Associate Professor of Internal Medicine at Tbilisi State Medical University, MD Consultant at LRA "David Tatishvili Medical Center".
Nonsteroidal antiinflammatory drug associated gastropathy is a specific syndrome, associated with use of NSAIDs. This syndrome is expressed by mucosal lesions in gastric antrum and less frequently in the duodenum. The lesions can be erythematous, erosive and/or ulcerative.
The term "NSAID gastropathy" was established in 1986, in order to differentiate classic ulcerative diseases from the specific lesions of gastric mucosa.
Gastropathy is one of the most common complication of NSAID treatment. According to data of Moscow Scientific Research Institute of Gastroenterology , treatment with NSAIDs causes acute gastritis in 100% of the cases in one week after beginning treatment. Gastrointestinal erosive lesions occur in 20-40% of patients, which receive NSAIDs regulary. Once or for a long time treatment with NSAIDs gastric ulcer expresses in 12-30%, and duodenal ulcer - in 2-19%.
Even small prophylactic doses of Aspirin (for example, in individuals with ischemic heart disease), increase bleeding complications of gastric and duodenal ulcers. According to British data, patients with ischemic heart disease who take Aspirin for prophylactic means , bleeding complications achieve 3500 annually. According to American data, NSAID associated gastropathy bleeding complications, ulcer perforation or both comprise 70000 of cases annually. Every tenth of these cases has lethal cause.
The patients with rheumatoid arthritis who take NSAID on a long term basis, complications associated with GI bleeding and mortality risks approximate 1.3-1.6 % per year. This makes possibility to conclude that in patients with rheumatoid arthritis gastrointestinal problems are one of most frequent complications of the disease treatment.
NSAID gastropathy pathogenesis is not completely revealed, but it is deemed that these medications have ability to penetrate mucosal layer in the acid media of stomach; they damage bicarbonate barrier, cause back-diffusion of hydrogen ions into the gastric lumen and so with the direct contact damage epithelial cells. With the direct contact they block mitochondrial enzyme systems of epithelial cells, which are essential in oxidative phosphorylation and so turn on cascade of necrobiosis in the cells.
Mechanisms of gastric and duodenal lesions are related to blockage of prostaglandin synthesis. Because of this amount of mucus and bicarbonate are reduced which are main protective barriers against aggressive gastric juice contents which damage gastric mucosa. NSAID use also reduce nitrous oxide and prostacyclin, this negatively influences sub-mucosal layer integrity that contributes to further gastric and duodenal mucosal lesions.
In clinical trials, effects of NSAIDs on gastric mucosa was evaluated. It was revealed that they had toxic effects on cells making lysophospatidylcholine. NSAIDs damage Trefoilpeptid regulation, which are necessary for gastric mucosal layer maintenance, one of the factors of NSAID induced gastropathy. Also protein Survivin which has anti-apoptotic activity in animal studies was shown to be reduced in Indometacin treated animals, in addition amount of Leukotriene 4 (LT4) was increased. Likopelon block synthesis of Leukotriene -4 and it is dual inhibitor of both Cyclooxygenase type II and Lipooxigenase-5.
In NSAID-associated gastropathy mechanism takes part mucosa damage lesions with urokinase like plasminogen activator and its receptor, which is situated in gastric fibroplasts and hold shares in prostaglandin E2 syntesis. NSAIDs block synthesis of urokinase like plasminogen activator and so inhibit endogenous prostaglandin production.
Last time much attention has been played on the connection between NSAID-associated gastropathy and Helicobacter Pylori infection.
In NSAID gastropathies there is high rate of Helicobacter Pylori infection manifestations. According to modern medical literature , Helicobacter Pylori eradication therapy reduces the risk of peptic ulcer disease in patients with NSAID-associated gastropathy.
According to modern medical data, there are multiple contributing factors in development of NSAID gastropathy, this makes researchers to continue studying its pathogenesis and contributing factors in detail.
In accordance with pathogenesis of NSAID gastropathy it is supposed that there is no difference in complication risks depending on routes of NSAIDs’ administration (per os, IM, or per rectum).
There are several factors that increase the risk of peptic ulcer disease:
· Age > 65 years
· Past medical history of peptic ulcer disease
· High doses of NSAIDs, or two NSAID drug combinations and/or log-term treatment regimens
· Co-treatment with corticosteroids
· Female gender
· Tobacco and alcohol
· Helicobacter Pylori infection
In elderly the high risk of peptic ulcer disease is explained by presence atherosclerosis.
