Treatment for Peptic Ulcer Disease
Peptic ulcers are thought to arise as a result of excessive amounts of gastric acid and pepsin or negligible mucosal resistance.14 It is logical, then, that any medication to combat the problem relates to the aforementioned factors and enhances the corresponding defense mechanism(s). Among the various categories of anti-ulcer drugs in the market, specific families contain aluminum. These include (a) anti-secretory medication and antacids and (b) mucosal protection agents. A significant discovery in the treatment of peptic ulcers has emerged from advancements in the research of histamine H2-receptors and their antagonists. Akin to the H2-antagonists are antacids, which are well known to the majority of people suffering from ulcers and ulcer-related ailments. Antacids are recognized as agents capable of (a) managing acute and chronic gastroduodenal ulcerations15 and (b) contributing to ulcer healing.16
Peptic ulceration commonly involves the stomach, duodenum, and lower oesophagus after gastric surgery it involves the gastro-enterostomy stoma. Healing can be promoted by general measures, stopping smoking and taking antacids and by antisecretory drug treatment, but relapse is common when treatment ceases. Nearly all duodenal ulcers and most gastric ulcers not associated with NSAIDs are caused by Helicobacter pylori.
One of the first CCK antagonists to be produced was the mixed CCK A and B antagonist proglumide. This has relatively weak receptor affinity but does also seem to possess inherent 8 opioid agonist effects. It was originally produced for the treatment of peptic ulcer disease until the H2 antagonists became available and were seen to be more effective in this
The ingestion of salicylates may result in epigastric distress, nausea, and vomiting. Salicylates also may cause gastric ulceration, exacerbation of peptic ulcer symptoms (heartburn, dyspepsia), GI hemorrhage, and erosive gastritis. These effects occur primarily with aspirin. Because nonacetylated salicylates lack the ability to acetylate COX and thereby irreversibly inhibit its activity, they are weaker inhibitors than aspirin.
Approximately 2 of patients develop mild GI irritation. The risk is increased at higher doses, and caution should be used in those with a history of peptic ulcer. It is ineffective in patients with renal insufficiency and should be avoided in those with creatinine clearance of
The side effects associated with the NMDA antagonists include sedation, dry mouth, headache, and constipation in some cases these effects may be prohibitively severe, limiting usefulness (e.g., ketamine may produce dissociation, hallucinations, frightening nightmares, and delirium) (Eide et al. 1994). Ketamine at a dosage of 50-60 mg four to six times daily (taken in juice or oral suspension) may produce pain relief without incurring these serious effects. Ketamine's hallucinogenic properties have rendered it popular with drug abusers (Dillon et al. 2003). Long-term use of ketamine is not currently advocated, partly because the long-term effects are unknown. It may result in long-term cognitive changes, hepatic dysfunction, and gastric ulcers.
Most adverse effects of reserpine are due to its effect on the CNS. Sedation and inability to concentrate or perform complex tasks are the most common adverse effects. More serious is the occasional psychotic depression that can lead to suicide. Depression usually appears insidiously over many weeks or months and may not be attributed to the drug because of the delayed and gradual onset of symptoms. Reserpine must be discontinued at the first sign of depression, which may last several months after the drug is discontinued. The risk of depression is likely dose related. Depression appears to be uncommon, but not unknown, with doses of 0.25 mg day or less. The drug should never be given to patients with a history of depression. Other adverse effects include nasal stuffiness and exacerbation of peptic ulcer disease, which is uncommon with small oral doses.
The Cag A surface protein is one of the most investigated putative virulence factors, encoded by the cag A gene.4'5 The gene is found in about 50 to 70 of H. pylori isolates in Western countries, and the production of the Cag A protein is reported to be associated with advanced gastrointestinal diseases, namely peptic ulcer disease, and gastric adenocarcinoma.6-13 Cag A-positive H. pylori strains are known to induce secretion of interleukin-8 (IL-8), a chemokine, from gastric epithelial cells.14 However, recent studies have indicated that it is not Cag A itself but the products of other genes in the cag pathogenicity island (PAI) that are responsible for IL-8 production.15 PAI, an approximately 40-kb region of genomic DNA in H. pylori, is observed in approximately 50 to 60 of H. pylori isolates in Western countries16 and in more than 90 of such isolates in Japan.17 In Western populations, patients carrying cag PAI-positive H. pylori have an increased risk for developing atrophic...
