Chapter 6 Anti-inflammatory Drugs PDF

FFG2414 Pharmacology II Chapter 6 Anti-inflammatory Drugs Learning outcome After completing this lesson, the students should be able to  Define inflammatory response  Describe the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs)  Describe the mechanism of action...

FFG2414 Pharmacology II Chapter 6 Anti-inflammatory Drugs Learning outcome After completing this lesson, the students should be able to  Define inflammatory response  Describe the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs)  Describe the mechanism of action of Steroidal anti-inflammatory drugs (NSAIDs) Structure of the lesson  Inflammation and mediators of inflammation  Eicosanoids, prostaglandins, cyclo-oxygenase  Non-steroidal anti-inflammatory drugs  Steroidal inflammatory drugs Introduction  The inflammation term is taken from the Latin word “inflammare” (to burn) (de oliveira).  Inflammation is the body’s effort to response to injury, inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair.  However, inappropriate activation of these systems results in a wide range of inflammatory disorders.  There are five cardinal signs of inflammation: - Pain (Dolor) - Heat (Calor) - Redness (Rubor) - Swelling (Tumor) - Loss of function (Functio laesa) 1 2 June 2024  FFG2414 Pharmacology II  The above signs are due to: - Vasodilation leading to redness - Increased vascular permeability leading to swelling of tissues (edema) - Pain - Recruitment of leukocytes into tissues - When inflammation occurs chronically, this can lead to alterations in tissue function.  Inflammation regularly progresses to acute or chronically.  Chronic inflammation may lead to neurodegenerative disorders, cancer, and cardiovascular diseases. Mechanism of inflammation  The inflammatory response is a complex response involves leukocytes such as macrophages, neutrophils, eosinophils and lymphocytes.  They are also known as inflammatory cells or immune cells.  A variety of chemical mediators are released from circulation system, inflammatory cells, and injured tissue actively  These chemical mediators (inflammatory mediators) contribute to and adjust the inflammatory response.  They include - vasoactive amines such as histamine and serotonin, - peptide (e.g., bradykinin), and - eicosanoids (e.g., thromboxanes, leukotrienes, and prostaglandins). Video  Inflammatory Response, Animation (2019) Alila Medical Media. Available at: https://youtu.be/uc6IV85mf3s (Accessed: 26/1/2024). 2 2 June 2024  FFG2414 Pharmacology II  Basic Inflammatory response (2017) Ryan Abbott. Available at: https://youtu.be/iVCXRa8FdP0 (Accessed: 16/1/2024). 3 2 June 2024  FFG2414 Pharmacology II Eicosanoids  Eicosanoids comprise many families of chemically related compounds.  These include prostaglandins, leukotrienes and thromboxanes.  They are all derived from arachidonic acid, which is component of cell membrane phospholipids.  Upon activation by hormones and other stimuli, free arachidonic acid is released from tissue phospholipids by the action of phospholipase A2.  This leads to the production of eicosanoids.  Prostaglandins and thromboxane are produced by the cyclo-oxygenase pathway; whereas the leukotrienes re produced by the lipoxygenase pathway. 4 2 June 2024  FFG2414 Pharmacology II Prostaglandins  Prostaglandins are mediators of the inflammatory response.  They are unsaturated fatty acid derivatives containing 20 carbons that include a cyclic ring structure, formed in the cell membranes of most organs.  Prostaglandins do not travel great distances (like hormones) to their receptors.  They act locally on the tissues wherever they are produced and are metabolized rapidly at the site of action (paracrine or autocrine signaling response)  Therefore they are also called autacoids.  There are different types of prostaglandins: prostaglandin I2 (PGI2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α).  Each of these types of prostaglandins has its specific function 5 2 June 2024  FFG2414 Pharmacology II Cyclo-oxygenase (COX)  Cyclooxygenase (COX) is a family of enzymes required to make prostaglandins from arachdonic acid.  The type of prostaglandin produced if dependent upon the specific cell and the type of of cyclooxygenase present.  Two subtypes of cyclooxygenase have been identified: COX1 and COX2.  COX-1 is believed to always be available in all cells, especially in the platelets, kidneys, and gastrointestinal tract, so that homeostasis in these cells is maintained.  COX-2, on the other hand, appears to be manufactured in activated macrophages in response to injury or damage to local tissues, at the site of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs)  Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) act by inhibiting the synthesis of prostaglandins.  