Prostaglandin E2

Dinoprostone has important effects in labor by inducing softening of the cervix and causing uterine contraction, and also stimulates osteoblasts to release factors that stimulate bone resorption by osteoclasts. Natural prostaglandins, including PGE1 and PGE2, are important in the structure and function of the ductus arteriosus in fetuses and newborns. They allow the ductus arteriosus to remain open, providing the necessary connection between the pulmonary artery and descending aorta that allows the blood to bypass the fetus's underdeveloped lungs and be transported to the placenta for oxygenation. In addition, PGE2 was used in another report to dilate the ductus arteriosus in newborns with various cardiovascular defects to allow for better perfusion of the lungs and kidneys. On the other hand, the post-partal synthesis of PGE2 in newborns is considered one cause of patent ductus arteriosus. When administered in aerosol form, PGE2 serves as a bronchodilator, but its use in this setting is limited by the fact that it also causes coughing. In addition, PGE2 limits the immune response by preventing B-lymphocyte differentiation and their ability to present antigens. PGE2 is also a predominant prostanoid that contributes to inflammation via enhancing edema and leukocyte infiltration from increased vascular permeability (allowing more blood flow into an inflamed area of the body) when acting on EP2 receptors. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) blocks the activity of COX-2, resulting in a decrease of PGE2 production. NSAIDs blocking COX-2 and decreasing the production of PGE2 remediates fever and inflammation. Additionally, PGE2 acting on EP1 and EP4 receptors are a component in feeling pain via inflammatory nociception. When PGE2 binds to EP1 and EP4 receptors, an increase in excitability via cation channels as well as inhibition of hyperpolarizing potassium (K+) channels, increase membrane excitability. As a result, this causes peripheral nerve endings to report painful stimuli. Neurological effects In response to physiologic and psychologic stress, prostaglandin E2 (PGE2) is involved in several inflammation and immunity pathways. As one of the most abundant prostaglandins in the body, PGE2 is involved in almost all typical inflammation markers such as redness, swelling, and pain. It regulates these responses through binding to G coupled protein prostaglandin E2 receptors (EP1, EP2, EP3, and EP4). The activation of these different EP receptors is dependent on the type of triggering stress stimuli and results in the corresponding stress response. Activation of EP1 via PGE2 results in the suppression of impulse behaviors in response to psychological stress. PGE2 is involved in regulating illness-induced memory impairment via activation of EP2. PGE2 activation of EP3 results in regulation of illness induced fever. In addition to inflammatory effects, PGE2 has been shown to have anti-inflammatory effects as well, due to its different actions on varying receptors. Within the gastrointestinal tract, PGE2 activates smooth muscles to cause contractions on longitudinal muscle when acting on EP3 receptors. In contrast, PGE2 effects on respiratory smooth muscle result in relaxation. Kidney effects Prostaglandin E2 (PGE2), along with other prostaglandins, are synthesized within the cortex and medulla of the kidney. The role of renal COX-2-derived PGE2 within the kidney is to maintain renal blood flow and glomerular filtration rate (GFR) through localized vasodilation. COX-2-derived prostanoids work to increase medullary blood flow as well as inhibit sodium reabsorption within kidney tubules. PGE2 also assists the kidneys with systemic blood pressure control by modifying water and sodium excretion. In addition, it is also thought to activate EP4 or EP2 to increase renin release, resulting in an elevation of GFR and sodium retention to raise systemic blood pressure levels within the body. == Medical uses ==

Cervical ripening In the setting of labor and delivery, cervical ripening (also known as cervical effacement) is a natural process that occurs before labor, in which the cervix becomes softer, thinner, and dilated, enabling the fetus to pass through the cervix. A ripe cervix is favorable prior to induction of labor, which is a common obstetric practice, and increases the chances for a successful induction. Pharmacological methods are sometimes required to induce cervical ripening that does not occur naturally. The natural ripening of the cervix is mediated by prostaglandins, thus a common pharmacological method is to use external prostaglandins such as PGE2, or dinoprostone. Prostaglandin E2 (PGE2) achieves cervical ripening and softening by stimulating uterine contractions as well as directly acting on the collagenase present in the cervix to soften it. However, PGE2 is not feticidal, and only induces abortion by stimulating uterine contractions. It is recommended that 20 mg of dinoprostone vaginal suppository be administered every three to five hours to evacuate the uterus. The abortion should occur within 24 hours after the beginning of administration of dinoprostone; if it does not, dinoprostone should no longer be given and other interventions would be required, such as dilation and curettage. ==Side effects==

A common side effect of prostaglandin E2 is its effect on gastrointestinal smooth muscle resulting in nausea, vomiting and diarrhea. Other side effects include headache, shivering, and chills. Other monitoring parameters include sustained uterine contractions and fetal distress. In babies there may be decreased breathing and low blood pressure. Care should be taken in people with asthma or glaucoma and it is not recommended in those who have had a prior C-section. ==Mechanism of action==

Prostaglandin E2 (PGE2) binds to G protein-coupled receptors (GPCRs) EP1, EP2, EP3, and EP4 to cause various downstream effects to cause direct contractions in the myometrium. In addition, PGE2 inhibits Na+ absorption within the Thick Ascending Limb (TAL) of the Loop of Henle and ADH-mediated water transport in collecting tubules. As a result, blockage of PGE2 synthesis with NSAIDs can limit the efficacy of loop diuretics. == Administration ==

Prostaglandin E2 (PGE2) should only be administered by, or under the direct supervision of, a physician and careful monitoring should be performed. In a quality improvement project done in UK, the switch from prostaglandin gel to the slow release dinoprostone pessary was able to lower cesarian section rates in women undergoing induction of labor in maternity care. Once the package is open, a water miscible lubricant may be used to insert the medication, using your finger place the device into the vagina and position the device transversely in the posterior vaginal fornix. == Contraindications ==

Contraindications to a medication are any reasons to not use the drug. Prostaglandin E2 (PGE2) is used to induce labor and should not be used in people that are contraindicated to give birth vaginally or spontaneous labor. PGE2 should not be used in people with allergies to prostaglandins or any components in the drugs formulations. PGE2 should be stopped before other oxytocic agents like oxytocin are given. Dinoprostone as a vaginal suppository is contraindicated for women with acute pelvic inflammatory disease or active disease of the cardiovascular, respiratory, hepatic, or renal systems. Caution is required for people with a history of cervical malignancy, hypo- or hypertension, anemia, epilepsy, jaundice, asthma, or pulmonary diseases. The suppository formulation is also not indicated for viable fetus evacuation. Endocervical gel is contraindicated in those with who have a history of C-sections or major uterine surgery, if the fetus is in distress and delivery is not imminent, vaginal bleeding throughout the pregnancy that is unexplained, history of difficult labors and deliveries, have cephalopelvic disproportion, less than six previous term babies with nonvertex presentation, hyper or hypotonic uterine patterns. == Toxicity ==

When prostaglandin E2 (PGE2) is given in excess, hyper-stimulation of the uterus occurs and immediate discontinuation of the drug usually results in resolution of toxic effects. == Pharmacokinetics ==

The synthetic PGE2 dinoprostone has a plasma half-life of approximately 2.5–5 minutes, after vaginal administration, with most metabolites being excreted in the urine. == History ==

Swedish physiologist Ulf von Euler and British physiologist M.W. Goldblatt, first discovered prostaglandins independently in 1935 as factors contained in human seminal fluid. Prostaglandins were noted for having blood pressure reducing effects and smooth muscle regulation effects. Prostaglandin E2 itself was identified in 1962 by Swedish biochemist Sune Bergström in the seminal fluid of sheep. == References ==