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MEDPHARM 03/22/2010 VIGNETTE A 58 YEAR OLD HEALTHY UNIVERSITY PROFESSOR IS ENJOYING A PERIOD OF ATTITUDE ADJUSTMENT WHEN HE BECOMES AWARE OF A TINGLING SENSATION IN THE LEFT GREAT TOE. WITHIN HOURS THE TOE PAIN IS 10/10 THE Dx IS ACUTE GOUT ANTIINFLAMMATORY-ANALGESIC-ANTIPYRETIC DRUGS NONSTEROIDAL(NSAIDs) STEROIDAL 7 million Rx per year 3.8% of all Rx + OTC Use increases with age Age >65 yr use 10-15% of NSAIDS RR of 3-5X for hospitalization/death due to PUD ADRs cost ~$ 1 billion per year NSAIDs NONSTEROIDAL ANTIINFLAMMATORY DRUGS Aspirin Ibuprofen ( Advil, Motrin) And many others of differing chemical classes Acetaminophen (Tylenol) Celecoxib (Celebrex) NSAIDs Major Actions ANALGESIA ANTIPYRETIC ANTIINFLAMMATORY Except acetaminophen Production and Actions of Prostaglandins and Thromboxane FitzGerald, G. A. et al. N Engl J Med 2001;345:433-442 The Effect of Aspirin Alone and of Ibuprofen plus Aspirin on Platelet Cyclooxygenase-1 Catella-Lawson F et al. N Engl J Med 2001;345:1809-1817 ASPIRIN Major Actions Antiinflammatory action Inhibits NFkB activation to limit production of proinflammatory mediators Changes in vascular permeability, leukocyte infiltration and organ dysfunction are prevented ASPIRIN Major Actions ANALGESIA Blocks production of PGs that sensitize nociceptors to inflammatory mediators ASPIRIN Major Actions Antipyretic action Block the production of PGE2 to reset the hypothalamic temperature set point ASPIRIN Major Actions Antiplatelet/antithrombotic Decreases platelet production of TXA2 by COX-1 to limit platelet aggregation and vasoconstrictiion Blood Vessel Wall Endothelial Cell (COX-2) Arachidonic acid PGH2 Prostacyclin (PGI2) cAMP/vessel smooth muscle relaxes Ca2+/vessel smooth muscle constricts Platelet (COX-1) Arachidonic acid PGH2 Thromboxane (TXA2) Ca2+ aggregation cAMP aggregation Normal physiologic interaction between PGI2 and TXA2 in platelet and endothelial cell biology ASPIRIN / NSAID - ADRs (NOT ACETAMINOPHEN) GASTROINTESTINAL BLEEDING PREGNANCY RENAL ASPIRIN/other NSAID SENSITIVITY All due to alteration of normal prostaglandin physiology USE IS AVOIDED IN CHILDREN with viral illness ASPIRIN/OTHER NSAID SENSITIVITY REACTIONS Non-immunologicaly mediated Signs and symptoms Rhinitis Nasal polyps Asthma Urticaria Laryngeal edema Bronchospasm AVOID ALL SALICYLATES/NSAIDs ACETAMINOPHEN IS OK TO USE Aspirin/Other NSAID Sensitivity Reactions via Inhibition of the Cyclooxygenase Pathway Gollapudi, R. R. et al. JAMA 2004;292:3017-3023. Copyright restrictions may apply. ASPIRIN/ NSAIDs ADVERSE GI EFFECTS BLEEDING ULCERATION OBSTRUCTION A 76-year-old woman had iron-deficiency anemia, a hematocrit of 24 percent, and a positive test for occult blood in stool Levy, D. J. N Engl J Med 2000;343:863 ASPIRIN/NSAIDs RISK FACTORS for GI EFFECTS Age > 65 years History of peptic ulcer or bleeding Multiple NSAID use High dose use Alcohol Anticoagulant use NSAIDs MECHANISM of GI EFFECTS LOSS of CYTOPROTECTIVE ACTIONS of GASTRIC PROSTAGLANDINS Acid secretion is unabated Decrease in protective mucus Decrease in mucosal blood flow NSAIDs BLEEDING ANTI-PLATELET ACTIONS Loss of Thromboxane A2 Actions Platelet aggregation inhibited Loss of vasoconstriction NSAIDs on GESTATION and DELIVERY BLEEDING