Prostaglandin inhibitors

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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.

Contents

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.

Oral NSAIDsRectal NSAIDsTopical NSAIDs
Available dosage formsTablets and capsules [6] Suppository [7] Gels, creams and suppository [8]

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

Oral NSAIDsRectal NSAIDsTopical NSAIDs
Medical Uses1. Common Cold and Flu

Oral NSAIDs are commonly prescribed for relieving the symptoms of common cold and flu. [9] They are shown to be effective to alleviate symptoms such as sneezing, [9] headache, ear pain, muscle pain and malaise. [10] However, studies show that NSAIDs are not effective in treating cough and 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]

Endoscopic retrograde cholangiopancreatography (ERCP) Detailed diagram of an endoscopic retrograde cholangio pancreatography (ERCP) CRUK 001.svg
Endoscopic retrograde cholangiopancreatography (ERCP)
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]

Manifestation of osteoarthritis in finger joints Osteoarthritis -- Smart-Servier.jpg
Manifestation of osteoarthritis in finger joints

Glucocorticoids

Glucocorticoids are potent anti- inflammatory drugs. [10] They are mainly administered via oral and pulmonary route. [10] Oral glucocorticoids are mainly prescribed for the prevention of chronic disease exacerbation. Inhalable glucocorticoids are effective in treating small airways inflammations. [10] They are commonly used in the maintenance of chronic diseases, and to relieve symptoms during acute flare up of airway inflammations such as asthma. [10] 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 GlucocorticoidsInhalable Glucocoticoids
Available dosage formsTablets, capsules and liquid [13] Dry powder [14]

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

Oral GlucocorticoidsInhalable Glucocorticoids
Medical usesRheumatoid arthritis

Rheumatoid arthritis is an auto- immune disorder that affect joints. [15] The common symptoms are warm, painful and swollen joints. [15] Glucocorticoids exert anti- inflammatory effects to relieve the symptoms by inhibiting the synthesis of prostaglandin and leukotriene, and the release of collagenase and lysosomal enzymes. [16]

Manifestation of rheumatoid arthritis in finger joints Rheumatoid arthritis -- Smart-Servier.jpg
Manifestation of rheumatoid arthritis in finger joints
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]

The use of inhalable glucocorticoids in asthma An Asthma patient taking medication using an inhaler.png
The use of inhalable glucocorticoids in asthma

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

An image illustrating gastric ulcer Gastric Ulcer.jpg
An image illustrating gastric ulcer

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. [18] This increases the risk of developing gastric ulcers. [18] This can be prevented by taking drugs such as proton pump inhibitors, H2 receptor antagonists which suppress gastric acid secretions together with NSAIDs. [18]

Congestive heart failure and hypertension

NSAIDs retain sodium and water in the circulation, which in turn increase the blood volume and blood pressure in the body. [18] The production of natural vasodilator (prostaglandin) is also inhibited at the same time. [18] Hence, the use of NSAIDs is associated with an increased risk of congestive heart failure and hypertension especially for elderly patients. [18] [19]

Glucocorticoids

Side effects in chronic use

Glucocorticoid pathway in suppression of HPA axis Methylprednisolone inhibits the HPA axis.png
Glucocorticoid pathway in suppression of HPA axis

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 renal ischemia and a decrease in glomerular filtration pressure. [22] As a result, the kidney functions of patients with chronic renal diseases is further worsen. [22]

Glucocorticoids

Patients with Systemic Fungal Infections

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 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. [24] All these raise blood glucose level and exacerbate diabetes mellitus. [24] Thus, the use of glucocorticoids should be minimized or avoided for diabetes patients.

Toxicity

NSAIDs

The most common signs of NSAIDs overdose are nausea, vomiting, blurred vision and drowsiness. [16] NSAIDs toxicity can be reversed by gastric lavage. [16] In severe cases, NSAIDs toxicity can lead to the following clinical conditions.

Central Nervous System (CNS) toxicity

Manifestation of nystagmus Rapid horizontal congenital nystagmus.gif
Manifestation of nystagmus

NSAIDs overdose can lead to acute central nervous system toxicity. [16] It can create CNS effects ranging from drowsiness to coma. [16] Other symptoms such as ataxia, nystagmus, headaches, seizure, and disorientation are also the reported manifestations of CNS toxicity. [16]

Acid- Base abnormalities

A large dose of NSAIDs, particularly ibuprofen, naproxen can lead to metabolic acidosis. [16] Metabolic acidosis can further deteriorate into cardiac arrhythmia and electrolyte imbalance which can be fatal. [16]

Glucocorticoids

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 corticotropin from the pituitary, leading to Cushing's Syndrome. [16] The symptoms are weight gain on the upper back and the area between shoulders, thinning of arms and legs, and moon face. [16]

Symptoms of Cushing's Syndrome. Cushing's syndrome (vector image).svg
Symptoms of Cushing's Syndrome.

