Mary Kay India: The Hair Care Product Line Opportunity Essay

1. How would you characterize the branded and packaged Indian hair care category in 2010? In 2010, with Lotus & Bamboo soap bar was introduced by Mary Kay in India, May Kay was approved a customized product for a specific country or region market for the first time. Moreover, the branded and packaged Indian care category of Mary Kay was growing up and expanding its product to attract more potential customers. Mary Kay brand has been developing massive products in India until 2010 with lower price compared with past several years. By late 2010, there were more independent beauty consultants in more regions in India, and most of the businesses were distributed in northern, western and northeastern area of India. Simultaneously, in the late 2010, Mary Kay also meets competition from other representative of hair care products. Market research has shown that the growth potential of around 50% for the coming 5 years between 2010 and 2014. 2. How would you assess the â€Å"fit† of a hair care product line with Mary Kay’s offering in India? The acceptance of hair care products line is growing with changes of hair care habit of customers in India. Personally, the â€Å"fit† project of hair care product line with Mary Kay’s offering in India was pretty successful and in time. Based on the unique hair care habit among Indians, it might be a slow process to introduce the products into a new Asian market for Mary Kay. After all, hair cares like shampoo and conditioner are not as easily as soap bars to be accepted in India, which means changing hair care lifestyle for most people there. Therefore, launching hair care products in 2012 is the very time for India. Additionally, independent beauty consultants are the positive factor to motivate to sell products in India. Furthermore, low price promotion strategy also worked for selling hair care in India, according to the data in the case, nearly 87 percent of hair care products were sold at mass-market prices, however, only 13 percent of the products were sold at  prestige or premium prices. 3.What is the market potential for a hair care marketed by Mary Kay India? According to the research, the Indian upper and consuming classes were growing and were expected to total over 500 million individual, which might be reckoned as potential consumers of hair care products. It seems that Mary Kay India is targeted to young, working people who are pursuing good look with an average age of 26, especially women group. Given to the increasing population in India, in the coming years, the number of young generation will also be expected to grow up. Meanwhile, the expected young generation will grow up under impact of new body care lifestyle in India, (who are accustomed to using shampoo and conditioner instead of oil, washing hair frequently, caring about the appearance),thus, it could be forecasted that the market of hair care products would be extended in the near future. 4.At what dollar sales volumes will the Mary Kay India hair care line be profitable? Give to the estimated scale of production of a total of 600,000 units of the 6-milliliter sachets, total cost of production and distribution would probably be $600,000. Then, the highest estimated total cost of production and delivery for the 100 milliliter bottles would be $1,410,000, but the lowest would sum up to $1,110,000. Moreover, when take advertising, promotion, and sales into consideration, the costs would probably come to $705,000, while the highest total amount of sales could be even more than $2,715,000. 5. Should Mary Kay introduce a hair care line in India? Why or Why not? As far as I am concerned, Mary Kay should introduce a hair care line in India. On the basis of the data above, the highest total amount of sales could come to $2,715,000 for Mary Kay, which means huge profit in India market. What is more, as the transformation of lifestyle among young Indians, the number of people who tend to use hair care products could rise up in the coming decades. Once hair care products are accepted by Indian people, it means more opportunities and profit growth point for Mary Kay brand. For instance, Mary Kay company could develop more hair care products with specific functions to satisfy the increasingly demand among people. Lastly, another  advantage to introduce Mary Kay to India is that labor price in India is pretty low, which illustrates that the cost to produce hair care products in India could be controlled easily. In general, introducing hair care products to India is a wise action for Mary Kay company.

