Pharmacology of NSAIDs Farmacología de los AINES --- 1. Salicilatos: Acido acetilsalicilico 2. Indoles: Indometacina 3. Pirazoles: Fenilbutazona 4. Fenamatos: Acido mefenamico 5. Derivados del acido propionico: Ibuprofeno, Ketoprofeno, Flurbiprofeno, Naproxeno 6. Derivados del acido fenilacetico: Diclofenaco, Aceclofenac 7. Oxicam: Piroxicam, Tenoxicam, Meloxicam 8. Sulphonanilide: Nimesulide 9.Coxibs (COX-2 selectivos): Celecoxib,Rofecoxib,Valdecoxib, Lumiracoxib (nota: diclofenaco también tiene mayor selectividad a COX-2 -> es como si fuera un « coxib ») —- No son AINEs - pero sí son analgésicos y antipiréticos: - Para-aminofenol: Acetaminofen (no es un AINE) - Pirazolonas: dipirona (no es un AINE)

1. AINEs
NSAIDs

5. 1. Salicilatos: Acido acetilsalicilico
2. Indoles: Indometacina
3. Pirazoles: Fenilbutazona
4. Fenamatos: Acido mefenamico
5. Derivados del acido propionico: Ibuprofeno, Ketoprofeno, Flurbiprofeno, Naproxeno
6. Derivados del acido fenilacetico: Diclofenaco, Aceclofenac
7. Oxicam: Piroxicam, Tenoxicam, Meloxicam
8. Sulphonanilide: Nimesulide
9.Coxibs (COX-2 selectivos): Celecoxib,Rofecoxib,Valdecoxib, Lumiracoxib
(nota: diclofenaco también tiene mayor selectividad a COX-2 -> es como si fuera un « coxib »)
—-
No son AINEs - pero sí son analgésicos y antipiréticos:
- Para-aminofenol: Acetaminofen (no es un AINE)
- Pirazolonas: dipirona (no es un AINE)

8. ?

9. COX-1, 2, 3?, 4?, etc?
Nomenclature COX-1
Previous and unofficial names
COX1, PGHS-1, COX-1, Cox-3,
cyclooxygenase 1, cyclooxygenase 3,
PGH synthase 1, prostaglandin G/H
synthase 1, prostaglandin G/H
synthase and cyclooxygenase,
prostaglandin H2 synthase
Nomenclature COX-2
Previous and unofficial names
PTGS2, COX2, cyclooxygenase 2,
PGH synthase 2, PGHS-2,
prostaglandin G/H synthase 2,
prostaglandin-endoperoxide
synthase 2 (prostaglandin G/H
synthase and cyclooxygenase)
En resumen: COX-1, COX-2 y punto.

