Prostaglandin inhibitors are drugs that inhibit the synthesis of prostaglandin in human body. There are various types of prostaglandins responsible for different physiological reactions such as maintaining the blood flow in

stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...

and

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

, regulating the contraction of involuntary muscles and

blood vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...

s, and act as a mediator of

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

and pain.

Cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as pr ...

(COX) and Phospholipase A2 are the major

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s 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

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) 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 verteb ...

s. In the following sections, the medical uses,

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

contraindication In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

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 An antipyretic (, from ''anti-'' 'against' and ' 'feverish') is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which r ...

and analgesic agents. They can be administered through different routes, namely

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or or ...

, rectal and

topical A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

. They can relieve mild to moderate pain. 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.

Glucocorticoids

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 A chronic condition is a health condition or disease that is persistent or otherwise long-lasting in its effects or a disease that comes with time. The term ''chronic'' is often applied when the course of the disease lasts for more than three m ...

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 Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

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

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.

Renal Failure

The chronic use of NSAIDs inhibit the synthesis of prostaglandins and

thromboxane Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring. Thromboxane is named for i ...

s, which leads to renal

vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...

. 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 Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxins ...

due to reduced renal perfusion.

Gastric Ulcers

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

mucous membrane A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It i ...

, 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 Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...

H2 receptor antagonists H2 antagonists, sometimes referred to as H2RAs and also called H2 blockers, are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of stom ...

which suppress gastric acid secretions together with NSAIDs.

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. 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 Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

and hypertension especially for elderly patients.

Glucocorticoids

Side effects in chronic use

Methylprednisolone inhibits the 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. HPA axis suppression results in a weakened immune system, making the patients more prone to infections in long term.Gordijn, M. S., Rensen, N., Gemke, R. J., van Dalen, E. C., Rotteveel, J., & Kaspers, G. J. (2015). Hypothalamic‐pituitary‐adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. ''Cochrane Database of Systematic Reviews'', (8).

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. These effects usually can be reversed once the glucocorticoids therapy is stopped.

Contraindications

NSAIDs

Patients taking Anticoagulants

As NSAIDs inhibit

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as pr ...

, the production of

, a natural coagulator, is inhibited. Therefore, the risk of bleeding during the use of NSAIDs is intensified by concomitant use of anticoagulants.

Patients with Chronic Renal Diseases

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

renal ischemia Renal ischemia also known as ''nephric ischaemia'', is the deficiency of blood in one or both kidneys or nephrons, usually due to functional constriction or actual obstruction of a blood vessel The blood vessels are the components of the circ ...

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

Glucocorticoids

Patients with Systemic Fungal Infections

Glucocorticoids reduces the number of healthy

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

s in human body, leading to neutropenia. 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.

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 Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

; 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 Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

. Thus, the use of glucocorticoids should be minimized or avoided for diabetes patients.

Toxicity

NSAIDs

The most common signs of NSAIDs overdose are

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

, blurred vision and

drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

. NSAIDs toxicity can be reversed by

gastric lavage Gastric lavage, also commonly called stomach pumping or gastric irrigation, is the process of cleaning out the contents of the stomach. Since its first recorded use in early 19th century, it has become one of the most routine means of eliminating ...

. In severe cases, NSAIDs toxicity can lead to the following clinical conditions.

Central Nervous System (CNS) toxicity

NSAIDs overdose can lead to acute

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

toxicity. It can create CNS effects ranging from

to coma. Other symptoms such as

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...

, headaches,

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

, and disorientation are also the reported manifestations of CNS toxicity.

Acid- Base abnormalities

A large dose of NSAIDs, particularly ibuprofen,

naproxen Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulat ...

can lead to

metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...

. Metabolic acidosis can further deteriorate into

cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

and

electrolyte imbalance Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function, ...

which can be fatal.

Glucocorticoids

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

Cushing's Syndrome

A high dose of glucocorticoids suppress the release of

corticotropin Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...

from the

pituitary In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...

, leading to

Cushing's Syndrome Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a ...

. The symptoms are weight gain on the upper back and the area between shoulders, thinning of arms and legs, and moon face. Cushing's syndrome (vector image)

Weakening the immune system

High- dose glucocorticoids increase the risk of patients' infection by

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsk ...

and

fungus A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from t ...

. The cells involved in the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...

are mainly

phagocyte Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

s, macrophages, natural killer cells, B cells,

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...

basophil Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammator ...

s and

mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...

s. Glucocorticoids significantly reduce the production of these cells in the human body, thereby weakening the immune system.

Pharmacology

Pharmacokinetics

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

Pharmacodynamics

Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ...

refers to the study of how the drugs exert their actions in human body.

NSAIDs

NSAIDs inhibits the synthesis of prostaglandin by inhibiting

(

COX-1 Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of two cyclooxygenases. ...

and

COX-2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...

). NSAIDs with higher selectivity on

such as

indomethacin 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 ...

, zomeoirac and

diclofenac Diclofenac, sold under the brand name Voltaren, among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. It is taken by mouth or rectally in a suppository, used by injection, or ...

have potent anti- inflammatory activity and fewer side effects on stomach and kidney.{{Cite journal, last1=Zarghi, first1=Afshin, last2=Arfaei, first2=Sara, date=2011, title=Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships, journal=Iranian Journal of Pharmaceutical Research , volume=10, issue=4, pages=655–683, issn=1735-0328, pmc=3813081, pmid=24250402

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. Glucocorticoids work by inhibiting phospholipase A2, hence indirectly inhibiting prostaglandin synthesis.

References

Anti-inflammatory agents