Reviewer for Science Quiz Bee Essay

1. A great Greek philosopher, he was the first person to study nature systematically. ARISTOTLE 2. He laid the foundation of modern scientific thought and assembled materials for an organized encyclopedia of all knowledge. ARISTOTLE 3. He was the foremost natural philosopher in ancient times. ARISTOTLE 4. A Benedictine nun, she contributed the medical work â€Å"Causea et Curae et Physica†. HILDEGARD OF BENGEN 5. An astronomer who proposed that the sun was the center of the universe. -NICOLAS COPERNICUS 6. He discovered the circulation of the blood which ushered in the new age in the study of medicine and biology. WILLIAM HARVEY 7. He was the first to raise the telescope to the sky to study the universe. GALILEO GALILEI 8. He formulated the 3 laws of planetary motion. JOHANNES KEPLER 9. He proposed the Theory of Evolution. CHARLES DARWIN 10. She discovered radioactivity. MADAME MARIE CURIE 11. He discovered the germ that causes tuberculosis. ROBERT KOCH 12. He became famous for his work on fermentation and decay. –LOUIS PASTEUR 13. He proposed the Theory of Relativity. ALBERT EINSTEIN 14. He won the Nobel Prize for his work on photoelectric effect. ALBERT EINSTEIN 15. She determined the structure of biochemical compounds essential I treating pernicious anemia. -DOROTHY HODGKIN 16. He is considered as the â€Å"father of geothermal energy development†. ARTURO ALCARAZ 17. He invented a fertilizer call farmer’s pure organic fertilizer. ABRAHAM Q. TADEJA 18. He invented a solar engine that can generate electricity for home use. JESUS ALVERO 19. A national scientist, is best remembered for his work on medicinal plants. He discovered over 4,000 plant species. EDUARDO A. QUISUMBING 20. It is the scientific way of solving problems. SCIENTIFIC METHOD 21. It is a systematic and logical procedure in solving problems. SCIENTIFIC METHOD 22. It is a challenge or a task which a scientist undertakes for scientific purposes. PROBLEM 23. It is an educated guess about a certain phenomenon. HYPOTHESIS 24. It refers to the general procedure on how to carry out an experiment. EXPERIMENTAL DESIGN 25. These are the factors that are multiplied or changed. INDEPENDENT VARIABLES 26. These are the factors that change in response to the independent variable. DEPENDENT VARIABLE 27. It is a unit of measure used by Egyptians. CUBIT 28. It is the distance from the elbow to the tip of the middle finger. CUBIT 29. It is a modernized version of the metric system. INTERNATIONAL SYSTEM OF UNITS/SI SYSTEM 30. It provides a logical and interconnected framework for all measurements in science, industry, and commerce. INTERNATIONAL SYSTEM OF UNITS/SI SYSTEM 31. It is used to weigh small masses of objects. PLATFORM BALANCE 32. It is equivalent to a foot and consists of 12 inches. RULER 33. It used in measuring length and distance. RULER 34. It used to measure length and distance. It consists of 100 centimeters. METERSTICK 35. Measures time in seconds, minutes, and hours. STOPWATCH 36. It measures volume of liquids. GRADUATED CYLINDER 37. It measures atmospheric temperature. THERMOMETER 38. It measures the force or weight of objects. SPRING BALANCE 39. These are the digits that indicate the certainty of the number of units in a measured quantity. SIGNIFICANT FIGURES 40. It is a shorthand writing of extremely large or small figures. SCIENTIFIC NOTATION 41. It is the changing from smaller to bigger unit and vice versa. CONVERSION 42. It is the distance from one point to another. LENGTH 43. It is the basic standard unit in the metric system. METER 44. It is the space occupied by matter. VOLUME 45. It is the amount of matter in an object. MASS 46. It refers to the quantity of matter. MASS 47. It is a quantity of matter which does not change with altitude of a place. MASS 48. It is used to measure the volume of an irregular object. WATER DISPLACEMENT METHOD 49. It is defined as the mass per unit volume. DENSITY 50. A Greek mathematician who discovered that the earth is round. PYTHAGORAS 51. A Greek mathematician who measured the circumference of the earth as 25,000 miles. ERATHOSTHENES 52. It is an information gathered using the five senses. OBSERVATION 53. It is a conclusion or an interpretation of events based from observed information. INFERENCE 54. It is used as a container and as a heating device. It measures volume of liquids. BEAKER 55. It is used as a heating apparatus, a container and may be used for measuring the volume of liquids. ERLENMEYER FLASK 56. It is used as a heating apparatus. It is also used as a distilling device for collecting gases. FLORENCE FLASK 57. It is used for the preparation of any solution. VOLUMETRIC FLASK 58. It is used as a container for liquid solutions and powderized chemicals. TEST TUBE 59. It is used to hold a test tube while heating. TEST TUBE HOLDER 60. It is used to pick up and hold any hot apparatus. TONGS 61. It is used to distribute evenly the heat of the flame. WIRE GAUZE 62. It is used as a container of liquids and solids being tested. WIDE-MOUTH BOTTLE 63. It is used to hold an apparatus especially when being heated. BURET CLAMP/TEST TUBE CLAMP 64. It is used to support heating apparatuses. TRIPOD 65. It is used for stirring/mixing liquid or solid mixtures. STIRRING ROD 66. It is used for measuring a small amount of liquid. MEDICINE DROPPER 67. It is used for cleaning any glass apparatus. TEST TUBE BRUSH 68. It is used to pick and hold hot objects. FORCEPS 69. It is used to pour liquids from one container to another. FUNNEL 70. It is used for grinding solid substances to powderized form. MORTAR AND PESTLE 71. It is used to allow liquids to evaporate. EVAPORATING DISH 72. It is used for scooping solids or any powderized substance. SPATULA AND SPOON 73. It is used to hold test tubes in place. TEST TUBE RACK 74. It is the main heating device in the laboratory in the absence of a Bunsen burner. LABORATORY BURNER 75. It is used to weigh chemicals and smaller masses of objects. PLATFORM BALANCE 76. It is used as a container for specimens being studied. WATCH GLASS 77. These are used to thicken printing dyes for the textile industry. ALGINATES 78. It is an herbal plant with medicinal value. It can cure stomach ache, diarrhea, and colic. TSAANG-GUBAT 79. It is anything that occupies space and has mass. MATTER 80. This is the attraction between molecules. INTERMOLECULAR ATTRACTION 81. A condition that causes the water molecules at the surface to behave as though they are being stretched. SURFACE TENSION 82. It is the rising action of a liquid inside a very fine tube. CAPILLARITY 83. The attraction between two different kinds of molecule. ADHESION 84. The attraction between the same kinds of molecule. COHESION 85. It consists of one phase with a definite composition. PURE SUBSTANCE 86. Is any material with uniform composition. SUBSTANCE 87. These are made up of atoms of the same identity. ELEMENTS 88. These are pure substances that can be resolved into unidentical atoms. COMPUNDS 89. A physical combination of two more substances. MIXTURE 90. It is a combination of two or more kinds of substance which can be separated by physical means. MIXTURE 91. A mixture that has only one distinct phase. HOMOGENOUS MIXTURE 92. A mixture that has two or more distinct phases. HETEROGENOUS MIXTURE 93. A mixture that is made up of 2 or more substances that are mixed together. HETEROGENOUS MIXTURE 94. It is the standard unit for mass based on the SI system of measurement. KILOGRAM 95. It is the measure of the pull of gravity on an object. WEIGHT 96. The standard unit for measuring weight. NEWTON 97. The ability of a matter to return to their original size and shape after being pushed, pulled or subjected to stress. ELASTICITY 98. The ability of a matter to be extended or flattened and shaped. MALLEABILITY 99. It is the temperature at which a solid begins to liquefy. MELTING POINT 100. It is the temperature at which a liquid starts changing into the gaseous phase. BOILING POINT 101. It describes that matter and energy cannot be created nor destroyed, however, they can be transformed. LAW OF CONSERVATION OF MASS 102. It was formulated to explain the composition and behavior of matter. MOLECULAR THEORY 103. Even smaller particles that make up a molecule.   