Uterus and its pharmacological regulation (uterotonics and. tocolytics).

1. uterotonics. Neurohypopheseal hormons

- oxytocin

- pituitrine

- dezaminoxitocine

prostaglandins

dinoprostone (Pg E2)

dinoprost (Pg F2)

2. tocolytics

Beta 2 adrenomimetics: fenoterolsalbutamol

Generale anesthetecs: sodium oxybutirate

various: magnezium sulfateII. Remedies with acton on miometrium tonus.Vegetale remedies (alcaloizii de ergot)

ergometrine maleate

methylergometrine

ergotamine hydrotartrate

ergotal

syntheics

cotarnine chloride III. Remedies decreasing tonus of uterin colum atropine sulphate

dinoprost

dinoproston

Oxytocin represents the endocrine component of a neuroendocrine reflex arc that mediates suckling-induced lactation (the milk let-down reflex). It is also a potent stimulant of uterine contraction, especially in an estrogen-primed uterus. This latter effect is exploited in its major pharmacological application - induction or augmentation of labor - but the precise contribution of endogenous oxytocin to normal labor is still controversial (i.e., parturition can occur in its absence). Release of oxytocin is triggered by stimulus of the nipples, as in suckling, and by distention of the cervix and vagina. Neural afferents convey the sensory stimuli to the hypothalamic PVN and SON, where increases in magnocellular neuronal activity result in enhanced oxytocin secretion from the posterior pituitary.

Oxytocin acts via a G protein-coupled receptor, coupled to activation of phospholipase C and increases in IP3 that release Ca2+ from intracellular stores. It also augments activity of voltage-gated Ca2+ channels, enhancing depolarization-induced calcium entry. The increases in intracellular calcium that ensue lead to increased contraction of smooth muscle via activation of myosin light chain kinase.

During suckling, oxytocin stimulates contraction of myoepithelial cells surrounding the alveolar channels in the mammary gland, squeezing milk out of the alveoli into the ducts and large sinuses where it is easily accessible (the milk let-down reflex). Oxytocin is critical for normal lactation.

Oxytocin increases the force and frequency of contraction of the uterine myometrium. Oxytocin receptor number in the uterus is upregulated by estrogen during pregnancy, leading to an enhanced sensitivity (100-fold) of the myometrium to oxytocin. Oxytocin receptors are also upregulated in uterine decidual cells during pregnancy; these cells respond to oxytocin by synthesizing the prostaglandin PGF2a, which itself is a potent stimulator of uterine contraction. Thus, the uterine response to oxytocin increases dramatically throughout pregnancy.

Oxytocin is also a powerful constrictor of umbilical arteries and veins. Oxytocin Pharmacology

Oxytocin is available for parenteral administration (intravenous, intramuscular). It may also be applied in buccal lozenges or intranasally, although these routes are less efficient. It is metabolized by the liver and kidney and has a circulating half-life of 5 to 10 minutes. Oxytocin is inactive as an oral agent.

It is principally used to induce labor at term and to augment dysfunctional labor, where it is the drug of choice. The most important consideration when using oxytocin in this application is that the contractions not become too frequent or forceful, which can result in damage to the fetus or mother (laceration, uterine rupture) or fetal distress due to compromised placental exchange and fetal oxygenation.

It may be given as an intravenous infusion or a bolus injection (im) to control post partum bleeding.

Intranasal application of oxytocin may be used to relieve engorged breasts or to assist with breast feeding (as long as milk production is otherwise adequate). Although not often successful, it is simple and relatively risk-free.

FYI Oxytocin antagonists are being evaluated for use as tocolytic agents (e.g. atosiban). These are appealing because they appear to have fewer side effects than drugs currently available for inhibiting uterine contractility (see Inhibition of Uterine Mobility, below).

Other Uterine Motility Agents

In addition to oxytocin, a number of other agents are used to affect uterine motility. These include prostaglandins and ergot alkaloids, which stimulate uterine contractions, and b-adrenergic agonists, Mg2+ and nifedipine, which inhibit uterine contractility. You are referred to previous lectures for discussions of the general pharmacology of some of these agents (i.e., prostaglandins, b-agonists, and nifedipine).

Stimulation of Uterine Motility

Prostaglandins Prostaglandins of the E and F type are found in the uterus and may be involved in cervical ripening (increasing the compliance of the cervix) and the initiation of labor. The sensitivity of the uterus to prostaglandins increases during pregnancy. For obstetric purposes, preparations of PGE2 (dinoprostone), PGF2a (carboprost) and its 15-methyl derivative (carboprost tromethamine) are available. A PGE1 analog (misoprostol) is under clinical investigation for obstetric use.

