NSAIDs skin reactions

Azapropazone is structurally related to phenylbutazone and probably shares the same adverse effects gastrotoxi-city, skin reactions, headache, vertigo, edema, and renal impairment. A review of a very large series described azapropazone adverse effects in 1724 patients (18%), causing withdrawal in 3.7%. Surprisingly, however, there were no phenylbutazone-type blood dyscrasias (SED-11, 176) (1). Azapropazone should be prescribed only for patients with active rheumatic diseases who have failed to respond to other NSAIDs (2). 

The NSAID dexindoprofen has a similar adverse effect pattern to the parent drug, indoprofen. Gastrointestinal, nervous system, and skin reactions are the most frequent (1). 

Diacerein (diacetylrhein), an anthraquinone derivative, is said to be effective in the treatment of osteoarthritis. Its active metabolite is rhein, about which there are very few clinical data. Diacerein does not affect arachidonic acid metabolism and might be better tolerated than other NSAIDs with regards to renal and gastric toxicity. Epigastric or abdominal pain and diarrhea are the most frequent adverse effects. Diarrhea occurred in 37% of patients with osteoarthritis taking diacerein (1). Acute hepatitis has been described (SEDA-22, 119), as have skin reactions. 

About 5% of patients have itching, rashes, or erythema multiforme (3). Circulating immune complexes have been found (4). The UK s Committee on Safety of Medicines issued a warning about the high rate of cutaneous adverse reactions with fenbufen and noted that some are followed by severe illnesses (SEDA-13,72) (SEDA-14, 94) (SEDA-15, 100). Toxic epidermal necrolysis, a life-threatening reaction, has also been reported (SEDA-6, 96) (SEDA-8, 106) and a 1981-85 review on its incidence in France identified fenbufen as the third most common NSAID, after isoxicam and oxyphenbutazone, as a causal factor (5). Another severe skin reaction with laboratory evidence of hepatotoxicity has been described (SEDA-22,115). 

The incidence of skin reactions to drugs has been analysed from spontaneous reports in Italy (200). Antibiotics most commonly caused skin reactions, followed by NSAIDs, analgesics, and radiocontrast agents, which were responsible for 2.7% of the reactions (71 cases) these included nine cases of exanthemas and 36 cases of urticaria. 

Lonazolac, an arylacetic acid derivative, causes adverse effects like those of other NSAIDs. Gastrointestinal disturbances are followed in frequency by nervous system and skin reactions. The extent of gastrointestinal blood loss is similar to that with diclofenac (1). Cholestatic hepatitis has also been reported (SEDA-8, 106). 

The acidic nature and lipid solubility of these compounds are important. The lipid solubility of an NSAID determines its penetration into the central nervous system and hence the incidence of nervous system-related adverse effects and perhaps adverse skin reactions (9,10). The weak acid nature affects tissue distribution, which explains why NSAIDs have actions at certain sites (for example synovial tissue of inflamed joints) and also contribute to triggering particular adverse reactions at others (for example the stomach and renal medulla) (11). 

Skin reactions are often reported with NSAIDs, but the true incidences with individual NSAIDs are unknown. There are very few specific epidemiological studies, and most information comes from single case reports and data from national spontaneous reporting systems. A major study on nearly 20 000 patients showed that 0.3% of 9118 patients taking analgesics and NSAIDs developed skin reactions that could be attributed to these drugs (164). 

There are various types of NSAID-induced rashes. The main morphological patterns are urticarial, maculo-papular, vesicular, and exfoliative. Skin reactions to NSAIDs are probably of phototoxic origin and can be associated with systemic hypersensitivity or other allergic reactions. More rarely, NSAIDs can exacerbate... 

Widespread use of naproxen, sulindac, diclofenac, and diflunisal probably explains why they were the most frequently rmphcated, rather than because they have a greater tendency to cause these adverse effects. NSAIDs differ in their ability to cause adverse skin reactions in terms of both frequency and severity pyrazolones, butazones, and oxicams are most often blamed, and among the arylalkanoic acid derivatives fenbufen and carprofen are most often incriminated. 

The reasons for these different effects of different NSAIDs are poorly understood. The only physicochemical characteristic that seems to be important in determining a particular propensity for adverse skin reactions is lipophilicity (10), which probably affects NSAID distribution to the skin. The longer half-lives of lipophilic compounds may concomitantly facilitate the persistence of skin reactions. Although there are no clear relations between the other pharmacological and kinetic characteristics of NSAIDs and effects on the skin, less lipophilic drugs with short half-lives might be preferable. 

Suxibuzone, a derivative of phenylbutazone, is an NSAID that has been used topically. Skin reactions, gastrotoxi-city, nephrotoxicity, headache, and vertigo have been noted. The carcinogenic potential of suxibuzone in animals has attracted attention (1) and put an end to sales in some countries. 

Plasma digoxin levels may decrease when the drug is administered with bleomycin. When bleomycin is used witii cisplatin, there is an increased risk of bleomycin toxicity Pulmonary toxicity may occur when bleomycin is administered with other antineoplastic drugs. Plicamycin, mitomycin, mitoxantrone, and dactino-mycin have an additive bone marrow depressant effect when administered with other antineoplastic drugs. In addition, mitomycin, mitoxantrone, and dactinomycin decrease antibody response to live virus vaccines. Dactinomycin potentiates or reactivates skin or gastrointestinal reactions of radiation therapy There is an increased risk of bleeding when plicamycin is administered witii aspirin, warfarin, heparin, and the NSAIDs. 

