Gastrointestinal effects of selective and non-selective non-steroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed group of drugs. Patients receiving NSAIDs often experience abdominal discomfort, and some of them develop serious gastrointestinal complications, such as ulceration, bleeding, perforation, or obstruction. Gastrointestinal side effects of NSAIDs are mostly attributed to cyclooxygenase (COX) inhibition resulting in reduction of prostaglandin in gastric mucosa. Topical irritant effects are also contributed to their systemic effect of prostaglandin inhibition. Anti-inflammatory effects of NSAIDs are mediated by COX-2 inhibition, while COX-1 inhibition is responsible for gastric prostaglandin inhibition. Management of gastrointestinal complications of NSAIDs is costly. In order to prevent or treat the gastrointestinal complications of NSAIDs, anti-ulcer drugs can be used concomitantly. Other alternative is the application or substitution of COX-2 selective inhibitors, which spare gastric mucosal prostaglandin synthesis and do not damage the gastric mucosa. Application of COX-2 selective inhibitors as a first line treatment for arthritic disorders may not be cost-effective, if patients do not have any risk factors including advanced age, history of complicating peptic ulcer, concomitant anticoagulant and corticosteroid medication. Patients with risk factors or those developing gastrointestinal complications during the course of NSAID treatment can be treated with COX-2 selective inhibitors if necessary.     

非甾体抗炎药致胃肠道黏膜损伤的研究进展

随着非甾体抗炎药(NSAIDs)在临床的广泛应用,其对胃肠道黏膜的损害已受到越来越多的关注。笔者就NSAIDs胃肠道黏膜损害的发病机制、临床表现和防治等做一综述。     

Systematic review: the lower gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs

BACKGROUND: Lower gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs) are much more poorly characterized than upper gastrointestinal effects. AIM: To determine if NSAIDs increase lower gastrointestinal adverse effects and if the risk with non-selective NSAIDs is greater than with cyclooxygenase-2-selective inhibitors (coxibs). METHODS: Computerized databases were searched to identify studies of NSAID use reporting on lower gastrointestinal integrity (e.g. permeability), visualization (e.g. erosions, ulcers) and clinical events. RESULTS: Designs in 47 studies were randomized (18), case-control (14), cohort (eight) and before-after (seven). Non-selective-NSAIDs had significantly more adverse effects vs. no NSAIDs in 20 of 22 lower gastrointestinal integrity studies, five of seven visualization studies, seven of 11 bleeding studies (OR: 1.9-18.4 in case-control studies), two of two perforation studies (OR: 2.5-8.1) and five of seven diverticular disease studies (OR: 1.5-11.2). Coxibs had significantly less effect vs. non-selective-NSAIDs in three of four integrity studies, one endoscopic study (RR mucosal breaks: 0.3), and two randomized studies (RR lower gastrointestinal clinical events: 0.5; haematochezia: 0.4). CONCLUSIONS: An increase in lower gastrointestinal injury and clinical events with non-selective-NSAIDs appears relatively consistent across the heterogeneous collection of trials. Coxibs are associated with lower rates of lower gastrointestinal injury than non-selective-NSAIDs. More high-quality trials are warranted to more precisely estimate the effects of non-selective-NSAIDs and coxibs on the lower gastrointestinal tract.     

Patient awareness of the adverse effects of aspirin and non-aspirin non-steroidal anti-inflammatory drugs

Objective — To determine the extent to which patients reported having been informed about the adverse effects of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) Method — Questionnaire survey of 26 patients who had suffered an acute gastrointestinal bleed while taking aspirin, and 100 patients who had suffered an acute gastrointestinal bleed while taking a non-aspirin NSAID Setting — Admissions to three United Kingdom hospitals. Patients were identified from endoscopy clinic records Key findings — Five (19 per cent) of the aspirin-treated patients and 45 (45 per cent) of the non-aspirin NSAID-treated patients remembered having been informed of potential adverse effects, an odds ratio of 3.4 (95 per cent confidence interval 1.2–9.8, P<0.05). Five (19 per cent) of the aspirin-treated patients recalled having been advised what to do should adverse symptoms develop, whereas 44 (44 per cent) of the non-aspirin NSAID-treated patients did so, an odds ratio of 3.3 (95 per cent CI 1.2–9.5, P<0.05). Three (12 per cent) of aspirin-treated patients reported having been given an information leaflet, whereas 29 (29 per cent) of non-aspirin NSAID-treated patients did so, an odds ratio of 3.1 (95 per cent CI 0.9–11.2, P=0.08) Conclusion — Our results suggest that aspirin-treated patients are less informed about their drug than are patients taking non-aspirin NSAIDs, in spite of the risk of gastrointestinal bleeding with which aspirin is associated     

