NSAIDS and Related Drugs 1 Act on enzyme COX Classical Non Selective NSAIDS o Aspirin ASA o Ibuprofen and most NAIDS COX II Inhibitors o Celecoxib Celebrex approved 1998 o Rofecoxib Vioxx approved 1999 withdrawn 2004 Caused blood clots strokes o Valdecoxib Bextra approved 2001 withdrawn 2005 By choice by company Acetaminophen doesn t have the same level of efficacy as aspirin not as great as classical and selective NSAIDS Used by patients with chronic and continuous use at large doses such as rheumatoid arthritis NSAIDS and Related Drugs 2 SAARDS Slowly Acting Anti Rheumatic Drugs DMARDS Products of rationale drug discovery Traditional o Methotrexate and other immunosuppressant Chemo o Anti malarial chloroquine hydroxychloroquine o Penicillamine ties up metal agents o Gold compounds Biologic o Leflunomid Arava o Infliximab Remicade o Etanercept Enbrel o Anakinra Kineret Drugs to Treat Gout Develops in response to elevated levels of uric acid which has limited solubility affects one side of the body such as the toe Body attacks tissues where crystals are formed inflammatory process Goal get uric acid level down Colchicine Xanthine Oxidase Inhibitors o Allopurinol Zyloprim o Febuxostat Uloric Uricosuric Agents o Probenecid o Sulfinpyrazone Pegloticase Krystexxa urate oxidase o Newest reserved for refractory gout The Inflammatory Process Erythema Edema slight elevation of tissues due to accumulation of edema fluid Tenderness Pain Three Stages of Inflammatory Process Acute Inflammation transient o Initial response to injury local vasodilation increased capillary permeability due to the release of local messengers o Caused by release of autacoids PG s Histamine 5 HT bradykinin LK Immune Response delayed subacute phase o Infiltration of site of inflammation by leukocytes and phagocytic cells o Outcome beneficial phagocytosis of foreign organisms or deleterious no resolution o Not as fast as inflammation Chronic Inflammation chronic proliferative stage o Tissue degeneration and fibrosis o PG s bradykinin histamine 5 Ht still being released o Leukocytes release lysosomal enzymes o More autacoids IL 1 IL 2 IL 3 GM CSF TNG a interferons o Best example chronic rheumatic arthritis bone and cartilage pain and o Autacoid substance produced and released by cell that comes back and binds on receptors on the outer surface to produce an effect Paracrine hormone is one released locally that acts on adjacent PDGH destruction cells Rheumatoid Arthritis Pathogenesis unknown Autoimmune disease Cytokine release IL 1 TNF a Only glucocorticoids block synthesis or actions PGE2 elevated in inflamed joints due to induction of COX II Synthesis of Prostaglandins Involves enzyme cyclooxygenase COX Arachidonic acid AA used as substrate Mechanism of NSAID Action Inhibition of COX to decrease PG formation Two isoforms of COX Shared Pharmacologic Actions of NSAIDS Therapeutic Effects o COX I constitutional blood vessels stomach kidney all healthy people have it o COX II inducible by cytokines Aspirin irreversibly acetylates COX o Platelets cannot regenerate COX because of no nucleus o Forms covalent bond between acetic acid and COX resulting in it being permanently inactivated Most NSAIDS non selective COX inhibitors and reversibly inhibit COX o Drug comes on and off enzyme so duration of action is related to the pharmacokinetics of drug levels NSAIDS act INDIRECTLY o Do not block PG receptors so no immediate effect o No effect on previously formed PG s o Most effective when given before tissue injury would have a much greater effect Possible additional mechanisms suggested but not confirmed o Analgesic relief from pain without loss of consciousness o Antipyretic reduces elevated body temperature o Anti inflammatory suppress and reduce inflammatory process o Treatment of primary dysmenorrhea due to PGF2 Alpha PG that is produced in uterus o Close a patent ductus arteriosus hole between left and right sides of the heart Side Effects o GI ulceration and intolerance o Blockade of platelet aggregation AKA most effective basis for use in thromboembolic disease used when patient has had heart attack o Tocolytic Action prolongs gestation delays labor complications delivery with post partum bleeding and hemorrhage relax smooth muscle in uterus causing an increase in the gestation period o NSAID induced renal toxicity acute renal failure is rare in healthy o Vulnerable patients have impaired renal function and or hemodynamic subjects instability o Reduced renal blood flow GFR o Salt and water retention hyperkalemia Hypersensitivity Reactions o Vasomotor rhinitis profuse watery secretions angioneurotic edema laryngeal edema bronchial asthma generalized urticarial bronchoconstriction hypotension shock o Predictable due to 20 25 incidence in middle aged with asthma nasal polyps or chronic urticarial o Rx caused by COX inhibition non immunological Aspirin and Salicylates Absorption delayed by food no effect of buffering o By neutralizing acids in the stomach can cause a gastric ulcer Dose Dependent Kinetics half life gets longer as dose gets bigger o T1 2 3 hours low dose o T1 2 12 hours usual anti inflammatory dose o T1 2 15 30 hours high therapeutic dose TDM useful to monitor therapy and toxicity Plasma salicylate levels o Single ASKA dose 60 ug mL o Optimal anti inflammatory in RA 15 300 ug mL o Peripherally induced nausea 270 ug mL o Central nausea 270 ug mL o Hyperventilation 250 ug mL Therapeutic Agents o Aspirin o Sodium salicylate o Salicylsalicylic acid salsalate o Choline salicylate oral liquid o Magnesium salicylate tabs o Choline and magnesium salicylate mix Trilisate o Methyl salicylate topical Aspirin and Salicylates Therapeutic Uses Rheumatoid arthritis 4 6 gm day Local uses poorly absorbed forms are used to tx inflammatory bowel disease also suppository and rectal enema Mesalamine 5 amino salicylate olsalazine sulfasalazine Aspirin and Salicylates Side Effects Nausea and vomiting Epigastric distress Gastric ulcers Heartburn Dyspepsia GI hemorrhage Erosive gastritis Gastric bleeding can be painless and unrecognized Hepatic Injury two forms o Dose Dependent Hepatotoxicity elevated hepatic enzymes o Reyes Syndrome severe hepatic injury contraindicated in patients with chicken pox or influenza mortality 23 45 Aspirin Effects on Blood 650 mg ASA doubles bleeding time for 4 7 days ASA should be stopped at least 1 week before surgery High caution in patients on anticoagulant therapy WARNING risk of hemorrhage in