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

FitzGerald, G. A. et al. N Engl J Med 2001;345: Production and Actions of Prostaglandins and Thromboxane

Catella-Lawson F et al. N Engl J Med 2001;345: The Effect of Aspirin Alone and of Ibuprofen plus Aspirin on Platelet Cyclooxygenase-1

ASPIRIN Major Actions Antiinflammatory action Inhibits NF  B 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 PGE 2 to reset the hypothalamic temperature set point

ASPIRIN Major Actions Antiplatelet/antithrombotic Decreases platelet production of TXA 2 by COX-1 to limit platelet aggregation and vasoconstrictiion

Normal physiologic interaction between PGI 2 and TXA 2 in platelet and endothelial cell biology Blood Vessel Wall Endothelial Cell (COX-2)  Ca 2+ /vessel smooth muscle constricts Arachidonic acid PGH 2 Prostacyclin (PGI 2 )  cAMP/vessel smooth muscle relaxes Arachidonic acid PGH 2 Thromboxane (TXA 2 )  cAMP  aggregation  Ca 2+  aggregation Platelet (COX-1)

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

Copyright restrictions may apply. Gollapudi, R. R. et al. JAMA 2004;292: Aspirin/Other NSAID Sensitivity Reactions via Inhibition of the Cyclooxygenase Pathway

ASPIRIN/ NSAIDs ADVERSE GI EFFECTS BLEEDING ULCERATION OBSTRUCTION

Levy, D. J. N Engl J Med 2000;343:863 A 76-year-old woman had iron-deficiency anemia, a hematocrit of 24 percent, and a positive test for occult blood in stool

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 A 2 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

Catella-Lawson F et al. N Engl J Med 2001;345: The Effect of Aspirin Alone and of Ibuprofen plus Aspirin on Platelet Cyclooxygenase-1 D-D-I

ASPIRIN DISPOSITION ABSORPTION DISTRIBUTION METABOLISM EXCRETION

ASPIRIN PHARMACOKINETICS DOSE-DEPENDENT HALF LIFE ASPIRIN 15 MINUTES SALICYLATE low dose 2-3 hours high dose 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 PGE 2 generation Poor antiinflammatory & antiplatelet activity: failure to inhibit platelet TXA 2 inflammatory PGE 2 synthesis Little GI toxicity Potentially hepatotoxic

ACETAMINOPHEN TOXICITY Hepatotoxic when dose >4 gm/day Hepatotoxicity may 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

Lee, W. M. N Engl J Med 2003;349: 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

DISASTER AT THE FARM