With continued presence of H. pylori in the stomach mucosa, acute gastritis makes the transition to chronic gastritis, causing atrophy of the gastric mucosa. This means that glandular cells secreting enzymes and acids are lost, and that surface mucin-secreting foveolar cells proliferate. There is a proportional association between atrophy of the gastric mucosa and the presence of H. pylori23 Recently, it was clearly shown in a Japanese study (1526 patients with an average follow-up of 7.8 years) that gastric cancer develops in persons infected with H. pylori but not in uninfected persons. Those with histology of severe gastric atrophy, corpus-predominant gastritis, or intestinal metaplasia are at increased risk. Persons with H. pylori infection and nonulcer dyspepsia, gastric ulcers, or gastric hyperplastic polyps are also at risk.24 pylori-positive peptic ulcers.28 Further, at the conference held in the Netherlands in 1997, eradication was recommended for low-grade MALT...
Prior to the mid-1970s the available medical therapy for the so-called acid-related diseases, i.e., peptic ulcer and gastroesophageal reflux disease (GORD), was inadequate. All these therapies are directed at the control of gastric acid, and to a lesser extent, pepsin secretion. This was because, until recently, acid was considered the primary factor in the etiology of peptic ulcer disease and GORD. Clearly the fact that acid-inhibiting or -neutralizing drugs were effective therapy in this disease area confirmed the importance of acid. However, the fact that not all individuals even with hyperacidity developed ulceration clearly indicated that other factors were involved and the concept of the gastrointestinal mucosal barrier and its breakdown evolved (2). More recently the role of the bacterium Helicobacter pylori has received much attention, and convincing evidence has accumulated for its etiological importance particularly in duodenal ulcer but also in gastric ulcer and perhaps...
Rebamipide acid) is used for ulcer therapy in parts of Asia. It appears to exert a cytoprotective effect both by increasing prostaglandin generation in gastric mucosa and by scavenging reactive oxygen species. Ecabet (gastrom 12-sulfodehydroabietic acid monosodium), which appears to increase the formation of PGE2 and PGI2, also is used for ulcer therapy, mostly in Japan. Carbenoxolone, a derivative of gly-cyrrhizic acid found in licorice root, has been used with modest success for ulcer therapy in Europe. Its exact mechanism of action is not clear, but it may alter the composition and quantity of mucin. Unfortunately, carbenoxolone inhibits the type 2 isozyme of 11 -hydroxysteroid dehydrogenase, which protects the mineralocorticoid receptor from activation by cortisol in the distal nephron it therefore causes hypokalemia and hypertension due to excessive mineralocorticoid receptor activation (see Chapter 59). Bismuth compounds (see Chapter 37) may be as effective as cimetidine in...
Although duodenal ulcer was the primary disease target for cimetidine, it has been shown to be effective in gastric ulcer (18) and to a lesser extent in GORD (19). It has also been used with some success in other acid-related diseases such as stress ulcer, Zollinger-Ellison syndrome, pulmonary acid aspiration syndrome, and drug-associated gastroduodenal lesions.
Patients with this syndrome develop pancreatic or duodenal gastrinomas that stimulate the secretion of very large amounts of acid,. This can lead to severe gastroduodenal ulceration and other consequences of uncontrolled hyperchlorhydria. Proton pump inhibitors are the drugs of choice, usually given at twice the routine dosage for peptic ulcers with the therapeutic goal of reducing acid secretion to 1 10 mmol h.
The relative lack of therapeutic success of H2 antagonists in GORD is primarily because they do not control gastric acid secretion adequately. The H+ K+-ATPase (proton pump) inhibitors such as omeprazole (25), which target the final step in acid production, provide more effective control of acid secretion and are a significant therapeutic advance in this field. Recently the recognition that the bacterium H. pylori, which occurs in the stomach, is a major etiological factor in duodenal ulcer disease and possibly in gastric ulcer and gastric cancer has led to the use of antibiotics to eradicate the organism (26). Current therapeutic regimens normally involve the use of two antibiotics plus a proton pump inhibitor. This combination of drugs has led to a marked reduction in the relapse rate of duodenal ulcers on cessation of therapy compared to that seen with H2 antagonists.
Finally, research in a particular disease area does not stand still even when a successful drug such as cimetidine is discovered. The proton pump inhibitors represent a significant further advance in antisecretory therapy, and if vaccination can eradicate H. pylori, then peptic ulcer may be a disease of the past.
Despite their widespread occurrence and a very considerable research effort, the use of prostaglandins or prostaglandin analogues themselves in medicine, has been limited. Among the reasons for this are the length of syntheses, problems in achieving selectivity and their rapid metabolism. Some applications include the use of prostaglandins E2 and F2 (dinoprostone 5.44 and dinoprostol 5.46) in the induction of childbirth, misoprostol 5.50 in the treatment of peptic ulcers and latanoprost 5.51 in the treatment of glaucoma.