Most currently used NSAIDs are somewhat selective for COX-1, but selective COX-2 inhibitors are available. i. Non-selective COX inhibitors Examples: acetylsalicylic acid (aspirin), indomethacin, naproxen, mefenamic acid, diclofenac sodium, piroxicam ii. Preferential COX-2 inhibitors Examples: nimesulide, meloxicam, nabumetone iii. Selective COX-2 inhibitors Examples: celecoxib, parecoxib, rofecoxib Note: These drugs cause little gastric mucosa damage. They do not inhibit platelet aggregation.  NSAIDs possess various pharmacological effects such as anti-inflammatory, analgesic, antipyretic and antiplatelet (aspirin) properties.  Therefore NSAIDs are commonly used in the treatment of pain (headache, toothache, myalgia, backpain), fever, arthritises and dysmenorrhoea.  However NSAIDs are contraindicated to pregnancy, peptic ulcers, viral infections mainly in children, hypersensitivity reactions and hemophilic patients.  There are several advantages of choosing selective COX-2 inhibitors over non-selective COX-2 inhibitors: - Highly selective inhibitors of COX-2 enzyme - Potent anti-inflammatory action - Have analgesic & antipyretic properties - Lower incidence of gastric upset 6 2 June 2024  FFG2414 Pharmacology II Steroidal anti-inflammatory drugs (SAIDs)  The adrenal cortex is a factory of steroid hormones.  10 – 30 different steroids are synthesized from this tissue, but two classes are of primary importance.  They are glucocorticoids and mineralocorticoids. Uses of corticosteroids as anti-inflammatory drugs  The anti-inflammatory effects of glucocorticoids are primarily attributable to their multiple actions on several types of leukocytes. i. Glucocorticoids suppress the action of T lymphocytes. ii. They suppress the production of cytokines by activated T helper cells. Cytokines normally play a major role in inflammation by recruiting and activating eosinophils and by stimulating antibody production by B cells. iii. Glucocorticoids prevent mast cells, basophils, and eosinophils from releasing various chemical mediators of inflammation, including histamine, prostaglandins, leukotrienes, and other substances that cause tissue damage, vasodilation, and edema. iv. Glucocorticoids stabilize, lysosomal membranes and prevent the release of catabolic enzymes from these organelles. 7 2 June 2024  FFG2414 Pharmacology II v. Glucocorticoids cause vasoconstriction and decrease capillary permeability by direct actions as well as inhibiting the actions of kinins, bacterial toxins, and chemical mediators released from mast cells and eosinophils. vi. Glucocorticoids suppress lymphoid tissue and reduce the number of circulating lymphocytes. They reduce the concentration of circulating eosinophils, basophils, and monocytes while at the same time increasing the concentration of erythrocytes, platelets, and polymorphonuclear leukocytes.  The corticosteroid agents are available as injectables , oral, topical and inahalational preparations. Adverse effects of corticosteroid agents  Fluid and Electrolyte Disturbance – sodium and water retention  Precipitation of Diabetes mellitus – hyperglycaemia  Increased susceptibility to infections – immune response suppression  Peptic ulceration – bleeding & perforation  Osteoporosis – flat spongy bones  Myopathy – weakness of muscles  Glaucoma – prolonged topical therapy Withdrawal corticosteroid agents  Hypothalamic-pituitary-adrenal (HPA) axis suppression occurs most commonly due to exogenous steroid use.  Adrenal suppression is the inadequate adrenal production of cortisol due to suppression of the hypothalamic-pituitary-adrenal axis.  Adrenal insufficiency may manifest in instances of rapid tapering or cessation of exogenous glucocorticoids.  In some autoimmune diseases a fast taper may lead to flares of the underlying disease.  Gradual withdrawal or tapering of the dose is to allow recovery of the normal pituitary- adrenal responsiveness to the secretion of endogenous corticosteroid without exacerbating the underlying disease state.  The adrenocorticotropic hormone stimulation test is generally the most useful test to detect adrenal suppression.  Preventive measures include minimizing corticosteroid dose and duration when possible. 8 2 June 2024  FFG2414 Pharmacology II Withdrawal of corticosteroid agents Symptoms of adrenal insufficiency due to rapid withdrawal of corticosteroids:  Headache, 9 2 June 2024  FFG2414 Pharmacology II  Dizziness,  Fainting,  Fatigue,  Lethargy  Joint pain  Nausea  Weight loss  Fever  Hypoglycaemia  Infection References  Rang H.P., Dale MM, Ritter JM, Moore PK, (2003). Pharmacology (5th ed.). Churchill Livingstone  Tripathi KD, Essentials of Medical Pharmacology, 2004 (5th ed.) Jaypee.  