Appearance and Reality in the School for Scandal Essay

The School for Scandal is a dramatic play written by Richard Sheridan. In this essay i’m going to discussed Appearance and Reality . There’s a characters who represent the false appearances and the really appearances. The School for Scandal’s member are the trust appearance and they distant reality. There’s a dramatic element like the disguise of Sir Oliver in his trial test on Joseph and Charles. We have the two brothers, Joseph Surface and Charles Surface. The dramatic tool used to know the good brother. And also the dramatic irony in the scene screen (the culmination of the play). The School for Scandal is formed by hypocritical characters. On the one hand Lady Sneerwell (young widow. She is attracted to Charles Surface and plots with Joseph Surface to break up Charles and Maria) , Lady Teazle (Young wife of Sir Peter. She and her husband have their little spats), Joseph Surface (Who pretends to be an honorable gentlemen but It is the bad brother. ) and Mrs Candour (A professedly kindhearted woman who speaks well of everyone in such a way as to ruin their reputations in the process. ). They are the appearance. On another hand we have the real characters. Sir Peter (Husband of Lady Teazle)and Sir Oliver Surface (Charles and Joseph’s uncle) and Charles Surface (really the good brother). Mrs. Candour and her love of gossip make her one of the most scandalous pupils of all; her true sentiment is seen only through the false accounts of others which she delivers to any listening ear, often using metaphors of money. If a scandal were to take place, she could risk losing it all, whether reputation or wealth. This can be seen as foreshadowing the fate of Joseph; he took such care to secure his financial success, and one scandal ruined it all. The object of Joseph’s financial success, Maria, who possesses neither a â€Å"screen† nor an interest in spreading lies, is greatly affected by the change in Lady Teazle, as it consequently means that her unwilling role in the scheme is over. Charles Surface has a reputation as a scoundrel. But beneath his flawed veneer, he is a decent fellow. Joseph Surface has a reputation as an upright man. But beneath his flawless veneer, he is a villain. Joseph Surface is appearance and Charles Surface is reality. Joseph is the bad brother and Charles is the good brother. Joseph lies because he wants the fortune of Maria and he wants to marry Maria for economical interest. Sir Peter and Sir Oliver want to discover the truth about the two brother, Charles and Joseph. (the reality). There’s a dramatic tool here. The disguise. Sir Oliver disguises and he makes a trial to Charles (for he known as Mr. Premium) and Joseph (for he known as Mr. Stanley) to know who is the good brother. In the scene screen, Joseph seizes upon Lady Teazle’s discontent with Sir Peter to mount a subtle argument that seeks to rationalize and justify adultery. Once the deception of hiding Lady Teazle behind the screen is in place, Sheridan fully exploits its potential for ironic double meanings and double dealings. The School For Scandal draws a humorous picture of an unfortunate reality; that many people will do anything to further elevate their characters, even if it means hurting friends and family. The characters of the play are willing to construct elaborate â€Å"screens† of sentiment in order to deceive those around them and increase their own wealth.

IHRM and HRM Difference

In a highly competitive global economy, where the other factors of production—capital, technology, raw materials, and information—are increasingly able to be duplicated, â€Å"the caliber of the people in an organization will be the only source of sustainable competitive advantage available to companies. Domestic HRM and international HRM are both concentrate on human resource management, but there are many differences also. No mater domestic HRM or international HRM an organization’s HRM activities are also include these 6 parts. The first part is human resource planning, before the company employs the employees the company should know what kind of employees their need. Then the second part is staffing (recruitment, selection, placement), the company select the employees what they need from the HR market. The third part is compensation (remuneration) and benefits. The company should set the employees’ wages. Then, the forth part is deal with the industrial relations. It is common in every company that there are many troubles in employees or in employees and the company, so the company should set a department which is especial deal with the problem. The fifth part is performance management. The company’s main project is to make profits, so at the end of the year the company will reward or punish according to the employee’s performance. The last part is training and development. And these parts are completed one by one. There are also many differences between domestic HRM and IHRM. IHRM complexity can be attributed to six factors. The first is more HR activities such as international taxation; international relocation and orientation; host-government relations; language translation services. For example, to a domestic company it is only concerned with the tax rates in his country, but for a international company it is not only focus on his PCN’s tax rates but also focus on his TCN’s tax rates. The second is need for a broader perspective such as program design and administration for several employee groups; long term consequences on key decisions made. For example, to a domestic company it pays all attention to his program design and administration in his country, but for a international company it is not only focus on his PCN’s program design and administration but also pays attention to his TCN’s program design and administration. The third one is more involvement in employees’ personal lives. One obvious difference between domestic and international HRM is that staff are moved across ational boundaries into various roles within the international firms foreign operations—these employees have traditionally been called expatriates. An expatriate is an employee who is transferred out of their home base into some other area of the firm’s international operations. There are many factors will determine the assignment succeed or failed such as level of support to handle for PCNs and TCNs, banking, investments, home rental while on assignment, coordinating home visits , final repatriation, level of explanations particularly on the comp. ackage components , marital status during selection process. The forth one is variations in the mix of expatriates and locals, for example if the company want maturity evolves, the company need to support expat and virtual team. All these such as foreign subsidiary increased autonomy, high potential selection and development, long term succession planning necessitates flexibility and focus fluctuation within the HR department, not needed for domestic HR to the same degree. The fifth one is risk exposure, the IHRM will face heavier financial and human consequences in case of assignment failure. The last one is broader external influences such as the type of government; the state of the economy ; generally accepted practices of doing business in host countries. We can conclude that HRM is important to every company no matter it is domestic company or international company, so the manager should pay more attention to the HRM or the company will fail.

