Uterine Stimulants

UTERINE STIMULANTS

(Oxytocics, Abortifacients)

These drugs increase uterine motility, especially at term.

1.   Posterior pituitary hormone Oxytocin, Desamino oxytocin

2.   Ergot alkaloids Ergometrine (Ergonovine), Methylergometrine

3.   Prostaglandins PGE₂, PGF_2α, 15methyl PGF_2α, Misoprostol

4.   Miscellaneous  Ethacridine, Quinine.

Oxytocin

Oxytocin is a nonapeptide secreted by the posterior pituitary along with vasopressin (ADH). Pituitary extract was first used in labour in 1909.

Controversy as to whether the antidiuretic and uterine stimulating activities were due to one substance or two separate principles was finally resolved by du Vigneaud in 1953 when he separated Oxytocin and Vasopressin, determined their chemical structure and synthesized them. Both are nonapeptides which differ at positions 3 and 8.

Both oxytocin and ADH are synthesized within the nerve cell bodies in supraoptic and paraventricular nuclei of hypothalamus; are transported down the axon and stored in the nerve endings within the neurohypophysis. They are stored in separate neurones as complexes with their specific binding proteins (neurophysins). Both are released by stimuli appropriate for oxytocin—coitus, parturition, suckling; or for ADH—hypertonic saline infusion, water deprivation, haemorrhage, etc., or nonspecific—pain and apprehension. However, the proportion of oxytocin to ADH can vary depending upon the nature of the stimulus.

Actions

1. Uterus

Oxytocin increases the force and frequency of uterine contractions. With low doses, full relaxation occurs in between contractions; basal tone increases only with high doses. Increased contractility is due to hightened electrical activity of the myometrial cell membrane— burst discharges are initiated and accentuated. Estrogens sensitize the uterus to oxytocin; increase oxytocin receptors. Nonpregnant uterus and that during early pregnancy is rather resistant to oxytocin; sensitivity increases progressively in the third trimester; there is a sharp increase near term and quick fall during puerperium. Progestins decrease the sensitivity, but this effect is not marked in vivo.

The increased contractility is restricted to the fundus and body; lower segment is not contracted, may even be relaxed at term.

Mechanism Of Action

Action of oxytocin on myometrium is independent of innervation. There are specific Gprotein coupled oxytocin receptors which mediate the response mainly by depolarization of muscle fibres and influx of Ca2+ ions as well as through phosphoinositide hydrolysis and IP₃ mediated intracellular release of Ca2+ ions. The number of oxytocin receptors increases markedly during later part of pregnancy. Oxytocin increases PG synthesis and release by the endometrium which may contribute to the contractile response. Distinct subtypes of oxytocin receptors have been shown on the myometrium and the endometrium.

2. Breast

Oxytocin contracts myoepithelium of mammary alveoli and forces milk into the bigger milk sinusoids—‘milk ejection reflex’ (milk letdown in cattle) is initiated by suckling so that it may be easily sucked by the infant. It has been used in milch cattle to facilitate milking.

3. CVS

Conventional doses used in obstetrics have no effect on BP but higher doses cause vasodilatation → brief fall in BP, reflex tachycardia and flushing. This action is most marked in chicken—used for bioassay. The umbilical vessels are markedly constricted; oxytocin may help in their closure at birth.

4. Kidney

Oxytocin in high doses exerts an ADHlike action—urine output is decreased: pulmonary edema can occur if large amounts of i.v. fluids and oxytocin are infused together. Conventional doses are without any effect.

Physiological Role

1. Labour

Oxytocin is released during labour and the uterus is highly sensitive to it at this time. However, it does not appear to be obligatory for initiating parturition—delivery occurs in hypophysectomized animals and humans, though labour may be prolonged in its absence. A facilitatory role is more plausible. PGs and PAF are complementary to oxytocin.

2. Milk Ejection Reflex

It is mediated by oxytocin. The myoepithelial cells in breast are more sensitive than myometrium to oxytocin; milk ejection reflex is absent in the hypophysectomized.

