UTERINE STIMULANTS Oxytocics

OXYTOCICS Oxytocics are the drugs of varying chemical nature that have the power to stimulate the contraction of uterine muscles. Also called Uterotonics The introduction of oxytocic drugs for the treatment of Post Partum Hemorrhage (PPH) has been regarded as “ one of the enduring achievements of modern science” (Moir, 1964)

Oxytocics These drugs increase uterine motility, especially at term. 1 Posterior pituitary hormone Oxytocin, Desamino oxytocin 2 Ergot alkaloids Ergometrine (Ergonovine), Methylergometrine 3 Prostaglandins PGE2, PGF2w 15-methyl PGF2a, Misoprostol 4 Miscellaneous Ethacridine, Quinine.

OXYTOCIN Oxytocin is a nonapeptide secreted by the Posterior pituitary along with vasopressin (ADH) . 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. 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 inbetween contractions; basal tone increases only with high doses. Increased contractility is due to hightened electrical activity of the myometrial cell membrane

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 fibres and influx of Ca2+ ions as well as through phosphoinositide hydrolysis and IP, mediated intracellular release of ca2+ ions. The number of oxytocin receptors increases markedly during later part of pregnancy. Oxvtocin increases PG synthesis and release by the endometrium which may contribute to the contractile response.

2. Breast Oxytocin contracts myoepithelium of mammary alveoli and forces milk into the bigger milk sinusoids It may be easily sucked by the infant. 3. CVS Higher doses cause vasodilatation --- brief fall in BP, reflex tachycardia and flushing.

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.

Physiological role 1. Labour Oxytocin is released during Labour and the uterus is highly sensitive to it at this time. 2. Milk ejection reflex It is mediated by oxytocin. The myoepithelial cells in breast are more sensitive than myometrium to oxytocin . 3 Neurotransmission Oxytocin appears to function as a peptide neurotransmitter in the hypothalamus and brainstem to regulate autonomic neurones.

PHARMACOKINETICS Being a peptide, Inactive orally Administered by i.m. or i.v. routes rarely by intranasal spray. Rapidly degraded in liver and kidney; Plasma T 1/2 -6 min.

Oxytocin Indications Induction of labour: Given as a slow i.v. infusion (5 i.u. in 500 ml of glucose or normal saline solution ). Started at 0.2 ml/ min and gradually increased, once optimal response ( 3 Conts. in 10 minutes, each lasting 45 seconds), continued at that rate Aim is to initiate and maintain uterine contractions not only till delivery but also 30 to 60 minutes beyond that. Usual rate is 16 to 32 m.I.U. / minute. For uterine inertia: Admn. Same as above. In active management of third stage of labor: (to reduce the blood loss) 5 I.U., i.m. or slow i.v. for an immediate response where ergometirne is contraindicated.

Oxytocin Indications For prevention/control of post partum haemorrhage (PPH); Oxytocin is administered by i.m. (2-5 i.u.) inj./ i. v. infusion (10 i.u./500ml) after the delivery of placenta, to produce a firm contraction of uterus and thus prevent PPH. To accelerate abortion, used along with prostaglandins, especially in second trimester abortion To stop bleeding following evacuation of uterus. In cases of breast engorgement to promote milk ejection. It is given intranasally, 40 i.u., 2-5 minutes before breast feeding. For contraction stress test, oxytocin sensitivity test ; not commonly done these days.

ADVERSE EFFECTS 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. (ii) 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.

Ergot derivatives Ergometrine & Methyl ergometrine(Methergine) Ergometrine, an alkaloid, isolated by Dudley and Moir,(1935) from Ergot, derived from a fungus, Claviseps purpurea, growing on rye,wheat etc. Methergine is semi synthetic, derived from lysergic acid. Onset of ergometrine is quicker (45-60 secs) than methergine (90 secs) Duration is similar (3hrs). METHERGINE “Speedy” 15 15

Pharmacological effects Act directly on myometrium and cause tonic uterine contractions without any relaxation in between. Action is through the partial agonistic action on 5HT2 /α adr. receptors. Should not be used for induction of labour/abortion, very effective for haemostasis, to stop bleeding from uterine sinuses following delivery/abortion. Higher doses can increase peristalsis. CVS effects: adrenergic agonists, cause contractions of smooth muscles, both arterial and venous vasoconstriction.