ATOMS 104. Smallest particle of an element. ATOM 105. Smallest particle of a compound. MOLECULE 106. It is characterized by a change in the phase or state of a substance. PHYSICAL CHANGE 107. It is characterized by the formation of new substances with new properties and compositions. CHEMICAL CHANGE 108. These are the materials that undergo a change. REACTANTS 109. These are the materials formed as a result of the chemical change or reaction between the reactants. PRODUCTS 110. It refers to the process in which the amount of living substances in the body increases. GROWTH 111. The process whereby organisms produce new organisms of the same kind. REPRODUCTION 112. It is that ability to respond to external stimuli. IRRITABILITY 113. It means transferring or shifting from one place or position to another. MOVEMENT 114. It allows an organism to change, helping it to cope with unfavorable changes in the environment. ADAPTATION 115. It is the basic structural unit of living things. CELL 116. He invented the microscope. ANTON VAN LEEUWENHOEK 117. It is an instrument used to magnify or enlarge minute objects. MICROSCOPE 118. An English scientist, the first person to see cells using a very simple microscope. ROBERT HOOKE 119. It is a thin layer that surrounds and holds the parts of the cell together. CELL MEMBRANE 120. It controls the activities of a cell. NUCLEUS 121. It is the jelly-like liquid material of the cell. It contains many cell materials. CYTOPLASM 122. It contains a variety of cell structures. CYTOPLASM 123. These are structures in the cell which generally contain pigments. PLASTIDS 124. These are colorless plastids that are found in sex cells and storage cells of roots and underground stems. LEUCOPLASTS 125. These carry pigments that give color to the plants. CHROMOPLASTS 126. It contains chlorophyll which traps light used in making food. CHLOROPLASTS 127. A green pigment that is essential to photosynthesis. CHLOROPHYLL 128. It provides shape and support to the cell. CELL WALL 129. These are filled with water cell sap which contains food, cell secretions, and wastes. VACUOLES 130. It stores water and dissolved materials. VACUOLES 131. Also known as â€Å"suicidal sac†, it contains the enzymes which promote the breakdown or digestion of carbohydrates, fats, and proteins. LYSOSOMES 132. It plays an important role in cell division, it is found in the cytoplasm of most animals and in some blue-green algae. CENTROSOME 133. It moves materials within the cells and it maintains its shape. ENDOPLASMIC RETICULUM 134. It controls the movement of materials in and out of nucleus. NUCLEAR MEMBRANE 135. It releases energy, powerhouse of the cell. MITOCHONDRIA 136. This is where proteins are made. RIBOSOME 137. It carries the code that controls a cell. CHROMOSOMES 138. It stores and releases chemicals. GOLGI BODIES 139. Small organs found in the cytoplasm of both plant and animal cells. ORGANELLES 140. The interaction between a community and its non-living environment. ECOSYSTEM 141. The study of interactions between living things and their environment. ECOLOGY 142. It includes the different species of living organisms in a particular habitat. BIOTIC COMPONENT 143. It refers to the place where organisms live. HABITAT 144. It is composed of non-living things. ABIOTIC COMPONENT 145. Are organisms that cannot make their own food. CONSUMERS 146. Plant eaters. HERBIVORES 147. Eats both plant and animal. OMNIVORE 148. It is a pathway of food and energy through an ecosystem. FOOD CHAIN 149. It is a complex network of feeding relationships made up of many interconnected food chains. FOOD WEB 150. This cycle involves photosynthesis and respiration. CARBON DIOXIDE-OXYGEN CYCLE 151. Microorganisms that acts upon the remaining nitrates in the soil. DENITRIFYING BACTERIA 152. It converts nitrates, nitrites, and ammonia into oxygen. DENITRIFYING BACTERIA 153. A relationship when both organisms are benefited. MUTUALISM 154. A relationship wherein one organism is benefited while the other is not harmed. COMMENSALISM 155. The organism that is actually benefited. COMMENSAL 156. The organism that is neither harmed nor benefited. HOST 157. A relationship wherein one organism is benefited while the other dies. PREEDATION 158. The organism which captures or kills another animal. PREDATOR 159. The organism which gets killed and eaten alive. PREY 160. A relationship where one organism is benefited and the other is harmed. PARASITISM 161. A relationship wherein organisms compete for food in order to survive. COMPETITION 162. Ecological relationship in which participating organisms belong to the same species. INTRASPECIFIC 163. Ecological relationship in which participating organisms belong to different species. INTERSPECIFIC 164. It is the process of manufacturing food in green plants. PHOTOSYNTHESIS 165. A condition in the environment that stops a population from increasing in size. LIMITING FACTOR 166. The destruction of forest. DEFORESTATION 167. It is the adding of harmful substances to the environment that can affect all living organisms. POLLUTION 168. It is caused by particulates from motor vehicles and the burning of fuels in homes and factories. AIR POLLUTION 169. The wise use of natural resources. CONSERVATION 170. It is the wearing away of soil by water, wind, ice, and gravity. EROSION 171. It is the practice of removing unhealthy trees and those with little commercial value. IMPROVEMENT CUTTING 172. It is the practice of removing only mature trees as younger trees are left to grow. SELECTIVE CUTTING 173. It is the practice of renewing a forest by seeding or planting small trees. REFORESTATION 174. It is the total number of organisms of a species in an ecosystem. POPULATION 175. It is a group of population in an ecosystem. COMMUNITY 176. These are the roles played by an organism in a community. ECOLOGICAL NICHES 177. It is a diagram which shows the flow of energy in a food chain. ENERGY PYRAMID 178. These are level of energy consumption. TROPHIC LEVELS 179. It refers to the land part of the earth. LITHOSPHERE 180. These are the basic building blocks of the lithosphere. ROCKS 181. It is the science that deals with the study of formation, composition, and classification of rocks. PETROLOGY 182. The water part of the earth. HYDROSPHERE 183. The continuous depression on the earth’s surface which holds ocean water. OCEAN BASIN 184. Sea of air that completely surrounds the earth. ATMOSPHERE 185. It is generated primarily by the northeast trade winds. NORTH EQUATORIAL CURRENT 186. It is generated by the southeast trade winds and flows from east to west. SOUTH EQUATORIAL CURRENT 187. It flows towards the east between the two equatorial currents. EQUATORIAL COUNTER CURRENT 188. Are movements of water which result from differences in density of adjoining water masses. DENSITY CURRENTS 189. The region drained by a river system. RIVER BASIN 190. The height of the land separating one river from another. DIVIDE 191. It is the layer nearest the earth. TROPOSPHERE 192. It contains the ozone layer. STRATOSPHERE 193. The coldest zone of the atmosphere. MESOSPHERE 194. Temperature in this layer increases quickly because of the absorption of energy from the sun. THERMOSPHERE 195. A layer of electrically-charged particles which are useful for communications. IONOSPHERE 196. It is the