NONSTEROIDAL ANTIINFLAMMATORY DRUGS NSAIDS NON NARCOTIC ANALGESICS ANTI GOUT DRUGS NSAIDS Related Drugs 1 o Classical Non Selective NSAIDS Aspirin ASA Ibuprofen most NSAIDS o COX II Inhibitors Only inhibit half of the enzymes that ASA and Ibuprofen do celecoxib Celebrex approved 1998 o Acetaminophen Not a drug with the same level of efficacy in regards to anti inflammatory action o SAARDS DMARDS slowly acting anti rheumatic drugs disease modifying anti rheumatic drugs anti malarials chloroquine hydroxychloroquine Penicillamine ties up certain cations like in wilson s disease ties up copper gold compounds Use to treat rheumatoid arthritis Traditional methotrexate other immunosuppresants Biologic o Drugs to Treat Gout leflunomide Arava infliximab Remicade etanercept Enbrel anakinra Kineret Gout develops as a result of large amounts of uricosuric agent Colchicine Only drug that can treat anti inflammatory only in gout Xanthine oxidase inhibitors Allopurinol Zyloprim Febuxostat Uloric Slow down the rate of production of uric acid uricosuric agents probenecid o Inhibits tubular secretion as well as reabsorption of a number of different drugs Pegloticase Krystexxa urate oxidase Newest reserved for refractory gout THE INFLAMMATORY PROCESS o Clinical Signs Erythema redness Edema swelling Tenderness heat Pain THE INFLAMMATORY PROCESS The 3 Stages o Acute Inflammation transient Initial response to injury local vasodilation increased capillary permeability caused by release of autacoids PG s prostygladins Histamine 5 HT bradykinin LK communication molecules released by a cell acts on the cell that released it and neighboring cells have an autocrine acting on same cell paracrine effect acting on the surrounding cells o Immune Response delayed subacute phase infiltration of leukocytes phagocytic cells outcome beneficial phagocytosis of foreign organisms or deleterious no resolution when there is resolution in this stage there is no need to progress to the next stage o Chronic Inflammation chronic proliferative stage tissue degeneration fibrosis more autacoids interleukins IL 1 IL 2 IL 3 GM CSF growth factor TNF a tumor necrosis factor no relation to its role in tumor necrosis in inflammation process interferons PDGH leukocytes release lysosomal enzymes best example chronic rheumatic arthritis bone cartilage pain and destruction RHEUMATOID ARTHRITIS o Pathogenesis unknown autoimmune disease cytokine release IL 1 TNF only glucocorticoids block synthesis or actions PGE2 elevated in inflamed joints due to induction of COX II Synthesis of Prostaglandins PG s o Involves enzyme cyclooxygenase COX Breaks down phosolipids arachidonic acid substrate for 2 major anti inflammatory classes On drugs that inhibit COX no prostaglandins are produced but NSAIDS do nothing about existing If acted on one COX enzyme prostaglandins etc see picture attached prostaglandins must wait for effect as the existing are degraded This is all occurring in the membrane o Arachidonic acid AA used as substrate MECHANISM OF NSAID ACTION o Inhibition of COX to decrease PG formation o Two isoforms of COX Glucocorticoids work further up to stop the production of this substrate COX I constitutional blood vessels stomach kidney COX II inducible by cytokines other mediators o Aspirin irreversibly acetylates COX platelets cannot regenerate COX covalent bond with the COX making this process irreversible only way reverse effect is to create more platelets COX o Most NSAIDS non selective COX inhibitors and reversibly inhibit COX no covalent bond formed MECHANISM OF NSAID ACTION o NSAIDS act INDIRECTLY do not block PG receptors no effect on previously formed PG s most effective when given before tissue injury o Possible additional mechanisms suggested not confirmed SHARED PHARMACOLOGIC ACTIONS OF NSAIDS o Therapeutic Effects analgesic antipyretic decreasing temperature back to normal anti inflammatory o other treatment of primary dysmenorrheal problem rises within the uterus due to large amounts of PGN2A close a patent ductus arteriosus o Side Effects GI ulceration intolerance most common blockade of platelet aggregation ASA most effective basis for use in thromboembolic disease tocolytic action prolongs gestation delays labor complicates delivery with post partum bleeding hemorrhage takes 1 2 weeks to return full clotting effect relaxes smooth muscle resulting in problems in pregnant women NSAID induced renal toxicity acute renal failure rare in healthy subjects vulnerable pts have impaired renal function and or hemodynamic instability reduced renal blood flow GFR salt water retention hyperkalemia o Hypersensitivity reactions vasomotor rhinitis profuse watery secretions angioneurotic edema generalized urticaria bronchial asthma laryngeal edema bronchoconstriction hypotension shock 20 25 incidence in middle aged with asthma nasal polyps or chronic urticaria rx caused by COX inhibition non immunoligical ASPIRIN SALICYLATES o Absorption delayed by food no effect of buffering o Dose dependent kinetics t1 2 3 hrs low dose t1 2 12 hrs usual anti inflammatory dose Tx of rheumatoid arthritis t1 2 15 30 hrs high therapeutic doses more advanced dose toxicity limits how high you can dose As you increase the dose as small as possible due to dose dependent kinetics o Therapeutic Drug Monitoring TDM useful to monitor therapy toxicity o Plasma salicylate levels single ASA dose 60 ug ml optimal anti inflammatory in RA 15 300 ug ml peripherally induced nausea 270 ug ml central nausea 270 ug ml hyperventilation 350 ug ml o Therapeutic Agents o Therapeutic Uses aspirin sodium salicylate salicylsalicylic acid salsalate choline salicylate oral liquid magnesium salicylate tabs choline magnesium salicylate mix Trilisate methyl salicylate topical used to treat pain because irritates and therefore blocks pain sodium thiosalicylate injectable see shared NSAID uses rheumatoid arthritis 4 6 gm day local uses poorly absorbed forms are used to tx inflammatory bowel disease also suppository rectal enema mesalamine 5 amino salicylate olsalazine sulfasalazine o Undesirable side effects see shared toxicities of NSAIDS nausea vomiting epigastric distress gastric ulceration heartburn dyspepsia GI hemorrhage erosive gastritis gastric bleeding may be painless unrecognized hepatic injury two forms Reyes Syndrome dose dependent hepatotoxicity usu No symptoms eleveted hepatic enzymes children adolescents with chicken pox or influenza mortality 23 45 severe hepatic injury