Oxytocin and Uterine Relaxants

Posterior pituitary gland secretes a number of hormones, out of which two are important:

Oxytocin
Vasopressin –anti diabetic

Previously it was thought that oxytocin and anti diabetic hormone resembled each other and had similar properties, but in 1953 it was discovered that oxytocin and ADH although had similar properties of uterine contractions, but differed in structure and properties.

They differ in structure at position 3 and 8, so labeled different groups of hormones.

Oxytocin

Biosynthesis of Oxytocin

Oxytocin is a cyclic peptide hormone, secreted from posterior pituitary.
It is synthesized in the cell bodies of para ventricular nucleus.
It goes down the axons, and is stored within neurohypophysis.
The precursor is rapidly converted by proteolysis to the active hormone and secreted from nerve endings.
Oxytocin is also synthesized in the luteal cells of the ovary, the endometrium and the placenta.
Stimuli include sensory stimuli from dilation of the cervix and vagina, suckling.

Structure

It is a nine amino acid peptide composed of 9 amino acid peptide, containing a six amino acid disulfide ring and a three membrane tail.

Pharmacokinetics

Orally not highly active, degraded when given orally.
Administered by I/V or IM route, at times intra nasal route may be used (to stimulate milk ejection)
Rapidly degraded by kidney and in liver.
Plasma half life is 6 min.
Not bound to plasma proteins.
Destroyed by Oxytocinase (present in kidneys).

Dosage

It is given I/V with fetal and maternal monitoring, so that fetal distress does not take place.
An infusion rate of 10mU/min is given and increased every 15-30 min.
Nasal puff in each nostril is sprayed for lactation, one puff in each nostril is used before nursing, mother is placed in sitting position, thus milk ejection is enhanced.

Mechanism of Action

Oxytocin acts via G protein coupled receptors which activate Ca²+ -IP³ pathway and intracellular release of Ca²+ ions.
Intracellular calcium release alters transmembrane ionic currents in myometrial smooth muscle cells to produce sustained uterine contractions (stimulate and enhance).
Increased sensitivity of uterus to oxytocin, prostaglandins are also synthesized leading to further augmentation of effects.
As pregnancy advances, activity of uterus (uterine contractions) increase and so does the sensitivity to oxytocin.
Weak ADH like activity.
Also affects myometrial smooth muscles and initiates contractions of smooth muscles leading to milk ejection.
Beta agonists, magnesium sulfate and inhalational anesthetics antagonize the effects.

Pharmacological actions

Uterus:

Activity increases as reaches 3^rd trimester, leading to force and frequency of uterine contractions.
Sensitivity is also enhanced and effects are mainly related to fundus and body of uterus.
Full relaxation may occur between contractions.

Breast

Cause contraction of myoepithelial cells of mammary alveoli surrounding collecting ducts, leading to milk ejection from mammary alvoli, one puff is given in each nostril.

CVS

Due to direct effect, oxytocin causes vasodilation and fall in blood pressure,
Increased heart rate and tachycardia,
Flushing might occur as well.

Kidney

Weak ADH like activity
May cause retention of fluids
Decreased urine output, if given in high doses
Pulmonary edema may occur

Clinical uses of Oxytocin

1. Induction of Labor

Normal labor is allowed to progress, manipulation is not advisable, only administered in certain conditions. (Rh incompatibility, DM, preeclampsia, ecclampsia, toxemia of pregnancy, rupture of membranes)

Initially 0.5-2 units/min administered, dose may be increased within 15-30 minutes till effective uterine contractions are achieved with maternal and fetal monitoring.

2. Augmentation of Labor

If labor is not progressing.

3. Third stage of Labor and puerperium

To decrease the post partal hemorrhage, usually administered at the time of delivery of placenta to decrease the chances of post partum hemorrhage.

10-40 units oxytocin in 1 litre of 5% dextrose is infused slowly. Ergot alkaloids (ergometrine) are also utilized for this purpose (o.2-0.3 mg are given). If ergometrine is contraindicated, oxytocin may be used.

4. Milk ejection

Enhances milk ejection.

Adverse Effects

Maternal and fetal deaths due to hypertensive episodes, uterine rupture, water intoxication if rapidly
Afibrinogenemia is also reported.

Prostaglandins

Prostaglandins are said to have similar effects, act as uterine analogs.

PGE2, PGF2α and 15 methyl PGF2α are potent uterine stimulants.
PG have been detected in maternal blood.
Also enhance uterine stimulant activity, may augment the contractions.

Ergometrine & Methylergometrine

Erogot alkaloids obtained from claviceps purpura.
They increase force, frequency and duration of uterine contractions.
Gravid uterus is more sensitive and involves the lower segment as well.
Partial agonist action on 5-HT2 and α adrenergic receptors.
Used to decrease post partum hemorrhage

Oxytocin Challenge Test

I/V oxytocin is given in a dose of 0.5 milli units/min, till three contractions are achieved in 10 minutes. Purpose of doing the test is to access fetal well being. We compare maternal blood flow with that of fetal heart rate. This is to try to access placental circulatory reserve.

Uterine Relaxants

Agents given to decrease the contractions of uterus to relax it, given in cases:

when there are chances of threatened abortion or prematurity
if we want to shift mother to better health facilities unit
in conditions where fetal lungs are not mature, glucocorticoids are given to allow maturation.

Labor may be slowed down for days or even weeks.

Ritodrine:

A β2 selective agonist.
It has a major uterine relaxant action.
Doses given as I/V infusion of 50 mcg/min, dose may be increased after every 10 minutes till tone is decreased.
Causes postponement of delivery in 70% cases.

Side Effects;

Hypertension,
hyperinsulinemia ,
hypokalemia,
anxiety,
arrhythmias,
pulmonary edema,
hyperglycemia,
restlessness,
headache

Salbutamol and terbutaline may also be used.

Contraindications

Diabetes

Severe hypertension

Ca+ Channel blockers

Ca+ influx causes uterine contractions while Ca channel blockers have opposing effects.
Nifedipine given orally every 20-30 min till uterine contractions subside.