Nonsteroidal anti-inflammatory drugs (NSAID) comprise a heterogeneous group
of medications, the majority of which are organic acids with analgesic, antipyretic
and anti-inflammatory actions. These drugs are widely used to control fever and
acute or chronic pain.
They are the most sold medications worldwide and, together with analgesics and
antipyretics, account for approximately 30% of all medicines used (prescribed
by physicians or otherwise).
of prostaglandins and leukotrienes
When there is damage to the cell membrane, which is basically made
up of phospholipids, the enzyme phospholipase A2, which is present
in leukocytes and platelets, is activated by proinflammatory cytokines,
such as interleukin (IL)-1. This enzyme leads to the degradation
of phospholipids, resulting in production of arachidonic acid .
This, when metabolized, forms leukotrienes through the action of
the enzyme lipoxygenase, and prostaglandins, prostacyclins and thromboxanes,
through the action of the cyclooxygenase enzyme (COX).
is the first enzyme involved in producing prostaglandins from arachidonic acid.
It converts, by oxygenation, the arachidonic acid into two unstable components:
prostaglandin G2 and prostaglandin H2. These prostaglandins are later transformed
by isomerases into prostacyclin, thromboxane A2, and prostaglandins D2, E2 and
F2a. Prostaglandin E2 is important because of its pyrogenic action and in increasing
sensitivity to pain. Arachidonic acid also leads to production of leukotrienes,
via lipoxygenase enzyme (Figure 1).
Figure 1 -
of action of nonsteroidal anti-inflammatories
An important advance in
anti-inflammatory therapy was the discovery of two isoforms of COX (also known
as synthetase prostaglandins): COX 1 and COX 2. Whereas COX 1 has 17 amino acids
at the terminal amino section, COX 2 has 18 amino acids at the terminal carboxyl
section. Although they are very similar in terms of their protein structure, these
enzymes are coded by different genes. Genetically, COX 1 and COX 2 are approximately
60% homologous and their genes are located at chromosomes 9 and 1, respectively.
1 and COX 2 exhibit minor differences, which confer distinct functions on them.
COX 1 is present in almost all tissues (blood vessels, platelets, stomach, intestine,
kidneys) and, for this reason, is defined as a constitutive enzyme. Cyclooxygenase
1 is associated with prostaglandin production and results in a variety of physiological
effects, such as gastric protection, platelet aggregation, vascular homeostasis
and maintenance of renal blood flow.
In contrast, COX 2 is present at the
site of inflammation, and because of this is defined as an inducible enzyme. It
is primarily expressed by cells that are involved in the inflammatory process,
such as macrophages, monocytes and synoviocytes. Nevertheless, it is known that
COX 2 can also be found in other tissues and organs, such as kidneys, brain, ovaries,
uterus, cartilage, bones and vascular endothelium. COX 2 is induced by cytokines
(IL-1, IL-2 and tumor necrosis factor [TNF]) and other mediators (such as growth
factor and endotoxins) at the site of inflammation. It is probably also expressed
in the central nervous system and plays a role in central mediation of pain and
fever. Expression of COX 2 can, however, be suppressed by glucocorticoids, IL-4,
IL-10 and IL-14. More recently a third COX type has been described, called COX
Prostaglandins are involved in several physiological and
pathological processes, including vasodilation or vasoconstriction, contraction
and relaxation of bronchial or uterine musculature, hypotension, ovulation, bone
metabolism, increase in renal blood flow (resulting in diuresis, natriuresis,
caliuresis and stimulation of renin secretion), suppression of gastric acid secretion,
immunoresponse, hyperalgesia, regulation of chemotactile cellular activity, endocrine
response and angiogenesis, among others.
