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 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
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;292:3017-3023.
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
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
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