11. AINEs: El Mito de los COX-2

12. AINEs: El Mito de los COX-2

14. PERSPECTIVE
On May 21, 1999, Merck was granted approval by
the Food and Drug Administration (FDA) to market
rofecoxib (Vioxx). On September 30, 2004, after
more than 80 million patients had taken this med-
icine and annual sales had topped $2.5 billion, the
company withdrew the drug because of an excess
riskofmyocardialinfarctionsandstrokes.Thisrep-
resents thelargest prescription-drug withdrawal in
history, but had the many warning signs along the
way been heeded, such a debacle could have been
prevented.
Neither of the two major forces in this five-
and-a-half-year affair — neither Merck nor the FDA
— fulfilled its responsibilities to the public. The
pivotal trial for rofecoxib involved 8076 patients
with rheumatoid arthritis and demonstrated that
this coxib had lower gastrointestinal toxicity than
naproxen.1 Even though the drug was approved in
1999 on the basis of data submitted to the FDA, the
data were not submitted to a peer-reviewed jour-
nal until the following year and did not appear in
print until November 23, 2000, one and a half years
after commercial approval had been granted. The
cardiovascular data reported in that article were
incomplete, in part because of incomplete ascer-
dial infarctions associated with rofecoxib and the
numerical, albeit not statistically significant, ex-
cess associated with celecoxib, was that “it is man-
datory to conduct a trial specifically assessing car-
diovascular risk and benefit of these agents.”2 Such
a trial needed to be conducted in patients with es-
tablished coronary artery disease, who frequently
have coexisting osteoarthritis requiring medication
and have the highest risk of further cardiovascular
events. Given the very high coincidence of coro-
nary disease and arthritis, this group may represent
the largest segment of the population for whom
rofecoxib was prescribed. In light of the insight
that arterial inflammation is the basis for myocar-
dial infarction and stroke and the knowledge that
coxibs reduce the production of biomarkers of in-
flammation such as C-reactive protein and improve
endothelial function, such a trial would also have
been quite attractive from the standpoint of po-
tential benefit. The trial would have prospectively
determined the incidence of cardiovascular events,
whose possible association with coxib treatment
had not been anticipated in the early and pivotal
trials of these drugs.
Unfortunately, such a trial was never done. The
Failing the Public Health — Rofecoxib, Merck, and the FDA
Eric J. Topol, M.D.
n engl j med 351;17 www.nejm.org october 21, 2004 1709
genase-1 (COX-1) was the source of the same pros-
taglandins in gastric epithelium, where they afford
cytoprotection. Three coxibs — celecoxib, rofecox-
ib, and valdecoxib — have been approved for use
by the Food and Drug Administration (FDA); a
fourth, etoricoxib, has been approved by the Euro-
pean regulatory authority, and it and a fifth, lumira-
coxib, are currently under consideration for FDA
approval.
Coxibshavebeenaggressivelymarketeddirectly
to consumers in the United States and have rapid-
ly dominated the prescription-drug market for
NSAIDs, accounting for worldwide sales of roughly
$10 billion. Rofecoxib has now been withdrawn
from the market by Merck, following the prema-
ture cessation, by the data and safety monitoring
board, of the Adenomatous Polyp Prevention on
Vioxx (APPROVe) study, which was designed to de-
termine the drug’s effect on benign sporadic co-
lonic adenomas. This action was taken because of
a significant increase by a factor of 3.9 in the inci-
dence of serious thromboembolic adverse events
in the group receiving 25 mg of rofecoxib per day
as compared with the placebo group. Blood pres-
sure was elevated in patients in the rofecoxib group
early in the course of the study, but the incidence of
myocardial infarction and thrombotic stroke in the
two groups began to diverge progressively after a
year or more of treatment.
Coincident with the approval of rofecoxib and
tion, and preventing the proliferation of vascular
smooth-muscle cells in vitro. However, it was as-
sumed that prostaglandin I2 was derived mainly
from COX-1, the only cyclooxygenase species ex-
pressed constitutively in endothelial cells. This as-
sumption later proved incorrect, since studies in
mice and humans showed that COX-2 was the
dominant source. The individual cardiovascular
effects of prostaglandin I2 in vitro contrast with
those of thromboxane A2, the major COX-1 prod-
uct of platelets, which causes platelet aggregation,
vasoconstriction, and vascular proliferation.
Whereas aspirin and traditional NSAIDs in-
hibit both thromboxane A2 and prostaglandin I2,
the coxibs leave thromboxane A2 generation unaf-
fected, reflecting the absence of COX-2 in platelets.
Increasing laminar shear stress in vitro increases
the expression of the gene for COX-2, leading our
group to suggest that COX-2 might be hemody-
namically induced in endothelial cells in vivo. If so,
suppression of the COX-2–dependent formation
of prostaglandin I2 by the coxibs might predispose
patients to myocardial infarction or thrombotic
stroke.
Thus, a single mechanism, depression of pros-
taglandin I2 formation, might be expected to ele-
vate blood pressure, accelerate atherogenesis, and
predispose patients receiving coxibs to an exagger-
ated thrombotic response to the rupture of an ath-
erosclerotic plaque. The higher a patient’s intrin-
The New England Journal of Medicine
Downloaded from nejm.org on May 9, 2016. For personal use only. No other uses without permission.
Copyright © 2004 Massachusetts Medical Society. All rights reserved.