Antepartum and postpartum Transfusion requirement is increased Gestation is prolonged Premature closure of the ductus RENAL PROSTAGLANDINS Modulate Na, K and water excretion NSAIDs (ibuprofen) block the above to reduce Na & K excretion and may cause inrease in blood pressure & weight NSAIDs RENAL EFFECTS Little effect on normal kidneys NSAIDs PROMOTE Na RETENTION When renal blood flow is impaired as in: Heart failure Dehydration Kidney disease Normal aging ANALGESIC USE & HEARING LOSS REGULAR USE OF ASPIRIN+NSAIDS+ ACETAMINOPHEN INCREASES THE RISK OF HEARING LOSS IN MEN The impact is greater in younger persons ASPIRIN & CHILDREN AVOID IN FEBRILE ILLNESS The risk is that of Reyes’ syndrome with liver injury and encephalopathy The Effect of Aspirin Alone and of Ibuprofen plus Aspirin on Platelet Cyclooxygenase-1 D-D-I Catella-Lawson F et al. N Engl J Med 2001;345:1809-1817 ASPIRIN DISPOSITION ABSORPTION DISTRIBUTION METABOLISM EXCRETION ASPIRIN PHARMACOKINETICS DOSE-DEPENDENT ASPIRIN SALICYLATE low dose high dose HALF LIFE 15 MINUTES 2-3 hours 12-15 hours ASPIRIN OVERDOSE Combined metabolic acidosis & respiratory alkalosis OTHER NSAIDs(IBUPROFEN) Several distinct chemical classes Kinetics and potency vary COX-1 and COX-2 inhibition COX inhibition is reversable Adverse event profile is like aspirin Great variability in individual response Change to another NSAID Not used as antiplatelet drugs COX – 2 INHIBITORS (COXIBS)) SELECTIVE COX-2 INHIBITION COX-1 COX-2 COXIBS SELECTIVE COX-2 INHIBITORS THE PROBLEMATIC ASSUMPTIONS: COX-1 PRODUCTS ARE CONSTITUTIVE, i.e., HOMEOSTATIC/PROTECTIVE COX-2 INDUCIBLE- PRODUCTS ARE ASSOCIATED WITH DISEASE STATES COXIBS SELECTIVE COX-2 INHIBITORS THE PROBLEM No clear distinction between the homeostatic and pathologic actions of the products of COX-1 and COX-2 The risk is that of MI & ischemic stroke COXIBs APRIL 2008 Rofecoxib(Vioxx) Withdrawn Valdecoxib(Bextra) Withdrawn Celecoxib No direct-to customer marketing FDA Panel: Keep COX-2 Drugs on Market,Caution urged for all NSAIDs STILL ON THE MARKET COXIB ALTERNATIVES FOR PATIENT AT RISK OF GI TOXICITY Salsalate,diclofenac,diflunisal & others May need to add: PPI(omeprazole) Misoprostol H-2 blocker(ranitidine) MISOPROSTOL A PROSTAGLANDIN ANALOG Actions Antisecretory Prevention of NSAID ulcers Adverse Effects Diarrhea Abortion ACETAMINOPHEN Analgesic and Antipyretic Inhibition of neuronal & vascular PGE2 generation Poor antiinflammatory & antiplatelet activity: failure to inhibit platelet TXA2 inflammatory PGE2 synthesis Little GI toxicity Potentially hepatotoxic ACETAMINOPHEN TOXICITY Hepatotoxic when dose >4 gm/day Hepatotoxicity may occur @ doses <4gm/d following binge drinking Hepatic centrilobular necrosis AST/ALT >1000 units Treat with n-acetylcysteine orally ACETAMINOPHEN ACUTE LIVER FAILURE 55% of ALF in US Median dose 24 gm Unintentional OD 48% Intentional(suicide) 44% Survival 65% Death 27% Tx 8% ACETAMINOPHEN /ALF RISK FACTORS Depression Chronic pain Alcohol or narcotic use Simultaneous use of multiple preparations of acetaminophen ALCOHOL The Role of Ethanol in the Formation of N-acetyl-p-benzoquinone-imine (NAPQI), the Toxic Metabolite of Acetaminophen (APAP), and the Dynamics of Enzyme Induction Lee, W. M. N Engl J Med 2003;349:474-485 DISASTER AT THE FARM