Reactions not mediated by IgE but produced by a pharmacologic reaction predominantly by the NSAID inhibitors COX-1 and -2 which can cause respiratory, skin or both types of reaction or severe anaphylaxis. These are the most frequent types of reaction. To date, only BAT has been validated as an in vitro diagnostic test with contrasted usefulness. In the best argued study [32], sensitivity of the test... 

Some patients with chronic idiopathic urticaria develop wheals and even angioedema after aspirin or NSAIDs. In others, aspirin causes an obvious increase in the underlying urticaria. The reaction may occur in just 15 min or up to 24 h following aspirin ingestion, but on average it develops within 1-4 h. Most cases resolve within a few hours, but in severe reactions bouts of multiform skin eruptions, covering most of the body, may continue for 10 days after aspirin intake [8,16,17]. 

Type B effects are not related to the pharmacological properties of these drugs. Serious side effects may occur. Allergic skin and liver reactions to aspirin and paracetamol have been reported with risk of fibrosis, particularly in the retroperitoneal region for methysergide and hypersensitivity reactions with NSAID and pure analgesics. 

Naproxen (Naprosyn) also has pharmacological properties and clinical uses similar to those of ibuprofen. It exhibits approximately equal selectivity for COX-1 and COX-2 and is better tolerated than certain NSAIDs, such as indomethacin. Adverse reactions related to the GI tract occur in about 14% of all patients, and severe GI bleeding has been reported. CNS complaints (headache, dizziness, drowsiness), dermatological effects (pruritus, skin eruptions, echinoses), tinnitus, edema, and dyspnea also occur. 

While the pattern of alclofenac toxicity resembles that of other NSAIDs, the frequency of adverse effects differs widely. Allergic reactions have been reported more frequently and skin rashes have been particularly common. Hypersensitivity reactions, including anaphylactic shock, severe generalized vasculitis, hepatotoxicity, and nephrotoxicity, have been observed. Alclofenac has therefore been withdrawn in several countries (1). Blood dyscrasias and neurological symptoms are rare. 

Bucloxic acid is an NSAID that is not widely used. The usual symptoms of gastrotoxicity, nephrotoxicity, and increased blood pressure have been reported, but the major adverse effects involve skin and allergic reactions. Quincke s edema has been observed (SED-9, 152) (1) (SEDA-1, 93). 

Nabumetone is a naproxen derivative, whose efficacy is related to its active metabolite, 6-methoxy-2-naphthyla-cetic acid. Not unexpectedly, a study in 2000 patients, mostly treated for more than 6 months, ehcited an adverse events pattern similar to the other derivatives of this class of NSAIDs (SEDA-13, 81). Adverse effects were reported in 18% of patients and 10% stopped taking the drug because of adverse reactions. Diarrhea was the most common problem (13%) followed by abdominal pain (9.9%), dyspepsia (9.3%), nausea (7.8%), and flatulence (4.7%). Ten ulcers were detected. Nervous system reactions, skin rashes, edema, unspecified eye disorders, and liver function test abnormahties aU occur (1). 

The types of skin adverse effect also vary with different compounds. The most serious life-threatening reactions, such as erythema multiforme and its variants (Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative erythroderma) are uncommon and occur mainly with the butazone derivatives and to a lesser extent with piroxicam, sulindac, and possibly fenbufen. In large series reported in France, Germany, and the USA, NSAIDs are most often implicated 12 (44%) of the most commonly implicated 29 drugs (168). 

Because local inflammatory reactions may comphcate some of the bum injuries, nonsteroidal antiinflammatory dmgs (NSAIDs) may be helpful. Additional bum treatment may include CO -laser debridement, artificial skin or skin grafting (3). Large amounts of fluid loss are uncommon compared to thermal bums, but patients should still receive careful monitoring of fluids and electrolytes (2,3,23). Signs of infection and cultures revealing responsible organisms are indications for systemic antibiotics (24-26). 

In addition to skin eruptions aspirin can cause a syndrome referred to as aspirin exacerbated respiratory disease (AERD) in which the classic triad of asthma, rhinitis, and aspirin sensitivity was first described by Sam ter. It is important to note that AERD has as its precursor an underlying respiratory disease such as asthma that is exacerbated by aspirin but not caused by aspirin. Briefly, the natural history of this disease indicates that the patient first develops an upper respiratory tract inflammation that persists rather than subsides. Sinusitis develops, which progresses to pansinusitis with nasal polyps and asthma noted. At some point the patient takes aspirin or some other COX-1 inhibitor and an AERD reaction occurs. Although this is truly an idiopathic reaction to NSAIDs, adult patients with chronic sinusitis and nasal polyps should be observed carefully for the potential development of AERD. 

C. Toxicity Cutaneous flushing is a common adverse effect. Pretreatment with aspirin or other NSAIDs reduces the intensity of this flushing, suggesting that it is mediated by prostaglandin release. Tolerance to the flushing reaction usually develops within a few days. Dose-dependent nausea and abdominal discomfort often occur. Pruritus and other skin conditions are reported. Moderate elevations of liver enzymes and even severe hepatotoxicity may occur. Hyperuricemia occurs in about 20% of patients, and carbohydrate tolerance may be moderately impaired. 

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