Download NSAIDs

PHC 426
MEDICINAL CHEMISTRYIII
introduction
Wed. 2/ 5/ 1432H
Prof. Dr. Wafaa Zaghary
[email protected]
Different ‘types’ of pain, not just different
degrees of pain
Multiple chemical mediators of pain
Optimal therapy matches the
analgesic(s) with the type(s) of pain
NSAIDs
(non steroidal antiinflammatory drugs)
Nonsteroidal AntiInflammatory Drug
A therapeutic agent which relieves pain
and fever by inhibiting the inflammatory
response.
These drugs are available over the
counter and by prescription.
Some common examples include
aspirin, ibuprofen, Celebrex, and less
commonly acetaminophen (Tylenol).
Benefits of NSAIDs
Decrease pain and inflammation
associated with rheumatic diseases.
Some studies show that Cox-2 inhibition
may play a role in the modulation of
intestinal polyps and colorectal cancer.
Other studies show that Cox-2 inhibition
may prevent Alzheimer’s disease.
NSAID use
NSAIDs are available OTC
NSAIDs can be toxic on their own
People who take NSAIDs (elderly
people) often take many drugs which
can lead to dangerous interactions
NSAIDs are metabolized by multiple
hepatic pathways
Common Side Effects
Common side effects to ALL NSAIDs
are:
Abdominal pain
 Diarrhea
 Nausea
 Fluid retention


These side effects occur in about 30% of all
people taking NSAIDs.
Adverse effects
Nephrotoxic
Bleeding problems
Increase blood pressure
FDA requires medication guide be dispensed
with every NSAID prescription –
www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.pdf
FDA fact:
>70,000 hospitalizations per year and 10,00020,000 deaths per year can be associated with
NSAID use
Possible Side Effects
Cox-1 inhibitors



GI ulceration, perforation,
toxicity
Kidney failure
Congestive heart failure
Cox-2 inhibitors
GI problems
 May delay ulcer healing
 Increased risk of CV
disease
 Kidney failure
* Increased risk factors
include being male,
advanced age, and
history of ulcers.

Startling Statistic
25,000
# of Deaths per Year
20,197
20,000
16,685 16,500
15,000
10,503
10,000
5,338
5,000
4,441
0
Leukemia AIDS
NSAIDs Multiple Asthma Cervical
Toxicity Myeloma
Cancer
N Engl J Med 1999;340:1888-1899
Categories of NSAIDs
There are two major categories for
non-steroidal anti-inflammatory drugs
The first is non-selective antiinflammatory drugs.
The second is selective antiinflammatory drugs, COX-2 inhibitors.
The Inflammatory
Response
The body’s response to a stimuli which
causes pain and/or tissue damage.
Physiologically capillaries become
“leaky” through vasodilation.
The response is initiated by the
chemical messengers prostaglandins.
Biosynthesis of
Prostaglandins
The goal is to inhibit the biosynthesis of
prostaglandins in order to relieve the
symptoms caused by the inflammatory
response.
Prostaglandins are synthesized from
arachidonic acid in a pathway mediated
by the Cyclooxygenase enzymes.
Production and Actions of Prostaglandins and Thromboxane
FitzGerald, G. A. et al. N Engl J Med 2001;345:433-442
COX
COX-1
Expression
constitutively
throughout the
body
Function
organ pain, platelet
function, stomach
protection
Inhibitors
NSAIDs
including aspirin
NSAIDs, COX 2
Inducible: inflammati
inhibitors
on, pain, fever
including
Constitutive: synaptic
celecoxib
plasticity
(Celobrex )
COX-2
Inducible and
constitutively in
brain, kidney
COX-3
Constitutively, high pain pathways, not
inflammation
in brain, heart
pathways
acetaminophen
some NSAIDs
Cox-1 vs. Cox-2
inhibitors
Selective COX-II
Inhibitors
Anti-inflammatory with less adverse
effects, especially GI events.
Potential toxicities: kidney and
platelets - ? increased risk of
thrombotic events
Role in Cancer prevention
Role in Alzheimer’s disease
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
ASPIRIN/ NSAIDs
ADVERSE GI
EFFECTS
BLEEDING
ULCERATION
OBSTRUCTION
Textbooks:
Williams, D.A. and Lemeke, T.L., Foye’s
Principle of Medicinal Chemistry, Lippincott
Williams & Wilkins, Philadelphia, PA., 5th
Edition, 2002.
References
1.
2.
3.
4.
5.
Tramer MR, et al. quantitative estimation of rare adverse
events which follow a biological progression: a new model
applied to chronic NSAID use. Pain. 2000 Mar;85(1-2):169-82.
DeBisschop M. What are the risks of long-term NSAIDs and
COX-2 inhibitors? J of Family Practice. 2003 Mar;52(3):199200.
Deviere J. Do selective cyclo-oxygenase inhibitors eliminate
the adverse events associated with nonsteroidal antiinflammatory drug therapy?
Oviedo JA, Wolfe MM. Clinical potential of cyclo-oxygenase-2
inhibitors. Biodrugs. 2001;15(9):563-72.
Hernandez-Diaz S, Rodriguez LA. Association between
nonsteroidal anti-inflammatory drugs and upper
gastrointestinal tract bleeding/perforation: an overview of
epidemiologic studies published in the 1990’s. Arch Internal
Medicine. 2000 Jul 24;160(14):2093-9.
References
6.
7.
8.
Hawkey CJ. Non-steroidal anti-inflammatory drug
gastropathy: causes and treatment. Scandinavian Journal of
Gastroenterology 1996; vol. 220: 124-7.
Wolfe MM, Liechenstein DO, Sigh G. Gastrointestinal toxicity
of nonsteroidal anti-inflammatory drugs. N Engl J Med
1999;340:1888-1899
FDA and International Guidelines on Efficacy and Safety of
Cox-2 Inhibitors