Prostaglandin inhibitors

From WikiProjectMed
Jump to navigation Jump to search

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.

Oral NSAIDs Rectal NSAIDs Topical NSAIDs
Available dosage forms Tablets 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 NSAIDs Rectal NSAIDs Topical NSAIDs
Medical Uses 1. 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)
 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

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 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

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
 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

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

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

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

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.

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]
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

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]

References

  1. ^ Yazid, Samia; Norling, Lucy V.; Flower, Rod J. (2012-08-01). "Anti-inflammatory drugs, eicosanoids and the annexin A1/FPR2 anti-inflammatory system". Prostaglandins & Other Lipid Mediators. Eicosanoids in Cardiovascular Disease. 98 (3): 94–100. doi:10.1016/j.prostaglandins.2011.11.005. ISSN 1098-8823. PMID 22123264.
  2. ^ Green, Gary A. (2001-01-01). "Understanding NSAIDs: From aspirin to COX-2". Clinical Cornerstone. 3 (5): 50–59. doi:10.1016/S1098-3597(01)90069-9. ISSN 1098-3597. PMID 11464731.
  3. ^ a b Ricciotti Emanuela; FitzGerald Garret A. (2011-05-01). "Prostaglandins and Inflammation". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (5): 986–1000. doi:10.1161/ATVBAHA.110.207449. PMC 3081099. PMID 21508345.
  4. ^ a b Ghlichloo, Ida; Gerriets, Valerie (2021), "Nonsteroidal Anti-inflammatory Drugs (NSAIDs)", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 31613522, retrieved 2021-03-12
  5. ^ a b c d Gupta, Anita; Bah, Maimouna (2016-11-13). "NSAIDs in the Treatment of Postoperative Pain". Current Pain and Headache Reports. 20 (11): 62. doi:10.1007/s11916-016-0591-7. ISSN 1534-3081. PMID 27841015. S2CID 22599479.
  6. ^ Goldstein, Jay L; Cryer, Byron (2015-01-22). "Gastrointestinal injury associated with NSAID use: a case study and review of risk factors and preventative strategies". Drug, Healthcare and Patient Safety. 7: 31–41. doi:10.2147/DHPS.S71976. ISSN 1179-1365. PMC 4310346. PMID 25653559.
  7. ^ a b c Hou, Yi-Chao; Hu, Qiang; Huang, Jiao; Fang, Jing-Yuan; Xiong, Hua (2017-04-25). "Efficacy and safety of rectal nonsteroidal anti-inflammatory drugs for prophylaxis against post-ERCP pancreatitis: a systematic review and meta-analysis". Scientific Reports. 7 (1): 46650. Bibcode:2017NatSR...746650H. doi:10.1038/srep46650. ISSN 2045-2322. PMC 5404221. PMID 28440297.
  8. ^ a b c d Argoff, Charles E; Gloth, F Michael (2011). "Topical nonsteroidal anti-inflammatory drugs for management of osteoarthritis in long-term care patients". Therapeutics and Clinical Risk Management. 7: 393–399. doi:10.2147/TCRM.S24458. ISSN 1176-6336. PMC 3208405. PMID 22076115.
  9. ^ a b Kim, Soo Young; Chang, Yoon-Jung; Cho, Hye Min; Hwang, Ye-Won; Moon, Yoo Sun (2015-09-21). "Non-steroidal anti-inflammatory drugs for the common cold". The Cochrane Database of Systematic Reviews. 2015 (9): CD006362. doi:10.1002/14651858.CD006362.pub4. ISSN 1469-493X. PMC 10040208. PMID 26387658.
  10. ^ a b c d e f "UpToDate". www.uptodate.com. Retrieved 2021-03-12.
  11. ^ a b c d Becker, Werner J. (2015). "Acute Migraine Treatment in Adults". Headache: The Journal of Head and Face Pain. 55 (6): 778–793. doi:10.1111/head.12550. ISSN 1526-4610. PMID 25877672. S2CID 23327034.
  12. ^ Yu, Lei-Min; Zhao, Ke-Jia; Lu, Bin (2018-02-08). "Use of NSAIDs via the Rectal Route for the Prevention of Pancreatitis after ERCP in All-Risk Patients: An Updated Meta-Analysis". Gastroenterology Research and Practice. 2018: 1–10. doi:10.1155/2018/1027530. ISSN 1687-6121. PMC 5822867. PMID 29576766.
