Prostaglandin E2
Prostaglandin E2, also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and in newborn babies to keep the ductus arteriosus open. In babies it is used in those with congenital heart defects until surgery can be carried out. It is also used to manage gestational trophoblastic disease. It may be used within the vagina or by injection into a vein.
PGE2 synthesis within the body begins with the activation of arachidonic acid by the enzyme phospholipase A2. Once activated, AA is oxygenated by cyclooxygenase enzymes to form prostaglandin endoperoxides. Specifically, prostaglandin G2 is modified by the peroxidase moiety of the COX enzyme to produce prostaglandin H2 which is then converted to PGE2.
Common side effects of PGE2 include nausea, vomiting, diarrhea, fever, and excessive uterine contraction. In babies there may be decreased breathing and low blood pressure. Caution should be taken in people with asthma or glaucoma and it is not recommended in those who have had a prior C-section. It works by binding and activating the prostaglandin E2 receptor which results in the opening and softening of the cervix and dilation of blood vessels.
Prostaglandin E2 was first synthesized in 1970 and approved for medical use by the FDA in the United States in 1977. It is on the World Health Organization's List of Essential Medicines. Prostaglandin E2 works as well as prostaglandin E1 in babies.
Physiological effects
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. The ductus arteriosus normally begins to close upon birth due to an increase of PGE2 metabolism, but in newborns with congenital heart disease, prostaglandins can be used to keep the ductus arteriosus open longer than normal to sustain healthy oxygen saturation levels in the blood. Although PGE1 is more commonly used in this setting, there has been a report of oral PGE2 being used to treat ductus-dependent congenital heart diseases in newborns to delay surgical treatment until the pulmonary arteries grew. 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.
PGE2, similarly to PGE1, acts as a direct vasodilator by acting on smooth muscle to cause dilation of blood vessels. In addition, PGE2 inhibits platelet aggregation.
PGE2 also suppresses T cell receptor signaling and proliferation, and may play a role in resolution of inflammation. In addition, PGE2 limits the immune response by preventing B-lymphocyte differentiation and their ability to present antigens.
Central and peripheral nervous systems effects
Prostaglandin E2 has a variety of functions within the central nervous system and peripheral nervous system. When PGE2 interacts with EP3 receptors, it increases body temperature, resulting in fever. PGE2 is also a predominant prostanoid that contributes to inflammation via enhancing edema and leukocyte infiltration from increased vascular permeability when acting on EP2 receptors. The use of nonsteroidal anti-inflammatory drugs 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 channels, increase membrane excitability. As a result, this causes peripheral nerve endings to report painful stimuli.
Immunity
As mentioned previously, prostaglandin E2 contributes to the inflammation when bound to EP2 receptors. In terms of immunity, prostaglandins have the ability to regulate lymphocyte function. PGE2 affects T-lymphocyte formation by regulating apoptosis of immature thymocytes. In addition, it can suppress an immune response by inhibiting B lymphocytes from forming into antibody-secreting plasma cells. When this process is suppressed, it causes a decrease in a humoral antibody response because of the decrease in production of antibodies. PGE2 also has roles in inhibition of cytotoxic T-cell function, cell division of T-lymphocytes, and the development of TH1 lymphocytes.Neurological effects
In response to physiologic and psychologic stress, prostaglandin E2 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. 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. EP4 is functionally similar to EP2 and has also been shown in studies to have a role in hypothermia and anorexia. In addition to inflammatory effects, PGE2 has been shown to have anti-inflammatory effects as well, due to its different actions on varying receptors.Smooth muscle effects
Prostaglandin E2 serves a significant role in vascular smooth muscle tone regulation. It is a vasodilator produced by endothelial cells. It promotes vasodilation of smooth muscles by increasing the activity of cyclic adenosine monophosphate to decrease intracellular calcium levels via the IP and EP4 receptors. Conversely, PGE2 can also induce vasoconstriction via activation of EP1 and EP3 receptors, which activates the Ca2+ pathway and decreased cAMP activity.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, 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 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 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. Results of a systematic review and meta-analysis of the literature found that outpatient cervical ripening with dinoprostone or single-balloon catheters did not increase the risk of cesarean deliveries.Prostaglandin E2 achieves cervical ripening and softening by stimulating uterine contractions as well as directly acting on the collagenase present in the cervix to soften it. There are currently two formulations of PGE2 analog available for use in cervical ripening: Prepidil, a vaginal gel, and Cervidil, a vaginal insert. PGE2 is similar to oxytocin in terms of successful labor induction and the time from induction to delivery.