Prostaglandin inhibitors

Prostaglandin inhibitors are drugs that inhibit the synthesis of prostaglandin in human body.^[1] There are various types of prostaglandins responsible for different physiological reactions such as maintaining the blood flow in stomach and kidney, regulating the contraction of involuntary muscles and blood vessels, and act as a mediator of inflammation and pain.^[2][3] Cyclooxygenase (COX) and Phospholipase A2 are the major enzymes involved in prostaglandin production, and they are the drug targets for prostaglandin inhibitors.^[3] There are mainly 2 classes of prostaglandin inhibitors, namely non- steroidal anti- inflammatory drugs (NSAIDs) and glucocorticoids. In the following sections, the medical uses, side effects, contraindications, toxicity and the pharmacology of these prostaglandin inhibitors will be discussed.

Medical Uses

Non- steroidal Anti- inflammatory drugs (NSAIDs)

NSAIDs are used as anti- inflammatory, antipyretic and analgesic agents.^[4] They can be administered through different routes, namely oral, rectal and topical.^[4] They can relieve mild to moderate pain.^[5] The dosage forms available for different NSAIDs and their respective medical uses are discussed as follows.

The available dosage forms for oral NSAIDs, rectal NSAIDs and topical NSAIDs are shown in the following table.

The common medical uses of oral NSAIDs, rectal NSAIDs and topical NSAIDs are shown in the following table.

	Oral NSAIDs	Rectal NSAIDs	Topical NSAIDs
Medical Uses	1. Common Cold and Flu Oral NSAIDs are commonly prescribed for relieving the symptoms of blocked nose.[10] 2. Postoperative Pain The American Society of Anesthesiologists Task Force on Acute Pain Management recommended the use of oral NSAIDs for managing postoperative pain in 2012.[5] The commonly used NSAIDs for postoperative pain are celecoxib and ibuprofen.[5] Trials have shown that these drugs can reduce pain to at least 50% and they are tolerable by most patients.[5] 3. Migraine The therapeutic goals for migraine treatment are migraine prevention and symptomatic relief.[11] The majority of oral NSAIDs such as ibuprofen, mefenamic acid, and indomethacin are shown to be effective to treat and prevent migraine.[11] They do not have significant differences in terms of their therapeutic effects and are almost equally potent in migraine therapy.[11] NSAIDs with less side effects are more preferred in migraine therapy.[11]	Prevention of pancreatitis Rectal NSAIDs such as diclofenac and indomethacin are administered for the prevention of pancreatitis due to endoscopic retrograde cholangiopancreatography (ERCP).[12] ERCP is a technique for treating liver and pancreatic disease.[7] Acute pancreatitis is the most common complication of ERCP. Therefore, rectal NSAIDs are given to patients before ERCP as a measure to prevent post- ERCP pancreatits. Trials showed that rectal NSAIDs are more effective than oral NSAIDs to prevent post ERCP pancreatitis as it exerts its effects faster and its degree of absorption is higher.[7]	Osteoarthritis Topical NSAIDs, mainly diclofenac, are prescribed for patients with osteoarthritis.[8] They are effectively absorbed in arms and knees. As osteoarthritis is a disease commonly found in the elderly (>65 years old), oral NSAIDs are seldom used as their systemic side effects are more severe in elderly patients.[8] Therefore, topical NSAIDs are used for osteoarthritis to exert its local analgesic effects and minimize their systemic side effects in elderly patients.[8]

Glucocorticoids

Glucocorticoids are potent anti- inflammatory drugs.

The dosage forms available for different glucocorticoids and their medical uses are discussed as follows.

The available dosage forms for oral glucocorticoids and inhalable glucocorticoids are shown in the following table.

	Oral Glucocorticoids	Inhalable Glucocoticoids
Available dosage forms	Tablets, capsules and liquid[13]	Dry powder[14]

The common medical uses of oral glucocorticoids and inhalable glucocorticoids are summarized in the following table.

