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