Combination treatment with NSAIDs and glucocorticosteroids increase peptic ulcer disease risk more than ten fold. Glucocorticosteroids inhibit phospholipase A2, which mediate release of Arachidonic acid from membrane phospholipids, regarding that Arachidonic acid is precursor for prostaglandin synthesis, their levels decrease markedly.
NSAID treatment with calcium channel blocking drugs is contraindicated because of increased risk of bleeding complications.
Gastro-Intestinal (GI) complications of NSAIDs depend on the group of the drug, selective COX II inhibitors have very uncommon GI complications.
NSAID gastropathy is characterized by misbalance between endoscopic and clinical picture of the disorder. Like patients with various symptoms, as epigastric discomfort and pain, dyspepsia , less often vomiting have minimal lesions on endoscopic studies . While patients with no or mild GI complaints have severe mucosal erosive and ulcerating lesions. Such insidious progression of the disease can lead the patients to the lethal complications.
30-40% of the patients who take NSAIDs on a long term basis (>6 weeks), have dyspeptic complaints which are in no correlation with endoscopic study results.
Nearly 40% of patients with no GI complaints have severe lesions revealed on endoscopic studies, and 50% of the patients with GI complaints have normal mucosal integrity.
NSAID gastropathy may be revealed by not only dyspeptic but also with pain symptoms, it may also have insidious onset with lethal causes such as ucler perforation and bleeding.
NSAID gastropathy apart from classic peptic ulcer disease more commonly damages stomach than duodenum. During gastroscopy erythematous lesions, diffuse erosions, ulcerations, micro hemorrhages and crater ulcers are visualized.
Perforation and hemorrhagic complications of NSAID gastropathy is rare (0.1-4% per year), despite this small number, it is serious medico-social problem because NSAIDs are used very often in today’s medical practice. That’s why when choosing NSAIDs for prescription, attention should be paid not only to clinical symptoms but to the risk factors that contribute to the GI complications.
From everything above it is interesting to consider continuation of treatment with NSAIDs, because cessation of NSAID therapy doesn’t result in ulcer healing in 60% of patients.
Antisecretory drugs are first choice in NSAID associated GI tract lesions. These drugs inhibit gastric acid and pepsin secretion by gastric parietal and chief cells and therefore lessen aggressive factors’ role in the erosive damage of mucosal barrier.
There are two main pharmacologic groups of antisecretory drugs: histamine (H2) receptor blockers and proton pump (H+/K+-ATP-ase) inhibitors. Their long-term use pose some problems. These medications decrease gastric acidity (increase in PH) that interfere with digestive processes and can cause gastric mucosal atrophy, clinical manifestations are mainly dyspeptic. Long-term gastric PH increase cause decreased resistance to pathogenic and co-mensal bacterial infections, also cause hyper-gastrinemia that predisposes to dysplasic and metaplasic changes in mucosal epithelial cells.
In maintenance treatment regimens , the use of non-absorbable medications has showed marked effectiveness (64%). Simalgel is one of such medications. It is antacid with component against meteorism. Each 5ml of suspension of Simalgel contains: 405mg of aluminium hydroxide dry gel, 100mg of magnesium hydroxide and 125 mg of Simeticone. Simalgel’s pharmacologic action is that its components aluminium and magnesium hydroxides neutralize gastric acid and decrease peptic activity of gastric contents; Aluminium hydroxide in addition increases PGE2 synthesis which is very important factor for mucosal protective barrier, it absorbs bile acids and pepsin; Magnesium hydroxide increases mucus secretion and possess gastro-protective effects and increases gastric mucosal resistance. Simalgel suspension has demarcating effects, creating protective layer on gastric mucosa , dissipating evenly on the whole gastric wall. After taking Simalgel it is recommended to take a bed rest and with changing positions. It inhibits air production and lessens intragastric and intraduodenal pressure. Simalgel’s acid neutralizing, absorbing, demarcating and cyto-protective abilities make it important medication for maintenance therapy for treatment of NSAID associated gastropathy.
Prophilactic measures to avoid unwanted NSAID side effects are the following:
· In the presence of the risk factors it is important to take gastro-protective medications. The treatment regimen is the same as for peptic ulcer treatment plan. Initially NSAIDs are discontinued and in the presence of Helicobacter Pylori infection its eradication therapy is started.
Inclusion of antisecretory, antacidic and gastroprotective medications in the treatment regimens for NSAID induced gastropathies is correct according to the pathogenesis of the disease.
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