Kaye M., Favaro, A. (2005). Introduction to Pharmacology (10th ed.).  WB Saunders. Holland LN, Adams MP. Core concepts in Pharmacology 2003, Prentice Hall. 10 2 June 2024  FFG2414 Pharmacology II Tutorial A. Multiple Choice Questions 1 The following are signs of inflammation, EXCEPT: A pain B heat C swelling D bleeding 2 Prostagladins and thromboxane are formed by the __________ pathway A cyclo-oxygenase B lipoxygenase C oxidative D glycolysis 3 Select the selective COX-2 inhibitor. A Acetylsalicylic acid B Diclofenac sodium C Meloxicam D Celecoxib 4 The following are clinical uses of NSAIDs, EXCEPT: A arthritis B fever C infection D pain 5 The following are adverse effects of corticosteroids, EXCEPT: A glaucoma B myopathy C osteoporosis D hypoglycemia 6 Select the INCORRECT description about inflammation. A Inflammation has a protective role to tissue injury. 11 2 June 2024  FFG2414 Pharmacology II B Inflammation is the body’s effort to inactivate or destroy invading organisms. C The signs of inflammation include pain, heat, redness and swelling. D Inflammation does not relate to diseases. 7 Thromboxane A2 causes __________. A platelet aggregation and vasoconstriction B the production of eicosanoids C the production of leukotrienes D the inhibition of prostaglandins 8 Select the selective COX-2 inhibitor. A Acetylsalicylic acid B Paracetamol C Celecoxib D Prenisolone 9 The following are clinical uses of NSAIDs, EXCEPT: A arthritis B fever C infection D pain 10 Select the CORRECT description for withdrawal of corticosteroid agents. A The treatment can be stopped abruptly. B The dose needs to be tapered down over 2 months or more. C The withdrawal enhances the pituitary-adrenal responsiveness. D The treatment should be replaced with different drug. 11 Select the functions of inflammation. I Inactivate or destroy invading organism II Remove irritants III Prepare for tissue repair IV Stop bleeding A I, II, III B I, III, IV C II, III, IV D I, II, III, IV 12 2 June 2024  FFG2414 Pharmacology II 12 __________ are formed by the cyclo-oxygenase pathway. A Leukotrienes B Prostanoids C Progesterones D Oestrogens 13 Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of __________. A leukotrienes B prostaglandins C glucose D cholesterol 14 Why is tapering down of dose is important in the withdrawal of corticosteroid? A To enhance inflammation B To recover the pituitary-adrenal responsiveness C To clear the stock of corticosteroid D To earn more money 15 Select the symptoms of inflammation. I Pain II Heat III Swelling IV Bleeding A I, II, III B I, III, IV C II, III, IV D I, II, III, IV 16 Eicosanoids are synthesized from __________. A proteins B carbohydrates C phospholipids D minerals 17 __________ is present at the site of inflammation. 13 2 June 2024  FFG2414 Pharmacology II A COX-1 B COX-2 C COX-3 D COX-4 18 Upon withdrawal, the dose of __________ should be tapered down over two months or more. A adrenaline B corticosteroid C COX-2 inhibitor D NSAID 19 Select a CORRECT statement regarding inflammation. A This is a form of injury B This is a form of homeostasis C This is a form of protective response D This is a form of excretion 20 Select the inflammatory mediators. I Bradykinin II Histamine III Serotonin IV Platelet activating factor A I, II, III B I, III, IV C II, III, IV D I, II, III, IV 21 The actions of prostaglandins are known as __________ response. I endocrine II paracrine III autocrine IV exocrine A I, II B I, III C II, III D II, IV 14 2 June 2024  FFG2414 Pharmacology II 22 Select the adverse effects of corticosteroid agents. I Precipitation of diabetes mellitus II Glaucoma III Osteoporosis IV Heart attack A I, II, III B I, III, IV C II, III,IV D I, II, III, IV 23 Which of the following are signs of inflammation? I Pain II Swelling III Redness IV Heat / fever A I and II only B II and III only C I, II and III only D I, II, III and IV 24 Based on the two statements below, select the correct choice of answers. 1) Leukotrienes belong to the family of eicosanoids. 2) Thromboxane A2(TXA2) is a type of prostanoid. A Statement 1) is TRUE,and statement 2) is FALSE B Statement 1) is FALSE, and statement 2) is TRUE C Both statements 1) and 2) are TRUE D Both statements 1) and 2) are FALSE 25 Which of the following acts by non-selective cyclooxygenase (COX) inhibition? A Aspirin B Nimesulide C Meloxicam D Nabumeton 26 Which of the following is a selective COX-2 inhibitor? A Piroxicam B Indomethacin 15 2 June 2024  FFG2414 Pharmacology II C Celecoxib D Diclofenac B. Short Essay Questions 1 Define inflammation. 2 What are the symptoms of inflammation? 3 List EIGHT (8) inflammatory mediators. 4 Illustrate the formation of eicosanoids with a diagram. 