Indications hypertensive episodes due to phaeo-chromocytoma e.g. during surgery diagnosis of phaeochromocytoma (but see notes above) Cautions monitor blood pressure (avoid in hypotension), heart rate gastritis, peptic ulcer elderly interactions Appendix 1 (alpha-blockers) Contra-indications hypotension history of myo-cardial infarction coronary insufficiency, angina, or other evidence of coronary artery disease Renal impairment manufacturer advises caution no
Since Helicobacter pylori was discovered in 1983 ( ) and soon after suggested as a cause of gastritis, 'peptic ulcers', and stomach cancer, a large body of evidence has been assembled that supports its classification as a human carcinogen. Unusual in cancer epidemiology, even controlled prospective longitudinal studies have been The outcome of an H. pylori infection can vary substantially. Most infected humans do not experience any symptoms over decades. So, one potential, frequent outcome appears to be a stable equilibrium between tissue damage by the bacterium and immune response by the host. In other cases, fulminant inflammation and permanent tissue damage lead to the symptoms of a peptic ulcer and in some individuals, cancer develops. Overall, while between 10 and 65 of individuals in different populations worldwide are infected, only a few percent of them develop chronic gastritis and again a fraction of these eventually come down with stomach cancer. Nevertheless, worldwide,...
There is abundant evidence that selective inhibitors of COX-2 elicit less gastric damage than conventional nonselective NSAIDs. A number of studies evaluated the effects of drugs with selectivity for COX-2 over COX-1 in animal models of pre-existing gastrointestinal injury and inflammation. The latter is important as most patients taking NSAIDs do not develop clinically significant gastric injury. Instead, it occurs in a subset that is more susceptible to the gastric-damaging actions of these drugs. Therefore, with respect to COX-2 inhibitors, it is more clinically relevant to study these drugs in animal models that more closely resemble the susceptible population in humans, i.e., in animals with experimentally induced ongoing GI inflammation. Thus, the majority of PGs produced by the colonic mucosa in a rat model of colitis are derived from COX-2. Daily treatment with a selective inhibitor of COX-2 (L745337) at doses that did not inhibit COX-1 resulted in significant inhibition of...
Approximately 15 of prescribed drugs are subject to this trait. Mephenytoin is a racemic mixture of R and S enantiomers. In most persons S mephenytoin is eliminated by hydroxylation more efficiently than R mephenytoin. The urinary R S ratio of 4-hydroxy (4-OH) mephenytoin is a determinant of CYP2C19 phenotypes, called EMs and PMs. CYP2C19 PMs may suffer acute side effects and chronic toxicity on usual drug doses. For mephenytoin these include drowsiness (acute) and skin rash, fever, and blood dyscrasias (chronic). Other drugs that are subject to CYP2C19 polymorphism are proguanil (antimalarial), omeprazole and lansoprazole (antacids), and some barbiturates (hypnotics). In persons with gastric ulcers, Helicobactor pylori eradication and response to therapy are reduced in EMs compared to PMs.
Sir James Black and colleagues synthesized and characterized the first H2 receptor antagonists, unequivocally demonstrating the existence of more than one type of HA receptor (Black et al. 1972). The work showed clearly a physiological role for gastric HA and revolutionized the treatment of peptic ulcer disease. Presently, there are four H2 antagonists in wide clinical use cimetidine, ranitidine, famotidine, and nizatidine. Surprisingly, cimetidine's Kd on the H2 receptor is only 0.8 M (Hill et al. 1997), yet the drug has been used successfully by millions of patients with only a few side effects. Cimetidine is known to inhibit some forms of cytochrome P450, which can lead to clinically significant drug-drug interactions (Furuta et al. 2001). Many other non-H2 actions of cimetidine have been found at higher drug concentrations (see table 3 in Hough et al. 1997). Because of its low potency and non-H2 actions, cimetidine is not a good experimental agent to study H2 receptor actions....
Salicylates may reduce the tubular secretion and decrease the diuretic efficacy of spironolactone, and spironolactone may alter the clearance of cardiac glycosides. Owing to its effects on other steroid receptors, spironolactone may cause gynecomastia, impotence, decreased libido, and menstrual irregularities. Spironolactone also may induce diarrhea, gastritis, gastric bleeding, and peptic ulcers (the drug is contraindicated in patients with peptic ulcers). CNS adverse effects include drowsiness, lethargy, ataxia, confusion, and headache. Spironolactone may cause rashes and, rarely, blood dyscrasias. Whether therapeutic doses of spironolactone can induce malignancies remains an open question. Strong inhibitors of CYP3A4 (see Chapter 3) may increase plasma levels of eplerenone such drugs should not be administered to patients taking eplerenone, and vice versa. Other than hyperkalemia and GI disorders, the rate of adverse events for eplerenone is similar to that of placebo.