IT-based management: Challenges and solutions. NTT DoCoMo Essay

NTT DoCoMo Introduction            NTT DoCoMo is one of the largest mobile communications companies in japan that has thrived for a long period. Despite of this factor, the company faces several challenges in terms of market saturation, competition from rival companies and rivalry in the mobile phone industry. NTT DoCoMo was found in the year 1992, a period when it was spun off by NNT (Nippon Telegraph and Telephone). Looking back at NTT’s history, it is noted that the company was privatized in 1986, but still the government of japan still held some shares of 46% and part of its equities in the year 2004. As a result of this, NTT owned 58% of DoCoMo’s equities.            Though DoCoMo poses great potential in terms of innovation, the company also faces competition, especially in the technology sector. Felica (part of DoCoMo) has over the years competed with Type A and Type B contactless IC technologies, where type A technology was mostly used in Europe, and Type being utilized in Japan extensively. With this type of competition, the company was able to form alliances with other stakeholders to come up with a technology (a chip tech) that would be utilized by credit card users.            DoCoMo’s strategy to pursue the wireless internet was achieved with the launch of i-mode. This is in consideration of the fact that i-mode technology enabled users to receive an incoming call while surfing the internet. The technology mostly targeted young consumers rather than business persons, in spite of the fact that business individuals would most probable use premium services of the product. Through this aspect, the various competitive advantages of the product are realized with its market limitations on the other hand. This concept introduces porter’s generic strategy into use, where one can increase profits through the reduction of costs while at the same time charging industry’s average price. Porter’s strategy (cost reduction strategy) also facilitates the increase in market shares through the lowering of prices, while at the same time making reasonable profits from the sale of each share. In consideration of the cost reduction strategy, DoCoMo Company was able to set up small transaction fees for its chip technology to its users. These transaction fees were on an average of about 2% to 3% for EDY services. Such a strategy poses a competition to credit card companies whose transaction fee run on an average of about 3% to 5%.            Porter’s generic strategy also incorporates the focus strategy, where a company concentrates on a particular market. This is usually through the understanding of the dynamics that exist in a particular market (understanding of the customer’s needs is one of the crucial factors to consider in this strategy). The main advantage of this strategy is that, customer loyalty is usually established especially when unique services are provided in a new market. Despite the DoCoMo’s extensive marketing strategies, the company was not able to utilize the focus strategy. Though DoCoMo’s success in Japan in the initial launch of i-mode, the company did not lay a strategic focus on the Japan market. Its foreign ventures especially in the USA and other countries also faced various challenges that were not considered prior to the venture. From the study, it is evident that DoCoMo’s partners also did not adopt i-mode technology, something that cont ributed to its disadvantages overseas.            In porters five model, four factors are perceived to have the capability of causing market rivalry. These factors are supplier power, threat of new entrants, threat of substitutes, and the buyer’s power (Hill & Jones,  2010). Through the analysis of DoCoMo’s market, it is realized that the company faces a high supplier’s power in its market, a factor that has made it loose its influence over the Japanese market. Government policies have also affected DoCoMo’s entrant to new markets, an element that has reduced the extent of expansion of the company.            Prior to taking any risk, companies and others organizations ought to come up with a model that will enable them to project the probable risk that is prone to affect their venture hence making it unsuccessful. DoCoMo is a company that has great ideas and innovations but the only issue affecting the company’s performance was the lack of well centered risk projection pattern or model. In a risk projection model, one has to identify the risk, analyze the risk qualitatively, assess the issues at hand quantitatively and finally come up with a risk response planning. With this model, DoCoMo Company would be able to come up with a solution to its market problem especially in the Japanese market. The model would also enable the company to choose selectively, the most appropriate countries to partner with (Grey,  2004). .            Competition is one of the problems that DoCoMo is facing. This problem can be addressed effectively through the implementation of a proper differentiation strategy. Product differentiation entails making once product different and more attractive than the competitors’ products. The extent of differentiation in this case will depend on the nature of technological products being produced by other companies in the market. In consideration of this concept, DoCoMo will be obliged to produce products that have more functionality, features and durability than the competitor’s products. I relation to this; i-mode (DoCoMo’s product) would have a higher competitive edge over its rival products (Joia,  2003).            Though DoCoMo tried to diversity its market extensively, the company was unable to come up with an effective focus strategy. By having a proper focus strategy, DoCoMo would be able to dominate in its market where the product supply would remain constant. In this case a proper focus can be achieved through the development of a uniquely low-cost and well-specified product market. Such a strategy would enable the company to create dominance over its market, hence establishing customer loyalty (Joia,  2003). Cost focus differentiation would also be an important strategy for the company to implement especially when attracting new customers. In consideration of all these factors that DoCoMo should consider in coming up with a solution to its problems. The management of the company is also expected to carry out a SWOT analysis of the company in order to solve its problems. A clear and well-set SWOT analysis would enable the company come-up with a measure to manage the s uppliers’ power and also the capability to reduce the buyer’s power. This would in-turn enable the company dominate its market and thrive in all its market ventures (Joia,  2003). Recommendation            From the study, it is realized that DoCoMo is a company that has been extensively to produce products that are of high innovation due to its mergers with other stakeholders. The company also faces problems in terms of competitors. As a result of all this, it would be recommendable for the company to set-up a proper management program. A program, that will be able to overlook all the necessary strategies that can enable the company thrive in both domestic and foreign markets. Implementation of both SWOT and porters five model would enable the DoCoMo thrive well in providing e-money services (Joia,  2003). References Grey,  S. (2004). Practical risk assessment for project management. Chichester: Wiley. Hill,  C.  W., & Jones,  G.  R. (2010). Strategic management theory: An integrated approach. Mason, OH: South-Western/Cengage Learning. Joia,  L.  A. (2003). IT-based management: Challenges and solutions. Hershey, PA: Idea Group Pub. Source document

Knowledge, Innovation, and Learning Essay Example | Topics and Well Written Essays - 500 words - 1

Knowledge, Innovation, and Learning - Essay Example The aim of our project was to highlight how 3M is capable of sharing knowledge across social networks, as well as sharing it within social networks to create new innovations. As a participant in this process, I gained experiences researching and understanding complex business resource issues as well as investigating and rating how one company implements these ideas. Our process was mainly twofold. First, we conducted a literature review. We investigated knowledge management, innovation as a competitive advantage, types of data, information and knowledge as well as how the cycle of knowledge works. Next, we analyzed how 3M applies these principals to the business world and made certain recommendations. As well as our project went, there is still room for improvement. There were pros and cons to the process, however. They are expressed as strong and weak points of the process, positive and negative experiences as well as positive and negative feelings. The process was strong in that we all had great ideas to proffer to our project, but weak in that we had a difficult time discerning which ideas to implement. Furthermore, the positive experience was that we were able to bring it all together in the end. The negative experience was that often times some of the group was hearing the other members but not really listening to them. His elicited some negative feelings along the way. When waves off the opinions of others as unimportant, it creates feelings of opposition instead of cooperation. In the end,  however,  the completion of our project made everyone feel accomplished. These are some of the dualistic challenges one meets while working with others.

Week 5 Assignment Example | Topics and Well Written Essays - 250 words

Week 5 - Assignment Example such as there is no positive outcome of resolving the conflict, it is too trivial, disruption would prove to be very costly, etc mangers tend to use the avoiding style of conflict management (Schyns & Hansbrough, 2010). Hence, it is first important to understand why the manager is avoiding conflict before confronting them. With the exception of the above two cases, an employee must confront the manager if a conflict is being avoided. It is very important for an employee to trust and believe in his or her manager. It is only when an employee trusts the manger to act in the best interest of the employee that he or she can dedicate completely and work for the manager. In the absence, of this trust an employee will not only lose confidence but also be de-motivated. This will affect both the performance of the employee as well as the overall output of the team. This attitude of the manager to avoid conflicts can disrupt the dynamics of a group as employees do not feel recognised or rewarded with respect to the work they do in comparison with other employees. This can further escalate the conflicts in a group. Also, the feedback given by a conflict avoiding manager can be very diplomatic and does not serve the purpose of a feedback. Employees need to have a clear understanding of where they stand in the workplace and how they can improve. This cannot be accomplished with a diplomatic feedback. Therefore, it is important that an employee confronts a conflict avoiding

