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Inês Mota, Ângela Gaspar, Mário Morais-Almeida

inhibition, whereas their adverse gastrointestinal and CROSS -REACTIVITY
renal effects occur through blockage of COX -1 activity,
with subsequent decrease of protective prostaglandins Most of reactions occur with exposure to more than
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(Figure 1) . one group of NSAIDs. The classical NSAIDs (ASA, di-
It has been described a third distinct COX isoenzyme, clofenac, ketorolac, ibuprofen and naproxen) belong to
COX -3, that might explain the mechanism of action of distinct chemical groups, even though they share the same
acetaminophen. Unlike other isoenzymes, COX -3 inhibi- pharmacological mechanism of action – preferable COX-
tion is not related to an increase of pro -inflammatory -1 inhibition. Indeed, this pharmacological effect, non-
mediators, but its selective inhibition explains its analge- -immunological, explains the occurrence of cross-
sic and antipyretic properties. At therapeutic doses, the -reactivity among chemically distinct groups. On the
acetaminophen has only a weak inhibitory effect on COX- other hand, some patients developed symptoms only
-1 and COX -2 with lack of anti -inflammatory effects con- when exposed to a single NSAID, from a specific group,
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sidering its selective target . and tolerate the remaining chemical groups.
In patients with aspirin hypersensitivity, there is a Classical NSAIDs such as ASA, ibuprofen and indo-
positive correlation between the potency of the drug methacin are preferential COX -1 inhibitors, whereas
to inhibit in vitro COX -1 activity and asthma worsening. diclofenac is considered almost equipotent to COX -1 and
It is also known the role of leukotriene antagonists in COX -2. Among NSAIDs with preferential COX -2 inhibi-
prevention of bronchoconstriction related to aspirin tion are nimesulide and meloxicam. At low doses, meloxi-
intake . In patients with NERD, chronic viral infections cam does not have cross -reactivity with remaining
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might explain the development and persistence of air- NSAIDs, showing selective COX -2 inhibition. At higher
way inflammation, promoted by specific cytotoxic lym- doses this selective profile can change, occurring also
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phocytes. Several genetic polymorphisms have been COX -1 inhibition .
associated with NERD . COX inhibition depends on drug concentration. Rela-
2
The pathogenesis of cutaneous inflammatory res- tive COX -1/COX -2 specificity varies among NSAIDs
ponse to NSAIDs is controversial, and arachidonic acid commonly used in clinical practice, with a more than
mediators are not eventually involved. In susceptible 50 -fold COX -2 selectivity to etoricoxib, from 5 to 50 -fold
subjects, NSAIDs can induce urticaria, angioedema COX -2 selectivity to celecoxib, meloxicam, nimesulide,
and/or anaphylactic reactions by activation of mast etodolac and diclofenac, and a less than 5 -fold COX -2
cells and eosinophils. Unlike NERD, the mechanism selectivity to indomethacin, ibuprofen, naproxen, aspirin,
IgE -mediated might have more relevance. In this case, ketoprofen and ketorolac (Figure 2) 20,24 .
the reactions are selective (compounds within the Selective COX -2 inhibitors (coxibs) provides a similar
same chemical group), regardless the COX inhibition. efficacy, but with less adverse reactions. Pharmacological
IgE -mediated mechanism has been described in imme- studies have demonstrated a relation between in vitro
diate reactions to diclofenac, acetaminophen, aspirin selective COX -2 inhibition and better gastrointestinal
and pyrazolones 5,11 . and renal tolerance . Despite potential cardiovascular
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A recent study, including only patients with immediate risk related to these drugs, clinical practice has confirmed
reactions to ibuprofen and other arylpropionic acid de- its good tolerance. Considering a reasonable lack of
rivatives, showed that 17% of them were classified as cross -reactivity with remaining NSAIDs, they appear to
selective reactors by both clinical history and drug chal- be good alternative drugs in most patients with hyper-
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lenge, with good tolerance to ASA . sensitivity to classical NSAIDs.

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