Pirenzepine, an antagonist with relatively high affinity for the muscarinic Mj and modest affinity for the muscarinic M4 receptor, is approved for clinical use in the treatment of peptic ulcer disease (84). Structurally related compounds in clinical development include telenzepine (13) and nuvenzepine (85). It is arguable that a selective muscarinic M3 receptor antagonist may be useful in the treatment of peptic ulcer disease, given the role of this subtype in regulating parietal cell secretion (86). Although this aspect of muscarinc receptor antagonism has not been extensively explored in clinical studies, nuvenzepine acts as a potent muscarinic M3 antagonist.
To evaluate the ulcer healing properties of any GI-sparing agent, a chronic ulcer model is generally employed with acetic acid being used to produce gastric ulcers in rats, which highly resemble human ulcers in terms of pathological features and healing mechanisms (Okabe & Amagase, 2005). These ulcers respond well to antiulcer drugs such as the proton pump inhibitors and sucralfate (Okabe & Amagase, 2005). In this model, induction of gastric ulceration was associated with a increase in expression of CSE and CBS enzymes as well has H2S levels, suggesting a defensive response (Wallace, Dicay, McKnight, & Martin, 2007). Ulcer healing was observed following administration of three chemically distinct (Lawesson's reagent, 4-hydroxyhiobenzamide, and H2S-5-ASA) H2S donors, and
Anticholinergic drugs have a minor role in the management of peptic ulcer disease.71 For the present, the most rational therapy involving anticholinergic drugs seems to be a combination of a nonirritating diet to reduce acid secretion, antacid therapy, and reduction of emotional stress. Most of the anticholinergic drugs are offered either as the chemical alone, or in combination with a CNS depressant such as phenobarbital, or with a neuroleptic drug to reduce the CNS contribution to parasympathetic hyperactivity. In addition to the antisecretory effects of anticholinergics on hydrochloric acid and gastric acid secretion, there have been some efforts to use them as antisialagogues and anhidrotics.
Peptic Ulcer Disease Peptide ulcer disease (PUD) is a group of upper GI tract disorders characterized by mucosal erosions equal to or greater than 0.5 cm that result from the erosive action of acid and pepsin.63 Duodenal ulcer and gastric ulcer are the most common forms, although PUD may occur in the esophagus or small intestine. Factors involved in the pathogenesis and recurrence of PUD include hypersecretion of acid and pepsin and GI infection by Helicobacter pylori, a Gram-negative spiral bacterium. H. pylori have been found in virtually all patients with duodenal ulcers and approximately 75 of patients with gastric ulcers. Some risk factors associated with recurrence of PUD include cigarette smoking, chronic use of ulcerogenic drugs (e.g., nonsteroidal anti-inflammatory drugs NSAIDs ), male gender, age, alcohol consumption, emotional stress, and family history. About 4 of gastric ulcers are caused by a malignancy, whereas duodenal ulcers are generally benign. The H2-antagonists...
5.4 HISTAMINE ANTAGONISTS IN THE TREATMENT OF PEPTIC ULCERS H2 Antagonists have been thoroughly studied in the context of the control of peptic ulcer disease. The development of anti-ulcer drugs based on histamine is one of the classical case histories of medicinal chemistry. The parietal cells in the stomach release acid under the stimulation of the peptide hormone, gastrin, and the local hormones, histamine 5.1 and acetylcholine. Stomach ulcers are formed partly as a result of trauma but also because of infection by a bacterium, He-licobacter pylori. If an ulcer has formed in the stomach lining, the presence of a strongly acidic environment inhibits the healing process. The development of selective histamine antagonists therefore provided a means of reducing the acidity of the stomach and allow the ulcer to heal. A side effect of this compound was noticed in a small number of patients. There was a decrease in the white blood cell count, a condition known as granulocytopenia. This...
These drugs inhibit central and peripheral prostaglandin formation, thus inhibiting pain transmission. They are broadly classified into two groups non-specific cyclo-oxygenase (COX) inhibitors (ibuprofen, naproxen, aspirin, acetaminophen, ketorolac, and diclofenac) and specific COX-2 inhibitors (celecoxib, rofecoxib, valdecoxib, and parecoxib). These drugs are effective for bone-related pain and are frequently used to treat mild to moderate acute pain, chronic pain, cancer-related pain, arthritic pain, inflammatory pain, and fever. Side effects of these medications limit their use in the elderly. Ibuprofen and naproxen can prolong prothrombin time in patients on warfarin which can lead to excessive bleeding (Schulman and Henriksson 1989, Dijk et al. 2004, Visser et al. 2005). They should be used with caution in patients with gastrointestinal ulcers, renal insufficiency, and hepatic sufficiency. Ketoralac is an intravenous analgesic and effective for orthopedic and somatic pain....
