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. 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.
NSAIDs are used as anti- inflammatory, antipyretic and analgesic agents. They can be administered through different routes, namely oral, rectal and topical. They can relieve mild to moderate pain.[4] 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.
| Available dosage forms | Tablets and capsules[5] | Suppository[6] | Gels, creams and suppository[7] |
Glucocorticoids are potent anti- inflammatory drugs. They are mainly administered via oral and pulmonary route. Oral glucocorticoids are mainly prescribed for the prevention of chronic disease exacerbation. Inhalable glucocorticoids are effective in treating small airways inflammations. They are commonly used in the maintenance of chronic diseases, and to relieve symptoms during acute flare up of airway inflammations such as asthma. 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.
| Available dosage forms | Tablets, capsules and liquid[12] | Dry powder[13] |
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.
The chronic use of NSAIDs inhibit the synthesis of prostaglandins and thromboxanes, which leads to renal vasoconstriction.[16] This results in a decreased blood flow to the kidneys. Therefore, patients taking NSAIDs in long term are in higher risk of developing chronic renal diseases and nephrotoxicity due to reduced renal perfusion.
As NSAIDs inhibit prostaglandin synthesis, it reduces the blood flow to the stomach and weakens the stomach mucous membrane, making it more prone to gastric acid attack. This increases the risk of developing gastric ulcers. This can be prevented by taking drugs such as proton pump inhibitors, H2 receptor antagonists which suppress gastric acid secretions together with NSAIDs.
NSAIDs retain sodium and water in the circulation, which in turn increase the blood volume and blood pressure in the body. The production of natural vasodilator (prostaglandin) is also inhibited at the same time. Hence, the use of NSAIDs is associated with an increased risk of congestive heart failure and hypertension especially for elderly patients.[17]
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. HPA axis suppression results in a weakened immune system, making the patients more prone to infections in long term.[18]
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.[19] These effects usually can be reversed once the glucocorticoids therapy is stopped.
As NSAIDs inhibit cyclooxygenase, the production of thromboxane, a natural coagulator, is inhibited. Therefore, the risk of bleeding during the use of NSAIDs is intensified by concomitant use of anticoagulants.[20]
As NSAIDs reduce blood flow to kidney by inhibiting prostaglandin synthesis, it leads to renal ischemia and a decrease in glomerular filtration pressure. As a result, the kidney functions of patients with chronic renal diseases is further worsen.
Glucocorticoids reduces the number of healthy neutrophils in human body, leading to neutropenia.[21] Neutropenia reduces the efficacy of antifungal drugs. Studies show that neutropenia together with high cumulative glucocorticoid concentration in circulation reduce the efficacy of invasive fungal infection treatment. Therefore, patients with fungal infections are not recommended with the use of glucocorticoids.
Glucocorticoids raise blood glucose level via different mechanisms. They can stimulate endogenous glucose production by activating the genes involved; reduce glucose uptake by muscle and adipose tissue; induce muscle and adipose tissues to produce substrates involved in glucose production and inhibit the section and production of insulin in pancreatic β cells. All these raise blood glucose level and exacerbate diabetes mellitus.[22] Thus, the use of glucocorticoids should be minimized or avoided for diabetes patients.
The most common signs of NSAIDs overdose are nausea, vomiting, blurred vision and drowsiness.[23] NSAIDs toxicity can be reversed by gastric lavage. In severe cases, NSAIDs toxicity can lead to the following clinical conditions.
NSAIDs overdose can lead to acute central nervous system toxicity. It can create CNS effects ranging from drowsiness to coma. Other symptoms such as ataxia, nystagmus, headaches, seizure, and disorientation are also the reported manifestations of CNS toxicity.
A large dose of NSAIDs, particularly ibuprofen, naproxen can lead to metabolic acidosis. Metabolic acidosis can further deteriorate into cardiac arrhythmia and electrolyte imbalance which can be fatal.
The overdose of glucocorticoids exacerbate its side effects. Most of the toxicities induced can be reversed by discontinuing the therapy.
A high dose of glucocorticoids suppress the release of corticotropin from the pituitary, leading to Cushing's Syndrome. The symptoms are weight gain on the upper back and the area between shoulders, thinning of arms and legs, and moon face.
High- dose glucocorticoids increase the risk of patients' infection by bacteria, virus and fungus. 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.
Pharmacokinetics refers to the study of absorption, distribution, metabolism and elimination of drugs in human body.[24]
| Absorption | A majority of NSAIDs have good oral absorption. (Degree of absorption ranged from 55%- 100%) | Most glucocorticoids have good oral absorption (Degree of absorption ranged from 60% to 100%) | |
| Distribution | NSAIDs are highly bound to plasma proteins, making them more difficult to distribute to the site of actions. | Glucocorticoids are distributed by binding with protein, mainly glycoprotein, transcortin and albumin. | |
| Metabolism | The majority of NSAIDs undergo glucoronidation during phase II metabolism in the liver | Glucocorticoids undergo phase I and phase II metabolism in the liver. The common phase I metabolisms that glucocorticoids undergo are oxidation and hydrogenation. Glucocorticoids undergo glucoronidation and sulphation during phase II metabolism in the liver | |
| Elimination | Renal Excretion | Renal Excretion |
Pharmacodynamics refers to the study of how the drugs exert their actions in human body.[26]
NSAIDs inhibits the synthesis of prostaglandin by inhibiting cyclooxygenase (COX-1 and COX-2). NSAIDs with higher selectivity on COX-2 such as indomethacin, zomepirac and diclofenac have potent anti- inflammatory activity and fewer side effects on stomach and kidney.[27] [28]
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. Glucocorticoids work by inhibiting phospholipase A2, hence indirectly inhibiting prostaglandin synthesis.