layer that extends out to interplanetary space. EXOSPHERE 197. It is the current state of the atmosphere. WEATHER 198. It is an instrument used to measure the force of air or air pressure. BAROMETER 199. A device that keeps the record of air pressure of force of air together with its changes for a longer period of time. BAROGRAPH 200. It is the movement of the air caused by varying density. WIND 201. It is the moisture in the atmosphere. HUMIDITY 202. It forms when a large part of air in the troposphere stops or moves slowly over a uniform land or water surface. AIR MASS 203. A high pressure area produced by the large pile of air over the earth’s surface. ANTICYCLONE 204. It appears as a depression or basin in an air mass. CYCLONE 205. It is the average state of all weather conditions in an area over a long period of time. CLIMATE 206. It has been developed to control and induced precipitation, it is used to disperse fog at airports. CLOUD SEEDING 207. A person who studies the weather. METEOROLOGIST 208. It measures wind speed. ANEMOMETER 209. It is used to measure the amount of rain fall. RAIN GAUGE 210. It is a compilation of weather data from many collecting stations. WEATHER MAP 211. It causes the wind’s direction to change. CORIOLIS EFFECT 212. The study or science of weather. METEOROLOGY 213. The prediction of weather. WEATHER FORECASTING 214. It describes a weather condition with a few clouds and no rain. FINE WEATHER 215. It means that clouds are present which may produce scattered rains but the greater portion of the day will be sunny or without rain. FAIR WEATHER 216. It refers to a condition in which rains occur during a greater portion of the day with light to moderate winds. RAINY WEATHER 217. It refers to a weather condition characterized by rains and strong winds. STORMY WEATHER 218. It is the agency responsible for providing information to the people on what to do before, during and after any natural phenomenon. PAG-ASA 219. He published the â€Å"Origin of Continents and Oceans†. ALFRED WEGENER 220. The theory that suggests that continents had once been one large land mass which had separated and moved apart. CONTINENTAL DRIFT THEORY 221. The great land mass. PANGEA (â€Å"ALL THE WORLD† or â€Å"ALL NATIONS† 222. The theory that explains not only the movements of continents, but also the changes on the earth’s crust as caused by internal forces. PLATE TECTONIC THEORY 223. According to the theory, the earth’s crust is broken into nine large plates and several smaller ones. PLATE TECTONIC THEORY 224. It is a minor plate between the Eurasian and the Pacific Plates. PHILIPPINE PLATE 225. Two plates are pulling apart, leaving a gap in between. DIVERGENT BOUNDARIES 226. Plates move past one another in opposite directions or in the same direction but at different rates. CONVERGENT BOUNDARIES 227. Two colliding plates cause one to go under the other. CONVERGENT BOUNDARIES 228. The process wherein successive separations and fillings continue to add new oceanic crusts between diverging plates. SEA FLOOR SPREADING 229. The average rate of spreading from a typical mid-ocean ridge. 6 CMS/YR 230. Highest mountain in the Philippines. MOUNT APO. 231. Highest mountain in the world. MOUNT EVEREST 232. The bending of rocks into folds. FOLDING 233. It is the result when the rock layer slides or slips over one another along the break or fracture. FAULTING 234. It is any vibration or shaking of the earth’s crust caused by faults. EARTHQUAKE 235. Earthquakes resulting from the movement of the crust or plate. TECTONIC ORIGIN 236. Earthquakes caused by molten magma as it forces its way up from deep under earth’s crust. VOLCANIC ORIGIN 237. It is an opening on the earth’s crust through which lava is thrown out. VOLCANO 238. These are cone-shaped structures composed of alternating flows of andesite lava and ash, cinders, and fragments. STRATO-VOLCANOES OR COMPOSITE VOLCANOES 239. These are volcanoes formed from basalt. SHIELD VOLCANOES 240. These volcanoes are formed from violent eruptions that expel fragments of lava in cinders. CINDER VOLCANOES 241. These are volcanoes that erupt periodically or had erupted in recent times. ACTIVE VOLCANOES 242. These are volcanoes that show signs of activity but have not erupted for a considerable length of time. DORMANT VOLCANOES 243. These are volcanoes in which all signs of volcanic activities have ceased. EXTINCT VOLCANOES 244. These are formed from cooling and hardening of molten materials which are heavy, usually dark in color, and unlayered. IGNEOUS ROCKS 245. These are formed from sediments, shells, or remains of plants and animal fossils, that were buried and later hardened into rocks. SEDIMENTARY ROCKS 246. These are formed from pre-existing igneous and sedimentary rocks as a result of temperature and pressure changes. METAMORPHIC ROCKS 247. The process where rocks change from one form to another as they are affected by natural processes, such as weathering, erosion, great heat, and pressure. ROCK CYCLE 248. The process of breaking down of rocks into fragments brought about by physical or chemical change. WEATHERING 249. The process by which rock fragments and soil are carried along by such agents as wind, water, and gravity. EROSION 250. The process of transferring soil from one place to another. EROSION 251. The process by which eroded rock fragments and soil are deposited in different places. DEPOSITION 252. The process by which deposited soil and rock fragments at the bottom of the sea become cemented and harden into rocks. COMPACTING 253. The process where compacted or cemented rock is subjected to great heat and pressure, changing the constitution of the rock. METAMORPHISM 254. It is naturally occurring, inorganic, crystalline solid with definite chemical composition. MINERAL 255. It refers to the way light is reflected from a mineral’s surface. LUSTER 256. It is a mineral’s resistance to being scratched. HARDNESS 257. A German mineralogist who worked out a scale of hardness used for mineral identification. FRIEDROCH MOHS 258. It is the hardest mineral. DIAMOND 259. It is the softest mineral. TALC 260. It is the color of a mineral in powderized form. STREAK 261. The way mineral breaks along smooth, flat planes. CLEAVAGE 262. It refers to the ratio of the mineral’s mass to the mass of an equal volume of water. SPECIFIC GRAVITY 263. It is the process of excavating and extracting ore or minerals in rocks. MINING 264. It is an organic matter from decayed plant and animal materials. HUMUS 265. It is a vertical section of all horizons that make up a soil. SOIL PROFILE 266. It consists of less fragmented rock materials, being less exposed to agents of weathering. BEDROCK 267. It refers to coarseness or fineness of the soil particles resulting from the weathering of rocks. SOIL TEXTURE 268. It has the smoothest and finest soil texture. SILT 269. It is the soil that is best for farming. LOAM 270. It is the uprising of water from the greater depths as the surface water is driven offshore. UPWELLING 271. A layer that absorbs or filters harmful rays from the sun. OZONE LAYER 272. It is a mountain-building process. VOLCANISM 273. The shape of the earth. OBLATE SPHEROID 274. The spinning or turning of the earth on its axis. ROTATION 275. It is the movement of the earth on its axis that gives rise to the occurrence of day and night. ROTATION 276. The movement of the earth around the sun. REVOLUTION 277. The imaginary line which separates the zones of day and night. TWILIGHT CIRCLE 278. The earth’s axis is tilted at 23  ½ degrees 279. The earth completes its revolution once in every 365 and  ¼ days. 280. Our planet’s only natural satellite. MOON 281. The rise and fall in sea level. TIDE 282. It occurs when the moon, the earth, and the sun are in line with one another. ECLIPSE 