Superior to fluoxetine, and both duloxetine and venlafaxine also may be effective) fibromyalgia peptic ulcer and irritable bowel syndrome hot flashes of menopause chronic fatigue cataplexy tics migraine and sleep apnea. These disorders may have some psychobiological relationship to mood or anxiety disorders.
Clinical uses of Epi are based on its actions on blood vessels, heart, and bronchial muscle. A major use is to provide rapid relief of hypersensitivity reactions, including anaphylaxis, to drugs and other allergens. Epi is used to prolong the action of local anesthetics, presumably by vasoconstriction and a consequent reduction in absorption (see Chapter 14). It may restore cardiac rhythm in patients with cardiac arrest. Epi also is used as a topical hemostatic agent on bleeding surfaces such as in the mouth or in bleeding peptic ulcers during endoscopy of the stomach and duodenum. Systemic absorption of the drug can occur with dental application. In addition, inhalation of Epi may be useful in the treatment of postintubation and infectious croup. The therapeutic uses of Epi, in relation to other sympathomimetic drugs, are discussed later in this chapter.
The molecular composition Al(NH2CH2COO)(OH)2, with two hydroxide moieties, reflects the full formulation of dihydroxy aluminum glycinate. The species has been tested experimentally11 and clinically as a new intragastric buffer solution for achievement of prolonged physiological pH value.12 The same species has been tested as a gastric acid neutralizer in the case of peptic ulcer. In contemporary pharmacological preparations, it is being administered in the formulation marketed as Gastralgine . This pharmaceutical was tested as an antacid and mucosal coating agent.13 Gastralgine contains Al(OH)3 and aluminum glycinate, magnesium trisilicate and simethicone (a nonprescription drug, which is used for short-term relief of excess gas in the gastrointestinal tract it is also used to relieve symptoms of infant colic) and works by promoting protective effects from ulcers.
Haque et al.35 at Bristol-Myers Squibb published a solid-phase synthetic approach for the optimization of pyrazoles as Helicobacter pylori dihydroorotate dehydrogenase (DHODH) inhibitors. H. pylori is a microaerophilic bacterium responsible for several gastrointestinal disorders, playing a role in afflictions such as gastritis, gastric ulcers, and even gastric cancer. Current treatment involves multi-drug therapy which, as a side effect, tends to eradicate normal gastrointestinal flora. Dihydroorotate dehydrogenase (DHODase) is involved in the de novo biosynthesis of pyrimidine. Pyrimidines are crucial for bacterial survival consequently, interrupting the pyrimidine production by DHODase could lead to the eradication of H. pylori, offering a viable treatment for gastrointestinal disorders.
PDGF was tested first for the prevention of acute ethanol-induced gastric erosions and subsequently for the acceleration of healing of indomethacin-induced gastric ulcers 43 In our studies, groups of fasted rats were given PDGF at doses of 500 ng 100 g, 1 or 2 . 5 pg 100 g s .c. or by i .g . gavage, 30 min prior to the per os administration of 1 mL of 75 ethanol . As a positive control, an additional group of rats received the SH-containing taurine (50 mg 100 g) . All animals were killed 1 h after receiving ethanol and the area of hemorrhagic mucosal lesions in the glandular stomach was measured by computerized stereomicroscopic planimetry The results indicated that only 2 . 5 pg 100 g of PDGF administered i .g . reduced the area of acute mucosal lesions (p 0 . 05), whereas pretreatment with taurine resulted in about 50 reduction of gastric damage (p 0.05) .44,45 bFGF administration by i.g . gavage 30 min prior to three ulcerogenic doses of cysteamine on the third day did not markedly...
Cimetidine (Tagemet, Fig. 2) is a drug that inhibits antihistamine H2 receptor binding and is used in the treatment of gastric ulcers. There is considerable literature on the inhibition of drug metabolism by cimetidine in both animal and human models (Gerber et al., 1985). A similar H2 receptor antagonist, ratinidine (Zantac), was developed by another company and was devoid of the inhibitory properties, a point that was exploited in marketing.
(proton pump inhibitors) Hepatic impairment in severe hepatic impairment max. 20mg daily (CHILD 1-12 years max. 10mg daily) for severe peptic ulcer bleeding in severe hepatic impairment, initial intravenous infusion of 80 mg, then by continuous intravenous infusion, 4mg hour for 72 hours By mouth duodenal ulcer associated with Helicobacter pylori, see eradication regimens on p. 50 NSAID-associated gastric ulcer, ADULT over 18 years, 20 mg once daily for 4-8 weeks prophylaxis in patients with an increased risk of gastroduodenal complications who require continued NSAID treatment, 20 mg daily By intravenous injection over at least 3 minutes or by intravenous infusion, ADULT over 18 years, gastro-oesophageal reflux disease, 40 mg once daily symptomatic reflux disease without oesophagitis, treatment of NSAID-associated gastric ulcer, prevention of NSAID-associated gastric or duodenal ulcer, 20 mg daily continue until oral administration possible Severe peptic ulcer bleeding (following...
