Analgesic Antipyretic Antiinflamatory Drugs
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Transcript of Analgesic Antipyretic Antiinflamatory Drugs
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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
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NSAIDs NONSTEROIDAL ANTIINFLAMMATORY DRUGS
Aspirin Ibuprofen ( Advil, Motrin) And many others of differing
chemical classes Acetaminophen (Tylenol) Celecoxib (Celebrex)
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NSAIDs Major Actions ANALGESIA ANTIPYRETIC ANTIINFLAMMATORY Except acetaminophen
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FitzGerald, G. A. et al. N Engl J Med 2001;345:433-442
Production and Actions of Prostaglandins and Thromboxane
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Catella-Lawson F et al. N Engl J Med 2001;345:1809-1817
The Effect of Aspirin Alone and of Ibuprofen plus Aspirin on Platelet Cyclooxygenase-1
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ASPIRIN Major Actions Antiinflammatory action Inhibits NFB activation to limit production
of proinflammatory mediators Changes in vascular permeability,
leukocyte infiltration and organ dysfunction are prevented
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ASPIRIN Major Actions ANALGESIA Blocks production of PGs that
sensitize nociceptors to inflammatory mediators
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ASPIRIN Major Actions Antipyretic action Block the production of PGE2 to
reset the hypothalamic temperature set point
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ASPIRIN Major Actions Antiplatelet/antithrombotic Decreases platelet production of
TXA2 by COX-1 to limit platelet aggregation and vasoconstrictiion
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Normal physiologic interaction between PGI2 and TXA2 in platelet and endothelial cell biology
Blood Vessel WallEndothelial Cell (COX-2)
Ca2+/vessel smooth muscle constricts
Arachidonic acid
PGH2
Prostacyclin (PGI2)
cAMP/vessel smooth muscle relaxes
Arachidonic acid
PGH2
Thromboxane (TXA2)
cAMP aggregation
Ca2+ aggregation
Platelet (COX-1)
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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
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ASPIRIN/OTHER NSAID SENSITIVITY REACTIONS Non-immunologicaly mediated Signs and symptoms Rhinitis Nasal polyps Asthma Urticaria Laryngeal edema BronchospasmAVOID ALL SALICYLATES/NSAIDs ACETAMINOPHEN IS OK TO USE
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Copyright restrictions may apply.Gollapudi, R. R. et al. JAMA 2004;292:3017-3023.
Aspirin/Other NSAID Sensitivity Reactions via Inhibition of the Cyclooxygenase Pathway
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ASPIRIN/ NSAIDs ADVERSE GI EFFECTS BLEEDING
ULCERATION
OBSTRUCTION
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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
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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
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NSAIDsMECHANISM of GI EFFECTS LOSS of CYTOPROTECTIVE ACTIONS of
GASTRIC PROSTAGLANDINS Acid secretion is unabated Decrease in protective mucus Decrease in mucosal blood flow
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NSAIDs BLEEDING ANTI-PLATELET ACTIONS Loss of Thromboxane A2 Actions Platelet aggregation
inhibited Loss of vasoconstriction
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NSAIDs on GESTATION and DELIVERY BLEEDING Antepartum and
postpartum Transfusion requirement is
increased Gestation is prolonged Premature closure of the ductus
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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
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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
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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
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ASPIRIN & CHILDREN AVOID IN FEBRILE ILLNESS The risk is that of Reyes’ syndrome
with liver injury and encephalopathy
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Catella-Lawson F et al. N Engl J Med 2001;345:1809-1817
The Effect of Aspirin Alone and of Ibuprofen plus Aspirin on Platelet Cyclooxygenase-1
D-D-I
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ASPIRIN DISPOSITION ABSORPTION DISTRIBUTION METABOLISM EXCRETION
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ASPIRIN PHARMACOKINETICS DOSE-DEPENDENT HALF LIFE ASPIRIN 15 MINUTES SALICYLATE low dose 2-3 hours high dose 12-15 hours
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ASPIRIN OVERDOSECombined metabolic acidosis &
respiratory alkalosis
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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
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COX – 2 INHIBITORS (COXIBS))
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SELECTIVE COX-2 INHIBITION
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COX-1 COX-2
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COXIBS SELECTIVE COX-2 INHIBITORSTHE PROBLEMATIC ASSUMPTIONS: COX-1 PRODUCTS ARE CONSTITUTIVE, i.e., HOMEOSTATIC/PROTECTIVE
COX-2 INDUCIBLE- PRODUCTS ARE ASSOCIATED WITH DISEASE STATES
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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
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COXIBs APRIL 2008
Rofecoxib(Vioxx) WithdrawnValdecoxib(Bextra) Withdrawn
Celecoxib No direct-to customer marketing
FDA Panel: Keep COX-2 Drugs on
Market,Caution urged for all NSAIDs
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STILL ON THE MARKET
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COXIB ALTERNATIVES FOR PATIENT AT RISK OF GI TOXICITY Salsalate,diclofenac,diflunisal & others May need to add: PPI(omeprazole) Misoprostol H-2 blocker(ranitidine)
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MISOPROSTOL
A PROSTAGLANDIN ANALOGActions Antisecretory Prevention of NSAID ulcersAdverse Effects Diarrhea Abortion
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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
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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
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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%
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ACETAMINOPHEN /ALF RISK FACTORS Depression Chronic pain Alcohol or narcotic use Simultaneous use of multiple
preparations of acetaminophen
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ALCOHOL
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Lee, W. M. N Engl J Med 2003;349:474-485
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
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DISASTER AT THE FARM