In the gastrointestinal tract,
prostaglandins I2 and E2 are cytoprotective of the gastric mucosa - because they
suppress acid secretion, increase local blood flow, provoke mucus production and
increase synthesis of glutathione (and consequently the capacity to eliminate
free radicals) and because they increase bicarbonate synthesis and blood flow
to the surface layers of the gastric mucosa. In the kidneys they increase glomerular
filtration because of their vasodilator effect. Finally, within the cardiovascular
system, they can cause several hemodynamic effects, such as vasodilation. They
also provoke smooth muscle relaxation. Thromboxane A2 (a substance that promotes
coagulation) is produced from platelet COX, and acts as a potent aggregant agent.
also have pathophysiologic effects such as erythema and increased local blood
flow, hyperalgesia, probably due to sensitization of pain receptors, and increased
body temperature at the hypothalamus through cytokine stimulation. When prostaglandin
production is increased, there is increased sensitivity to pain and fever and
increased inflammatory response. Nevertheless, prostaglandins are also capable
of anti-inflammatory action due to suppression of IL-1 and TNF synthesis.
The mechanism of action of NSAIDs consists in suppression
of COX enzymes, resulting in reduction of the production of prostaglandins, thus
controlling inflammation, pain and fever.
There are some anti-inflammatories
that selectively or specifically inhibit wither COX 1 or COX 2.
Only COX 1 inhibits thromboxane formation. COX 1 inhibition is associated with
increased risk of gastrointestinal bleeding and damage. Selective and specific
COX 2 inhibitors were developed in an attempt to reduce the incidence of adverse
effects of COX 1 inhibition.
These inhibitors include piroxicam, meloxicam, diclofenac, naproxen and nimesulide
(first-generation selective COX 2 inhibitors), and celecoxib, etoricoxib, valdecoxib,
parecoxib and lumiracoxib
(second-generation, more specific, selective COX 2 inhibitors).
dose necessary to reduce inflammation is larger than that needed to inhibit prostaglandin
formation, suggesting that other mechanisms mediate the anti-inflammatory effects.
In addition to suppressing prostaglandin production, current anti-inflammatories
inhibit specific proteases involved in breaking down proteoglycans and collagens
in cartilage, and inhibit the generation of oxygen free radicals, particularly
These medications also interfere with the liberation of bradykinin, with the lymphocyte
response to antigen stimulus, with phagocytosis and with chemotaxis of granulocytes
following are characteristics of NSAIDs:
- rapid absorption;
- the majority of absorption takes place in the stomach and the upper portion
of the small intestine;
- absorption is reduced when taken at night;
the majority binds with plasma proteins;
- the pharmacological effect comes
from the drug in its free state (unbound);
- metabolism is predominantly hepatic
and is faster in children;
- excretion is renal;
- elimination is faster
in children than in adults, requiring more frequent doses.
study of 11 children with neoplasias assessed the pharmacokinetics of celecoxib.
The authors observed significant differences in terms of the availability of celecoxib
in children compared with in adults, such as elimination that is twice as fast
and a half-life that is half as long. They also observed that absorption of the
medication is optimized when taken with a fat-rich meal.
In a study undertaken
with 18 patients with juvenile rheumatoid arthritis, the pharmacokinetics of meloxicam
suspension was evaluated, with greater elimination of the medication being observed
in the younger children, although with a similar half-life to other age groups.
most common indications for NSAIDs in childhood and adolescence are control of
fever, acute and chronic pains and inflammation. Acetylsalicylic acid, naproxen,
ibuprofen and tolmetin are the only ones approved for pediatric use by the Food
and Drug Administration (FDA). Despite not being licensed for the pediatric age
group, indomethacin is used to control fever and pain in children and adolescents
with juvenile idiopathic arthritis (JIA).
Selective COX 2 inhibitors are indicated for patients who exhibit
adverse effects that are confirmed to be related to nonselective
NSAID use, such as gastric intolerance that cannot be controlled
by combination with gastroprotective medication. In the pediatric
age group, the use of COX 2 is limited since a majority of these
medicines are contraindicated before 18 years of age. Table 1 lists
dosage, posology and minimum age recommended for NSAIDs by the FDA
and the Brazilian National Agency for Sanitary Vigilance (Agência
Nacional de Vigilância Sanitária - ANVISA).
