Non steroidal Anti-inflammatory drugs NSAIDs

1. Non steroidal Anti-inflammatory drugsNSAIDs Anti-inflammatory drugs

2. Inflammation: is a normal, protectiveresponse to tissue injury caused by physical trauma, noxious trauma, or microbiologic agents. It is triggered by the releaseofchemicalmediators from injured tissues and migrating cells. .

3. The specific chemical mediatorsvary with the type of inflammatory process and include:- amines such as histamine and 5- hydroxytryptamine; lipids such as the prostaglandins; small peptides such as bradykinin; and larger peptides such as interleukin-1

4. AA esterified in cell membrane phospholipids Physical, chemical, inflammatory phospholipase A2 And mitogenic stimuli AA LOX COX HETEs Prostaglandins Leukotrienes Prostacyclin prostanoids Lipoxins Thromboxane

5. Arachidonic acid is stored mainly in phospholipids of cell membranes from which it is mobilized largely by the action of phospholipase. Glucocorticoids (inhibiting phospholipase A2) prevent the formation of arachidonic acid by inducing the synthesis of an inhibitory polypeptide called lipocortin-1.

6. Arachidonic acid is further metabolized by cyclo-oxygenase (COX) which changes the linear fatty acids into the cyclical structures of prostaglandins. COX exists as two different types COX-1 and COX-2. COX-1 is increased by 2-4 folds in inflammation and present in most tissues. COX-2 is increased by 10-20 folds in inflammation and present in macrophages, synoviocytes, chondrocytes and fibroblasts . Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory effects by inhibitingCOX, and selective COX-2 inhibitors have less adverse effects

7. Arachidonic acid is also metabolized by lipo-oxygenase to leukotrienes ( which causeincreased vascular permeability , vasoconstriction, bronchoconstriction as well as chemotactic activity for leukocytes) and inhibition of lipo-oxygenase by zileuton.

8. Nonsteroidal anti-inflammatory drugs (NSAIDs)Mode of action:- The members of this class of drugs, although structurallyheterogeneous, posses a single common mode of action which is blockprostaglandin synthesis by inhibiting COX. They can be categorized according to their COX selectivity as:- COX-2 selective and nonCOX-2 selective

9. Pharmacokinetics:- In general, NSAIDs are 1-absorbed almost completely from GIT 2- highly bound to plasma albumin. 3-Most of them are weaklyacidic drugs 4- localized preferentially in the synovial tissue of inflamed joints. 5-Their t1/2 values are differ from short to long

10. Uses:- 1- Analgesia: they are effective for mild to moderate pain like musculoskeletal, postoperative, osteoarthritis and inflammatory arthritis. They have advantage of notcausingdependence ( unlike opioids ). 2-Anti-inflammntory action as in arthritis ,pericarditis and musculoskeletal conditions. 3-Antipyrticaction by blocking cytokine –induced PG synthesis in hypothalamus, reducing fever.

11. 4-Antiplateletfunction like aspirin useful in treatment and or prevention of MI ,transient ischemic attacks (TIA) and embolic strocks. It reduces the level of platelet TXA2, resulting in inhibition of platelet aggregation and a prolonged bleeding time. For this reason, aspirin should not be taken for at least 1 week prior to surgery with careful monitoring

12. 5- prolongation of gestation and labour:- PG produce powerful uterine contraction so that inhibition by NSAIDs will prolong labour. 6-Patency of the ductus arteriosus: as PG maintain the patency, Indomethcin given to a newborn child with a patent ductus can result in closure. 7- primary dysmenorrheaMefenamic acid is used to reduce the production of PGs by uterus (which cause uterine hyper contractility and pain).

13. Adverse Effects:Gastrointestinal effects : gastric and intestinal mucosal damage is the commonest adverse effect of NSAID. The physiological function of mucosal PG is cytoprotective, damage to mucosa can be happened lead to indigestion ,gastro- intestinal reflux , erosions, peptic ulcer, gastrointestinal hemorrhage and perforation. SelectiveCOX-2 inhibitors are as effective as , but have feweradverseeffects than nonCOX2 selective compounds regarding serious gastrointestinal effect.

14. In practice , a minority of patients are intolerant of all NSAIDs .They may benefit from the co-administration of a protonpump inhibitor ,H2receptor blocker or PG analogue misoprostol.

15. Renal effects: renal blood flow is reducedbecause the synthesis of vasodilator renal PGs is inhibited result in Na and H2O retention and hypertension, renalfailure may occur especially in elderly and pre-existing renal disease, hepatic cirrhosis, cardiac failure or with diuretic therapy. Mixture of NSAIDs taken repeatedly for years with highdoses may result in irreversible renal damage appears in part due to local ischemia. Cutaneous effects include urticuria, photosensitivity and erythema multiform

16. Other general effects include hypersensitivity, sever rhinitis, asthma, cholestaisis, hepatocellular toxicity, thrombocytopenia, neutropenia and hemolytic anemia. Ovulation may be reduced or delayed (reversible).

17. Interactions: certain types of NSAIDS have pharmacokinetic and dynamic interactions with the following drugs:- 1- angiotensin converting enzyme inhibitors and angiotensin receptor blockers as this increase the risk of hyperkalemia and renalimpairment. 2-antiplatelets and anticoagulants as this increase risk of bleeding.

18. 3-quinolone antimicrobials as this may causes convulsion. 4-oral hypoglycemic drugs inhibit their metabolism lead to increase their actions • 5-antiepileptic inhibit their metabolism lead to increase toxicity (especially phenytoin and valproate).

19. 6-antihypertensive drugs their effect is decrease by Na retention. 7-cytotoxic drugs excretion is reduced. 8-lithium excretion is reduced.

20. Classification of NSAIDs A- Aspirin and other salicylates B- Propionic acid derivatives C- Indoleacetic acids D- Oxicam derivatives E- Fenamates F- Phenylbutazone G- Miscellaneous include diclofenac,ketorolac,tolmetin,nabumeton, acetaminophen and phenacetin.

21. Aspirin: is a weakorganic acid that is the only NSAIDs can irreversibly acetylating COX. It is rapidly metabolized in the body by esterase to salicylates which has anti-inflammatory, antipyretic and analgesic effects. Diflunisal :is a derivative of salicylic acid is 3-4 times more potent than aspirin as an analgesic and an anti-inflammatory agent but it has noantipyretic effects as it does not enter the CNS. Mesalamine ( 5- aminosalicylic acid ) used in irritable bowel syndrome

23. Uses :- 1- antipyretic, anti-inflammatory and analgesics aspirin and sodium salicylate used in treatment of headache, fever, gout, rheumatic fever, rheumatoid arthritis, arthralgia and myalgia. 2-external application : salicylic acid is used topically to treat corn, calluses and epidermophytosis. Methylsalicylate is used externally as cutaneous counterirritant.

24. 3- low dose aspirin used prophylactically to decrease incidence of IHD. 4- recurrent abortion (antiphospholipid syndrome ). 5- colonic cancer , chronic use of aspirin reduces incidence

25. Others side effects: on Respiration: In toxic doses, salicylates cause respiratory depression and a combination of uncompensated respiratory and metabolic acidosis. Metabolic processes: Large doses of salicylates uncouple oxidative phosphorylation. The energy normally used for the production of adenosine triphosphate is dissipated as heat, which explains the hyperthermia caused by salicylates when taken in toxic quantities.

26. In pregnancy: Aspirin is classified as FDA pregnancy category C risk during 1st Trimesters and 2 and category D during Trimester 3. Because salicylates are excreted in breast milk, aspirin should be avoided during pregnancy and while breast-feeding.

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