Misuse of ethanol is associated with detrimental effects on several body organs and is one of several predisposing factors for gastrointestinal disorders. The pathophysiology of the gastric ulcer centers on an imbalance between aggressive and protective factors in the stomach when aggressive factors (such as secretion of acid, pepsin, and emotional stress) have stronger effects than those of protective factors (such as cellular regeneration, prostaglandins, and EGF), gastric ulcer may occur. Many pharmaceutical products have been developed to treat gastrointestinal diseases such as ulcer hemorrhage and perforation (Higham et al., 2002). An increase in these disorders has been attributed to the increased use of NSAIDs, which have significant side effects despite the large amount of money and effort poured into their development by pharmaceutical companies. Hence, there is a need for new therapeutic compounds without side effects.
There is a strong connection between gastric cancer and atrophic gastritis. The most common cause of atrophic gastritis is chronic infection with H. pylori, a Gram-negative curved bacillus that colonizes the mucin layer of the gastric lining. Its presence has been implicated in several upper gastrointestinal conditions, including nonulcer dyspepsia, acute and chronic gastritis, duodenal and gastric ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma.
Ulceration, to a frank mass (Figure 10.3). Early gastric cancer may be more difficult to detect, and in Japan, dyes administered through the scope are sometimes used in an attempt to improve diagnostic accuracy. These techniques are not widely used in the U.S. Gastric cancer can often present with gastric ulceration, and sometimes distinguishing between peptic ulcer and cancer can be difficult. When a gastric ulcer is identified, repeat endoscopy after an appropriate course of acid suppression is recommended to document healing. Nonhealing ulcers should be extensively biopsied at their margins to assess for neoplasia. Linitis plastica (leather bottle stomach) is the result of an aggressively infiltrative tumor, with high-grade tumor cells spreading throughout most of the stomach yielding a coarse, noncompliant stomach. This form carries a poor prognosis, but is quite uncommon.
A few years after the discovery of Helicobacter pylori (H. pylori), fundamental revision had to be made at the sections of gastritis and gastric cancer in the textbooks of pathology and gastroenterology. Nobody had imagined such a high incidence of H. pylori infection in humans, since it was thought that no bacteria could survive such a high pH in the gastric cavity. Almost 20 years have passed since the report of Marshall and Warren in 1984.1 Now it is clear that there is a category of gastritis associated with H. pylori infection, leading to high incidence of gastric cancer and malignant lymphoma. There was a great impact in the report that removal of the bacteria by antibiotics cures longstanding uncontrollable gastric ulcer. The International Agency for Research on Cancer (LARC) has defined H. pylori as a Group 1 carcinogen.2 Therefore, extensive studies are now in progress. Recent animal experiments revealed that H. pylori works mainly as a promoter. The question is still...
Peptic Ulcer Disease The pathophysiology of peptic ulcer disease is best viewed as an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, and other peptides and growth factors) and injurious factors (acid and pepsin). On average, patients with duodenal ulcers produce more acid
Stress ulcers are ulcers of the stomach or duodenum that occur in the context of a profound illness or trauma requiring intensive care. The etiology of stress-related ulcers differs somewhat from that of other peptic ulcers, involving acid and mucosal ischemia. Because of limitations on the oral administration of drugs in many patients with stress-related ulcers, intravenous H2 receptor antagonists have been used extensively to reduce the incidence of GI hemorrhage due to stress ulcers. Now that intravenous preparations of proton pump inhibitors are available, it is likely that they will prove to be equally beneficial.
Activation of plasminogen to plasmin produces several events. The primary event is the dissolution breakup of any fibrin-containing clots encountered, including those found obstructing blood vessels. However, clots formed to prevent bleeding caused by injuries, such as cuts (surgical), puncture wounds, or pathological sites such as bleeding ulcers, would also be degraded. This constitutes an undesirable interference with the integrity of the vascular system. Excessive circulating plasmin is continuously destroyed by the plasmin inhibitors to control or to minimize such effects. As mentioned, circulating plasmin continuously breaks down fibrinogen and other clotting factors. Another factor to be considered is that the plasmin-produced FDPs prevent the production of more fibrin by inhibiting the conversion of fibrinogen to fibrin by thrombin (Fig. 11-1). This will reduce available circulating fibrinogen, thereby producing an anticoagulant effect that FDPs will continue to have even...