Patient awareness of the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs)

We set out to determine the extent to which two groups of patients reported having been informed about the adverse effects of NSAIDs. These consisted of 50 patients who had suffered an acute gastrointestinal bleed while taking a NSAID, and 100 age, sex and drug matched controls who had not. Eight (16%) of the index patients, and 41 (41%) of the control patients remembered having been informed of potential adverse effects, an odds ratio of 3.65 (95% CI 1.55–8.58, P <0.002). Two (4%) of the index patients recalled having been advised what to do should adverse symptoms develop, whereas 21 (21%) of the control patients did so, an odds ratio of 6.38 (95% CI 1.4–28.4, P <0.01). Eighteen (36%) of patients who bled had experienced gastrointestinal pain prior to the bleed, but of these only two (11%) admitted reduced compliance with NSAID therapy. In contrast, 10 (67%) of the 15 control patients who had suffered epigastric discomfort admitted reduced compliance, an odds ratio of 16.0 (95% CI 2.6–98.8, P <0.001). Our results suggest that patients who report not having been informed of adverse effects of NSAIDs are less likely to reduce intake in response to epigastric pain than patients who report having received such information. If the patients who bled had reduced their intake of NSAIDs to the same extent as apparently better informed control patients in response to epigastric pain, it is possible that some episodes of acute gastrointestinal bleeding would have been avoided.     

Spontaneous reporting of adverse drug reactions to non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are the third most commonly prescribed group of drugs in Spain. We present here the profile of adverse drug reactions (ADRs) attributed to them and reported to the Spanish System of Pharmacovigilance (SSPV) between 1983 and 1991, together with a preliminary analysis of topical, slow-release (SR) and enteric-coated (EC) preparations.Out of 18 348 reports of ADRs included in the SSPV database, 1609 (8.8%) implicated an NSAID. NSAIDs ranked second after antibiotics (15.1% of all reports) among the most commonly implicated drugs. Half of the patients were more than 55 years old, and 60% were women.Diclofenac (364 reports), piroxicam (282), indomethacin (197), naproxen (155), and ketoprofen (137) were the most commonly implicated NSAIDs in reports of ADRs.The most commonly reported ADRs were gastrointestinal (39%), cutaneous (20%), and those affecting the central and peripheral nervous system (9%). Seven reactions had a fatal outcome, and 138 were considered life threatening. Forty-nine reports included previously undescribed ADRs.There were 98 reports describing ADRs attributed to topical NSAIDs; 5 of these described 11 general reactions, such as duodenal ulcer, gastrointestinal bleeding, diarrhoea, dyspnoea, facial oedema, aggravation of bronchospasm, and angioedema.One hundred and sixty-eight reports referred to SR and EC preparations. The ratio of gastrointestinal to non-gastrointestinal reactions to SR-EC diclofenac was higher in the case of SR-EC diclofenac than in the case of plain diclofenac (P=0.037); similarly, the ratio of CNS to non-CNS reactions to SR-EC indomethacin was also higher than the corresponding ratio with plain indomethacin (P=0.002). Although differential selective reporting of these preparations cannot be excluded, these results raise doubts about the relative safety of SR and EC preparations of NSAIDs in practice.     

重视非甾体抗炎药不良反应的监测及合理应用

非甾体类抗炎药（nonsteroid anti-inflammatory drugs,NSAIDs）是指一大类具有镇痛、抗炎、解热等功能的药物,也是目前临床上应用最广泛的药物之一,全世界每天约有3000万人在使用此类药物.但是,NSAIDs在为亿万患者减轻病痛的同时,也给患者和社会带来了一些不必要的痛苦和经济负担.在美国,由于非甾体类抗炎药的各种不良反应,每年可导致103 000人次需要住院治疗,16500人死亡[1,2].因此,NSAIDs引发的药物不良反应使其在临床的应用受到一定程度的限制.最近,昔布类药物所引发的心血管不良反应事件,使广大患者和医务工作者分外关注NSAIDs的安全性.     