16. 2007
2015

19. e PNG, 602 × 364 pixels) data:image/png;base64,iVBORw0KGgoAAAAN

25. 1. Salicilatos: Acido acetilsalicilico
2. Indoles: Indometacina
3. Pirazoles: Fenilbutazona
4. Fenamatos: Acido mefenamico
5. Derivados del acido propionico: Ibuprofeno, Ketoprofeno, Flurbiprofeno, Naproxeno
6. Derivados del acido fenilacetico: Diclofenaco, Aceclofenac
7. Oxicam: Piroxicam, Tenoxicam, Meloxicam
8. Sulphonanilide: Nimesulide
9.Coxibs (COX-2 selectivos): Celecoxib,Rofecoxib,Valdecoxib, Lumiracoxib
(nota: diclofenaco también tiene mayor selectividad a COX-2 -> es como si fuera un « coxib »)
—-
No son AINEs - pero sí son analgésicos y antipiréticos:
- Para-aminofenol: Acetaminofen (no es un AINE)
- Pirazolonas: dipirona (no es un AINE)

27. º

29. Consumer Health Information
www.fda.gov/consumer
FDA is strengthening an existing
warning in prescription drug labels
and over-the-counter (OTC) Drug
N
ext time you reach into
the medicine cabinet
seeking relief for a
headache, backache or arthritis,
be aware of important safety
information for non-steroidal
anti-inflammatory drugs.
FDA Strengthens Warning
of Heart Attack and Stroke
Risk for Non-Steroidal Anti-
Inflammatory Drugs

30. r
1 / FDA Consumer Health Infor mat ion / U. S. Food and Dr ug Adminis t r at ion JULY 2015
FDA is strengthening an existing
warning in prescription drug labels
and over-the-counter (OTC) Drug
Facts labels to indicate that non-
steroidal anti-inflammatory drugs
(NSAIDs) can increase the chance of a
heart attack or stroke, either of which
can lead to death. Those serious side
effects can occur as early as the first
few weeks of using an NSAID, and the
risk might rise the longer people take
NSAIDs. (Although aspirin is also an
NSAID, this revised warning doesn’t
apply to aspirin.)
The OTC drugs in this group are
used for the temporary relief of pain
and fever. The prescription drugs in
this group are used to treat several
kinds of arthritis and other painful
conditions. Because many prescrip-
tion and OTC medicines contain
NSAIDs, consumers should avoid
taking multiple remedies with the
same active ingredient.
N
ext time you reach into
the medicine cabinet
seeking relief for a
headache, backache or arthritis,
be aware of important safety
information for non-steroidal
anti-inflammatory drugs.
The Risks and What’s New
Prescription NSAIDs are an impor-
tant treatment for the symptoms
of many debilitating conditions,
including osteoarthritis, rheuma-
toid arthritis, gout and other rheu-
matological and painful conditions.
OTC NSAIDs are used to temporar-
ily reduce fever and to treat minor
aches and pains such as headaches,
toothaches, backaches, muscular
aches, tendonitis, strains, sprains and
menstrual cramps. Common OTC
NSAIDs include ibuprofen (Motrin,
Advil) and naproxen (Aleve). In addi-
tion, some combination medicines
that relieve various symptoms, such
as multi-symptom cold products,
contain NSAIDs.
“Be careful not to take more than
oneproductthatcontainsanNSAIDat
a time,” says Karen M. Mahoney, M.D.,
deputy director of FDA’s Division
of Nonprescription Drug Products.
How will you know? Check the list
of active ingredients in the Drug
Facts label (http://www.fda.gov/drugs/
resourcesforyou/ucm133411.htm).
The labels for both prescription
NSAIDs and OTC NSAIDs already

