AINEs

NSAIDs

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)

?

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.

AINEs: El Mito de los COX-2

AINEs: El Mito de los COX-2

n engl j med

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On May 21, 1999, Merck was granted approval bythe Food and Drug Administration (FDA) to marketrofecoxib (Vioxx). On September 30, 2004, aftermore than 80 million patients had taken this med-icine and annual sales had topped $2.5 billion, thecompany withdrew the drug because of an excessrisk of myocardial infarctions and strokes. This rep-resents the largest prescription-drug withdrawal inhistory, but had the many warning signs along theway been heeded, such a debacle could have beenprevented.

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. Thepivotal trial for rofecoxib involved 8076 patientswith rheumatoid arthritis and demonstrated thatthis coxib had lower gastrointestinal toxicity thannaproxen.

1

Even though the drug was approved in1999 on the basis of data submitted to the FDA, thedata were not submitted to a peer-reviewed jour-nal until the following year and did not appear inprint until November 23, 2000, one and a half yearsafter commercial approval had been granted. Thecardiovascular data reported in that article wereincomplete, in part because of incomplete ascer-tainment: the design and execution of the trial hadnot anticipated that untoward cardiovascular eventsmight occur.

1

It was not until February 8, 2001, that the FDAArthritis Advisory Committee met to discuss con-cern about the potential cardiovascular risks asso-ciated with rofecoxib. It remains unclear why theFDA waited two years after its review and approvalof rofecoxib to conduct this meeting. My colleaguesand I reviewed the data from the meeting that weremade publicly accessible and published an analy-sis of all the available data on rofecoxib and cele-coxib on August 22, 2001.

2

Our primary conclusion,based on the clear-cut excess number of myocar-

dial infarctions associated with rofecoxib and thenumerical, 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

Sucha trial needed to be conducted in patients with es-tablished coronary artery disease, who frequentlyhave coexisting osteoarthritis requiring medicationand have the highest risk of further cardiovascularevents. Given the very high coincidence of coro-nary disease and arthritis, this group may representthe largest segment of the population for whomrofecoxib was prescribed. In light of the insightthat arterial inflammation is the basis for myocar-dial infarction and stroke and the knowledge thatcoxibs reduce the production of biomarkers of in-flammation such as C-reactive protein and improveendothelial function, such a trial would also havebeen quite attractive from the standpoint of po-tential benefit. The trial would have prospectivelydetermined the incidence of cardiovascular events,whose possible association with coxib treatmenthad not been anticipated in the early and pivotaltrials of these drugs.

Unfortunately, such a trial was never done. TheFDA has the authority to mandate that a trial beconducted, but it never took the initiative. Insteadof conducting such a trial at any point — and espe-cially after the FDA advisory committee meeting in2001 — Merck issued a relentless series of publi-cations, beginning with a press release on May 22,2001, entitled “Merck Reconfirms Favorable Car-diovascular Safety of Vioxx” and complemented bynumerous papers in peer-reviewed medical litera-ture by Merck employees and their consultants. Thecompany sponsored countless continuing medi-cal “education” symposiums at national meetings inan effort to debunk the concern about adverse car-diovascular effects. The message that was duly re-

Failing the Public Health — Rofecoxib, Merck, and the FDA

Eric J. Topol, M.D.

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.

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context of serious, life-threatening cardiovascularcomplications. Certainly there are many facts thatwe are not privy to, such as the direct communica-tion between the FDA and Merck, but all the factscan and should be scrutinized closely in a Congres-sional review in order to avert such a catastrophe inthe future.

From the Cleveland Clinic Foundation, Cleveland.

1.

Bombardier C, Laine L, Reicin A, et al. Comparison of upper gas-trointestinal toxicity of rofecoxib and naproxen in patients withrheumatoid arthritis. N Engl J Med 2000;343:1520-8.

2.

Mukherjee DM, Nissen SE, Topol EJ. Risk of cardiovascularevents associated with selective COX-2 inhibitors. JAMA 2001;286:954-9.

3.

Topol EJ, Falk GW. A coxib a day won’t keep the doctor away.Lancet 2004;364:639-40.

The coxibs are a subclass of nonsteroidal anti-inflammatory drugs (NSAIDs) designed to inhib-it selectively cyclooxygenase-2 (COX-2).