283. When the sun, moon, and earth fall in one straight line, the sun cannot be sun from a spot on earth because the moon covers it. SOLAR ECLIPSE 284. When the sun, earth, and the moon are aligned, the moon cannot be seen from earth because the earth covers it. LUNAR ECLIPSE 285. The dark inner part of the eclipse. UMBRA 286. The lighter outer part of the eclipse. PENUMBRA 287. It is the term used when the sun’s disk is completely covered by the moon. TOTAL ECLIPSE 288. It is the term used where only a part of the sun’s disk is covered. PARTIAL ECLIPSE 289. It is defines as the mean distance of the earth from the sun equivalent to 150,000,000km. ASTRONOMICAL UNIT (AU) 290. It considered as the most massive or the biggest planet. JUPITER 291. It is the densest among the planets. EARTH 292. It is the farthest planet and has the longest period of revolution. PLUTO 293. Are celestial objects made of ice and dust that revolve around the sun. COMETS 294. Are small, stony matters located in the space which passes through the earth in orbiting the sun. METEORS also known as â€Å"SHOOTING STARS† 295. Meteors that do not burn completely and fall on earth. METEORITES 296. Are meteor chunks that fall on earth.METEORITES 297. Are gigantic balls of flaming gases. STARS 298. It is the measure of the brightness of a star. MAGNITUDE 299. It refers to the apparent brightness of a star. MAGNITUDE 300. It is the nearest star to the earth. SUN 301. It is a medium-sized, middle-aged star of average brightness. SUN 302. An instrument used to learn about the composition of stats. SPECTROSCOPE 303. The process used to determine the size of the stars. INTERFEROMETRY 304. A technique that obtains an image in the surface of a big star. SPECKLE PHOTOGRAPHY 305. It is used to compute the diameter of the star. STEFAN-BOLTZMAN LAW 306. These are loose groups of stars that move through space as a unit. STAR CLUSTERS 307. These are group of stars that form a definite pattern. CONSTELLATIONS 308. It is the area where the star groups that are always visible are located. NORTH STAR OR POLARIS 309. These are huge systems of billions of stars and other celestial bodies. GALAXIES 310. It is the galaxy to which our sun belongs. MILKY WAY 311. It is a spiraling or rotating group of some 100 billion stars and clouds of dust and gases. MILKY WAY 312. It is composed of millions of galaxies. UNIVERSE 313. The planet that has the highest temperature because of its thick clouds of carbon dioxide. VENUS 314. It is anything that changes the motion and direction of moving objects or that causes an object at rest to start moving. FORCE 315. It is a push or a pull. FORCE 316. The force that attracts all objects on earth. GRAVITATIONAL FORCE 317. The force of attraction or repulsion between charged bodies. ELECTRICAL FORCE 318. The force that attracts any metal to the magnet. MAGNETIC FORCE 319. A very strong force that holds protons and neutrons together in the nucleus of an atom. NUCLEAR FORCE 320. It resists or opposes the movement of two surfaces in contact with one another. FRICTION 321. A force that is present on two surfaces in contact with each other. CONTACT FORCE 322. It arises when two bodies collide as a result of squeezing, stretching, or bending. CONTACT FORCE 323. A force that acts on bodies over great distance. NON-CONTACT FORCE 324. It is done when the force applied to an object actually moves the object. WORK 325. It is always a product of a force applied and the distance along which the force acted. WORK 326. These are devices which transform force or energy into useful work. MACHINES 327. It is a rigid bar which is pivoted around a point called fulcrum. LEVER 328. It is made up of a grooved wheel over which a rope passes. PULLEY 329. It consists of a wheel attached to an axle. WHEEL AND AXLE 330. It is a spiral, inclined plane. SCREW 331. It is a flat surface with one end higher than the other. INCLINED PLANE 332. It is a double inclined plane with either one or two sloping sides. WEDGE 333. It is a unit used to express work. JOULE (J) or NEUTRON METER (Nm) 334. It is the distance and direction through which an object moves. DISPLACEMENT 335. He discovered work. JAMES PRESCOTT JOULE 336. It is defined as the capacity to do work. ENERGY 337. It is the ability to do work or the capacity to move matter from one place to another. ENERGY 338. The energy of position or condition. POTENTIAL ENERGY 339. The energy of motion. KINETIC ENERGY 340. According to this law, energy can change from one form or another, but it can never be created nor destroyed. LAW OF CONSERVATION OF ENERGY 341. It is the total energy coming from the attractive and repulsive forces of all the molecules in a body. THERMAL ENERGY 342. It is the energy transferred from an object with a high temperature to one with a lower temperature. HEAT ENERGY 343. It is the energy stored in matter due to forces of attraction and the arrangement of subatomic particles in atoms and of atoms in the molecules of substance. CHEMICAL ENERGY 344. It is the energy of electrons flowing through conductors. ELECTRICAL ENERGY OR ELECTRICITY 345. It is defined as the changing of one form of energy into another form. ENERGY TRANSFORMATION 346. It involves the transfer of heat energy from one material or system to another. HEAT TRANSFER 347. It is the transfer of heat from one matter to another. It occurs when two objects at different temperatures are in direct contact. CONDUCTION 348. Energy transfer through solid particles. CONDUCTION 349. Materials that conduct heat easily. CONDUCTORS 350. Materials in which heat energy cannot pass through. INSULATORS 351. It is the transfer of heat in a gas or liquid. CONVECTION 352. It is the transfer of energy that does not require matter. RADIATION 353. Energy transfer through an empty space in the form of waves. RADIATION 354. These were formed during the decay of organisms that lived millions years ago. FOSSIL FUELS 355. It forms as a result of the decay of plants in the absence of oxygen. COAL 356. The brownish substance in the decaying materials of plants. PEAT 357. The second stage of coal formation. It is a brown coal composed of compressed woody matter that has lost all its moisture. LIGNITE 358. The third stage of coal formation. It is a dense, dark, brittle material that has lost all its moisture and impurities. BITUMINOUS COAL 359. It is the final stage of coal formation. It has the least impurities because it is mostly carbon. ANTHRACITE COAL 360. It is an important hydrocarbon found in nature within pores and fractures of rocks. PETROLEUM OR CRUDE OIL 361. It is the easiest fossil fuel to transport and the cleanest when burned. NATURAL GAS 362. It refers to the production of electricity by means of generators driven by water turbines as an energy source. HYDROELECTRIC POWER 363. It comes from the internal heat of the earth. GEOTHERMAL ENERGY 364. It is produced by fission or the splitting of the atom’s nucleus. NUCLEAR ENERGY 365. It is the abnormal increase in the temperature of bodies of water. THERMAL POLLUTION 366. A waste product which destroys cells, changes genetic materials, and even kills the plant and animal population living near the power plant. RADIATION 367. It is the harnessing of wind for energy needs. WIND POWER 368. It is the radiant energy from the sun. SOLAR ENERGY 369. A device which collects energy from the sun and transforms it directly into electricity. SOLAR CELL OR PHOTOVOLTAIC CELL 370. It is a possible generator of electricity with the two-way flow of water through narrow passages. TIDAL POWER 371. These are burnable fuels which are made from organic matter. BIOMASS FUELS 372. This is a combination of alcohol and gasoline. GASOHOL OR ALCOGAS 373. It is the wise and careful use of energy resources. ENERGY CONSERVATION