3. Neurotransmission

Oxytocin appears to function as a peptide neurotransmitter in the hypothalamus and brainstem to regulate autonomic neurones.

Pharmacokinetics

Being a peptide, oxytocin is inactive orally and is generally administered by i.m. or i.v. routes, rarely by intranasal spray. It is rapidly degraded in liver and kidney; plasma t½ ~6 min, and is still shortened at term. Pregnant uterus and placenta elaborate a specific aminopeptidase called oxytocinase—which can be detected in maternal plasma.

Unitage And Preparations

1 IU of oxytocin = 2 μg of pure hormone. Commercially available oxytocin is produced synthetically.

OXYTOCIN, SYNTOCINON 2 IU/2 ml and 5 IU/ml inj., PITOCIN 5 IU/0.5 ml inj.

Use

1. Induction Of Labour

Labour needs to be induced in case of postmaturity or prematurely in toxaemia of pregnancy, diabetic mother, erythroblastosis, ruptured membranes or placental insufficiency. For this purpose oxytocin is given by slow i.v. infusion: 5 IU is diluted in 500 ml of glucose or saline solution (10 milli IU/ ml)—infusion is started at a low rate and progressively accelerated according to response (0.2–2.0 ml/min). Before starting infusion, confirm that presentation is correct, foetal lungs are adequately mature, there is no cephalopelvic disproportion, no placenta previa, no foetal distress and no uterine scar (due to previous surgery). Uterine contractions are then closely monitored: the drug is discontinued when they are strong enough. Usually a total of 2–4 IU is needed.

2. Uterine Inertia

When uterine contractions are feeble and labour is not progressing satisfactorily—oxytocin can be infused i.v. (as described above) to augment contractions. It should not be used to hasten normally progressing labour. Too strong contraction can be catestrophic: use should only be made in selected cases and by experienced people.

Oxytocin is the drug of choice and is preferred over ergometrine/PGs for the above two purposes:

(a) Because of its short t½ and slow i.v. infusion, intensity of action can be controlled and action can be quickly terminated.

(b) Low concentrations allow normal relaxation inbetween contractions—foetal oxygenation does not suffer.

(c) Lower segment is not contracted: foetal descent is not compromised.

(d) Uterine contractions are consistently augmented.

3. Postpartum Haemorrhage, Cesarean Section

Oxytocin 5 IU may be injected i.m. or by i.v. infusion for an immediate response, especially in hypertensive women in whom ergometrine is contraindicated. It acts by forcefully contracting the uterine muscle which compresses the blood vessels passing through it to arrest haemorrhage from the inner surface exposed by placental separation.

4. Breast Engorgement

It may occur due to inefficient milk ejection reflex—oxytocin is effective only in such cases: an intranasal spray may be given few minutes before suckling. It does not increase milk production.

5. Oxytocin Challenge Test

It is performed to determine uteroplacental adequacy in high risk pregnancies. Oxytocin is infused i.v. at very low concentrations till uterine contractions are elicited every 3–4 mins. A marked increase in foetal heart rate indicates uteroplacental inadequacy. The test is risky.

Adverse Effects

1)  Injudicious use of oxytocin during labour can produce too strong uterine contractions forcing the presenting part through incompletely dilated birth canal, causing maternal and foetal soft tissue injury, rupture of uterus, foetal asphyxia and death.

2)  Water intoxication: because of ADH like action of large doses given along with i.v. fluids, especially in toxaemia of pregnancy and renal insufficiency. It is a serious (may be fatal) complication.

Desamino-oxytocin

It has been developed as a buccal formulation; action is similar to injected oxytocin, but less consistent. Its indications are:

Induction of labour: 50 IU buccal tablet repeated every 30 min, max 10 tabs.

Uterine inertia: 25 IU every 30 min.

Promotion of uterine involution 25–50 IU 5 times daily for 7 days.

Breast engorgement 25–50 IU just before breast feeding. BUCTOCIN 50 IU tab

Ergometrine, Methylergometrine

The pharmacology of ergot alkaloids is described in Ch. No. 12. Only the amine ergot alkaloid ergometrine (ergonovine) and its derivative methylergometrine are used in obstetrics. Both have similar pharmacological property.