Is the punishment of Prometheus in Aeschylus' Prometheus Bound just or Essay

Is the punishment of Prometheus in Aeschylus' Prometheus Bound just or unjust How does the play itself define justice - Essay Example To be just is to act in total obedience to the will of Zeus, because men are not free, but only Zeus is: â€Å"Why, all things are a burden save to rule/ Over the Gods; for none is free but Zeus† (Aeschylus). On the other hand the play also points to another conception of justice, and that is justice in reference to how men and gods honor the value of friendship, and in the way actions of gods and men favor the development of men, the intellect, and human reason, over the arbitrary whims of a god like Zeus who has no regard for any of that. In this second sense then one can say that the punishment of Prometheus, who gave men the gifts of fire, hope, and the many different arts that have helped human civilization progress against blind and furious nature, and who helped Zeus besides in Zeus’ battle against the Titan, that that punishment is unjust. The rest of the paper develops this idea (Aeschylus; Allen; Irby-Massey). II. On the Justice of the Punishment Meted on Prom etheus by Zeus In the beginning of the play we see that Prometheus was being punished, and that continuing punishment throughout the play also consisted in his public humiliation. The continued messages that Zeus sent to him while tied to a rock, through Zeus’ messengers in a way is also a form of punishment, of the gods sending messages to the chained intellect and human power. The crime, of course, consists in Aeschylus making use of his intellect and his developed abilities to give men not only hope but also the gift of fire, and with it we see later in the play that Prometheus further gifted man with the knowledge to better himself and his society, through the medical arts and the other beneficial sciences. This is a sin to Zeus and the gods, who seemed intent to keep men in an inferior and totally supplicated state in relation to them, totally dependent and obedient to whim. On the other hand, Prometheus’ gifts to men threatened to make them independent and in con trol of their fates, even in control of nature and its whims, as proxy of the gods itself. The continuing sin moreover is the defiance and the pride of Prometheus against his punishment and against Zeus himself and his agents. Instead of currying the favor of Zeus and asking for his mercy, Prometheus chooses to stand defiant and to find his comfort in the company of his friends. We see here two conceptions of justice, one in the eyes of the gods and the faithful and obedient servants of the gods, who see justice as what they see as fitting, what they want. Justice is the will of the gods, and the place of men is to obey that will, no matter how arbitrary and whimsical. The second conception of justice on the other hand takes into consideration human welfare, human progress, and values such as friendship and loyalty to friends, the trust in the wisdom of men and the capacity of men to better themselves. Justice in this second sense is also friendship with men and caring for their ind ependence and capacity for self-reliance. Hence we make sense of the fire from Prometheus as in keeping with this intent. In this second sense it is the actions of Prometheus which are just and the actions of Zeus, who went against friendship values and who punished Prometheus, even though Prometheus helped Zeus to

Financial viability within a health care organization Essay

Financial viability within a health care organization - Essay Example On the other hand, finance deals with concepts, methods, and principles of managing the relevant accounting data for the purposes of attaining certain goals for the business or any given organization (Wiedemann, 2009). Finance involves an aspect of management precisely because it anchors on decision making using available information. Generally, the process of financial management involves the determination of a range of factors that determine the performance of a business or organization. Alternative definitions have explained the difference between accounting and finance by terming finance as a decision science, which relies on the rational methods and means supplied by accounting to arrive at informed decisions, which appertain to the performance of an organization (Wiedemann, 2009). Some theorists have extended this definition to infer that accounting is subordinate to financial management to the extent that it supplies the raw data on which it builds its synthesis. However, experts emphasize on the complementary relationship between the two fields with clear demarcations of areas of specialization. Finance is largely used within the ranks of management although it applies to all levels that have particular interest in financial predictions, budgeting, risk analyses, performance projections, and many other attributes the determine the daily running of businesses and non-profit organizations. The multiple natures of application of the theories and principles of fin ance lend itself to various interpretations in connection with nature of processes and type of organization. The accounting processes and financial management in a healthcare sector are special and different from the usual processes as they relate to normal businesses. According to some financial analysts, the major distinguishing aspect of healthcare finance and accounting is that sources of income are not directly connected to the beneficiaries of

Career Development through International Mobility Essay

Career Development through International Mobility - Essay Example The LVMH Company came into existence as a result of the merger of Moet et Chandon, one of the largest manufacturers of champagne in the world, with a renowned manufacturer of cognac, Hennessey. In 1987, this group further merged with a fashion house, Louis Vuitton. LVMH is a France based group with over 56000 human resources out of which 63% employees work in different locations of the world. There exist 50 prestigious brands under this group, making it recognized as a global giant. It deals with various activities that include business in fashion goods and leather, spirits and wines, perfumes and cosmetics, watches and jewelry, among others. In this assignment, is going to major in the company of Christian Dior, because it is LVMH’s major holding company. It possesses 42.38% of its shareholding and voting rights of 59.3%. Christian Dior’s mass shareholder is also the chairman of both companies. He is LVMH’s CEO. By successfully integrating various famous inspira tional brands, other companies that offer luxurious products, e.g.  Richemont and Gucci, which are now the division of French conglomerate, are doing the same. The assignment also covers Chateau d’Yquem, which is a part of the oldest variety of the group, the manufacturer of first-class vintage wine. In order to make possible the adjustments of cross-cultures, a challenge to train its expatriates for international projects is being faced by LVMH. Therefore, the process of adjustment, involving the training of the employee along with his/her family, would be accelerated. Currently, the language courses are being developed by both pre-departure and post-arrival training. Intercultural training needs to be completed shortly as there exists an international position that needs to be filled without any delay. Due to this short training, the pressure to perform is not executed on such employees. In few cases, new joiners are helped by subsidiaries and the permission is granted to trainees for preliminary field trips. However, as per rule, before sending a candidate to an international exposure, some former international exposure, for instance, through studies or previous professional exposure, must be possessed by him. The kind of business conducted by LVMH requires its employees to possess the mobility factor. Usually, the employees are not found turning down international projects and assignments but it has been observed that the factor that hinders the mobility of an employee is related to the spouse. To tackle this, those young graduates are offered international assignments who are mostly single and who realize the importance of such international assignments as these are likely to help them develop effectively.  

English Composition 1 Essay Example | Topics and Well Written Essays - 250 words - 6

English Composition 1 - Essay Example One hour of active physical activity like walking, swimming or other exercising per day is now recommended by the National Academies’ Institute of Medicine. It is a half an hour per day more that the previous recommendation advised (half an hour five days a week). However, even that old goal is hardly reached by many Americans. This fact is related mostly to using cars and labor-saving devices that free people from long walks and physical activity they had, for example, a century ago. In the modern highly technological and busy world most people spend their days sitting at work, in from of computers or TV sets, and find no time for exercising. Focus, an ability concentrate, is one of the most important skills of a student. It is so because a concentrated person can complete a piece of work, such as homework or test, faster and more effectively since one’s mind is not disturbed by external irritants. Though different people have different abilities to concentrate, this valuable skill can be learned and improved by means of constant practice. One of the methods to reinforce the skill is establishing a rule of having the same time and place to study every day. This, soon, will become a habit to help one in the studying process. Afterwards one can use an established timer to make oneself concentrate on one particular task for, for instance, fifteen minutes. And, of course, one should reward oneself for each small achievement – even the fifteen minutes of focusing on one thing. Finally, with time concentrating becomes a habit, and benefits its owner by the ability to be more attentive during the class or on the t est. Therefore, thought the ability to concentrate is extremely important for achieving success in any process, the good thing is that it can be learned and

