Prostaglandin E2


Prostaglandin E2, also known as dinoprostone, is a naturally occurring prostaglandin 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 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, PGG2 is modified by the peroxidase moiety of the COX enzyme to produce PGH2 which is then converted to PGE2.
Common side effects include vomiting, fever, diarrhea, and excessive uterine contraction. 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. Prostaglandin E2 is in the oxytocics family of medications. 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 made in 1970 and approved for medical use 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 labour and also stimulates osteoblasts to release factors that stimulate bone resorption by osteoclasts.
It is also implicated in duct-dependent congenital heart diseases and is used in infusion in order to open the duct although PGE1 is more commonly used.
It is a direct vasodilator, relaxing smooth muscles, and it inhibits the release of noradrenaline from sympathetic nerve terminals. It does not inhibit platelet aggregation, whereas prostacyclin does.
Prostaglandin E2 also suppresses T cell receptor signaling and may play a role in resolution of inflammation. Up-regulation of PGE2 has been implicated as a possible cause of nail clubbing. Furthermore, its postpartal synthesis in newborns is considered as one cause of patent ductus arteriosus.

Central and Peripheral Nervous Systems Effects

PGE2 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. 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.

Neurological effects

In response to physiologic and psychologic stress, Prostaglandin E2 is involved in several inflammation and immunity pathways. It regulates these responses through binding to G coupled protein PGE2 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 vis PGE2 results in the suppression of impulse behaviors in response to psychological stress. Prostaglandin E2 is involved in regulating illness induced memory impairment via activation of EP2. Prostaglandin E2 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. Generally, Prostaglandin E2, has been shown to increase psychological stress and impair memory.

Smooth Muscle Effects

PGE2 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.
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

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 through localized vasodilation. COX-2-derived prostanoids work to increase medullary blood flow as well as inhibit sodium reabsorption within kidney tubules. PGE2 also assist 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 birth. 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. There are currently two formulations of PGE2 analog available for use in cervical ripening: Prepidil®, a vaginal gel, and Cervidil®, a vaginal insert.

Termination of intrauterine pregnancy

PGE2 has become a common pharmacological method of termination of pregnancy, specifically in the first and second trimesters.

Side effects

A common side effect of Prostaglandin E2 is its effect on gastrointestinal smooth muscle resulting in nausea, vomiting and diarrhea. The suppository form of prostaglandin E2 is associated with increased severity of these symptoms. Fever is also a common side effect with use of Prostaglandin E2. The insert and gel forms have been shown to have minimal gastrointestinal effects, but are more associated with increase stimulation of the uterus. Uterine hyperstimulation is effectively treated by stopping use of Prostaglandin E2. 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 is a potent activator of the Wnt signaling pathway. It has been implicated in regulating the developmental specification and regeneration of hematopoietic stem cells through cAMP/PKA activity. PGE2-mediated Wnt pathway activation has also been shown to promote hair follicle regeneration in a mouse model of skin wounding.
Prostaglandin E2 binds to G protein-coupled receptors 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 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

PGE2 comes in many dosage forms with varying pharmacokinetic properties. For example PGE2 can come in a gel formulation that requires six hour dosing or it can come as a slow release dinoprostone pessary that does not need to be re-administered and can be taken out if necessary. 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.
For the vaginal insert Cervidil, the manufacturer recommends keeping the medication frozen until use since it does not need to be warmed to room temperature. 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. The patient should remain laying down for 2 hours after administration of the insert is complete. The manufacturer also recommends waiting 30 minutes after removal of insert before starting oxytocin.
The vaginal gel is administered through a prefilled syringe and the medication is placed in the posterior fornix of the vagina. Patients should stay laying down for at least 30 minutes after they have received the drug.
If the vaginal suppository is indicated, bring the medication to room temperature, unwrap the medication, insert high into the vagina, and advise the patient to remain laying down for 10 minutes after administration.

Contraindications

Contraindications to a medication are any reasons to not use the drug. PGE2 is used to induce labor and should not be used in patients that are contraindicated to give birth vaginally or spontaneous labor. PGE2 should not be used in patients with allergies to prostaglandins or any components in the drugs formulations. PGE2 should be stopped before other oxytocic agents like oxytocin are given to patients.
Furthermore there are manufacturer specific contraindications for specific dosage forms.

Endocervical gel: (Prepidil)

This dosage form is contraindicated in patients 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, past history of difficult labors and deliveries, have cephalopelvic disproportion, less than 6 previous term babies with nonvertex presentation, hyper or hypotonic uterine patterns. This drug should be avoided in patients with heart disease, glaucoma, or asthma.

Suppository: (Prostin E2)

Patients with acute pelvic inflammatory disease and active disease of the cardiovascular, respiratory, hepatic, or renal systems.

Toxicity

When PGE2 is given in excess, hyper-stimulation of the uterus occurs and immediate discontinuation of the drug usually results in resolution of toxic effects. If symptoms continue a beta adrenergic drug can be used.
There are many different dosage forms of PGE2. The pharmacokinetic properties vary between dosage forms and should not be interchanged. A medication error was cited in the Institute for Safe Medication Practices where Prostin E2 was used in place of Cervidil. The hospital had run out of Cervidil which is a 10 mg endocervical insert and the provider decided to use half of a 20 mg Prostin E2 vaginal suppository. Cervidil delivers the drug at a constant rate and can be removed as necessary while Prostin E2 dissolves immediately and can not be removed. This error resulted in the patient requiring an emergency C-section since the fetus's heart rate dropped suddenly.

Society and culture

Prostaglandin E2 is sold under many brand names with different dosage forms. Cervidil® is an endocervical insert; Prepidil® is an endocervical gel; Prostin E2® is a vaginal suppository; and Propess® is a vaginal delivery system.
Because there are many formulations of PGE2, an interprofessional health team should be implemented in the monitoring of safe use of this medication.