Drugs affecting function of Uterus
They are divided on
(1) substances, strengthening of uterus rhythmic contractions,
(2) substances, lowering tonus of cervix uteri,
(3) substances, increasing tonus of myometrium, and
(4) substances, weakening uterus contractions.
These drugs are used for regulation of labor activity and stopping of uterus bleeding.
Drugs, strengthening rhythmic contractions of uterus
This group include oxytocin, desaminooxytocin, pituitrine, hyphotocine, dinoprost, dinoprostone, pachycarpine, and proserine. They are indicated during weakness of labor activity, for normalization of uterus involution in postpartum period, during hypotonic uterus bleeding. Oxytocin is a hormone secreted by the neurons of the hypothalamus and stored in the posterior pituitary in mammals. Commercially available oxytocin preparations are prepared synthetically. Oxytocin stimulates contraction of uterine smooth muscle by increasing the sodium permeability of uterine myofibrils. High estrogen concentrations lower the threshold for uterine response to oxytocin. Uterine response to oxytocin increases with the duration of pregnancy. In the term uterus, oxytocin increases the amplitude and frequency of uterine contractions, which in turn tend to decrease cervical activity producing dilation and effacement of the cervix and to transiently impede uterine blood flow. Oxytocin elicit milk ejection in lactating women. Also it produces vasodilation of vascular smooth muscle, increasing renal, coronary, and cerebral blood flow.
In pharmacologic doses, oxytocin can be used for induction and augmentation of labor. It can also be used for control of postpartum uterine hemorrhage. Oxytocin is administered intravenously or intramuscularly. It has a circulating half-life of 5 minutes. Contraindications include fetal distress, prematurity, abnormal fetal presentation, cephalopelvic disproportion, and other predispositions for uterine rupture.
Desaminooxytocin is a synthetic analog of oxytocin. It is act longer than parental agent and is used subglossal.
Pituitrine and hyphotocine are the extracts of bovine pituitary gland. They contain two posterior pituitary hormones: vasopressin and oxytocin. Pituitrine and hyphotocine possess the activity of oxytocin, which is described beyond, and vasopressin that cause vasoconstriction and hypertension. These agents have the same indications as oxytocin. Hyphotocine contain less vasopressin than pituitrine, thus hyphotocine is more prefer, especially in patients with hypertension.
Prostaglandins are the class of physiologically active substances present in many tissues, with effects such as vasodilation, vasoconstriction, stimulation of intestinal or bronchial smooth muscle, uterine stimulation, and antagonism to hormones influencing lipid metabolism. Prostaglandins as well as leukotrienes and thromboxanes are synthesized from arachidonic acid via a cascade pathway. Prostaglandin F2α (dinoprost) and prostaglandin E2 (dinoprostone) possess expressed influence on contractility of myometrium.
Dinoprostone stimulates uterine and GI smooth muscle. Although it is believed that the drug exerts its uterine effects via direct myometrial stimulation, the exact mode of this and other actions has not been fully elucidated. Dinoprostone increases the amplitude and frequency of uterine contractions throughout pregnancy, but uterine response to the drug increases with the duration of pregnancy. In early pregnancy, the uterus is more responsive to dinoprostone than to oxytocin. Dinoprostone-induced uterine contractions are usually sufficient to cause evacuation of both the fetus and the placenta. The drug also produces cervical dilation and softening. Dinoprostone causes stimulation of the circular smooth muscle of the GI tract, causes bronchodilation, and increases permeability of the vessels. Large doses of dinoprostone may cause vasodilation and hypotension.
Dinoprostone is widely distributed in the mother and is rapidly metabolized in the maternal lungs, kidneys, and other tissues.
Dinoprostone is used intravenously to induce abortion during the second trimester of pregnancy (beyond the 12th week of gestation) and to improve cervical inducibility (cervical "ripening") near or at term in pregnant women for labor induction. Adverse GI effects (e.g., diarrhea), phlebitis, fever are the most frequent adverse reactions of dinoprostone. Since dinoprostone, like dinoprost, is metabolized rapidly, discontinuing administration of the drug and supportive therapy are usually adequate treatments for serious adverse effects.
Dynoprost is similar in structure, action and uses to dynoprostone. It is administered intravenously, vaginally, and as intra-amniotic injection. Dynoprost, unlike dynoprostone, causes bronchospasm. That’s why it is not recommended during bronchial asthma.
Pachycarpine hydroiodide is a ganglion-blocking agent. It increases the tonus and force of the uterus contractions. Agent lowers blood pressure, so it can be administered during labor in patients with hypertonia. It is used intramuscularly, subcutaneously and orally. Pachycarpine is indicated for the weakness of labor. Anti-cholinesterase substances (proserine) and β-adrenoblockers (anapriline) also stimulate activity of the uterus.