Business Law Essay Example | Topics and Well Written Essays - 1250 words - 14

Business Law - Essay Example ct to gain the protection of the law, it must satisfy the element of offer, acceptance, purpose to create legal representation, and there must be a consideration. Under the element of offer, a promisor invites a promisee to a responsibility and he makes it in such a way that he expects an acceptance from the promisee1. For example, person A offers to rent out his building to person X, for business purposes. In this example, â€Å"responsibility† is denoted by the building that person A wants to rent to person X, for business purposes. In acceptance, a promisee agrees to take up the responsibility offered by the promisor. For example, after person A offered to rent out his building to person X, person X agree to become a tenant under the conditions offered. This amounts to acceptance. For a contract to exist, it must be legally binding document. It must be recognizable by the law, and its provision acceptable by the legal principles of the nation. Finally, a valid contract must have some values exchanged, and this is termed as consideration. For instance, take our case above. He can pay either in cash, or through some valuable products. This paper also identifies the public, social and business issues that influenced the courts in their rulings. This paper has a conclusion, which is a summary of the main points addressed2. One key fact that relates to the enforceability of a contract is whether there is an element of substantial performance within a contract. This fact is better portrayed in the case involving, Jacob and Young vs. Kent (1921). In this case, the plaintiff did not build the house as per the contractual agreement with the defendant. However, the portion left was minimal, and redoing the work would have meant demolishing a large percentage of the whole building, and on this basis, the plaintiff refused to re-do it. The plaintiff won the case, as the court ruled that when there is a defect in contract performance, and it is minimal, then the concept of