Renal adverse effects of nonsteroidal anti-inflammatory drugs

NSAIDs depress prostaglandins synthesis through inhibition of COX-1 that is involved in maintaining cell integrity and COX-2 that, although presents particularly in the kidneys, is overexpressed in response to inflammation. Both the beneficial and side effects of NSAIDs are, therefore, through their inhibition of COX enzymes. Introduction of COX-2-selective inhibitors has improved the safety profile of the drugs with regard to their most common side effect which occurs at the gastrointestinal level but has not rendered them less cardio-nephrotoxic. Renal side effects of NSAIDs are rare, sometimes transient and often reversible upon drug withdrawal. The incident rate and the severity of the renal side effect, however, increase in patients with risk factors such as those with diabetes, heart failure, renal dysfunction and in the elderly. The side effects range from electrolyte retention and reduce glomerular filtration to nephritic syndrome and chronic renal failure. These effects are shared among NSAIDs with evidence of dose and exposure dependency. There is no known predictor for the nephrotoxicity. However, a relationship has been found between high plasma concentration and the renal adverse effect of NSAIDs. The usefulness of therapeutic drug monitoring in patients with risk factors needs to be explored.     

Managing the adverse effects of nonsteroidal anti-inflammatory drugs

Conventional medical treatment for rheumatoid arthritis and osteoarthritis includes the use of NSAIDs (traditional and selective inhibitors of cyclooxygenase [COX]-2), because they provide unmistakable and significant health benefits in the treatment of pain and inflammation. However, they are associated with an increased risk of serious gastrointestinal (GI) and cardiovascular (CV) adverse events. Both beneficial and adverse effects are due to the same mechanism of action, which is inhibition of COX-dependent prostanoids. Since CV and GI risk are related to drug exposure, a reduction in the administered dose is recommended. However, this strategy will not eliminate the hazard owing to a possible contribution of individual genetic background. Further studies will be necessary to develop genetic and/or biochemical markers predictive of the CV and GI risk of NSAIDs.     

Clinical pharmacokinetics of non-steroidal anti-inflammatory drugs

The number of non-steroidal anti-inflammatory drugs (NSAIDs) available for clinical use has dramatically increased during the last decade. As a general rule, NSAIDs are well absorbed from the gastrointestinal tract, with the exception of aspirin (and possibly diclofenac, tolfenamic acid and fenbufen) which undergoes presystemic hydrolysis to form salicylic acid. Concomitant administration of NSAIDs with food or antacids may in some cases lead to delayed or even reduced absorption. The NSAIDs are highly bound to plasma proteins (mainly albumin), which limits their body distribution to the extracellular spaces. Apparent volumes of distribution of NSAIDs are, therefore, very low and usually less than 0.2 L/kg. The elimination of these drugs depends largely on hepatic biotransformation; renal excretion of unchanged drugs is usually small (less than 5% of the dose). Total body clearance is low and for most NSAIDs is less than 200 ml/min. The effect of age and disease on the disposition of NSAIDs has not been extensively studied. Due to the central role of the liver in the overall elimination of the majority of these compounds, hepatic disease will most likely lead to a significant alteration in their pharmacokinetic behaviour. NSAIDs have been reported to be involved in numerous pharmacokinetic drug interactions. Aspirin decreases the plasma concentrations of many other NSAIDs, although the clinical significance of this is uncertain. Due to the extremely high plasma protein binding of NSAIDs (around 99% in many cases), competition for the same binding sites on plasma proteins may be at least partly responsible for some interactions of NSAIDs with other highly bound drugs; however, another mechanism such as decreased metabolism or decreased urinary elimination is usually involved as well. The most important interactions with NSAIDs are those involving the oral anticoagulants and oral hypoglycaemic agents, though not all NSAIDs have been found to interact with these drugs. In clinical practice, there appear to be no clear-cut guidelines to assist the clinician in the selection of the most appropriate drug for an individual patient. The selection of an anti-inflammatory drug should be based on clinical experience, patient convenience (e.g. once or twice daily dosage schedule), side effects and cost. Since a marked interindividual variability exists in the clinical response to a given NSAID, clinicians prescribing these agents may try several of them sequentially until an adequate response is obtained.     

Assessment of topical non-steroidal anti-inflammatory drugs

A new non-invasive technique for assessing the efficacy of topical non-steroidal anti-inflammatory drugs (NSAID) in man is proposed. The NSAID are initially applied to the skin under occlusion before inflammation is induced by a methyl nicotinate solution. The inflammatory response is quantified in terms of cutaneous blood flow by a laser Doppler velocimeter (LDV). The efficacy of NSAID preparations is calculated by comparing the responses of the LDV to the methyl nicotinate challenge on the pretreated and the non-treated skin sites. This protocol has been used to investigate the effect of three different NSAID preparations (indomethacin, niflumic acid, palmitoyl collagenic acid) and the influence of the vehicle on the efficacy of indomethacin. The three preparations tested gave positive results but with different amplitudes in response. The efficacy of indomethacin varied with the vehicle used.     