Liver Transplant Essay Example for Free

Liver Transplant Essay Organ transplants are some of the hardest surgeries that doctors can do. They require many trained personnel, time, and complicated procedures. Liver transplants are among the most difficult organ transplants that can be done. There are also many risks involved with the surgery and patients must face all of them in order to come out with a new and working liver. According to the American Liver Foundation patients that undergo a liver transplant have a 75% chance of survival after five years. In other words, one in four patients will die in five years due to their new liver. Even for organ transplants, that is a very low chance of survival. Organ transplants tend to be very complex in nature. Since livers have so many functions they are among the hardest to transplant safely. The surgeon must first make a cut in the upper abdomen. Then they must remove the old liver by cutting it off from the blood vessels and bile ducts. The surgeon must then place the new liver into the patient’s body and connect it to the old blood vessels and bile ducts. Most operations usually take around 12 hours and since there is so much blood lost new blood must be continually added through a transfusion for the whole of the operation. There are many problems with this surgery and the first one is the act of moving the donated liver to the patient that will receive it. The liver can only stay functioning for a short period of time outside of the body. That means that as soon as a liver is taken from a donor it must be immediately transported to the recipient. This requires that many people work together as one to set up an appointment for the patient and the donor, to remove the liver from the donor, ship the donor’s liver to the recipient, put the liver into the recipient, close them up, and manage the finances of the whole operation. All of this requiring much time, effort, and money. There is yet an even larger risk that the new liver might be seen as an invader of the body by the immune system. This would mean that the body would start to break apart the new liver and attack it with cells that were made to fight off disease. The immune system would essentially be fighting off the thing trying to help it. Unfortunately all transplant patients also become dependent on immunosuppressive drugs that keeps the immune system from attacking the liver. While these drug may be helpful they also keep patients from fighting off infections, so all patients have a harder time fighting off disease. The patients must also use these drugs for as long as they live, adding up to thousands of dollars over the patient’s life. Luckily there are many new procedures that will make the chance of survival even higher. For instance, doctors can now take a small piece of a living donor’s liver and graft it onto the recipient’s liver. This can be done since the body only needs a small part of the a liver to carry out its normal functions, things like transporting the bile from the gallbladder to the intestines and detoxifying the blood. The procedure usually has to be done with donors and patients that have the same blood type and other major body factors. This means that a surgery is usually done with members of the same family. Another great thing for liver transplant patients is a new liquid that organs can be placed in for transportation. It keeps the organ as fresh as if it were inside the body. This allows the organ to be moved much farther than it would have otherwise. Instead of it being moved just 30 minutes away it can be moved across the country. But even this is not perfect, even in this liquid organs can still break down and fail to work inside of the new body. In the end, the benefits of liver transplantations far outweigh the risks for only one reason. Every patient will die if they do not receive a new liver.