The major use of dinoprostone and carboprost is for midtrimester abortions (vaginal suppositories or im injections), although this is considered less reliable and less safe than dilatation and evacuation. They can be used to evacuate the uterus after spontaneous or therapeutic abortion. For abortion early in prenancy, misoprostol has been used with mifepristone (a progesterone receptor antagonist; RU 486), a (politically) controversial procedure only recently approved in the U.S. Prostaglandins can be used to induce cervical ripening in order to facilitate normal or induced labor (e.g., dinoprostone as a locally applied gel). In addition, 15-methyl PGF2a, the trade name of which is HEMABATE, can be used as an alternative to ergonovine (see below) or oxytocin to treat postpartum hemorrhage.

Nausea, vomiting and diarrhea (and sometimes fever) can accompany the use of these agents.

Therefore, antiemetics and antidiarrheal drugs are often coadministered. Misoprostol is associated with lower incidence of these side effects.

NSAIDS inhibit prostaglandin synthesis and can delay or prolong labor. They are not useful in most cases as a tocolytic agent (labor-delaying) because they can cause premature closure of the fetal ductus arteriosus.

Ergot Alkaloids Ergot is the product of a fungus in grains and has been recognized since ancient times as a poison and as an abortifacient. Ergonovine is a natural alkaloid of ergot that retains the uterotonic activity of all the natural ergot alkaloids, but is less toxic than ergotamine. Methylergonovine is a semisynthetic congener of ergonovine with similar uterotonic actions. They are orally available with a half-life of 0.5 to 2 hours.

These agents cause powerful uterine contractions, perhaps via partial agonist activity at uterine a1-adrenergic and 5-HT receptors, which can result in sustained contracture. Although once used to promote labor, they are now considered too powerful to be safe. The primary use of ergonovine and methylergonovine is to control postpartum bleeding. They may be administered orally or by IM injection for this purpose. Oral administration of either alkaloid can be used to stimulate delayed uterine involution.

At the doses used for controlling postpartum bleeding, severe side effects are minimal. They are partial agonists at a1-adrenergic and 5-HT receptor, causing vasoconstriction and potentially hypertension and should not be used in hypertensive women. Care should be taken with long-term administration (e.g. for uterine involution) to avoid ergotism (ergot poisoning). In addition, both alkaloids may interfere with lactation.

Inhibition of Uterine Motility (tocolysis)

b2-adrenoceptor Agonists The mechanism of b2-adrenoceptor inhibition of smooth muscle is via cAMP-dependent protein kinase-mediated inhibitory phosphorylation of myosin light chain kinase. In obstetric use, the b2-agonists are the preferred treatment for premature labor. Ritodrine is the agent approved for this use in the United States, although terbutaline is frequently substituted. Ritodrine is available for oral and iv administration; terbutaline is effective orally, intravenously or subcutaneously.

Cardiovascular and metabolic side effects are as expected for b2 agonists. For example, peripheral vasodilation and decreases in diastolic blood pressure result in a reflex tachycardia and increased cardiac

output with little change in mean arterial pressure. Renin secretion is enhanced by b2 agonists, leading to

decreased renal excretion of Na+, K+, and H2O, which could lead to edema. Ritodrine can cause hyperglycemia and therefore the use of b2 agonists is contraindicated in patients with insulin-dependent diabetes.

Others

Magnesium sulfate can be used as a second-line therapy when b2 agonists are contraindicated. Raising serum concentrations of magnesium can inhibit uterine contractions by interfering with the calcium entry necessary for excitation-contraction coupling. A number of protocols have been devised, usually involving intravenous administration.

The concentration of magnesium must be closely monitored because it can interfere with a number of other processes dependent on extracellular calcium, including conduction and force generation in the heart, neuromuscular transmission, and with neural transmission and lead to respiratory depression and cardiac arrest.

Nifedipine is a calcium channel antagonist (see earlier lecture for information on pharmacology and side effects of nifedipine). It inhibits uterine contractions by interfering with calcium entry through voltage-dependent Ltype calcium channels. In clinical trials, it was found to be as effective as oral b2-adrenergic agonists.

Expected side effects resulting from use of nifedipine include vasodilation and decreases in total peripheral resistance, with reflex tachycardia and increased cardiac output. Ethanol can be used as a tocolytic in an emergency. It acts primarily by decreasing the release of oxytocin but also may have direct effects on uterine motility. High concentrations are required. There is little danger of fetal alcohol syndrome because use of ethanol in this situation would be temporary and late in gestation.