Chapter 10-Drug Affecting Uterine Contraction.pptx

Drugs affecting uterine motility are those drugs which modify the progress of labor and parturition. There are two types of drugs affecting uterine motility –

Uterine stimulants: They stimulate uterine contraction.
Uterine relaxants: They relax the uterine smooth muscle i.e. prevent uterine contractions.
Signal transduction mechanism for the oxytocin receptor in the myometrium.

This receptor is a classic 7-transmembrane domain receptor linked through a G protein to phospholipase C. After receptor stimulation with oxytocin (OT), the α-subunit of the heterotrimeric G protein hydrolyses GTP to GDP and releases the βγ-subunit to stimulate phospholipase C


This enzyme converts phosphatidyl inositides to diacylglycerol and inositol-1,4,5-trisphosphate (IP3 ). Diacylglycerol stimulates protein kinase C activity causing phosphorylation of substrates which will characterize the response of the specific cell type


The IP 3 stimulates flux of Ca2+ into the cytoplasm through calcium channels, principally from the sarcoplasmic reticulum


The increased Ca2+ will combine with calmodulin to stimulate myosin light chain kinase (MLCK) to produce myometrial contraction. In the decidua, a characteristic response would be synthesis and release of prostaglandins.  

1. Drugs Affecting Uterine Contraction

2. Introduction: Drugs affecting uterine motility are those drugs which modify the progress of labor and parturition. There are two types of drugs affecting uterine motility – Uterine stimulants : They stimulate uterine contraction. Uterine relaxants: They relax the uterine smooth muscle i.e. prevent uterine contractions. Uterine stimulants (oxytocic agents): Classification: Uterine stimulants can be classified as – 1. Peptide hormones: e.g. Oxytocin 2. Prostaglandins: e.g. PGE 2 , Ergot alkaloids: e.g. Ergometrine Progesterone receptor antagonists: e.g. Mifepristone (this class is not very important in this context because it is basically an aborfacient ). Mifepristone is a medication typically used in combination with misoprostol to bring about an abortion during pregnancy. Mifepristone works by blocking the action of progesterone to cause the pregnancy to stop progressing. Misoprostol causes the cervix to soften and the uterus to contract to allow the pregnancy to be expelled from the uterus.

3. Clinical use of uterine stimulants: The uterine stimulants have following clinical use – To induce labor To augment labor in uterine inertia To prevent post-partum hemorrhage To terminate pregnancy in the early periods of gestation (not exactly a clinical use)   Obstetrics: Obstetrics is the part of the medical care that deals with pregnancy, parturition and post-partum period.

4. Oxytocin: Oxytocin is an endogenous substance produced in the posterior pituitary. Oxytocin is a nonapeptide (composed of 9 amino acids) with a intra-chain disulfide bridge. Pharmacodynamics: Oxytocin mediates its action through oxytocin receptors. It is a GPCR and activation leads of the receptor activates PLC (Phospholipase C). As a result IP 3 is produced and eventually muscle contraction occurs though signal transduction. It causes increase in frequency and force of contraction of uterine muscle at low dose and and causes sustained contraction at high dose. Oxytocin also causes contraction of myoepithelial cells surrounding the mammary alveoli leading to milk ejection. Without oxytocin, lactation doesn’t occur.

5. Pharmacokinetics: Oxytocin is administered via IV or IM route. It is not given by oral route because it is a peptide. It is not bound to plasma proteins and eliminated by liver and kidney. It has a very short half-life of 5 minutes.

6. Signal transduction mechanism for the oxytocin receptor in the myometrium. This receptor is a classic 7-transmembrane domain receptor linked through a G protein to phospholipase C. After receptor stimulation with oxytocin (OT), the α-subunit of the heterotrimeric G protein hydrolyses GTP to GDP and releases the βγ-subunit to stimulate phospholipase C This enzyme converts phosphatidyl inositides to diacylglycerol and inositol-1,4,5-trisphosphate (IP3 ). Diacylglycerol stimulates protein kinase C activity causing phosphorylation of substrates which will characterize the response of the specific cell type The IP 3 stimulates flux of Ca2+ into the cytoplasm through calcium channels, principally from the sarcoplasmic reticulum The increased Ca2+ will combine with calmodulin to stimulate myosin light chain kinase (MLCK) to produce myometrial contraction. In the decidua, a characteristic response would be synthesis and release of prostaglandins.  

