Prostaglandins and Therapeutic use of Prostaglandins

Last Updated on June 11, 2020 by Sagar Aryal

Actions of Prostaglandins

Prostaglandins act by binding to different G-protein coupled receptors that in return activate or inhibit adenylyl cyclase or stimulate phospholipase C. That eventually results in an enhanced formation of diacylglycerol and inositol 1,4,5-trisphosphate. Prostaglandin F2α (PGF2α), the leukotrienes, and thromboxane A2 (TXA2) activate phosphatidylinositol metabolism to perform certain functions. Thus, activation of phosphatidylinositol metabolism leads to an increase in intracellular Ca2+.

Prostaglandins, produced inside tissues, serve as local signals and the response depends on specific cell types. The functions of prostaglandins and other eicosanoids are diverse and depend on the tissue and enzymes present at the site of action.

For instance, TXA2 released from platelets due to tissue injury, cause an increase in bringing up new platelets for aggregation to the site of injury and also contributes to local vasoconstriction. Whereas PGI2 is produced by endothelial cells and its role is opposite to TXA2, PGI2 inhibits platelet aggregation and produces vasodilation.

Prostaglandins

Figure: Prostaglandins. Image Source: The Lipid Web (William W. Christie)

Therapeutic use of Prostaglandins

Prostaglandins play an important role in the regulation of pain, inflammation, and fever.  They are also involved in the regulation of many physiological functions, such as acid secretion and mucus formation in the gastrointestinal (GI) tract, contractions of the uterus, and blood flow of the kidney. Prostaglandins also play a role as chemical mediators that are released during allergic and inflammatory processes.

Major drugs targeting Prostaglandins

DRUGPROPERTIESMECHANISM OF ACTIONSIDE EFFECTS
MisoprostolA PGE1 analog and used to protect the mucosal lining of the stomach by decreasing the occurrence of gastric and duodenal ulcers during chronic NSAID treatment. It is also used off -label in obstetric settings for labor induction.Misoprostol interacts with prostaglandin receptors on parietal cells present in the stomach and reduces gastric acid secretion. It shows a gastric intestinal cytoprotective effect by stimulation of mucus and bicarbonate production. It enhances uterine contractions by interacting with prostaglandin receptors in the uterus.It has a potential risk of abortion, thus, contraindicated during pregnancy.

Common side effects are diarrhea headache, abdominal pain, and spotting (in women).

If used off -label for labor induction, for termination of pregnancy, or for cervical ripening, misoprostol can cause maternal or fetal complications such as death, uterine damage, infection, and fetal bradycardia.

IloprostA synthetic analog of PGI2(prostacyclin) and is a potential agent for pulmonary vasodilation so it can be used as a therapeutic drug for pulmonary arterial hypertension.

Iloprost is given as pulmonary inhalation and causes a localized effect of a decrease in pulmonary hypertension. The administration of drugs through pulmonary inhalation is beneficial as it provides a more localized effect with less systemic blood pressure reduction. The repeated doses are required due to the short half-life of the drug.

Iloprost causes a notable reduction in pulmonary arterial resistance following by increase in cardiac index and oxygen delivery. Iloprost mediates its function by activating the IP receptors (prostacyclin receptors), elevating the formation of intracellular cAMP (cyclic adenosine monophosphate). Iloprost also inhibits TXA2 production.Due to iloprost inhalation, cough and bronchospasm can be the adverse effects. Common side effects include headache, dizziness, flushing, and fainting.
Latanoprost, travoprost, and bimatoprostLatanoprost is a PGF2α analog that is used as a therapeutic drug for elevated intraocular pressure and open-angle glaucoma.

Travoprost is a pro-drug and become active after metabolized to free acid. This drug is given as ophthalmic solution once per day and as effective as timolol(a synthetic compound) or even better in decreasing intraocular pressure.

Bimatoprost mimics endogenous prostanoids (prostaglandin-ethanolamides) and has similar effectiveness in decreasing the intraocular pressure. Bimatoprost enhances prominence, length, and darkness of eyelash and also used for treating eyelash hypotrichosis.

latanoprost and travoprost bind to the prostaglandin FP receptors and cause an increase in uveoscleral outflow (any nontrabecular outflow in a normal eye), decreasing intraocular pressure. Bimatoprost causes similar effects as latanoprost and travoprost.These drugs can cause adverse effects like blurred vision, ocular irritation, iris color change (increased brown pigmentation), increased number and pigment of eyelashes, and foreign body sensation.
AlprostadilIt is a PGE1 produced naturally in tissues, for example, seminal vesicles and cavernous tissues, in the ductus arteriosus of the fetus and in the placenta.

Therapeutic importance of alprostadil is in the treatment of erectile dysfunction or in keeping the ductus arteriosus open in those neonates that have congenital heart conditions until surgery has done. However, usually, the ductus closes soon after delivery in order to allow normal blood circulation between the heart and the lungs.

The administration of alprostadil is localized either by suppository or by injection. The drug action occurs by causing an increase in intracellular cAMP which subsequently leads to the activation of protein kinase and relaxation of smooth muscle. Blood is then entrapped by dilation of cavernosal arteries and by the relaxation of trabecular smooth muscles.Major side effects, when used as therapy for erectile dysfunction, are dizziness, symptomatic hypotension, and syncope. Local adverse reactions include urethral, penile, and testicular pain; prolonged erections; and priapism. When administered intravenously (IV) in neonates, fever, sepsis, apnea, and seizures may be the adverse effects.
LubiprostoneLubiprostone is a PGE1 derivative used as a therapeutic drug for irritable bowel syndrome with constipation and chronic idiopathic constipation.It exerts its effects by stimulation of chloride channels (ClC-2) in the luminal cells of the intestinal epithelium, thus cause an increase in intestinal fluid secretion. This results in the softening of the stool and increases intestinal motilityThe common side effect is nausea that can be decreased if drug is taken with food. The second most reported adverse effect is dose-dependent diarrhea that is followed by headache and abdominal pain.

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