MEDPHARM 03/22/2010

VIGNETTEA 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;345:433-442

Production and Actions of Prostaglandins and Thromboxane

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

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

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

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)

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 BronchospasmAVOID ALL SALICYLATES/NSAIDs ACETAMINOPHEN IS OK TO USE

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

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

NSAIDsMECHANISM 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

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

ASPIRIN DISPOSITION

ABSORPTION DISTRIBUTION METABOLISM EXCRETION

ASPIRIN PHARMACOKINETICS

DOSE-DEPENDENT HALF LIFE ASPIRIN 15 MINUTES SALICYLATE low dose 2-3 hours high dose 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

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

DISASTER AT THE FARM