anti-inflammatory_drugs-QG-1.pdf

or Anti-inflammatory drugs Farzana Alam, PhD Learning Objectives Introduction to anti-inflammatory drugs Pharmacology of exogenous steroids (Glucocorticoids) and Aspirin Anti-inflammatory drugs NSAIDs Salicylates: Aspirin, Diflunisal Propionic acid de...

or Anti-inflammatory drugs Farzana Alam, PhD Learning Objectives Introduction to anti-inflammatory drugs Pharmacology of exogenous steroids (Glucocorticoids) and Aspirin Anti-inflammatory drugs NSAIDs Salicylates: Aspirin, Diflunisal Propionic acid derivatives: Ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen Indole and indene derivatives: Etodolac Pyrrole derivatives: Keterolac Glucocorticoids as Promises Glucocorticoids: Mechanism Glucocorticoids have broad anti-inflammatory effects on multiple components of cellular immunity but relatively little effect on humoral immunity. Glucocorticoids bind to receptors inside cells and regulate the transcription of numerous other genes. Glucocorticoids also curtail activation of nuclear factor-κB, suppress formation of proinflammatory cytokines such as IL-1 and IL-6, inhibit T cells from making IL-2 and proliferating, and inhibit the activation of cytotoxic T lymphocytes. In addition, glucocorticoid-treated neutrophils and monocytes display poor chemotaxis and decreased release of lysosomal enzymes. Glucocorticoids: Chronic adverse- Oirat effects Selected drug-drug interactions: Glucocorticoids NSAIDs musclebonepain  bindsirreversibly WI COX13.2 Aspirin Aspirin is a weak organic acid that irreversibly acetylates and, thus, inactivates cyclooxygenase. The structure of aspirin and how it is broken down to salicylate and acetic acid Anti-inflammatory effects: Inhibition of cyclooxygenase diminishes the formation of prostaglandins and, thus, modulates aspects of inflammation mediated by prostaglandins. NSAIDs inhibit inflammation in arthritis, but they neither arrest the progression of the disease nor induce remission. Pharmacokinetics t  g 9 Adverse-effects For all NSAIDS Gastrointestinal Increased risk of bleeding Renal effects Cardiac effects Can be used as anticoagulants Other adverse effects inducingasthma Drug-drug interactions warfarin CWITT p References Lippincott’s illustrated pharmacology, 7ed Pharmacology and therapeutics in dentistry Goodman and Gillman’s pharmacology basis of therapeutics Supplement slides Inhibitors of endogenous steroids (adrenocorticoids) secretion or function Several substances are therapeutically useful as inhibitors of the synthesis or function of adrenal steroids: ketoconazole, spironolactone, and eplerenone. 1.Ketoconazole: Ketoconazole [kee-toe-KON-ah-zole] is an antifungal agent that strongly inhibits all gonadal and adrenal steroid hormone synthesis. It is used in the treatment of patients with Cushing syndrome when surgical management is not an option. 2.Spironolactone: This antihypertensive drug competes for the mineralocorticoid receptor and, thus, inhibits sodium reabsorption in the kidney. Spironolactone [speer-oh-no-LAK-tone] also antagonizes aldosterone and testosterone synthesis. Spironolactone is effective for the management of hyperaldosteronism, resistant hypertension, and hepatic cirrhosis. It can be used with other standard therapies for treatment of heart failure with reduced ejection fraction. It is also useful in the management of hirsutism in women, probably due to antiandrogen activity on the hair follicle. Adverse effects include hyperkalemia, gynecomastia, menstrual irregularities, and skin rashes. 3.Eplerenone: Eplerenone [e-PLER-ih-none] specifically binds to the mineralocorticoid receptor, where it acts as a selective aldosterone antagonist. The drug has a much lower affinity for the androgen receptor, and this lessens the potential for gynecomastia and irregular menstrual bleeding associated with spironolactone. Eplerenone is approved for the treatment of hypertension and for heart failure with reduced ejection fraction after an acute myocardial infarction. Adverse effects of Aspirin Gastrointestinal: These are the most common adverse effects of NSAIDs, ranging from dyspepsia to bleeding. Normally, production of prostacyclin (PGI2) inhibits gastric acid secretion, and PGE2 and PGF2α stimulate synthesis of protective mucus in both the stomach and small intestine. Agents that inhibit COX-1 reduce beneficial levels of these prostaglandins, resulting in increased gastric acid secretion, diminished mucus protection, and increased risk for GI bleeding and ulceration. Agents with a higher relative selectivity for COX-1 may have a higher risk for GI events compared with those with a lower relative selectivity for COX-1 (that is, higher COX-2 selectivity). NSAIDs should be taken with food or fluids to diminish GI upset. If NSAIDs are used in patients at high risk for GI events, proton pump inhibitors or misoprostol should be used concomitantly to prevent NSAID- induced ulcers  Increased risk of bleeding (antiplatelet effect): As described above, aspirin inhibits COX-1–mediated formation of TXA2 and reduces platelet aggregation for the lifetime of the platelet (3-7 days). Platelet aggregation is the first step in thrombus formation, and the antiplatelet effect of aspirin results in a prolonged bleeding time. For this reason, aspirin is often withheld for at least 1 week prior to surgery to reduce the risk of bleeding. NSAIDs other than aspirin are not utilized for their antiplatelet effect but can still prolong bleeding time, especially when combined with anticoagulants. Concomitant use of NSAIDs and aspirin can prevent aspirin from binding to cyclooxygenase. Patients who take aspirin for cardioprotection should avoid concomitant NSAID use if possible or take aspirin at least 30 minutes prior to the NSAID.  Renal effects: NSAIDs prevent the synthesis of PGE2 and PGI2, prostaglandins that are responsible for maintaining renal blood flow. Decreased synthesis of prostaglandins can result in retention of sodium and water and may cause edema. Patients with a history of heart failure or kidney disease are at particularly high risk. These effects can also mitigate the beneficial effects of antihypertensive medications. In susceptible patients, NSAIDs have led to acute kidney injury. Cardiac effects: Agents such as aspirin, with a very high degree of COX-1 selectivity at low doses, have a cardiovascular protective effect thought to be due to reduced production of TXA2. Agents with higher relative COX-2 selectivity have been associated with an increased risk for cardiovascular events, possibly by decreasing PGI2 production mediated by COX-2. An increased risk for cardiovascular events, including MI and stroke, has been associated with all NSAIDs except aspirin. All NSAIDs carry a boxed warning regarding the increased risk for cardiovascular events. Use of NSAIDs, other than aspirin, is discouraged in patients with established cardiovascular disease. For patients with cardiovascular disease in whom NSAID treatment cannot be avoided, naproxen may be the least likely to be harmful.  Other adverse effects: NSAIDs are inhibitors of cyclooxygenases and, therefore, inhibit the synthesis of prostaglandins but not of leukotrienes. For this reason, NSAIDs should be used with caution in patients with asthma, as inhibition of prostaglandin synthesis can cause a shift toward leukotriene production and increase the risk of asthma exacerbations. Central nervous system (CNS) adverse events, such as headache, tinnitus, and dizziness, may occur. Approximately 15% of patients taking aspirin experience hypersensitivity reactions. Symptoms of true allergy include urticaria, bronchoconstriction, and angioedema. Patients with severe hypersensitivity to aspirin should avoid using NSAIDs.