Case study in business competitve strategy Essay

Case study in business competitve strategy - Essay Example The main problem was the hygiene factor that the plant lacked in and CFIA recommended shutting down the plant in Winnipeg for the purpose of deep cleaning and revised cleaning protocols (Ewing, 2006). The external constraints in this case are that after the news became prominent in the media and newspapers, the customers were reluctant to buy their products. The Company CEO however assured the mass that the health and safety of the million Canadian families are their responsibility and they will take care of it. But few internal constraints made it difficult for the company to improve its grounded image before the customers. One of the employee of another plant of Oaktree Mills tweeted confidential news on social networking site. The female employee did not limit herself to the leakage of the confidential news of the company only but also blamed the company for using unsafe practices for processing of meat. She even informed the mass by tweeting not to trust the company and their pro ducts and to beware of the company’s false assurance. The Director of Communications and the Human Resource Head of Oaktree Mills are shocked to see the deed of the employee. The problem that was faced by the company was mainly because it did not have any social media policy. As the company did not have the policy thus they could not take any step against the female employee. The CEO of the company has the least to do other than ordering the director and human resource head to look after the situation seriously and take appropriate steps for handling the situations (Ewing, 2006). Situation analysis Oaktree Mills is a family owned large meat processing company based in Calgary and the processing firms are in Winnipeg, Montreal and Toronto. The company is famous for the product quality it serves to its customers. It has created good relation with their employees and concentrates highly on the retention of the employees, when other companies go for layoffs. It has also undertake n corporate social responsibility activities, so as to take care of the environment it works in and also their neighbours. Recently, the uninterrupted business faced a serious situation, which harmed the image of the company. About 13 peoples in Saskatchewan were hospitalized after being affected from salmonella poisoning. The situation was noticed by Canadian Public Health Authority, who informed the matter to the Canadian Food Inspection Agency (CFIA). CFIA investigated the matter and found that the illness was due to consumption of the sandwich meats. They identified the fact that the methods that are undertaken by the Winnipeg processing plant are not adequate for the hygiene factor that a processing plant should possess. The agency reported that the two industrial meat grinders are not clean and thus it processed the meats in an unhygienic manner. The agency even recommended the company to shut down the plant in Winnipeg for deep cleaning and for revising the cleaning protocols . Oaktree declared the suspension of operation of the plant and assured full cooperation with CFIA. Thus, 1.2 million kilogram of processed meat products was recalled. The Director of Communication, Ashok Fraser worked together with the senior management for controlling the situation and informed the public to avoid causing panic

Performance Oriented Change Case Study Example | Topics and Well Written Essays - 3250 words

Performance Oriented Change - Case Study Example This extraordinary happening presents a universal point of disappearance for conjecture concerning the future of NPM inventiveness in three nations. The paper will expound on New Zealand as well the UK, as the two nations that have been frontiers of NPM, Australian Council of Social Services. (1998).The period commences with a description of NPM. The pressures for changing the public domain have also been investigated. More so, the paper develops in debating the emerging variations, conclusions as well as unrestricted realm transformation, Hood, C. and M.W. Jackson. (1991). The backdrop through which administrators operate is increasingly being altered, vastly diverse from that reflect by preliminary intellectual stalwarts of society management, Moore, Mark Harrison (1995). Societal bureaus are anticipated to correlate with each other, with nonprofit corporations and with citizen groups and to employ contemporary expertise methodically to administer and execute utility. Commanding demands that entail proficient resource use are evident owing to transnational markets as well as quasi-bazaar variables that have been asserting turbulent market forces. This framework is significant in the intellect that bureaus need to administer individual resources consequently but also compassionately and officially, Moore, Mark Harrison (1995). ... Moderately, the disciplines need to be incorporated in the civic administration prospectus in modes that ensure they will be integrated in learners' minds and hence their practice. Most essentially, civic administration pedagogy should be embedded to helping learners regarding civic corporations, government as well as governance, and the functionality of the collective department in an assortment of communal and financial system, Moore, Mark Harrison (1995). Universal Archetype The Institution for Fiscal Integration and Progression observed in 1995 that a modern archetype for public administration has materialized, aimed at fostering a concert slanting culture in a less federal communal subdivision. The description implied that implementation of modern archetype was not complete and differed from nation to nation (OECD 1995:8). During this interlude, a corporate entity known as the Commonwealth Association for Public Administration and Management (CAPAM), a corporate for unrestricted management suppliers and scholars in fifty four nations of the British Commonwealth, seized its introductory symposium. The New Public Management can be defined as an agreement flanking the public; designated legislatures; on one end and collective overhaul on the excessive end. The civic societies and politicians want elevated-quality unrestricted services as well as eminent performance by domain corporate, what Al Gore referred 'the administration that functions better yet co sts less' Gore 1993). In realizing this, they are willing to give communal workers excessive administrative sovereignty, human capital in addition to scientific capital towards realizing

Facilities Management Essay Example | Topics and Well Written Essays - 2750 words

