Non-steroidal anti-inflammatory drug gastropathy: Causes and treatment
Non-steroidal anti-inflammatory drug gastropathy: Causes and treatment
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DOI：
10.3109/00365529609094763
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发表时间：
1996-01-01
影响因子：
1.9
通讯作者：
Hawkey, CJ
中科院分区：
文献类型：
--
作者：
Hawkey, CJ
阿司匹林和非阿司匹林非类固醇抗炎药(NSAIDs)几乎都会导致急性胃十二指肠损伤，并可能导致英国每年约12000例溃疡出血和1200例死亡。临床上显著的肠道毒性也被认识到，但定义不太清楚。与NSAID相关的消化性溃疡并发症的主要危险因素是年龄、既往病史、使用高危个体NSAIDs、药物剂量、同时使用华法林或皮质类固醇。使用非甾体抗炎药和幽门螺杆菌状态的潜在原因并不明显与风险增加有关。非甾体抗炎药是否会导致药物引起的非溃疡性消化不良也存在争议。服用阿司匹林比服用非阿司匹林非类固醇抗炎药更容易发生急性损伤，与不同的非类固醇抗炎药相比，急性损伤谱在预测临床有意义的终点方面价值不大。然而，联合处方保护剂的急性研究对临床实践中的表现具有很高的预测性。胃粘膜的完整性是通过三个保护网络的相互作用来维持的：前列腺素合成、一氧化氮合成和肠道神经系统的活动。阿司匹林和非甾体抗炎药通过抑制由两种环氧合酶催化的前列腺素合成来发挥作用。现有的大多数非甾体抗炎药是非选择性的，对胃中结构性环氧合酶(COX)1酶的活性的抑制程度与环氧合酶(COX)2酶的抑制程度相同，后者是在关节疾病等炎症部位诱导的。然而，选择性环氧合酶2抑制剂是有前景的。一些非甾体抗炎药，特别是阿司匹林，有额外的局部毒性，这可能在一定程度上反映了粘膜陷阱。一些数据支持非甾体抗炎药抑制线粒体氧化磷酸化的作用。非甾体抗炎药使用损害的主要生理机制是粘膜血流、粘液和碳酸氢盐的分泌以及维持疏水的粘膜表面。动物数据表明，多形核白细胞(PMN)对急性损伤很重要，尽管与人类的相关性尚未确定。除了破坏粘膜，非类固醇抗炎药还会损害溃疡愈合，并与上皮细胞增殖减少和血管生成减少有关。前列腺素和生长因子之间的相互作用，以及花生四烯酸代谢的抗增殖产物的合成可能参与其中。用常规剂量的H-2拮抗剂治疗非甾体抗炎药溃疡愈合缓慢，在预防胃溃疡发展或复发方面效果不佳。这些问题可以通过使用更有效的酸抑制来克服。米索前列醇可以治愈非甾体类抗炎药相关的溃疡，尽管愈合速度是否与非非类固醇抗炎药相关的溃疡一样快还没有正式确定。米索前列醇是有效的预防性治疗，但有显著的不良事件发生率，特别是腹泻。据报道，米索前列醇可以预防溃疡并发症，在内窥镜研究中，米索前列醇的预防效果优于标准剂量的雷尼替丁。与质子泵抑制剂相比，其疗效的结果还有待观察。对于许多患者来说，适当的处理是避免非甾体抗炎药或使用效力/毒性较低的替代品，如布洛芬。由于事先授权计划而导致的处方减少表明，这是可以实现的。对于需要继续使用非甾体类抗炎药的高危患者，应考虑联合使用奥美拉唑或米索前列醇。
Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) almost invariably cause acute gastroduodenal injury and probably account for approximately 12 000 ulcer bleeding episodes and 1200 deaths per annum in the United Kingdom. Clinically significant intestinal toxicity is also recognized but less clearly defined. The main risk factors for NSAID-related peptic ulcer complications are age, past history, use of higher risk individual NSAIDs, drug dose, concurrent use of warfarin or corticosteroids. The underlying reason for NSAID use and Helicobacter pylori status is not clearly associated with increased risk. Whether NSAIDs cause drug-induced non-ulcer dyspepsia is also controversial. Acute injury occurs more readily with aspirin than with non-aspirin NSAIDs, and the spectrum of acute injury is of little value in predicting clinically significant end points in comparison with different NSAIDs. However, acute studies of co-prescribed protective agents are highly predictive of performance in clinical practice. Gastric mucosal integrity is maintained by the interplay of three protective networks: prostaglandin synthesis, nitric oxide synthesis and the activity of the enteric nervous system. Aspirin and NSAIDs act by inhibiting prostaglandin synthesis catalysed by two cyclooxygenase enzymes. Most existing NSAIDs are unselective and inhibit the activity of the constitutive cyclooxygenase (COX) 1 enzyme in the stomach as much as the cyclooxygenase (COX) 2 enzyme which is induced at sites of inflammation such as joint disease. There are, however, prospects for selective cyclooxygenase 2 inhibitors. Some NSAIDs, particularly aspirin, have additional topical toxicity, which may in part reflect mucosal trapping. Some data favour an effect of NSAIDs in inhibiting mitochondrial oxidative phosphorylation. The principal physiological mechanisms which are compromised by NSAID use are mucosal blood flow, secretion of mucus and bicarbonate and maintenance of a hydrophobic mucosal surface. Animal data suggest that polymorphonuclear leukocytes (PMNs) are important for acute damage though the relevance to humans has yet to be established. As well as damaging the mucosa, NSAIDs impair ulcer healing and are associated with reduced epithelial proliferation and evidence of diminished angiogenesis. An interaction between prostaglandins and growth factors, as well as the synthesis of antiproliferative products of arachidonic acid metabolism may be involved. Healing of NSAID ulcers by conventional doses of H-2 antagonists is slow and H-2 antagonists are poor at preventing gastric ulcer development or recurrence. These problems can be overcome by the use of more potent acid suppression. Misoprostol heals NSAID-associated ulcers, though whether healing is as fast as with non-NSAID ulcers has not been formally established. Misoprostol is effective prophylactic treatment but has a significant incidence of adverse events, particularly diarrhoea. Misoprostol has been reported to prevent ulcer complications, and in endoscopic studies has been superior as prophylaxis to standard dose ranitidine. Results of its efficacy compared to proton-pump inhibitors are awaited. For many patients appropriate management is avoidance of NSAIDs or use of less potent/toxic alternatives such as ibuprofen. Reductions in prescribing arising from a prior authorization scheme show that this can be achieved. For high-risk patients requiring continuing NSAID use co-prescription of omeprazole or misoprostol should be considered.