Dose and posology of nonsteroidal anti-inflammatories (information obtained from
Nonsteroidal anti-inflammatories are routinely employed by many
specialties. Pediatricians, otorhinolaryngologists, rheumatologists, gynecologists
and orthopedists prescribe these medicines the most often. Habitual indications
for NSAIDs are shown in Table 2.
Habitual indications for nonsteroidal anti-inflammatories
COX 2 inhibitors and atopic disease
We should be cautious when prescribing
NSAIDs for atopic patients with sensitivity to acetylsalicylic acid (ASA), since
there is a possibility of exacerbating the allergic condition. In these cases,
selective COX 2 inhibitor NSAID could be a treatment option since the response
mechanism of sensitivity to ASA particularly involves the COX 1 enzyme. It is
important to point out that this recommendation is based on the results of few
studies involving small numbers of patients, and there are reports of sporadic
cases with significant worsening of asthma with the use of selective COX 2 inhibitors.
et al. did not observe asthma exacerbation after use of celecoxib (200 mg/day
for 7 days), a highly selective COX 2 inhibitor, in 33 patients with asthma induced
In a placebo-controlled study, Bavbek et al. assessed the safety of three NSAIDs
(nimesulide, meloxicam and rofecoxib) with a group of 137 patients with history
of allergy to this class of medication.
Cutaneous and respiratory reactions were observed in 24 patients: nimesulide 14.3%,
meloxicam 8.1% and rofecoxib 2%. Only the subset given rofecoxib did not exhibit
any exacerbation of preexisting asthma. Etoricoxib, another selective COX 2 inhibitor,
was also shown to be safe when used on patients with urticaria and angioedema.
exacerbation related to nonselective COX inhibitors has been known for a long
time. Nonselective anti-inflammatories are COX inhibitors and the theoretical
explanation for this mechanism may be based on the fact that these enzymes are
responsible for synthesis of proinflammatory (PGD2) and anti-inflammatory
prostaglandins (PGE2). PGE2 inhibits synthesis of leukotrienes
(LTB4); therefore blocking production of PGE2 could increase
production of leukotrienes, with deterioration of clinical symptoms. Selective
COX 2 inhibitors preferentially block synthesis of PGD2 and, to a lesser
extent, PGE2. This mechanism could explain improvements in the urticaria of some
patients treated with a combination of antileukotrienes and COX 2 specific NSAIDs.
There is no overwhelming
evidence that demonstrates the superiority of one NSAID over another in terms
of effectiveness and, very often, the choice is based on lower frequency and intensity
of side effects and on the cost of the medication.
Although age over 60
years, previous history of gastrointestinal complications and concurrent corticosteroid
use are the principal risk factors for severe gastrointestinal complications from
NSAID use, we must not forget that chronic use of these medicines can result in
esophagitis, gastritis or duodenitis, gastric or duodenal ulcers, even if subclinical,
in children and adolescents. A study carried out at our service with 14 children
with juvenile rheumatoid arthritis on chronic NSAID use found that while just
27% presented gastrointestinal complaints, on endoscopy macroscopic lesions were
observed in 43% and microscopic injuries in 57% of the patients. Although in general
children complain less than adults, especially about gastropathy secondary to
NSAID use, this does not mean that they are free from endoscopic lesions, as has
major debate and the greatest uncertainties perhaps reside in sporadic or short-term
(a few days) use of NSAIDs. What are the true risks? There are no studies in the
literature that prove the safety of these medications under these treatment regimes.
This does not rule out the possibility of erosive damage and even bleeding from
gastro-duodenal mucosa after three or four doses.
Advanced age, previous peptic ulcer, previous bleeding and
concurrent use of another NSAID or corticosteroids are risk factors for gastric
complications such as mucosal ulceration, reflux esophagitis, esophageal thinning
and peptic ulcers.
Since these effects are primarily mediated by COX 1 inhibition, it is believed
that selective COX 2 inhibitors are a safer alternative. Nevertheless, although
some studies have reported lower frequencies of gastrointestinal complications
with COX 2 inhibitors than with traditional NSAIDs, recent concerns regarding
cardiovascular safety have limited the use of these medications.