  13. ^ a b "UpToDate". www.uptodate.com. Retrieved 2021-03-28.
  14. ^ Daley-Yates, Peter T. (2015). "Inhaled corticosteroids: potency, dose equivalence and therapeutic index". British Journal of Clinical Pharmacology. 80 (3): 372–380. doi:10.1111/bcp.12637. ISSN 1365-2125. PMC 4574823. PMID 25808113.
  15. ^ a b Firestein, Gary S.; McInnes, Iain B. (2017-02-21). "Immunopathogenesis of Rheumatoid Arthritis". Immunity. 46 (2): 183–196. doi:10.1016/j.immuni.2017.02.006. ISSN 1074-7613. PMC 5385708. PMID 28228278.
  16. ^ a b c d e f g h i j k l m n "UpToDate". www.uptodate.com. Retrieved 2021-03-13.
  17. ^ a b Barnes, Peter J. (1998-10-01). "Efficacy of inhaled corticosteroids in asthma". Journal of Allergy and Clinical Immunology. 102 (4): 531–538. doi:10.1016/S0091-6749(98)70268-4. ISSN 0091-6749. PMID 9802359.
  18. ^ a b c d e f g h i Wongrakpanich, Supakanya; Wongrakpanich, Amaraporn; Melhado, Katie; Rangaswami, Janani (2018-02-01). "A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly". Aging and Disease. 9 (1): 143–150. doi:10.14336/AD.2017.0306. ISSN 2152-5250. PMC 5772852. PMID 29392089.
  19. ^ Varga, Zoltan; Sabzwari, Syed rafay ali; Vargova, Veronika (2017). "Cardiovascular Risk of Nonsteroidal Anti-Inflammatory Drugs: An Under-Recognized Public Health Issue". Cureus. 9 (4): e1144. doi:10.7759/cureus.1144. ISSN 2168-8184. PMC 5422108. PMID 28491485.
  20. ^ a b c 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).
  21. ^ Williams, Dennis M. (2018-06-01). "Clinical Pharmacology of Corticosteroids". Respiratory Care. 63 (6): 655–670. doi:10.4187/respcare.06314. ISSN 0020-1324. PMID 29794202. S2CID 44128968.
  22. ^ a b c d Saxena, Aaruni; Balaramnavar, Vishal M.; Hohlfeld, Thomas; Saxena, Anil K. (2013-12-05). "Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets". European Journal of Pharmacology. 721 (1): 215–224. doi:10.1016/j.ejphar.2013.09.032. ISSN 0014-2999. PMID 24075938.
  23. ^ a b c d Lionakis, Michail S; Kontoyiannis, Dimitrios P (2003-11-29). "Glucocorticoids and invasive fungal infections". The Lancet. 362 (9398): 1828–1838. doi:10.1016/S0140-6736(03)14904-5. ISSN 0140-6736. PMID 14654323. S2CID 12087010.
  24. ^ a b Kwon, Soonho; Hermayer, Kathie L.; Hermayer, Kathie (2013-04-01). "Glucocorticoid-Induced Hyperglycemia". The American Journal of the Medical Sciences. 345 (4): 274–277. doi:10.1097/MAJ.0b013e31828a6a01. ISSN 0002-9629. PMID 23531958. S2CID 46056913.
  25. ^ Hamidi, Mehrdad; Azadi, Amir; Rafiei, Pedram; Ashrafi, Hajar (2013). "A Pharmacokinetic Overview of Nanotechnology-Based Drug Delivery Systems: An ADME-Oriented Approach". Critical Reviews in Therapeutic Drug Carrier Systems. 30 (5): 435–467. doi:10.1615/CritRevTherDrugCarrierSyst.2013007419. ISSN 0743-4863. PMID 24099328.
  26. ^ Czock, David; Keller, Frieder; Rasche, Franz Maximilian; Häussler, Ulla (2005). "Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids". Clinical Pharmacokinetics. 44 (1): 61–98. doi:10.2165/00003088-200544010-00003. ISSN 0312-5963. PMID 15634032. S2CID 24458998.
  27. ^ Keller, Frieder; Hann, Alexander (2018-09-07). "Clinical Pharmacodynamics". Clinical Journal of the American Society of Nephrology. 13 (9): 1413–1420. doi:10.2215/CJN.10960917. ISSN 1555-9041. PMC 6140566. PMID 29769182.
  28. ^ a b c Vane, J. R.; Botting, R. M. (1998-10-01). "Anti-inflammatory drugs and their mechanism of action". Inflammation Research. 47 (2): 78–87. doi:10.1007/s000110050284. ISSN 1420-908X. PMID 9831328. S2CID 1866687.
  29. ^ Zarghi, Afshin; Arfaei, Sara (2011). "Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships". Iranian Journal of Pharmaceutical Research. 10 (4): 655–683. ISSN 1735-0328. PMC 3813081. PMID 24250402.
Retrieved from "https://mdwiki.org/wiki/Prostaglandin_inhibitors"