M-cholinolytic (atropine sulfate), prostaglandins (dynoprost, dynoprostone), and narcotic analgesic (promedole) are used for the relaxation and softening of cervix uteri, and bettering of labor current.
Drugs, increasing tonus of myometrium
These drugs (ergot alkaloids, cotharnine, oxytocin, and pituitrine) are used basically during atonic uterus hemorrhages and for fastening of uterus involution in postpartum period. Mechanism of bleeding stop is related with stable increasing of uterus tonus and pressing due to it of small vessels in myometrium.
Ergot alkaloids are produced by Claviceps purpurea, a fungus that infects grain - especially rye - under damp growing or storage conditions. Ergot alkaloids are the derivatives of lysergic acid. The main alkaloids are ergotamine and ergometrine. Their effects include agonist, partial agonist, and antagonist actions at α-adrenoreceptors and serotonin receptors. Ergotamine and related compounds constrict most human blood vessels in a predictable, prolonged, and potent manner. In the same time they blockade the response of α-receptors to other agonists including noradrenaline. Dihydro derivatives of ergot alkaloids have much more selective α-receptor-blocking actions and they cause vasodilation.
Ergot alkaloids possess stimulant action on the uterus. The uterus at term is more sensitive to ergot than earlier in pregnancy and far more sensitive than the nonpregnant organ. These drugs induce powerful and prolonged tonic contraction of the uterus. Ergometrine is more selective than other ergot alkaloids in affecting the uterus and is the agent of choice in obstetric applications of these drugs. Ergometrine can be administrated enterally and parenterally. The onset of action is 10-15 minutes after ingestion and lasts a few hours. Certain of the naturally occurring alkaloids are powerful hallucinogens. Lysergic acid diethylamide (LSD, "acid") is the ergot compound that most clearly demonstrates this action.
Even moderate ergot doses produce a prolonged and powerful spasm of the muscle quite unlike natural labor. Their use at that time to accelerate delivery caused an asphyxia and fetus death. Therefore, ergot derivatives are useful only for control of late uterine bleeding and should never be given before delivery.
In medical practice are used: Galen’s (extract of thick ergot), neo-Galen’s drugs (ergotal) and pure alkaloids (ergometrine maleate, methylergometrine, ergotamine hydrotartrate). Ergotamine is used for the treatment of migraine. Favorable effect of ergotamine is related with weakening of cerebral vessel’s pulsation and lowering of irritation of the cerebral cover’s receptors.
Ergot alkaloids are contraindicated during angina pectoris, atherosclerosis, and spasm of peripheral vessels. They are excreted in breast milk, so they are not to be used during feeding.
The accidental ingestion of ergot alkaloids in contaminated grain as well as overdosing ergot agents causes ergot poisoning (ergotism). The most dramatic effects of poisoning are hallucinations and convulsions, prolonged vasospasm and damage of endothelium that may result in gangrene, and stimulation of uterine smooth muscle, which in pregnancy may result in abortion.
Cotharnine chloride also increases tonus of uterus and administered orally and parenterally during uterus bleeding.
Expressed action during atonic uterus bleeding is exhibited by oxytocin, pituitrine and prostaglandins that are discussed beyond.
During atonic uterus bleeding some plant drugs are used in form of extracts, decocts and tinctures: tincture of barberries, water paper, etc.
Drugs, weakening contractile activity of myometrium
Those drugs are used, basically, for stopping of premature labor and weakening of labor activity during fastened labor, for preventing of labor ways traumas. For those purposes β2-adrenomimetics (fenoterol), magnesium sulfate, narcotic substances are used.
Partusisten (fenoterol) is a β2-adrenomimetic. It causes tocolytic (uterine relax) action. Also it leads to bronchodilation. Agent is effective drug for prevention of premature labor and doesn’t cause negative action on fetus. It is administered intravenously by drops and orally in tablets. It may cause tachycardia, muscular weakness, tremor, and hypotension. It is contraindicated during cardiac defects, arrhythmia, thyrotoxicosis, and glaucoma.
Magnesium sulfate during parenteral administration decreases uterus contractions. It acts as calcium antagonist. Also agent possesses sedative, hypotensive effects. In higher doses – soporific, anticonvulsive, and narcosis effects are occur. Substances for narcosis (nitrogen oxide, phtorotane, sodium oxybutirate, etc.) and tranquilizers (sibazone) as well as progesterone, tocopherol (vitamin E) inhibit contractile activity of uterus.