Conditions such as congestive heart failure, cirrhosis, diabetes,
hypertensive nephropathy, advanced age and volume depletion constitute risk factors
that can predispose patients to renal complications. Salt retention, acute reversible
renal insufficiency and tubulointerstitial nephritis are some of the undesirable
effects. While selective specific COX 2 inhibitors may cause less renal alterations,
they are not free from inducing some of these alterations.
Photosensitivity, erythema multiforme, urticaria and Steven-Johnson
syndrome have all been observed with NSAIDs in general. One study with 381 adults
who exhibited "pseudoallergic" reactions to NSAIDs showed that nimesulide
and meloxicam were well-tolerated.
events: liver toxicity with elevated transaminases, cholestasis and necrosis may
occur, especially with COX 1 inhibitors.
anemia, neutropenia, thrombocytopenia and medulla aplasia are observed rarely
with NSAIDs nowadays, especially with COX 2 inhibitors.
Central nervous system
events: headaches, tingling sensations and dizziness, although possible, are rarely
reported by children and adolescents.
studies have been published recently on the cardiovascular toxicity of several
NSAIDs, especially the selective COX 2 inhibitors.
It has not yet been established whether the risk is specific to one COX 2 inhibitor
in particular, applicable to all COX 2 inhibitors, or characteristic of all NSAIDs.
Acute myocardial infarction, cerebrovascular ischemia, hypertension and exacerbation
of congestive heart failure appear to be associated with the use of at least some
The mechanism responsible for the cardiovascular toxicity of COX 2 inhibitors
has not yet been fully explained. The most probable hypothesis involves an imbalance
between prostacyclin and thromboxane A2. Prostacyclin is a vasodilator and inhibits
platelet aggregation and vascular proliferation, while thromboxane A2 causes platelet
aggregation, vasoconstriction and proliferation of smooth muscle. Platelets, which
only express COX 1, are the primary products of thromboxane A2, and endothelial
cells produce prostacyclin in response to COX 2.
Those NSAIDs that inhibit both COX 1 and COX 2 maintain a certain homeostasis
between prostacyclin and thromboxane A2. In contrast, selective COX 2 inhibitors
predominantly suppress prostacyclin, upsetting the balance in favor of thromboxane.
In a recent study with 33,309 patients who presented myocardial infarction, it
was observed that any NSAID used at habitual doses can increase the risk of this
complication, especially in older patients.
Although children and adolescents do not, in general, belong to a group at major
risk of cardiovascular complications, we should be alert, particularly when dealing
with patients with chronic diseases whose underlying disease already represents
a risk for the development of atherosclerosis and thromboembolic phenomena.
major concern is the growing number of children and adolescents observed during
recent years with hypertension and/or obesity as a result of inadequate diet and
Nonsteroidal anti-inflammatory drugs are contraindicated
for children and adolescents in the following situations: dyspeptic syndromes,
viral diseases, compromised renal function, cardiac disease, (especially congestive
heart failure), liver failure, systemic arterial hypertension, coagulation disorders,
history of allergic reaction to NSAIDs and the use of oral anticoagulants and
In a randomized double-blind study of 225 children with juvenile
idiopathic arthritis, the authors evaluated the efficacy and safety of two doses
of meloxicam compared with naproxen, observing at least one adverse effect in
74% of the patients who were given 0.125 mg/kg/day of meloxicam, 80% in the group
who were given 0.25 mg/kg/day of meloxicam and 85% in the naproxen group.
Gastrointestinal disorders such as pain, diarrhea, nausea and vomiting were the
most frequent complaints, (Table 3).
Principal adverse effects observed in children given meloxicam or naproxen
bind strongly to plasma proteins and as a result they may displace other medications
from their binding sites, which can occurs with methotrexate, phenytoin and sulfonylureas,
increasing their activity and toxicity.
Summing up, in general NSAIDs should
only be used when there is a precise indication, since they can cause adverse
effects even when used for short periods. Selective COX 2 inhibitors are not yet
licensed for use with children. Long-term randomized controlled studies are needed,
especially in order to confirm safety.