5 What are prostaglandins? 6 Write a summary about cyclo-oxygenase. 7 State TWO (2) isoforms of cyclooxygenase (COX) enzyme. 7 What is the mechanism of NSAIDs? 8 List types of NSAIDs and give ONE (1) example for each type. 9 List the clinical uses of NSAIDs. 10 List 3 differences between glucocorticoids and mineralocorticoids. 11 List the adverse effects of corticosteroids. 12 Why is gradual withdrawal of corticosteroid important? 13 a) Diagram below shows the kidney and adrenal gland. Corticosteroids are steroid hormones produced by the adrenal cortex. Name TWO (2) groups of hormones that are released by the adrenal cortex. b) Refer to answer in part (a), which group of hormones controls immune response and inflammation? Which group of hormone regulates the electrolytes and water in the kidneys? c) Define inflammation. d) Illustrate the production of prostaglandin from membrane phospholipids in a diagram. 16 2 June 2024  FFG2414 Pharmacology II e) Non-steroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation. Briefly explain the mechanism of action of this group of drugs. f) Give ONE (1) example of NSAID. g) Steroidal anti-inflammatory drugs (SAIDs) are also used to reduce inflammation. However, if the dose of corticosteroid is stopped immediately, the patient may experience some symptoms. Why do these symptoms appear? State the reason. C. Fill in the blanks Passage 1 The _____(1)_____ process is a normal response to injury. When tissues are damaged, inflammatory mediators such as ____(2)______, ____(3)______, ____(4)______ and ____(5)______ are released. These substances produce vasodilation and increased permeability of the capillary walls. Pain receptors are stimulated, and proteins and fluid leak out of the injured cells. As blood flow to the damaged area increases, phagocytes (leukocytes) migrate to the area to destroy harmful substances introduced by the injury. These effects result in the development of the cardinal signs of inflammation: _____(6)_____, _____(7)_____, ____(8)______, _____(9)_____ and _____(10)_____. Inflammation is usually considered the first step in the process of healing. However, in some instances, the inflammatory process becomes exaggerated or prolonged, which results in further tissue damage. In these situations, inflammation itself becomes a disease process and requires treatment with anti-inflammatory drugs, which interrupts the inflammatory response. Prostaglandins are mediators of the inflammatory response. Prostaglandins are formed in the cell membranes of most organs. Membrane phospholipids are converted to ____(11)______, a fatty acid by phospholipase A2.This fatty acid undergoes further conversion through the enzyme cyclo-oxygenase to form prostaglandins and ____(12)______. Two subtypes of cyclo-oxygenase have been identified: 17 2 June 2024  FFG2414 Pharmacology II (i) ____(13)______ is believed to always available in all cells, especially in the platelets, kidneys, and gastrointestinal tract, so that homeostasis in these cells is maintained. (ii) ____(14)______, on the other hand, appears to be manufactured in activated macrophages in response to injury or damage to local tissues. ____(15)______ (NSAIDs) act by inhibiting the cyclo-oxygenase and the synthesis of prostaglandins. Examples of NSAID are _____(16)_____ and _____(17)_____. NSAIDs are commonly used in _____(18)_____ and _____(19)_____. Selective COX-2 inhibitors are available. An example of this is ____(20)_____. Passage 2 (i) __________ is the body’s effort to response to injury, inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair. There are five classical signs of inflammation: (ii) __________, (iii) __________, (iv) __________, (v) __________ and (vi) __________. The inflammatory response is a complex response involves leukocytes and a variety of chemical mediators such as eicosanoids. Eicosanoids are families of chemically related compounds include (vii) __________, (viii) __________ and (ix) __________. They are derived from (x) __________, which is component of cell membrane phospholipids. Free arachidonic acid is released from tissue phospholipids by the enzyme (xi) __________ upon the activation by hormones and other stimuli. Then, prostaglandins and thromboxane are produced by the enzyme (xii) __________ whereas the leukotrienes are produced by the enzyme (xiii) __________ from arachindonic acid. There are two main groups of anti-inflammatory drugs, namely: (a) (xiv) __________ act by inhibiting the synthesis of prostaglandins. (b) (xv) __________ suppress the action of leukocytes and prevent the release various chemical mediators of inflammation, including histamine, prostaglandins and leukotrienes. 18 2 June 2024