Uterus

They increase force, frequency and duration of uterine contractions. At low doses, contractions are phasic with normal relaxation in between, but only moderate increase in dose raises the basal tone, contracture occurs with high doses. Gravid uterus is more sensitive, especially at term and in early puerperium. Their stimulant action involves the lower segment also. The uterotonic action is believed to result from partial agonistic action on 5HT₂ and α adrenergic receptors.

CVS

Ergometrine and methylergometrine are much weaker vasoconstrictors than ergotamine and have low propensity to cause endothelial damage. Though they can raise BP, this is not significant at doses used in obstetrics.

CNS

No overt effects occur at usual doses. However, high doses produce complex actions— partial agonistic/antagonistic interaction with adrenergic, serotonergic and dopaminergic receptors in the brain have been shown.

GIT

High doses can increase peristalsis. Methylergometrine is 1½ times more potent than ergometrine on the uterus, but other actions are less marked. It has thus replaced ergometrine at many obstetric units.

Pharmacokinetics

In contrast to the amino acid ergot alkaloids, ergometrine and methylergometrine are rapidly and nearly completely absorbed from the oral route. The onset of uterine action is: Oral—15 min; i.m.—5 min; i.v.—almost immediate.

They are partly metabolized in liver and excreted in urine. Plasma t½ is 1–2 hours. Effects of a single dose last 3–4 hours.

Adverse Effects

Ergometrine and methylergometrine are less toxic than ergotamine. When correctly used in obstetrics—hardly any complications arise, especially with methylergometrine. Nausea, vomiting and rise in BP occur occasionally. It can decrease milk secretion if higher doses are used for many days postpartum; this is due to inhibition of prolactin release (dopaminergic action).

Ergometrine should be avoided in—

1. patients with vascular disease, hypertension, toxaemia.

2. presence of sepsis—may cause gangrene.

3. liver and kidney disease.

They are contraindicated during pregnancy and before 3rd stage of labour.

Use

1) The primary indication for ergometrine/ methylergometrine is to control and prevent postpartum haemorrhage (PPH): 0.2–0.3 mg i.m. at delivery of anterior shoulder reduces postpartal blood loss and prevents PPH. However, routine use in all cases is not justified—only in those expected to bleed more, e.g. grand multipara, uterine inertia. Multiple pregnancy should be excluded before injecting.

If PPH is occurring—0.5 mg i.v. is recommended.

These drugs produce sustained tonic uterine contraction: perforating uterine arteries are compressed by the myometrial meshwork— bleeding stops.

2) After cesarean section/instrumental delivery —to prevent uterine atony.

3) To ensure normal involution: A firm and active uterus involutes rapidly. To ensure this: 0.125 mg of ergometrine or methylergometrine has been given TDS orally for 7 days. However, routine use in all cases is not justified because normal involution is not hastened. Multipara and others in whom slow involution is feared—may be given prophylactically.

4) Diagnosis of variant angina: A small dose of ergometrine injected i.v. during coronary angiography causes prompt constriction of reactive segments of coronary artery that are responsible for variant angina.

ERGOMETRINE 0.25, 0.5 mg tab, 0.5 mg/ml inj. Methylergometrine: METHERGIN, METHERONE, ERGOMET 0.125 mg tab, 0.2 mg/ml inj.

Prostaglandins

PGE₂, PGF_2α and 15methyl PGF_2α are potent uterine stimulants, especially in the later part of pregnancy and cause ripening of cervix. Their actions and use in obstetrics is described in Ch. No. 13. Since misoprostol (a PG analogue used for peptic ulcer) produces less side effects, it is being used for obstetric indications also.

Ethacridine

Available as 50 mg/50 ml solution (EMCREDIL, VECREDIL) for extraamniotic infusion: 150 ml (containing 150 mg) is injected slowly for medical termination of pregnancy in the 2nd trimester. This is an alternative method used occasionally.