1

Theirdevelopment was based on the hypothesis thatCOX-2 was the source of prostaglandins E

2

and I

2

,which mediate inflammation, and that cyclooxy-genase-1 (COX-1) was the source of the same pros-taglandins in gastric epithelium, where they affordcytoprotection. Three coxibs — celecoxib, rofecox-ib, and valdecoxib — have been approved for useby the Food and Drug Administration (FDA); afourth, etoricoxib, has been approved by the Euro-pean regulatory authority, and it and a fifth, lumira-coxib, are currently under consideration for FDAapproval.

Coxibs have been aggressively marketed directlyto consumers in the United States and have rapid-ly dominated the prescription-drug market forNSAIDs, accounting for worldwide sales of roughly$10 billion. Rofecoxib has now been withdrawnfrom the market by Merck, following the prema-ture cessation, by the data and safety monitoringboard, of the Adenomatous Polyp Prevention onVioxx (APPROVe) study, which was designed to de-termine the drug’s effect on benign sporadic co-lonic adenomas. This action was taken because ofa significant increase by a factor of 3.9 in the inci-dence of serious thromboembolic adverse eventsin the group receiving 25 mg of rofecoxib per dayas compared with the placebo group. Blood pres-sure was elevated in patients in the rofecoxib groupearly in the course of the study, but the incidence ofmyocardial infarction and thrombotic stroke in thetwo groups began to diverge progressively after ayear or more of treatment.

Coincident with the approval of rofecoxib and

celecoxib in 1999, my colleagues and I reportedthat both drugs suppressed the formation of pros-taglandin I

2

in healthy volunteers.

2

ProstaglandinI

2

had previously been shown to be the predomi-nant cyclooxygenase product in endothelium, in-hibiting platelet aggregation, causing vasodilata-tion, and preventing the proliferation of vascularsmooth-muscle cells in vitro. However, it was as-sumed that prostaglandin I

2

was derived mainlyfrom COX-1, the only cyclooxygenase species ex-pressed constitutively in endothelial cells. This as-sumption later proved incorrect, since studies inmice and humans showed that COX-2 was thedominant source. The individual cardiovasculareffects of prostaglandin I

2

in vitro contrast withthose of thromboxane A

2

, 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 A

2

and prostaglandin I

2

,the coxibs leave thromboxane A

2

generation unaf-fected, reflecting the absence of COX-2 in platelets.Increasing laminar shear stress in vitro increasesthe expression of the gene for COX-2, leading ourgroup to suggest that COX-2 might be hemody-namically induced in endothelial cells in vivo. If so,suppression of the COX-2–dependent formationof prostaglandin I

2

by the coxibs might predisposepatients to myocardial infarction or thromboticstroke.

Thus, a single mechanism, depression of pros-taglandin I

2

formation, might be expected to ele-vate blood pressure, accelerate atherogenesis, andpredispose patients receiving coxibs to an exagger-ated thrombotic response to the rupture of an ath-erosclerotic plaque. The higher a patient’s intrin-

Coxibs and Cardiovascular Disease Garret A. FitzGerald, M.D.

Failing the Public Health — Rofecoxib, Merck, and the FDA

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.

2007

2015

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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)

º

1 / FDA Consume r Hea l t h In fo r ma t ion / U . S . F ood and D r ug Admin i s t r a t i on JULY 2015

Consumer Health Informationwww.fda.gov/consumer

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.

Next 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

The Risks and What’s NewPrescription 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 one product that contains an NSAID at 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

r

1 / FDA Consume r Hea l t h In fo r ma t ion / U . S . F ood and D r ug Admin i s t r a t i on JULY 2015

Consumer Health Informationwww.fda.gov/consumer

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.

Next 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

The Risks and What’s NewPrescription 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 one product that contains an NSAID at 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

2 / FDA Consume r Hea l t h In fo r ma t ion / U . S . F ood and D r ug Admin i s t r a t i on JULY 2015

Consumer Health Informationwww.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, par ticularly 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 cardiovascular disease,” Racoosin adds.

What Consumers Should DoNSAIDs 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.”

Acetaminofen (paracetamol)

NAPQ1, N-acetyl-p-benzoquinoneimine

« 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. »