Without rest pain and no peripheral tissue necrosis Cautions atrial or ventricular ectopy, atrial fibrillation, atrial flutter diabetes mellitus (higher risk of intraocular bleeding) concomitant drugs that increase risk of bleeding interactions Appendix 1 (cilostazol) Contra-indications predisposition to bleeding (e.g. active peptic ulcer, haemorrhagic stroke in previous 6 months, surgery in previous 3 months, proliferative diabetic retinopathy, poorly controlled hypertension)
The Cancer Pain Relief Program of the World Health Organization (WHO) developed an analgesic ladder for the management of pain of increasing intensity (Jacox et al. 1994). For mild pain, the recommendations start with NSAIDs. This drug class must be used with caution in those patients receiving steroids as part of their oncologic management. NSAIDs are also contraindicated for patients who have renal insufficiency, intravascular volume depletion as seen with intractable vomiting, congestive heart failure, or peptic ulcer disease. A ceiling effect may occur and increasing doses will lead to side effects without additional benefits. Opioids have no ceiling effect. In the WHO ladder, moderate pain is treated with traditionally weak opioids. Agents such as codeine, oxycodone, hydrocodone, and meperidine are used. Mixed agonists-antagonists are incorrectly considered as protection against respiratory depression but may have greater side effects. These mixed agonists also have a ceiling...
Indications prevention of deep-vein thrombosis in general or orthopaedic surgery thromboembolic disease in patients with history of heparin-induced thrombocytopenia Cautions recent bleeding or risk of bleeding concomitant use of drugs that increase risk of bleeding antibodies to heparins (risk of antibody-induced thrombocytopenia) body-weight over 90 kg (monitor anti factor Xa activity) Contra-indications haemophilia and other haemor-rhagic disorders, thrombocytopenia (unless patient has heparin-induced thrombocytopenia), recent cerebral haemorrhage, severe hypertension, active peptic ulcer (unless this is the reason for operation), diabetic retinopathy, acute bacterial endocarditis, spinal or epidural anaesthesia with treatment doses of danaparoid
Evidence that endogenous PGs are crucial to maintaining gastroduodenal integrity has led to the suggestion that PUD might be a prostaglandin deficiency disease. Along these lines, this also partially explains the ulcerogenic character of all presently available NSAIDS. The fact that the stomachs of gastric ulcer patients contained significantly lower levels of PGEs than did those of normal subjects is an important piece of supportive evidence for the central role of PGs in PUD. Finally, with the recognition of a new receptor in the cell membrane of parietal cells from canine, porcine, and rabbit sources,6 an explanation for the antisecretory effects of E-type PGs is now at hand (Fig. 13-2). By Lederle, to treat gastrointestinal ulcers and other hypersecretory states
Vollenbroich and coworkers36 showed that a surfactin treatment improved proliferation rates and lead to changes in the morphology of mammalian cells that had been contaminated with mycoplasma. Furthermore, the low cytotoxicity of surfactin to mammalian cells allowed specific inac-tivation ofmycoplasmas without significant damaging effects on cell metabolism.42,43 Additionally, surfactin and surfactin analogs have been reported as antiviral agents, namely it was demonstrated a significant inhibitory effect of pumilacidin on herpes simplex virus 1 (HSV-1)44 and an inhibitory activity against H+, K+-ATPase and protection against gastric ulcers in vivo. The potential of surfactin against human immunodeficiency virus 1 (HIV-1) was reported by Itokawa et al.41 The antiviral action of surfactin was suggested to be due to physicochemical interactions between the membrane-active surfactant and the virus lipid membrane, which causes permeability changes and at higher concentrations leads...
Hyperkalaemia Inhibition of aldosterone secretion by unfractionated or low molecular weight heparin can result in hyperkalaemia patients with diabetes mellitus, chronic renal failure, acidosis, raised plasma potassium or those taking potassium-sparing drugs seem to be more susceptible. The risk appears to increase with duration of therapy, and plasma-potassium concentration should be measured in patients at risk of hyperkalaemia before starting the heparin and monitored regularly thereafter, particularly if treatment is to be continued for longer than 7 days Contra-indications haemophilia and other haemor-rhagic disorders, thrombocytopenia (including history of heparin-induced thrombocytopenia), recent cerebral haemorrhage, severe hypertension peptic ulcer after major trauma or recent surgery to eye or nervous system acute bacterial endocarditis spinal or epidural anaesthesia with treatment doses of unfrac-tionated or low molecular weight heparin hyper-sensitivity to unfractionated or...