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]

NSAIDs [18] Glucocortiocids [26]
AbsorptionA 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%)

DistributionNSAIDs 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.
MetabolismThe majority of NSAIDs undergo glucoronidation during phase II metabolism in the liverGlucocorticoids 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
EliminationRenal ExcretionRenal Excretion

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 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. [28] [29]

Glucocorticoids

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]

Related Research Articles

<span class="mw-page-title-main">Nonsteroidal anti-inflammatory drug</span> Class of therapeutic drug for relieving pain and inflammation

Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

<span class="mw-page-title-main">Ibuprofen</span> Medication used for treating pain, fever, and inflammation

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be used orally or intravenously. It typically begins working within an hour.

<span class="mw-page-title-main">Cyclooxygenase</span> Class of enzymes

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. A member of the animal-type heme peroxidase family, it is also known as prostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid to prostaglandin H2 via a short-living prostaglandin G2 intermediate.

<span class="mw-page-title-main">Naproxen</span> Nonsteroidal anti-inflammatory drug (NSAID) used to treat pain

Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, and inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulations. Onset of effects is within an hour and lasts for up to twelve hours.

<span class="mw-page-title-main">Glucocorticoid</span> Class of corticosteroids

Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The name "glucocorticoid" is a portmanteau and is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure.

<span class="mw-page-title-main">Celecoxib</span> Nonsteroidal anti-inflammatory medication

Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It may also be used to decrease the risk of colorectal adenomas in people with familial adenomatous polyposis. It is taken by mouth. Benefits are typically seen within an hour.

Anti-inflammatory or antiphlogistic is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as opposed to opioids, which affect the central nervous system to block pain signaling to the brain.

Cyclooxygenase-2 inhibitors, also known as coxibs, are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly target cyclooxygenase-2 (COX-2), an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration and is the main feature of celecoxib, rofecoxib, and other members of this drug class.

<span class="mw-page-title-main">Prostacyclin</span> Chemical compound

Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.

<span class="mw-page-title-main">Loop diuretic</span> Diuretics that act along the loop of Henle in the kidneys

Loop diuretics are pharmacological agents that primarily inhibit the Na-K-Cl cotransporter located on the luminal membrane of cells along the thick ascending limb of the loop of Henle. They are often used for the treatment of hypertension and edema secondary to congestive heart failure, liver cirrhosis, or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.

<span class="mw-page-title-main">Indometacin</span> Anti-inflammatory drug

Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.

Cyclooxygenase-3 (COX-3) is an enzyme that is encoded by the PTGS1 (COX1) gene, but is not functional in humans. COX-3 is the third and most recently discovered cyclooxygenase (COX3050) isozyme, while the first two to be discovered were COX-1 and COX-2. The COX-3 isozyme is encoded by the same gene as COX-1, with the difference that COX-3 retains an intron that is not retained in COX-1.

<span class="mw-page-title-main">Ketorolac</span> Nonsteroidal anti-inflammatory drug (NSAID; analgesic)

Ketorolac, sold under the brand name Toradol among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain. Specifically it is recommended for moderate to severe pain. Recommended duration of treatment is less than six days, and in Switzerland not more than two days. It is used by mouth, by nose, by injection into a vein or muscle, and as eye drops. Effects begin within an hour and last for up to eight hours.

<span class="mw-page-title-main">Etodolac</span> Nonsteroidal anti-inflammatory drug

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID).

A prostaglandin antagonist is a hormone antagonist acting upon one or more prostaglandins, a subclass of eicosanoid compounds which function as signaling molecules in numerous types of animal tissues.

<span class="mw-page-title-main">Fenoprofen</span> NSAID analgesic and anti-inflammatory drug

Fenoprofen, sold under the brand name Nalfon among others, is a nonsteroidal anti-inflammatory drug (NSAID). Fenoprofen calcium is used for symptomatic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain. It has also been used to treat postoperative pain. It is available as a generic medication.

Cyclooxygenases are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids to prostaglandins and thromboxane(s). Their main role is to catalyze the transformation of arachidonic acid into the intermediate prostaglandin H2, which is the precursor of a variety of prostanoids with diverse and potent biological actions. Cyclooxygenases have two main isoforms that are called COX-1 and COX-2. COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets. COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells and in the central nervous system. Prostaglandin synthesis in these sites is a key factor in the development of inflammation and hyperalgesia. COX-2 inhibitors have analgesic and anti-inflammatory activity by blocking the transformation of arachidonic acid into prostaglandin H2 selectively.

<span class="mw-page-title-main">Polmacoxib</span> COX-2 selective NSAID medication

Polmacoxib is a nonsteroidal anti-inflammatory drug (NSAID) used to treat osteoarthritis. It was developed as CG100649 and approved for use in South Korea in February 2015. It inhibits the enzymes carbonic anhydrase and COX-2. A study in healthy volunteers showed drug effects on urinary prostaglandin metabolites for both polmacoxib and celecoxib that suggest a similar cardiovascular risk profile. Further work by this group developed dose-exposure relationships of polmacoxib to guide clinical development strategies.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

<span class="mw-page-title-main">Lysine acetylsalicylate</span> Chemical compound

Lysine acetylsalicylate, also known as aspirin DL-lysine or lysine aspirin, is a more soluble form of acetylsalicylic acid (aspirin). As with aspirin itself, it is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, antithrombotic and antipyretic properties. It is composed of the ammonium form of the amino acid lysine paired with the conjugate base of aspirin.

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