7. Clinical use: 1. It is used to induce labor and to augment labor in case of uterine inertia. For this purpose it is given by IV infusion containing 1-5 units of oxytocin per liter of 5% dextrose. Initially the drop rate is kept at 5mU/min but if no sign of incipient labor is seen within 30 minutes the drop rate is increased to 20mU/min. 2. It is also used to induce first uterine contraction after parturition and expulsion of placenta. This reduces the likelihood of post-partum hemorrhage. Usually ergot alkaloids are used for this purpose but when they are contraindicated oxytocin is used via IM route.   Toxicity and contraindications: When used judiciously, severe toxicity is rare. Some toxicities result from activation of vasopressin receptors. Adverse effects include – Hypo-natremia (vasopressin effect) Fetal distress, placental abruption, uterine rapture (excess stimulation) Hypotension (when bolus injection is given, this is why IV infusion is preferred). It is contraindicated when there is fetal distress, prematurity and predispositions for uterine rapture.

8. Ergot alkaloids: Ergot alkaloids are produced by a fungus called Claviceps purpurea , it infects grain specially rye. The fungus synthesizes histamine, acetylcholine, tyramine and a handful of ergot alkaloids. Pharmacodynamics:   The mechanism of the actions elicited by the ergot alkaloids is not clear. It is however understood that they can act as agonists, partial agonists and antagonists on α-adrenoceptor, 5-HT receptors and dopamine receptors respectively. The effects of ergot alkaloids are attributed to α- agonism , effects on serotonin and others. Perhaps as the pregnancy progresses, the α-receptors begins to increase in the uterine muscle. Alpha adrenoreceptor ligands mimic the action of epinephrine and norepinephrine signaling in the heart, smooth muscle and central nervous system, with norepinephrine being the highest affinity. The activation of α1 stimulates the membrane bound enzyme phospholipase C, and activation of α2 inhibits the enzyme adenylate cyclase. Inactivation of adenylate cyclase in turn leads to the inactivation of the secondary messenger cyclic adenosine monophosphate and induces smooth muscle and blood vessel constriction. Ergometrine is most widely used ergot alkaloid in obstetrics. Its major action occurs on the uterus but it is almost devoid of activity against blood vessels. It is responsible for abortion in ergotism but it is less toxic than ergotamine (which has effects on blood vessels).

9. Pharmacokinetics: The ergot alkaloids can be given by IV, IM and oral route. It is extensively metabolized in the body. Ergometrine is effective within 1-5 minutes when given by IM route.   Clinical use: 1. Nowadays Ergometrine is used to prevent post-partum hemorrhage. It is given after the placenta has been expelled but it can be given immediately after child-birth. 2. It is also valuable for involution of uterus if it is delayed. A dose of 0.2mg by IV or IM route or orally is used to promote uterus involution. Oral regimen of 0.2mg three times daily for upto 12 weeks can also be used.   Adverse effects: Nausea, vomiting, elevated blood pressure and decreased pain threshold.

10. Prostaglandins: Prostaglandins play an important role in parturition. Oxytocin itself stimulates release of prostaglandins and leukotrienes which help in augmentation of labor. Among the prostaglandins PGE1, PGE2, PGF1ᾳ , PGF2ᾳ are most important in obstetrics. Physiologic function of PGs in female reproductive system: Induction of labor: PGs are essential for the induction of normal labor. During labor the PGs mentioned above appear in high quantity in amniotic fluid and the maternal blood (total concentration is more than 150ng/mL). The F varieties are most abundant. Before labor sets in small amount of E 1 is detected. The sensitivity of the uterus to PGs increase towards the end of pregnancy. Menstruation and dysmenorrhea: Excessive production of the PGs may be responsible for the pain. Probably they intensify the uterine contractions.  

11. Clinical use: PGs are used as – Aborfacient Oxytocic agent   PGs are sometimes preferred over oxytocin because they are devoid of the ADH activity shown by oxytocin. They are equally efficacious as oxytocin. PGE 2 is more active than PGF2ᾳ variety and 20-40µg is sufficient to increase the tone of the uterus and to increase the amplitude and frequency of uterine muscle contraction. The drug can be given by IV infusion and effective at 0.5-2.0µg/min infusion rate. The effects of PG last for an hour or longer after infusion is stopped. Adverse effects: The adverse effects of prostaglandins are moderate and only slightly higher incidence of nausea, vomiting and diarrhea than oxytocin seen.

12. Uterine relaxants: Clinical use: To prevent or arrest preterm labor. To reverse inadvertent overstimulation. To facilitate intrauterine manipulations, such as conversion of a fetus from a breech to a cephalic presentation, surgical procedures, or postpartum replacement of an inverted uterus. To relieve painful contractions during menstruation, referred to as dysmenorrhea.   Used agents: β-agonists: e.g. ritodrine , terbutaline . NSAIDs and PG synthesis inhibitors Calcium channel blockers: e.g. Nifedipine . Oxytocin antagonist: Atosiban . cephalic presentation Breech presentation

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