A system of stratification or subgroupings of patients by morphological or functional criteria has never been agreed upon.19 Differential diagnoses must include pancreatic cancer but also include peptic ulcer disease, irritable bowel syndrome, gallstones, and endometriosis. An initial first step in the management of pain in patients with chronic pancreatitis is the exclusion of complications that can be the cause of the pain such as pseudocysts or compression of adjacent visceral structures.24
Niacin, in doses that range above the DRI but below that required for dyslipidemias, is unlikely to produce adverse effects. However, adverse effects of niacin are seen when this vitamin is used at pharmacological doses above 1 g day in the treatment of dyslipidemia. Notable adverse effects include flushing because of vasodilation dermatological effects including dry skin, pruritus and hyperkeratosis gastrointestinal effects including peptic ulcer, stomach pain, nausea, and diarrhea elevations in serum uric acid and glucose (in Type 2 diabetics) and rare hepatotoxic-ity.159-161 Traditionally, hepatotoxicity has been more associated with the sustained release as compared to the immediate release formulations however, recent analysis of niacin-ER adverse events suggests the opposite may be true for this formulation.162
Telenzepine is an analog of pirenzepine that has higher potency and similar selectivity for Mj muscarinic receptors. Both drugs are used in the treatment of acid-peptic disease in Europe, Japan, and Canada, but not currently in the U.S. At therapeutic doses of pirenzepine, the incidence of dry mouth, blurred vision, and central muscarinic disturbances are relatively low. Central effects are not seen because of the drug's limited penetration into the CNS. Pirenzepine's relative selectivity for Mj receptors is a marked improvement over atropine. Pirenzepine (100-150 mg day) produces about the same rate of healing of duodenal and gastric ulcers as the H2 antagonists cimetidine or ran-itidine. Side effects necessitate drug withdrawal in
The induction of labor can also be stimulated by prostaglandins, natural substances synthesized from fatty acids, that are involved in many physiological processes (see page 40). In addition to causing uterine contraction, prostaglandins assist in ripening of the cervix. Currently, only PGE2 (dinoprostone) is approved for the induction of labor (Cervidil, Forest Laboratories Prostin E2, Pfizer), but PGF2ct (dinoprost), another natural prostaglandin used earlier, is also effective. Dinoprostone is administered locally. Misoprostol, an orally active synthetic PGE, derivative (see page 92), is also efficacious for induction of labor, but it is used in the US mainly for the prevention of NSAID-induced gastric ulcer.
In the rat stomach, opioid agonists have been shown to prevent the formation of gastric ulcers in response to acidified ethanol or other irritants. This action is mediated through delta opioid receptors present in both the ENS and CNS 74,75 and is not due to a reduction in gastric acid output 76 . Agonist stimulation of delta opioid receptors in the brainstem appears to increase vagal outflow to the stomach, resulting in the release of cytopro-tective nitric oxide and prostaglandins from vagal efferent neurons 77,78 . Interestingly, both naloxone and naltrindole also prevent the gastroprotec-tive action of clonidine, an a2-adrenergic agonist 79 . Although the nature of
Unlike aspirin, NSAIDs do not produce irreversible platelet inhibition. Patients at risk for GI disturbances are those of advanced age, those with histories of prior ulcers, and those simultaneously receiving steroids. To reduce the risk of GI complications, the lowest doses possible should be used. Use of misoprostol or omeprazole may be efficacious in preventing ulcers. Ranit-idine and cimetidine are not useful in preventing ulceration, but they may be employed to treat the gastric ulcers produced by NSAID use. NSAIDs may reduce renal blood flow and glomerular filtration. As a consequence, there is increased water and electrolyte reabsorption in the proximal tubule, predisposing vulnerable persons to increased blood pressure and congestive heart failure. Other toxic effects of NSAIDs include hepatotoxicity and acute renal failure.
Indications prophylaxis of embolisation in rheumatic heart disease and atrial fibrillation prophylaxis after insertion of prosthetic heart valve prophylaxis and treatment of venous thrombosis and pulmonary embolism transient ischaemic attacks Cautions see notes above also recent surgery recent ischaemic stroke history of gastro-intestinal bleeding peptic ulcer concomitant use of drugs that increase risk of bleeding bacterial endocarditis (increased risk of bleeding use only if warfarin otherwise indicated) avoid cranberry juice interactions Appendix 1 (coumarins)
Indications hyperlipidaemias of types IIb and IV in patients who have not responded adequately to diet and other appropriate measures Contra-indications peptic ulcer Renal impairment reduce dose if eGFR 30-60 mL minute 1.73 m2 avoid if eGFR less than 30 mL min-ute 1.73m2 Pregnancy manufacturer advises avoid Breast-feeding manufacturer advises avoid Side-effects vasodilatation, flushing, itching, rashes, urticaria, erythema heartburn, epigastric pain, nausea, diarrhoea, headache, malaise, dry eyes rarely angioedema, bronchospasm, anaphylaxis Dose