非甾体抗炎药的合理应用

1899年阿司匹林问世开创了人类用合成抗炎药的历史.百余年来,以其为代表相继开发的一大批具有独特药理作用的抗炎药在临床上占有重要治疗地位,成为一日不可或缺的药品.为此临床医师应了解并合理地应用.     

NSAIDs抗炎作用机制研究进展

NSAIDs的抗炎作用机制被认为主要是抑制COX2的活性。NSAIDs还可以抑制COX2的表达,并可通过COX非依赖性的途径产生抗炎作用,包括抑制转录因子NFκB与AP1,作用于蛋白激酶如Erk、p38MAPK、及核糖体S6激酶2等,激活PPARγ及热休克转录因子1,抑制诱导型NO合酶及前列腺素转运等。     

上海地区非甾体抗炎药不良反应回顾与分析

目的 调查上海市长期使用非甾体抗炎药(NSAIDs)人群药物不良反应发生情况及相关参数。方法 用整群抽样,回顾性询问填表法,获取了1002例患者的基本情况、NSAID s使用情况、合并用药情况和药物不良反应(发生、治疗、预后)等情况。结果 调查显示,患者使用NSAIDs均在1年以上,药物不良反应发生率较高(66％),症状主要集中在胃肠道、皮疹、中枢症状,严重药物不良反应约7％,药物不良反应预后较好。结论 NSAID s药物不良反应受多种因素影响。     

Renal effects of non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors

Nonsteroidal antiinflammatory drugs (NSAID) are one of the most commonly used medications worldwide to inhibiting COX activity for the treatment of pain and inflammation. Their nephrotoxicity has been well documented. With the development and clinical implementation of new COX-2 inhibitors, the safety, including the effects on renal function and blood pressure, is attracting increasing attention. In the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion and maintenance of renal blood flow. Similar to conventional NSAIDs, inhibition of COX-2 may cause edema and modest elevations in blood pressure in a minority of subjects. COX-2 inhibitors may also exacerbate preexisting hypertension or interfere with other antihypertensive drugs. Occasional acute renal failure has also been reported. Caution should be taken when COX-2 inhibitors are prescribed, especially in high-risk patients (including elderly and patients with volume depletion). Recently, agents with combined lipooxygenase/COX inhibition and agents that combine NSAIDs with a nitric oxide (NO) donor have been reported to reduce adverse renal effects.     

Cardiovascular hazard and non-steroidal anti-inflammatory drugs

Selective inhibitors of cyclooxygenase (COX)-2 depress prostacyclin (PGI(2)) without a concomitant inhibition of platelet COX-1-derived thromboxane (Tx)A(2). Experiments in gene-deleted mice have shown that ablation of the PGI(2) receptor (the IP) predisposes to an exaggerated response to agonists which elevate blood pressure, accelerate atherogenesis and induce thrombosis. Such a class-based effect would be expected to be modulated by the underlying risk of cardiovascular disease in patients, elements of drug exposure, such as dose, duration of action and duration of dosing, and inter-individual variability of drug response. Five placebo-controlled trials of three structurally distinct selective inhibitors of COX-2 have revealed an increased hazard of myocardial infarction and stroke consistent with a mechanism-based class-specific cardiovascular hazard. Sustained inhibition of platelet TxA(2) by aspirin affords cardiovascular benefit, despite concomitant inhibition of PGI(2). Although there is no information from randomized placebo-controlled trials, traditional non-steroidal anti-inflammatory drugs, such as naproxen, dicofenac and ibuprofen, might differ in their effects of cardiovascular biology.     

Cutaneous reactions to non-steroidal anti-inflammatory drugs

We retrospectively reviewed the records of 195 patients with suspected cutaneous reactions from NSAIDs. Two hundred and six different non-steroidal anti-inflammatory drugs (NSAIDs) were suspected of causing cutaneous reactions, and the most frequent suspected causative NSAID was ibuprofen (25.7%). Angioedema and/or urticaria were the most frequent cutaneous reactions (54.4%), and the foremost suspected causative drug for these reactions was ibuprofen. The second most frequently found cutaneous reaction was maculopapular eruption (26.2%), and celecoxib was the most commonly suspected causative NSAID for it. The primary suspected NSAIDs causing fixed drug eruption were in enolic acid group. Furthermore, drug hypersensitivity syndrome was diagnosed in five patients, and Stevens-Johnson syndrome and toxic epidermal necrolysis were detected in five patients.