Mechanism of Action Acts through serotonin receptors (5HT 2) and αadrenergic receptors During pregnancy, the uterine sensitivity to ergot increases dramatically Causes uniform contraction of uterus (nonphysiological) In very small doses can cause rythmic contraction of uterus Ergonovine is more selective in affecting uterus

ERGOMETRINE, METHYLERGOMETRINE 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. Their stimulant uterotonic action is believed to result from partial agonistic action on 5-HT2 and a adrenergic receptors.

2. CVS effects: adrenergic agonists, cause contractions of smooth muscles, both arterial and venous vasoconstriction 3. 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. 4. GIT High doses can increase peristalsis.

Pharmacokinetics 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. Metabolized in liver and excreted in urine. Plasma t 1/2 is 1-2 hours.

Adverse effects Nausea, vomiting and rise in BP occur occasionally. 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- (i) patients with vascular disease, hypertension, toxaemia. (ii) presence of sepsis-may cause gangrene. (iii) liver and kidney disease. They are contraindicated during pregnancy and before 3rd stage of labour.

Use 1. The primary indication for to control an postpartum haemorrhage (PPH) 2. After cesarean section/ instrumental d -to prevent uterine atony 3. Incomplete abortion

Prostaglandins (PGs) C 20 fatty acid compounds containing cyclopentane ring, derivatives of Prostanoic acid Were first isolated from human seminal fluid with probable origin from prostate gland, hence named Prostaglandins. Act as local hormones. PGE2, PGF2α and recently PGE1, found useful for the induction of abortion, induction/augmentation of labor and control of PPH.

Prostaglandins (PGs) Clinical effects: The pharmacological effects are: Contraction of smooth muscles of uterus, blood vessels, GIT and bronchioles Clinical effects: Myometrial contraction Softening and dilatation of cervix Inhibition of secretion of progesterone by corpus luteum. Response of the uterus to PGs is maximum in the middle trimester (13th to 20th weeks). Prior administration of mifepristone (anti-progestin drug) sensitizes the uterus to the action of PGs.

Prostaglandins (PGs) Pharmacokinetics: Rapidly metabolized in lungs and liver. About 90% inactivated in one circulation. Given by intra vaginal, oral, rectal, intra muscular or intra myometrial routes. Prostin 15m (carboprost) has longer duration of action. Side effects: Nausea, vomiting, diarrhea, fever, flushing and bronchospasm. CVS side effects: tachycardia, increased mean arterial pressure and pulmonary artery pressure. Use caution in hypertension, diabetes, angina epilepsy and raised intra- ocular pressure. Contraindicated in bronchial asthma, uterine scar, cardiac renal or hepatic diseases.

PG analogues & Common ROA PGE1 (methyl ester) – MISOPROSTOL (vaginal, oral, rectal) PGE2 – DINOPROSTONE (vaginal, extra amniotic) (NOTE: less toxic, more effective so widely used.) PGF 2ά- DINOPROSTONE TROMETHAMINE PGF2ά (methyl analogue) – CARBOPROST (i.m., intra/extra-amniotic) -:Preparations:- Tablet-0.5mg dinoprostone (prostinE2) Vaginal suppository- 20mg PGE2 /50mg PGF2ά lipid base Vaginal pessary- 3mg PGE2 ProstinE2 gel- 500μg into cervical canal, below internal OS/1-2mg in the posterior fornix. -:Parenteral:- PGE2 - ProstineE2 1mg/ml PGF2ά-ProstinF2 ά(Dinoprost tromethamine) 5mg/ml Methyl analogue of PGF2ά- Carboprost 2.5mg/10ml vial

THANK YOU -PHARMA STREET