergonovine also increase contractions of the cervix. Ergonovine and methylergonovine produce vasoconstriction, mainly of capacitance vessels; increased central venous pressure, elevated blood pressure, and, rarely, peripheral ischemia and gangrene may result. Methylergonovine reportedly may interfere with prolactin secretion, but this effect has not been definitely established. ... The effect of /Ergonovine/ on isolated canine tracheobronchial smooth muscle was analyzed to investigate the mechanism of ergonovine-induced airway smooth muscle contraction. Both ergonovine and serotonin (5-hydroxytryptamine, 5HT) contracted canine tracheal smooth muscle with EC50 1.4 X 10(-8) M and 5.1 X 10(-7) M, respectively. The maximal contractile response observed with ergonovine was approximately 30% less than that observed with 5HT. In diverse blockers such as methysergide, atropine, prazosin, propranolol, pyrilamine and cimetidine, only methysergide competitively blocked both ergonovine and 5HT responses with a similar calculated dissociation constant (pKB); 8.3 +/- 0.2 against ergonovine and 8.5 +/- 0.2 against 5HT (n = 6, p = 0.9). The relative affinity and efficacy of ergonovine and 5HT were determined by use of a partial irreversible antagonist, phenoxybenzamine. The calculated affinity of ergonovine was about 16 times higher than that of 5HT. The relative efficacy of EC100 for ergonovine was 0.2 but at EC10 it was 41.9 (5HT efficacy = 1). Ergonovine 10(-9) M or 10(-8) M shifted the 5HT dose-response curve to the right without reducing the maximal response, but the shift was nonparallel. Ergonovine and 5HT also contracted canine bronchial smooth muscle in a dose dependent manner with EC50 6.4 X 10(-8) M and 1.8 X 10(-7) M, respectively. The dose-responses curve of these two agonists were competitively blocked by methysergide 10(-6) M. These data indicate that ergonovine directly contracts canine tracheobronchial smooth muscle as a result of its combination with 5HT receptors. ... Although commonly classified as alpha-adrenergic blocking agents, most important effects of all ergot alkaloids are due to action on CNS and direct stimulation of smooth muscle. Latter occurs in many different organs... In some organs stimulation ... shown to be due to action on same receptors involved in responses to catecholamines. Thus ergot alkaloids can be considered to be series of partial agonists with blocking activity...

Pharmacodynamics

Ergonovine belongs to the group of medicines known as ergot alkaloids. These medicines are usually given to stop excessive bleeding that sometimes occurs after abortion or a baby is delivered. They work by causing the muscle of the uterus to contract.

Mechanism of action

Oxytocin plays a vital role in labour and delivery. The hormone is produced in the hypothalamus and is secreted from the paraventricular nucleus to the posterior pituitary where it is stored. It is then released in pulses during childbirth to induce uterine contractions. The concentration of oxytocin receptors on the myometrium increases significantly during pregnancy and reaches a peak in early labor. Activation of oxytocin receptors on the myometrium triggers a downstream cascade that leads to increased intracellular calcium in uterine myofibrils which strengthens and increases the frequency of uterine contractions. In humans, most hormones are regulated by negative feedback; however, oxytocin is one of the few that is regulated by positive feedback. The head of the fetus pushing on the cervix signals the release of oxytocin from the posterior pituitary of the mother. Oxytocin then travels to the uterus where it stimulates uterine contractions. The elicited uterine contractions will then stimulate the release of increasing amounts of oxytocin. This positive feedback loop will continue until parturition. Since exogenously administered and endogenously secreted oxytocin result in the same effects on the female reproductive system, synthetic oxytocin may be used in specific instances during the antepartum and postpartum period to induce or improve uterine contractions. The pharmacologic and clinical properties of oxytocin are identical with those of naturally occurring oxytocin principle of the posterior lobe of pituitary. Oxytocin exerts a selective action on the smooth musculature of the uterus, particularly toward the end of pregnancy, during labor, and immediately following delivery. Oxytocin stimulates rhythmic contractions of the uterus, increases the frequency of existing contractions, and raises the tone of the uterine musculature. Oxytocin indirectly stimulates contraction of uterine smooth muscle by increasing the sodium permeability of uterine myofibrils. High estrogen concentrations lower the threshold for uterine response to oxytocin. Uterine response to oxytocin increases with the duration of pregnancy and is greater in patients who are in labor than those not in labor; only very large doses elicit contractions in early pregnancy. Contractions produced in the term uterus by oxytocin are similar to those occurring during spontaneous labor. In the term uterus, oxytocin increases the amplitude and frequency of uterine contractions which in turn tend to decrease cervical activity producing dilation and effacement of the cervix and to transiently impede uterine blood flow. Oxytocin contracts myoepithelial cells surrounding the alveoli of the breasts, forcing milk from the alveoli into the larger ducts and thus facilitating milk ejection. The drug possesses no galactopoietic properties. Oxytocin produces vasodilation of vascular smooth muscle, increasing renal, coronary, and cerebral blood flow. Blood pressure is usually unchanged, but following iv administration of very large doses or undiluted solutions, blood pressure may decrease transiently, and tachycardia and an increase in cardiac output may be reflexly induced. Any initial fall in blood pressure is usually followed by a small but sustained increase in blood pressure. In contrast to vasopressin, oxytocin has minimal antidiuretic effects; however, water intoxication may occur when oxytocin is administered with an excessive volume of electrolyte-free iv fluids and/or at too rapid a rate. For more Mechanism of Action (Complete) data for Oxytocin (15 total), please visit the HSDB record page.

Pharmacodynamics

Oxytocin is a nonapeptide, pleiotropic hormone that exerts important physiological effects. It is most well known to stimulate parturition and lactation, but also has important physiological influences on metabolic and cardiovascular functions, sexual and maternal behaviour, pair bonding, social cognition, and fear conditioning. It is worth noting that oxytocin receptors are not limited to the reproductive system but can be found in many peripheral tissues and in central nervous system structures including the brain stem and amygdala.