Oxytocin and Other Drugs Acting on Uterus

 Chapter 23

Oxytocin and Other Drugs Acting on Uterus

Drugs acting on uterus can primarily affect the endometrium or the myometrium. The most important drugs affecting endometrium are estrogens, progestins and their antagonists. Myometrium receives both sympathetic and parasympathetic innervation: autonomic drugs can affect its motility. However, directly acting drugs are more important and have more selective action. The responsiveness of myometrium to drugs is markedly affected by the hormonal and gestational status.

UTERINE STIMULANTS

(Oxytocic's, Abortifacients)

These drugs increase uterine motility, especially at term.

1. Posterior pituitary hormone Oxytocin, Desamito oxytocin.
2. Ergot alkaloids Ergometrine (Ergonovine), Methylergometrine.
3. ProstaglandinsPGE2, PGF2α, 15-methyl PGF2α, 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 lab our 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 Vigneau 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 neurons as complexes with their specific binding proteins (NeuroPhysics). Both are released by stimuli appropriate for oxytocin—coitus, parturition, suckling; or for ADH—hypertonic saline infusion, water deprivation, hemorrhage, 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 heightened 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 G-protein coupled oxytocin receptors which mediate the response mainly by depolarization of muscle fibers 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 ADH-like 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

• Labour Oxytocin is released during labor 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 hypophysectomies animals and humans, though labor may be prolonged in its absence. A facilitatory role is more plausible. PGs and PAF are complementary to oxytocin.

• 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 hypophysectomies.

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

PHARMACOKINETICS     

• Being a peptide, oxytocin is inactive orally and is generally administered by a.m. or i.e. 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 oxytocin Ase—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 lab our

• Labour needs to be induced in case of post maturity or prematurely in toxemia of pregnancy, diabetic mother, erythroblastosis, ruptured membranes or placental insufficiency. For this purpose, oxytocin is given by slow i.e. 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, fetal lungs are adequately mature, there is no cephalopelvic disproportion, no placenta previa, no fetal 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 

a When uterine contractions are feeble, and lab our is not progressing satisfactorily—oxytocin can be infused i.e. (as described above) to augment contractions. It should not be used to hasten normally progressing labor. Too strong contraction can be catastrophic: 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

• Because of its short t½ and slow i.e., infusion, intensity of action can be controlled, and action can be quickly terminated. 

• Low concentrations allow normal relaxation in-between contractions—fontal oxygenation does not suffer.

•  Lower segment is not contracted: fetal descent is not compromised.

•  Uterine contractions are consistently augmented.

3. Postpartum hemorrhage, Cesarean section

• Oxytocin 5 IU may be injected a.m. or by i.e. 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 hemorrhage 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 utero-placental adequacy in high-risk pregnancies. Oxytocin is infused i.e. at very low concentrations till uterine contractions are elicited every 3–4 mins. A marked increase in fetal heart rate indicates utero-placental inadequacy. The test is risky.

Adverse effects

• Injudicious use of oxytocin during labor can produce too strong uterine contractions forcing the presenting part through incompletely dilated birth canal, causing maternal and fetal soft tissue injury, rupture of uterus, fetal asphyxia and death. 
• Water intoxication: because of ADH like action of large doses given along with i.v. fluids, especially in toxemia of pregnancy and renal insufficiency. It is a serious (may be fatal) complication.

Desimini-oxytocin

• It has been developed as a buccal formulation; action is similar to injected oxytocin, but less consistent. Its indications are Induction of labor: 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. 12. Only the amine ergot alkaloid ergometrine (ergonovine) and its derivative methylergometrine are used in obstetrics. Both have similar pharmacological property.

1. 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 5-HT2 and α adrenergic receptors.

2. 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. 

3. CNS

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

4. 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—

•   patients with vascular disease, hypertension, toxemia. 

•   presence of sepsis—may cause gangrene. 

•   liver and kidney disease. They are contraindicated during pregnancy and before 3rd stage of     labor.

Use

• The primary indication for ergometrine/ methylergometrine is to control and prevent postpartum hemorrhage (PPH): 0.2–0.3 mg a.m. at delivery of anterior shoulder reduces postpartum 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.

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

• 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.

• 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, PGF2α and 15-methyl PGF2α 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. 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 Available as 50 mg/50 ml solution. (EMCREDIL, VECREDIL) for extra-amniotic infusion: 150 ml (containing 150 mg) is injected slowly for medical.

YUTOPAR, RITROD 10 mg/ml inj (5 ml amp), 10 mg tab. RITODINE 10 mg tab, 10 mg in 1 ml inj.

Isospins oral/a.m. has been used to stop threatened abortion, but efficacy is uncertain.

2. Calcium channel blockers 

• Because influx of Ca2+ ions play an important role in uterine contractions, Ca2+ channel blockers (see Ch. 39) reduce the tone of myometrium and oppose contractions. These drugs, especially nifedipine, which has prominent smooth muscle relaxant action, can postpone labor if used early enough. Efficacy comparable to β2 adrenergic agonists has been shown in some reports. Oral nifedipine 10 mg every 20–30 min till uterine contractions subsides, followed by 10 mg 6 hourly has been used. Tachycardia and hypotension are prominent at doses which suppress uterine contractions. Reduced placental perfusion causing fontal hypoxia is apprehended. However, in one multicentric trial, its use in preterm labor was found to produce fewer maternal side effects than ritodrine. Also, fewer babies delivered after nifedipine needed intensive care.

3. Magnesium sulfate

• e Given by i.e. infusion, it has been used for long to control convulsions and to reduce BP in toxemia of pregnancy. As per WHO, it is the drug of choice for prevention and treatment of seizures in preeclampsia and eclampsia. An i.e. bolus (2–4 g over 10–20 min) is followed by 1 g/her i.e. infusion regulated by the response. The international ’Magpie trial’ (2002) among >10,000 preeclamptic women found that it halved the risk of developing eclampsia and reduced maternal mortality. Adverse effects were minor both in the mother and the baby.

• Magnesium sulfate (i.e.) also suppresses uterine contractions and has been used to delay preterm labor. The efficacy is rated similar to β2 agonists. However, a recent review (2002) has concluded that it is ineffective in preventing preterm birth. Higher infant mortality was noted in one trial after the use of mag. sulfate. It appears to increase perinatal mortality in low birth-weight offspring, though it may be safer at term. Toxicity of i.v. mag. sulfate includes cardiac arrhythmias, muscular paralysis, CNS and respiratory depression in the mother as well as the neonate. Thus, its use as a tocolytic appears risky.

4. Oxytocin antagonist

• Atos Iban is a peptide analogue of oxytocin that acts as antagonist at the oxytocin receptors. In clinical trials, it has been found to suppress premature uterine contractions and postpone preterm delivery with fewer cardiovascular and metabolic complications than β2 adrenergic agonists. However, benefit in terms of infant survival is uncertain, because in one trial higher neonatal mortality was recorded in the group treated with artesian compared to placebo.

5. Miscellaneous drugs 

• Ethyl alcohol, nitrates, progesterone, general anesthetics and PG synthesis inhibitors are the other drugs, which can depress uterine contractions. However, their effect is not dependable, and they are rarely used clinically as tocolytics. Progesterone has been found to prevent miscarriage in some high-risk cases.

• Halothane is an efficacious uterine relaxant that has been used as the anesthetic when external or internal version is attempted.