Drugs in the Treatment of Gastrointestinal Disease

Drugs in the Treatment of Gastrointestinal Disease Introduction Many of the drug groups discussed elsewhere in this book have important applications in the treatment of diseases of the gastrointestinal tract and other organs. Other groups are used almost exclusively for their effects on the gut; these are discussed in the following text according to their therapeutic uses. Drugs Used in Acid-Peptic Diseases Acid-peptic diseases include gastroesophageal reflux, peptic ulcer (gastric and duodenal), and stress-related mucosal injury. In all these conditions, mucosal erosions or ulceration arise when the caustic effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the gastrointestinal mucosa (mucus and bicarbonate secretion, prostaglandins, blood flow, and the processes of restitution and regeneration after cellular injury). Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs). Drugs used in the treatment of acid-peptic disorders may be divided into two classes: agents that reduce intragastric acidity and agents that promote mucosal defense. Agents that Reduce Intragastric Acidity Physiology of Acid Secretion The parietal cell contains receptors for gastrin (CCK-B), histamine (H2), and acetylcholine (muscarinic, M3) (Figure 62-1). When acetylcholine (from vagal postganglionic nerves) or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+,K+ ATPase (the proton pump) on the canalicular surface. In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells also have receptors for gastrin and acetylcholine, which stimulate histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinases that stimulate acid secretion by the H+,K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. In contrast, acetylcholine provides potent direct parietal cell stimulation. Antacids Antacids have been used for centuries in the treatment of patients with dyspepsia and acid-peptic disorders. They were the mainstay of treatment for acid-peptic disorders until the advent of H2-receptor antagonists and proton pump inhibitors. They continue to be used commonly by patients as nonprescription remedies for the treatment of intermittent heartburn and dyspepsia. Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Their principal mechanism of action is reduction of intragastric acidity. After a meal, approximately 45 mEq/h of hydrochloric acid is secreted. A single dose of 156 mEq of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours. However, the acid-neutralization capacity among different proprietary formulations of antacids is highly variable, depending on their rate of dissolution (tablet versus liquid), water solubility, rate of reaction with acid, and rate of gastric emptying. Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with hydrochloric acid (HCL) to produce carbon dioxide and sodium chloride. Formation of carbon dioxide results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency. Calcium carbonate (eg, Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and calcium chloride (CaCl2). Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis. Calcium carbonate is used for a number of other indications apart from its antacid properties (see Chapter 42). Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency , and metabolic alkalosis (milk-alkali syndrome). Formulations containing magnesium hydroxide or aluminum hydroxide react slowly with HCl to form magnesium chloride or aluminum chloride and water. Because no gas is generated, belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together in proprietary formulations (eg, Gelusil, Maalox, Mylanta) to minimize the impact on bowel function. Both magnesium and aluminum are absorbed and excreted by the kidneys. Hence, patients with renal insufficiency should not take these agents long-term. All antacids may affect the absorption of other medications by binding the drug (reducing its absorption) or by increasing intragastric pH so that the drugs dissolution or solubility (especially weakly basic or acidic drugs) is altered. Therefore, antacids should not be given within 2 hours of doses of tetracyclines, fluoroquinolones, itraconazole, and iron. H2-Receptor Antagonists From their introduction in the 1970s until the early 1990s, H2-receptor antagonists (commonly referred to as H2 blockers) were the most commonly prescribed drugs in the world (see Clinical Uses). With the recognition of the role of H pylori in ulcer disease (which may be treated with appropriate antibacterial therapy) and the advent of proton pump inhibitors, the use of prescription H2 blockers has declined markedly. Chemistry Pharmacokinetics Four H2 antagonists are in clinical use: cimetidine, ranitidine, famotidine, and nizatidine. All four agents are rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%. Nizatidine has little first-pass metabolism. The serum half-lives of the four agents range from 1.1 to 4 hours; however, duration of action depends on the dose given (Table 62-1). H2 antagonists are cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. Dose reduction is required in patients with moderate to severe renal (and possibly severe hepatic) insufficiency. In the elderly, there is a decline of up to 50% in drug clearance as well as a significant reduction in volume of distribution. BID, twice daily; HS, bedtime. Clinical Uses H2-receptor antagonists continue to be prescribed but proton pump inhibitors (see below) are steadily replacing H2 antagonists for most clinical indications. However, the over-the-counter preparations are heavily used by the public. Gastroesophageal Reflux Disease (GERD) Patients with infrequent heartburn or dyspepsia (fewer than 3 times per week) may take either antacids or intermittent H2 antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H2 antagonists. However, the effect of antacids is short-lived (1-2 hours) compared with H2 antagonists (6-10 hours). H2 antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice-daily H2 antagonists (Table 62-1) or proton pump inhibitors. In patients with erosive esophagitis (approximately 50% of patients with GERD), H2 antagonists afford healing in less than 50% of patients; hence proton pump inhibitors are preferred because of their superior acid inhibition. Peptic Ulcer Disease Proton pump inhibitors have largely replaced H2 antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H2 antagonists are still sometimes used. Nocturnal acid suppression by H2 antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime, resulting in ulcer healing rates of more than 80-90% after 6-8 weeks of therapy. For patients with ulcers caused by aspirin or other NSAIDs, the NSAID should be discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given instead of an H2 antagonist to more reliably promote ulcer healing. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. H pylori should be treated with a 10- to 14-day course of therapy including a proton pump inhibitor and two antibiotics (see below). This regimen achieves ulcer healing and eradication of the infection in more than 90% of patients. For the minority of patients in whom H pylori cannot be successfully eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose to prevent ulcer recurrence (eg, ranitidine, 150 mg; famotidine, 20 mg). Nonulcer Dyspepsia H2 antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated. Prevention of Bleeding from Stress-Related Gastritis Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1-5% of critically ill patients as a result of impaired mucosal defense mechanisms caused by poor perfusion. Although most critically ill patients have normal or decreased acid secretion, numerous studies have shown that agents that increase intragastric pH (H2 antagonists or proton pump inhibitors) reduce the incidence of clinically significant bleeding. However, the optimal agent is uncertain at this time. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferable over intravenous proton pump inhibitors because of their proven efficacy and lower cost. Continuous infusions of H2 antagonists are generally preferred to bolus infusions because they achieve more consistent, sustained elevation of intragastric pH. Adverse Effects H2 antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation. Some studies suggest that intravenous H2 antagonists (or proton pump inhibitors) may increase the risk of nosocomial pneumonia in critically ill patients. Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H2 antagonists, especially in patients in the intensive care unit who are elderly or who have renal or hepatic dysfunction. These events may be more common with cimetidine. Mental status changes rarely occur in ambulatory patients. Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H2 antagonists. Although there are no known harmful effects on the fetus, H2 antagonists cross the placenta. Therefore, they should not be administered to pregnant women unless absolutely necessary. The H2 antagonists are secreted into breast milk and may therefore affect nursing infants. H2 antagonists may rarely cause blood dyscrasias. Blockade of cardiac H2 receptors may cause bradycardia, but this is rarely of clinical significance. Rapid intravenous infusion may cause bradycardia and hypotension through blockade of cardiac H2 receptors; therefore, intravenous injections should be given over 30 minutes. H2 antagonists rarely cause reversible abnormalities in liver chemistry. Drug Interactions Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4). Hence, the half-lives of drugs metabolized by these pathways may be prolonged. Ranitidine binds 4-10 times less avidly than cimetidine to cytochrome P450. Negligible interaction occurs with nizatidine and famotidine. H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels. Proton Pump Inhibitors Since their introduction in the late 1980s, these efficacious acid inhibitory agents have assumed the major role for the treatment of acid-peptic disorders. Proton pump inhibitors (PPIs) are now among the most widely prescribed drugs worldwide due to their outstanding efficacy and safety. Chemistry Pharmacokinetics Five proton pump inhibitors are available for clinical use: omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. All are substituted benzimidazoles that resemble H2 antagonists in structure (Figure 62-3) but have a completely different mechanism of action. Omeprazole is a racemic mixture of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations . Proton pump inhibitors are administered as inactive prodrugs. To protect the acid-labile prodrug from rapid destruction within the gastric lumen, oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. For children or patients with dysphagia or enteral feeding tubes, capsules may be opened and the microgranules mixed with apple or orange juice or mixed with soft foods (eg, applesauce). Lansoprazole is also available as a tablet formulation that disintegrates in the mouth, or it may be mixed with water and administered via oral syringe or enteral tube. Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100-1680 mg NaHCO3 ; 304-460 mg of sodium) to protect the naked (non-enteric-coated) drug from acid degradation. When administered on an empty stomach by m outh or enteral tube, this immediate-release suspension results in rapid omeprazole absorption (Tmax The proton pump inhibitors are lipophilic weak bases (pKa 4-5) and after intestinal absorption diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H+,K+ ATPase, irreversibly inactivating the enzyme. From a pharmacokinetic perspective, proton pump inhibitors are ideal drugs: they have a short serum half-life, they are concentrated and activated near their site of action, and they have a long duration of action. Pharmacodynamics In contrast to H2 antagonists, proton pump inhibitors inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, the proton pump. In standard doses, proton pump inhibitors inhibit 90-98% of 24-hour acid secretion (Figure 62-2). When administered at equivalent doses, the different agents show little difference in clinical efficacy. In a crossover study of patients receiving long-term therapy with all five proton pump inhibitors, the mean 24-hour intragastric pH varied from 3.3 (pantoprazole, 40 mg) to 4.0 (esomeprazole, 40 mg) and the mean number of hours the pH was higher than 4 varied from 10.1 (pantoprazole, 40 mg) to 14.0 (esomeprazole, 40 mg). Clinical Uses Gastroesophageal Reflux Disease (GERD) Proton pump inhibitors are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease (peptic stricture or Barretts esophagus), and extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and tissue healing in 85-90% of patients; up to 15% of patients require twice-daily dosing. GERD symptoms recur in over 80% of patients within 6 months after discontinuation of a proton pump inhibitor. For patients with erosive esophagitis or esophageal complications, long-term daily maintenance therapy with a full-dose or half-dose proton pump inhibitor is usually needed. Many patients with nonerosive GERD may be treated successfully with intermittent courses of proton pump inhibitors or H2 antagonists taken as needed (on demand) for recurrent symptoms. In current clinical practice, many patients with symptomatic GERD are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. Empiric treatment with proton pump inhibitors provides sustained symptomatic relief in 70-80% of patients, compared with 50-60% with H2 antagonists. Because of recent cost reductions, proton pump inhibitors are being used increasingly as first-line therapy for patients with symptomatic GERD. Sustained acid suppression with twice-daily proton pump inhibitors for at least 3 months is used to treat extraesophageal complications of reflux disease (asthma, chronic cough, laryngitis, and noncardiac chest pain). Peptic Ulcer Disease Compared with H2 antagonists, proton pump inhibitors afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers. All the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6-8 weeks. H pylori-Associated Ulcers For H pylori-associated ulcers, there are two therapeutic goals: to heal the ulcer and to eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a proton pump inhibitor. Proton pump inhibitors promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and—by raising intragastric pH—lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 14-day regimen of triple therapy: a proton pump inhibitor twice daily; clarithromycin, 500 mg twice daily; and either amoxicillin, 1 g twice daily, or metronidazole, 500 mg twice daily. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4-6 weeks to ensure complete ulcer healing. Recently, 10 days of sequential treatment consisting on days 1-5 of a proton pump inhibitor twice daily plus amoxicillin, 1 g twice daily, and followed on days 6-10 by five additional days of a proton pump inhibitor twice daily, plus clarithromycin, 500 mg twice daily, and tinidazole, 500 mg twice daily, has been shown to be a highly effective treatment regimen. NSAID-Associated Ulcers For patients with ulcers caused by aspirin or other NSAIDs, either H2 antagonists or proton pump inhibitors provide rapid ulcer healing so long as the NSAID is discontinued; however continued use of the NSAID impairs ulcer healing. In patients with NSAID-induced ulcers who require continued NSAID therapy, treatment with a once- or twice-daily proton pump inhibitor more reliably promotes ulcer healing. Asymptomatic peptic ulceration develops in 10-20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1-2% of persons per year. Proton pump inhibitors taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs. Prevention of Rebleeding from Peptic Ulcers In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of rebleeding from ulcers that have a visible vessel or adherent clot is increased. Rebleeding of this subset of high-risk ulcers is reduced significantly with proton pump inhibitors administered for 3-5 days either as high-dose oral therapy (eg, omeprazole, 40 mg orally twice daily) or as a continuous intravenous infusion. It is believed that an intragastric pH higher than 6 may enhance coagulation and platelet aggregation. The optimal dose of intravenous proton pump inhibitor needed to achieve and maintain this level of near-complete acid inhibition is unknown; however, initial bolus administration (80 mg) followed by constant infusion (8 mg/h) is commonly recommended. Nonulcer Dyspepsia Proton pump inhibitors have modest efficacy for treatment of nonulcer dyspepsia, benefiting 10-20% more patients than placebo. Despite their use for this indication, superiority to H2 antagonists (or even placebo) has not been conclusively demonstrated. Prevention of Stress-Related Mucosal Bleeding As discussed previously (see H2-Receptor Antagonists) proton pump inhibitors (given orally, by nasogastric tube, or by intravenous infusions) may be administered to reduce the risk of clinically significant stress-related mucosal bleeding in critically ill patients. The only proton pump inhibitor approved by the Food and Drug Administration (FDA) for this indication is an oral immediate-release omeprazole formulation, which is administered by nasogastric tube twice daily on the first day, then once daily. For patients with nasoenteric tubes, immediate-release omeprazole may be preferred to intravenous H2 antagonists or proton pump inhibitors because of comparable efficacy, lower cost, and ease of administration. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferred to intravenous proton pump inhibitors because of their proven efficacy and lower cost. Although proton pump inhibitors are increasingly used, there are no controlled trials demonstrating efficacy or optimal dosing. Gastrinoma and Other Hypersecretory Conditions Patients with isolated gastrinomas are best treated with surgical resection. In patients with metastatic or unresectable gastrinomas, massive acid hypersecretion results in peptic ulceration, erosive esophagitis, and malabsorption. Previously, these patients required vagotomy and extraordinarily high doses of H2 antagonists, which still resulted in suboptimal acid suppression. With proton pump inhibitors, excellent acid suppression can be achieved in all patients. Dosage is titrated to reduce basal acid output to less than 5-10 mEq/h. Typical doses of omeprazole are 60-120 mg/d. Adverse Effects General Proton pump inhibitors are extremely safe. Diarrhea, headache, and abdominal pain are reported in 1-5% of patients, although the frequency of these events is only slightly increased compared with placebo. Proton pump inhibitors do not have teratogenicity in animal models; however, safety during pregnancy has not been established. Nutrition Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton pump inhibition, potentially leading to subnormal B12 levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (iron, calcium, zinc); however, no mineral deficiencies have been reported with proton pump inhibitor therapy. Recent case-control studies have suggested a modest increase in the risk of hip fracture in patients taking proton pump inhibitors over a long term compared with matched controls. Although a causal relationship is unproven, proton pump inhibitors may reduce calcium absorption or inhibit osteoclast function. Pending further studies, patients who require long-term proton pump inhibitors—especially those with risk factors for osteoporosis—should have monitoring of bone density and should be provided calcium supplements. Respiratory and Enteric Infections Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Increases in gastric bacterial concentrations are detected in patients taking proton pump inhibitors, which is of unknown clinical significance. Some studies have reported an increased risk of both community-acquired respiratory infections and nosocomial pneumonia among patients taking proton pump inhibitors. A small increased risk of enteric infections may exist in patients taking proton pump inhibitors, especially when traveling in underdeveloped countries. Hospitalized patients may have an increased risk for Clostridium difficile infection. Potential Problems Due to Increased Serum Gastrin Gastrin levels are regulated by intragastric acidity. Acid suppression alters normal feedback inhibition so that median serum gastrin levels rise 1.5- to 2-fold in patients taking proton pump inhibitors. Although gastrin levels remain within normal limits in most patients, they exceed 500 pg/mL (normal, The rise in serum gastrin levels in patients receiving long-term therapy with proton pump inhibitors raises a theoretical concern because gastrin may stimulate hyperplasia of ECL cells. In female rats given proton pump inhibitors for prolonged periods, gastric carcinoid tumors developed in areas of ECL hyperplasia. Although humans who take proton pump inhibitors for a long time may exhibit ECL hyperplasia in response to hypergastrinemia, carcinoid tumor formation has not been documented. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged proton pump inhibitor therapy. Other Potential Problems Due to Decreased Gastric Acidity Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasia—known risk factors for gastric adenocarcinoma. A special FDA Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged proton pump inhibitor therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is not recommended in patients who require long-term proton pump inhibitor therapy. Long-term proton pump inhibitor therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients, which may disappear after stopping the drug and are of uncertain clinical signifi cance. Drug Interactions Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability, eg, ketoconazole, itraconazole, digoxin, and atazanavir. All proton pump inhibitors are metabolized by hepatic P450 cytochromes, including CYP2C19 and CYP3A4. Because of the short half-lives of proton pump inhibitors, clinically significant drug interactions are rare. Omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin. Esomeprazole also may decrease metabolism of diazepam. Lansoprazole may enhance clearance of theophylline. Rabeprazole and pantoprazole have no significant drug interactions. Mucosal Protective Agents The gastroduodenal mucosa has evolved a number of defense mechanisms to protect itself against the noxious effects of acid and pepsin. Both mucus and epithelial cell-cell tight junctions restrict back diffusion of acid and pepsin. Epithelial bicarbonate secretion establishes a pH gradient within the mucous layer in which the pH ranges from 7 at the mucosal surface to 1-2 in the gastric lumen. Blood flow carries bicarbonate and vital nutrients to surface cells. Areas of injured epithelium are quickly repaired by restitution, a process in which migration of cells from gland neck cells seals small erosions to rees Drugs in the Treatment of Gastrointestinal Disease Drugs in the Treatment of Gastrointestinal Disease Introduction Many of the drug groups discussed elsewhere in this book have important applications in the treatment of diseases of the gastrointestinal tract and other organs. Other groups are used almost exclusively for their effects on the gut; these are discussed in the following text according to their therapeutic uses. Drugs Used in Acid-Peptic Diseases Acid-peptic diseases include gastroesophageal reflux, peptic ulcer (gastric and duodenal), and stress-related mucosal injury. In all these conditions, mucosal erosions or ulceration arise when the caustic effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the gastrointestinal mucosa (mucus and bicarbonate secretion, prostaglandins, blood flow, and the processes of restitution and regeneration after cellular injury). Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs). Drugs used in the treatment of acid-peptic disorders may be divided into two classes: agents that reduce intragastric acidity and agents that promote mucosal defense. Agents that Reduce Intragastric Acidity Physiology of Acid Secretion The parietal cell contains receptors for gastrin (CCK-B), histamine (H2), and acetylcholine (muscarinic, M3) (Figure 62-1). When acetylcholine (from vagal postganglionic nerves) or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+,K+ ATPase (the proton pump) on the canalicular surface. In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells also have receptors for gastrin and acetylcholine, which stimulate histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinases that stimulate acid secretion by the H+,K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. In contrast, acetylcholine provides potent direct parietal cell stimulation. Antacids Antacids have been used for centuries in the treatment of patients with dyspepsia and acid-peptic disorders. They were the mainstay of treatment for acid-peptic disorders until the advent of H2-receptor antagonists and proton pump inhibitors. They continue to be used commonly by patients as nonprescription remedies for the treatment of intermittent heartburn and dyspepsia. Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Their principal mechanism of action is reduction of intragastric acidity. After a meal, approximately 45 mEq/h of hydrochloric acid is secreted. A single dose of 156 mEq of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours. However, the acid-neutralization capacity among different proprietary formulations of antacids is highly variable, depending on their rate of dissolution (tablet versus liquid), water solubility, rate of reaction with acid, and rate of gastric emptying. Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with hydrochloric acid (HCL) to produce carbon dioxide and sodium chloride. Formation of carbon dioxide results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency. Calcium carbonate (eg, Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and calcium chloride (CaCl2). Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis. Calcium carbonate is used for a number of other indications apart from its antacid properties (see Chapter 42). Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency , and metabolic alkalosis (milk-alkali syndrome). Formulations containing magnesium hydroxide or aluminum hydroxide react slowly with HCl to form magnesium chloride or aluminum chloride and water. Because no gas is generated, belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together in proprietary formulations (eg, Gelusil, Maalox, Mylanta) to minimize the impact on bowel function. Both magnesium and aluminum are absorbed and excreted by the kidneys. Hence, patients with renal insufficiency should not take these agents long-term. All antacids may affect the absorption of other medications by binding the drug (reducing its absorption) or by increasing intragastric pH so that the drugs dissolution or solubility (especially weakly basic or acidic drugs) is altered. Therefore, antacids should not be given within 2 hours of doses of tetracyclines, fluoroquinolones, itraconazole, and iron. H2-Receptor Antagonists From their introduction in the 1970s until the early 1990s, H2-receptor antagonists (commonly referred to as H2 blockers) were the most commonly prescribed drugs in the world (see Clinical Uses). With the recognition of the role of H pylori in ulcer disease (which may be treated with appropriate antibacterial therapy) and the advent of proton pump inhibitors, the use of prescription H2 blockers has declined markedly. Chemistry Pharmacokinetics Four H2 antagonists are in clinical use: cimetidine, ranitidine, famotidine, and nizatidine. All four agents are rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%. Nizatidine has little first-pass metabolism. The serum half-lives of the four agents range from 1.1 to 4 hours; however, duration of action depends on the dose given (Table 62-1). H2 antagonists are cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. Dose reduction is required in patients with moderate to severe renal (and possibly severe hepatic) insufficiency. In the elderly, there is a decline of up to 50% in drug clearance as well as a significant reduction in volume of distribution. BID, twice daily; HS, bedtime. Clinical Uses H2-receptor antagonists continue to be prescribed but proton pump inhibitors (see below) are steadily replacing H2 antagonists for most clinical indications. However, the over-the-counter preparations are heavily used by the public. Gastroesophageal Reflux Disease (GERD) Patients with infrequent heartburn or dyspepsia (fewer than 3 times per week) may take either antacids or intermittent H2 antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H2 antagonists. However, the effect of antacids is short-lived (1-2 hours) compared with H2 antagonists (6-10 hours). H2 antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice-daily H2 antagonists (Table 62-1) or proton pump inhibitors. In patients with erosive esophagitis (approximately 50% of patients with GERD), H2 antagonists afford healing in less than 50% of patients; hence proton pump inhibitors are preferred because of their superior acid inhibition. Peptic Ulcer Disease Proton pump inhibitors have largely replaced H2 antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H2 antagonists are still sometimes used. Nocturnal acid suppression by H2 antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime, resulting in ulcer healing rates of more than 80-90% after 6-8 weeks of therapy. For patients with ulcers caused by aspirin or other NSAIDs, the NSAID should be discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given instead of an H2 antagonist to more reliably promote ulcer healing. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. H pylori should be treated with a 10- to 14-day course of therapy including a proton pump inhibitor and two antibiotics (see below). This regimen achieves ulcer healing and eradication of the infection in more than 90% of patients. For the minority of patients in whom H pylori cannot be successfully eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose to prevent ulcer recurrence (eg, ranitidine, 150 mg; famotidine, 20 mg). Nonulcer Dyspepsia H2 antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated. Prevention of Bleeding from Stress-Related Gastritis Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1-5% of critically ill patients as a result of impaired mucosal defense mechanisms caused by poor perfusion. Although most critically ill patients have normal or decreased acid secretion, numerous studies have shown that agents that increase intragastric pH (H2 antagonists or proton pump inhibitors) reduce the incidence of clinically significant bleeding. However, the optimal agent is uncertain at this time. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferable over intravenous proton pump inhibitors because of their proven efficacy and lower cost. Continuous infusions of H2 antagonists are generally preferred to bolus infusions because they achieve more consistent, sustained elevation of intragastric pH. Adverse Effects H2 antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation. Some studies suggest that intravenous H2 antagonists (or proton pump inhibitors) may increase the risk of nosocomial pneumonia in critically ill patients. Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H2 antagonists, especially in patients in the intensive care unit who are elderly or who have renal or hepatic dysfunction. These events may be more common with cimetidine. Mental status changes rarely occur in ambulatory patients. Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H2 antagonists. Although there are no known harmful effects on the fetus, H2 antagonists cross the placenta. Therefore, they should not be administered to pregnant women unless absolutely necessary. The H2 antagonists are secreted into breast milk and may therefore affect nursing infants. H2 antagonists may rarely cause blood dyscrasias. Blockade of cardiac H2 receptors may cause bradycardia, but this is rarely of clinical significance. Rapid intravenous infusion may cause bradycardia and hypotension through blockade of cardiac H2 receptors; therefore, intravenous injections should be given over 30 minutes. H2 antagonists rarely cause reversible abnormalities in liver chemistry. Drug Interactions Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4). Hence, the half-lives of drugs metabolized by these pathways may be prolonged. Ranitidine binds 4-10 times less avidly than cimetidine to cytochrome P450. Negligible interaction occurs with nizatidine and famotidine. H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels. Proton Pump Inhibitors Since their introduction in the late 1980s, these efficacious acid inhibitory agents have assumed the major role for the treatment of acid-peptic disorders. Proton pump inhibitors (PPIs) are now among the most widely prescribed drugs worldwide due to their outstanding efficacy and safety. Chemistry Pharmacokinetics Five proton pump inhibitors are available for clinical use: omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. All are substituted benzimidazoles that resemble H2 antagonists in structure (Figure 62-3) but have a completely different mechanism of action. Omeprazole is a racemic mixture of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations . Proton pump inhibitors are administered as inactive prodrugs. To protect the acid-labile prodrug from rapid destruction within the gastric lumen, oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. For children or patients with dysphagia or enteral feeding tubes, capsules may be opened and the microgranules mixed with apple or orange juice or mixed with soft foods (eg, applesauce). Lansoprazole is also available as a tablet formulation that disintegrates in the mouth, or it may be mixed with water and administered via oral syringe or enteral tube. Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100-1680 mg NaHCO3 ; 304-460 mg of sodium) to protect the naked (non-enteric-coated) drug from acid degradation. When administered on an empty stomach by m outh or enteral tube, this immediate-release suspension results in rapid omeprazole absorption (Tmax The proton pump inhibitors are lipophilic weak bases (pKa 4-5) and after intestinal absorption diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H+,K+ ATPase, irreversibly inactivating the enzyme. From a pharmacokinetic perspective, proton pump inhibitors are ideal drugs: they have a short serum half-life, they are concentrated and activated near their site of action, and they have a long duration of action. Pharmacodynamics In contrast to H2 antagonists, proton pump inhibitors inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, the proton pump. In standard doses, proton pump inhibitors inhibit 90-98% of 24-hour acid secretion (Figure 62-2). When administered at equivalent doses, the different agents show little difference in clinical efficacy. In a crossover study of patients receiving long-term therapy with all five proton pump inhibitors, the mean 24-hour intragastric pH varied from 3.3 (pantoprazole, 40 mg) to 4.0 (esomeprazole, 40 mg) and the mean number of hours the pH was higher than 4 varied from 10.1 (pantoprazole, 40 mg) to 14.0 (esomeprazole, 40 mg). Clinical Uses Gastroesophageal Reflux Disease (GERD) Proton pump inhibitors are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease (peptic stricture or Barretts esophagus), and extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and tissue healing in 85-90% of patients; up to 15% of patients require twice-daily dosing. GERD symptoms recur in over 80% of patients within 6 months after discontinuation of a proton pump inhibitor. For patients with erosive esophagitis or esophageal complications, long-term daily maintenance therapy with a full-dose or half-dose proton pump inhibitor is usually needed. Many patients with nonerosive GERD may be treated successfully with intermittent courses of proton pump inhibitors or H2 antagonists taken as needed (on demand) for recurrent symptoms. In current clinical practice, many patients with symptomatic GERD are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. Empiric treatment with proton pump inhibitors provides sustained symptomatic relief in 70-80% of patients, compared with 50-60% with H2 antagonists. Because of recent cost reductions, proton pump inhibitors are being used increasingly as first-line therapy for patients with symptomatic GERD. Sustained acid suppression with twice-daily proton pump inhibitors for at least 3 months is used to treat extraesophageal complications of reflux disease (asthma, chronic cough, laryngitis, and noncardiac chest pain). Peptic Ulcer Disease Compared with H2 antagonists, proton pump inhibitors afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers. All the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6-8 weeks. H pylori-Associated Ulcers For H pylori-associated ulcers, there are two therapeutic goals: to heal the ulcer and to eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a proton pump inhibitor. Proton pump inhibitors promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and—by raising intragastric pH—lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 14-day regimen of triple therapy: a proton pump inhibitor twice daily; clarithromycin, 500 mg twice daily; and either amoxicillin, 1 g twice daily, or metronidazole, 500 mg twice daily. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4-6 weeks to ensure complete ulcer healing. Recently, 10 days of sequential treatment consisting on days 1-5 of a proton pump inhibitor twice daily plus amoxicillin, 1 g twice daily, and followed on days 6-10 by five additional days of a proton pump inhibitor twice daily, plus clarithromycin, 500 mg twice daily, and tinidazole, 500 mg twice daily, has been shown to be a highly effective treatment regimen. NSAID-Associated Ulcers For patients with ulcers caused by aspirin or other NSAIDs, either H2 antagonists or proton pump inhibitors provide rapid ulcer healing so long as the NSAID is discontinued; however continued use of the NSAID impairs ulcer healing. In patients with NSAID-induced ulcers who require continued NSAID therapy, treatment with a once- or twice-daily proton pump inhibitor more reliably promotes ulcer healing. Asymptomatic peptic ulceration develops in 10-20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1-2% of persons per year. Proton pump inhibitors taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs. Prevention of Rebleeding from Peptic Ulcers In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of rebleeding from ulcers that have a visible vessel or adherent clot is increased. Rebleeding of this subset of high-risk ulcers is reduced significantly with proton pump inhibitors administered for 3-5 days either as high-dose oral therapy (eg, omeprazole, 40 mg orally twice daily) or as a continuous intravenous infusion. It is believed that an intragastric pH higher than 6 may enhance coagulation and platelet aggregation. The optimal dose of intravenous proton pump inhibitor needed to achieve and maintain this level of near-complete acid inhibition is unknown; however, initial bolus administration (80 mg) followed by constant infusion (8 mg/h) is commonly recommended. Nonulcer Dyspepsia Proton pump inhibitors have modest efficacy for treatment of nonulcer dyspepsia, benefiting 10-20% more patients than placebo. Despite their use for this indication, superiority to H2 antagonists (or even placebo) has not been conclusively demonstrated. Prevention of Stress-Related Mucosal Bleeding As discussed previously (see H2-Receptor Antagonists) proton pump inhibitors (given orally, by nasogastric tube, or by intravenous infusions) may be administered to reduce the risk of clinically significant stress-related mucosal bleeding in critically ill patients. The only proton pump inhibitor approved by the Food and Drug Administration (FDA) for this indication is an oral immediate-release omeprazole formulation, which is administered by nasogastric tube twice daily on the first day, then once daily. For patients with nasoenteric tubes, immediate-release omeprazole may be preferred to intravenous H2 antagonists or proton pump inhibitors because of comparable efficacy, lower cost, and ease of administration. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferred to intravenous proton pump inhibitors because of their proven efficacy and lower cost. Although proton pump inhibitors are increasingly used, there are no controlled trials demonstrating efficacy or optimal dosing. Gastrinoma and Other Hypersecretory Conditions Patients with isolated gastrinomas are best treated with surgical resection. In patients with metastatic or unresectable gastrinomas, massive acid hypersecretion results in peptic ulceration, erosive esophagitis, and malabsorption. Previously, these patients required vagotomy and extraordinarily high doses of H2 antagonists, which still resulted in suboptimal acid suppression. With proton pump inhibitors, excellent acid suppression can be achieved in all patients. Dosage is titrated to reduce basal acid output to less than 5-10 mEq/h. Typical doses of omeprazole are 60-120 mg/d. Adverse Effects General Proton pump inhibitors are extremely safe. Diarrhea, headache, and abdominal pain are reported in 1-5% of patients, although the frequency of these events is only slightly increased compared with placebo. Proton pump inhibitors do not have teratogenicity in animal models; however, safety during pregnancy has not been established. Nutrition Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton pump inhibition, potentially leading to subnormal B12 levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (iron, calcium, zinc); however, no mineral deficiencies have been reported with proton pump inhibitor therapy. Recent case-control studies have suggested a modest increase in the risk of hip fracture in patients taking proton pump inhibitors over a long term compared with matched controls. Although a causal relationship is unproven, proton pump inhibitors may reduce calcium absorption or inhibit osteoclast function. Pending further studies, patients who require long-term proton pump inhibitors—especially those with risk factors for osteoporosis—should have monitoring of bone density and should be provided calcium supplements. Respiratory and Enteric Infections Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Increases in gastric bacterial concentrations are detected in patients taking proton pump inhibitors, which is of unknown clinical significance. Some studies have reported an increased risk of both community-acquired respiratory infections and nosocomial pneumonia among patients taking proton pump inhibitors. A small increased risk of enteric infections may exist in patients taking proton pump inhibitors, especially when traveling in underdeveloped countries. Hospitalized patients may have an increased risk for Clostridium difficile infection. Potential Problems Due to Increased Serum Gastrin Gastrin levels are regulated by intragastric acidity. Acid suppression alters normal feedback inhibition so that median serum gastrin levels rise 1.5- to 2-fold in patients taking proton pump inhibitors. Although gastrin levels remain within normal limits in most patients, they exceed 500 pg/mL (normal, The rise in serum gastrin levels in patients receiving long-term therapy with proton pump inhibitors raises a theoretical concern because gastrin may stimulate hyperplasia of ECL cells. In female rats given proton pump inhibitors for prolonged periods, gastric carcinoid tumors developed in areas of ECL hyperplasia. Although humans who take proton pump inhibitors for a long time may exhibit ECL hyperplasia in response to hypergastrinemia, carcinoid tumor formation has not been documented. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged proton pump inhibitor therapy. Other Potential Problems Due to Decreased Gastric Acidity Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasia—known risk factors for gastric adenocarcinoma. A special FDA Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged proton pump inhibitor therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is not recommended in patients who require long-term proton pump inhibitor therapy. Long-term proton pump inhibitor therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients, which may disappear after stopping the drug and are of uncertain clinical signifi cance. Drug Interactions Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability, eg, ketoconazole, itraconazole, digoxin, and atazanavir. All proton pump inhibitors are metabolized by hepatic P450 cytochromes, including CYP2C19 and CYP3A4. Because of the short half-lives of proton pump inhibitors, clinically significant drug interactions are rare. Omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin. Esomeprazole also may decrease metabolism of diazepam. Lansoprazole may enhance clearance of theophylline. Rabeprazole and pantoprazole have no significant drug interactions. Mucosal Protective Agents The gastroduodenal mucosa has evolved a number of defense mechanisms to protect itself against the noxious effects of acid and pepsin. Both mucus and epithelial cell-cell tight junctions restrict back diffusion of acid and pepsin. Epithelial bicarbonate secretion establishes a pH gradient within the mucous layer in which the pH ranges from 7 at the mucosal surface to 1-2 in the gastric lumen. Blood flow carries bicarbonate and vital nutrients to surface cells. Areas of injured epithelium are quickly repaired by restitution, a process in which migration of cells from gland neck cells seals small erosions to rees