	Oral Glucocorticoids	Inhalable Glucocorticoids
Medical uses	Rheumatoid arthritis lysosomal enzymes.[16]	Asthma Inhalable glucocorticoids are the major drugs used for asthma treatment and maintenance.[13] They suppress airway inflammation in asthma by inhibiting prostaglandin synthesis, enhancing gene expression of anti- inflammatory proteins, and suppressing inflammatory genes.[17] They also dilate airway by reducing the production of leukotriene, a potent bronchoconstrictor in the circulation.[17]

Side Effects

NSAIDs

The short term use of NSAIDs are rather safe, the manifestations of severe side effects are more commonly seen in the chronic use of NSAIDs.[16]

Renal Failure

The chronic use of NSAIDs inhibit the synthesis of prostaglandins and thromboxanes, which leads to renal vasoconstriction.^[18] This results in a decreased blood flow to the kidneys.^[18] Therefore, patients taking NSAIDs in long term are in higher risk of developing chronic renal diseases and nephrotoxicity due to reduced renal perfusion.

Gastric Ulcers

As NSAIDs inhibit prostaglandin synthesis, it reduces the blood flow to the stomach and weakens the stomach

The chronic use of glucocorticoids suppress the activity of hypothalamic- pituitary-adrenal (HPA) axis. The severity of HPA axis suppression is directly proportional to the dose and the duration of therapy.^[20] HPA axis suppression results in a weakened immune system, making the patients more prone to infections in long term.^[20]

Side effects in short- term use

Short- term use of glucocorticoids creates minor disturbance in human body. The examples of short- term effects created by glucocorticoids are hyperglycemia, oscillation in blood pressure, psychiatric events and electrolyte disorders.^[21] These effects usually can be reversed once the glucocorticoids therapy is stopped.^[20]

Contraindications

NSAIDs

Patients taking Anticoagulants

As NSAIDs inhibit cyclooxygenase, the production of thromboxane, a natural coagulator, is inhibited.^[22] Therefore, the risk of bleeding during the use of NSAIDs is intensified by concomitant use of anticoagulants.^[22]

Patients with Chronic Renal Diseases

As NSAIDs reduce blood flow to kidney by inhibiting prostaglandin synthesis, it leads to

Glucocorticoids reduces the number of healthy neutrophils in human body, leading to neutropenia.^[23] Neutropenia reduces the efficacy of antifungal drugs.^[23] Studies show that neutropenia together with high cumulative glucocorticoid concentration in circulation reduce the efficacy of invasive fungal infection treatment.^[23] Therefore, patients with fungal infections are not recommended with the use of glucocorticoids.^[23]

Patients with Diabetes Mellitus

Glucocorticoids raise blood glucose level via different mechanisms. They can stimulate

NSAIDs overdose can lead to acute

The overdose of glucocorticoids exacerbate its side effects. Most of the toxicities induced can be reversed by discontinuing the therapy.[16]

Cushing's Syndrome

A high dose of glucocorticoids suppress the release of

Weakening the immune system

High- dose glucocorticoids increase the risk of patients' infection by bacteria, virus and fungus.^[16] The cells involved in the immune system are mainly phagocytes, neutrophils, monocytes, macrophages, natural killer cells, B cells, T cells, eosinophils, basophils and mast cells. Glucocorticoids significantly reduce the production of these cells in the human body, thereby weakening the immune system.^[16]

Pharmacology

Pharmacokinetics

Pharmacokinetics refers to the study of absorption, distribution, metabolism and elimination of drugs in human body.^[25]

Pharmacodynamics

Pharmacodynamics refers to the study of how the drugs exert their actions in human body.^[27]

NSAIDs

NSAIDs inhibits the synthesis of prostaglandin by inhibiting

Phospholipase A2 is an enzyme to catalyze the release of arachidonic acid in our body. After arachidonic acid is released, it can be converted to prostaglandins by cyclooxygenase.^[28] Glucocorticoids work by inhibiting phospholipase A2, hence indirectly inhibiting prostaglandin synthesis.^[28]

References