31. Consumer Health Information
www.fda.gov/consumer
have information on heart attack and
stroke risk. In the coming months,
FDA will require manufacturers of
prescription NSAIDs to update their
labels with more specific information
about heart attack and stroke risks.
FDA will also request that the manu-
facturers of OTC NSAIDs update the
heart attack and stroke risk informa-
tion in Drug Facts labels.
FDA added a boxed warning to
prescription drug labels for this risk
in 2005. More recent data and infor-
mation are prompting FDA to update
NSAID labeling. Today we know that
the risk of heart attack and stroke may
occur early in treatment, even in the
first weeks.
“There is no period of use shown to
be without risk,” says Judy Racoosin,
M.D., M.P.H., deputy director of FDA’s
Division of Anesthesia, Analgesia,
and Addiction Products.
People who have cardiovascular
disease, particularly those who
recently had a heart attack or cardiac
bypass surgery, are at the greatest
risk for cardiovascular adverse events
associated with NSAIDs.
FDA is adding information in the
drug label for people who already
have had a heart attack. This vulner-
able population is at an increased
risk of having another heart attack or
dying of heart attack-related causes
if they’re treated with NSAIDs,
according to studies.
But the risk is also present in people
without cardiovascular disease.
“Everyone may be at risk – even
people without an underlying risk for
cardiovasculardisease,”Racoosinadds.
What Consumers Should Do
NSAIDs are effective treatments
for pain, inflammation and fever.
Consumers can still take them but
should be aware of this increased risk
of heart attack or stroke, especially
at higher doses.
“As always, consumers must care-
fully read the Drug Facts label for all
nonprescription drugs. Consumers
should carefully consider whether
the drug is right for them, and use
the medicine only as directed. Take
the lowest effective dose for the
shortest amount of time possible,”
Mahoney says.
When using prescription NSAIDs,
read the consumer-friendly Medica-
tion Guide attached to your filled pre-
scription, which provides important
safety information.
If you have heart disease or high
blood pressure, consult a health care
provider before using an NSAID.
Balance the benefits of NSAIDs with
the possible risks and weigh your
options. If you take low-dose aspirin
for protection against heart attack
and stroke, you should know that
some NSAIDs, including ibuprofen
and naproxen, can interfere with that
protective effect.
Stop taking NSAIDs and seek
medical help if you experience
symptoms that might signal heart
problems or stroke, such as chest
pain, trouble breathing, sudden
weakness in one part or side of the
body, or sudden slurred speech.
Reduce your risk factors for heart
disease and stroke. “Smoking, high
blood pressure, high cholesterol and
diabetes are significant risk factors
for these conditions,” Mahoney says.
“If you smoke, work on quitting. See
your doctor regularly to find out if you
have these other strong risk factors,
and commit yourself to taking care of
them and of your health.”
Find this and other Consumer
Updates at www.fda.gov/
ForConsumers/ConsumerUpdates
Sign up for free e-mail
subscriptions at www.fda.gov/
consumer/consumerenews.html
“As always, consumers must carefully read the
Drug Facts label for all nonprescription drugs.
Consumers should carefully consider whether the
drug is right for them, and use the medicine only
as directed. Take the lowest effective dose for the
shortest amount of time possible.”

32. Acetaminofen
(paracetamol)

33. NAPQ1, N-acetyl-p-benzoquinoneimine

34. « Renal papillary necrosis. Note
the necrotic renal papillae.The
patient consumed large quantities
of aspirin and acetaminophen for
chronic pain »
Fuente: USMLE Pathology Slides.
« Figure 4 Areas of renal papillary necrosis (arrows)
that developed secondary to analgesic nephropathy
and chronic tubulointerstitial nephritis can be
observed in this cross section of kidney. »