Facilities Management - Essay Example Factors Influencing Growth of Facility Management. 7 2.5. Facilities Management Transformation 8 2.6. Support Service Facilities Management at HSBC 8 3.0. Facilities Management Strategy 10 3.1. Facilities Management Development Strategy 11 3.2. Strategic Analysis of Facilities Management 11 3.4. Developing Solutions 12 4.0. Strategic Implementation 12 5.0. Conclusion 13 6.0. References 14 HSBC (Hong Kong Banking Corporation Limited) 1.1. Introduction HSBC is has its headquarters in London and is among the largest banking and financial services organizations in the world. Its international network comprises or close to 8, 000 offices in more than 80 countries and territories in Europe, the Asia-Pacific region, the Americas, the Middle East and Africa. In the United States alone, HSBC has more than 460 bank branches and has its listings on the London, Hong Kong, New York, Paris and Bermuda stock exchanges. The shares at HSBC are held by over 220,000 shareholders in 132 countries and te rritories. With respect to the New York Stock Exchange, the shares are traded in form of American Depositary Receipts. On close observation, it is clear to note that HSBC provides a comprehensive range of financial services to close to 89 million customers through four global businesses. These constitute: Retail Banking and wealth Management (prior referred to as Personal Financial Services); Commercial Banking; Global Banking and Markets; and Global Private Banking. 1.2. Background Information HSBC Private Bank is the marketing name for the private banking business. With its established presence in virtually every financial market in the world, HSBC possibly has the most valuable place in multinational banking giants. HSBC has many facilities to the distinguished customers in Retail and Wealth Management, as well as commercial bank offering financial services to small, medium and middle market enterprises. HSBC was founded in Hong Kong Shanghai in 1865 and the banking facility rega rds Asia as its most crucial market region; with America, Asia Pacific and Europe each represent a third of its business. HSBC offers the following financial services to its customers; Customer’s personal financial services. Current and savings accounts. Mortgage Car Financing 1.3. Objectives and importance of Study The main objective of this study is to develop a facilities management strategic framework for HSBC support services with respect to the contracts to other companies to make the service delivery effective. With greater insights in the contemporary world towards the improvement of the global economy, the world has been rocked by major financial crisis in the recent past orchestrating for strategic measures to ensure that the global economy remains well functional. The main focus is aimed at the transformation strategy for Facilities Management in the public sector. 1.4. Organizational Framework of HSBC HSBC organizational structure is specially designed to be dynam ic and customer focused. On the same note, it seeks to ensure effective control, supervision and enhance consistency in all standards across the organization and align all areas of operations to achieve overall organizational objectives. HSBC organizational structure is divided into six principal groups namely: - Retail Banking. The Retail Banking Group is in charge for the products and services for retail customers and small enterprises including various credit products, liability products, distribution of third party investment and

Marketing Essay Example | Topics and Well Written Essays - 1500 words - 24

Marketing - Essay Example Stuffed animals need stuffing. By looking at the raw material inputs that are used in stuffed animals, it was thought that these hole punch scraps can be used as alternative. The major concern in deciding on which products to choose, where the hole punch scraps can be useful is the question of volume. Hole punch scraps can only be valuable if they are sold in huge volumes. The answer to this question has been found on the stuffed animals alternatives for raw material inputs. Hole punch scraps are waste materials, that in essence when they are manufactured they are very minimal in terms of costs. The materials that are used to stuff animals like â€Å"straw, beans, plastic pellets, cotton, synthetic fibres, or other similar materials (Wikipedia 2010),† are naturally produced for the stuffing, thus maybe more costly to manufacture. The demand for these products come from children and adults who look for comfort objects (Fisher 2010). From a psychological perspective, the fascination for comfort objects has sprung up during the late 1800s when life is hard and comfort objects like stuffed animals tend to cheer people up for unique psychological situations (FoxNews.com 2008). The origin of stuffed animals businesses is traced back to practices of taxidermy, where skins of hunted animals are stuffed in order to mimic their appearances even when they are no longer alive. The demand for these products can be traced to a need using Maslows hierarchy of needs framework (Kotler & Armstrong 2004). A comfort object provides the consumer with security and partly, some social needs. During unique situations such as personal tragedies, problems and moments of loneliness, and stressful events, comfort objects somehow provide the feeling of having company as well as the feeling of being safe holding something (FoxNews.com 2008). Pricing is a

Leadership Essay Example | Topics and Well Written Essays - 5000 words

Leadership - Essay Example It would be wise to say that a leader is not born but is developed by experience, knowledge and practice. A good leader is one who can motivate his followers spontaneously and lead them to the path of success in a smooth manner. According to (Curry) â€Å"It goes without saying that good leadership is crucial to any successful business. But, what makes a good leader and how can someone develop himself or herself into a good leader if they are not one to begin with? The answer is that there are many factors that contribute to a good leadership. And, whether someone is naturally a good leader or not, anyone can become a good leader†. A good leader is one who sets himself as a role model and example for next generation to look upon and get inspire to follow a successful path. The leadership quality is at times inherited, while sometimes it is cultivated by practice, experience and knowledge. Leadership is the process by which a person influences people around him to achieve a par ticular target or goal. A leader needs to make use of his best ability and power to bring about changes in the atmosphere he is working to get a desired result. However, there are different styles of leadership and as well different types of personality in leaders. Some people have gained popularity being a good King, and some as dictators; nonetheless, they all had the ambition to rule the world by any means. But, currently the leaderships which are in vogue are the authoritative leader, transformational leader, aristocratic leader and so on. Leadership where in the leaders has the quality of being innovative, authoritative, has visionary skills and goal oriented can be termed as transformational leader. Today the world has changed in to a global business arena and the emergence of numerous businesses corporate and international business chains have made business leaders to be demanding and evolutionary. The capacity to lead a team or organization is a very tedious task and it requ ires a lot of skill and ability to perform a task faultless and successfully. Being a leader requires an immensely high level of vision, creative thoughts and energy and one should be able to bring up aspiration and motivation in people around him. A good leadership is performed through a social influence where in number of people are spontaneously motivated to work according to the style of the specific leader. Steve Jobs is one such leader, who has changed the face of computer technology by his intense passion and love for electronic world. History and Background of Steve Jobs Steve Jobs is a renowned business magnate of America and also the CEO of Apple Incorporation. His official name is Steve Paul Jobs has much professional experience in business world before entering his own venture of selling personal computer. His venture was initiated in early 1970s, and later years progressed to become one of the famous and successful business the American business world .Jobs have previou sly held positions in Pixar Animation Studio as CEO, and also has been a board member of The Walt Disney Company before starting his own venture .He has also been the executive producer for the movie â€Å"Toy Story† in 1995 which can be counted as a worthy experience in movie business. It is a matter of credit that Steve with his other business associates designed and marketed first line of commercially successful

The Relevance of the Capital Asset Pricing Model to a Company Seeking Essay

The Relevance of the Capital Asset Pricing Model to a Company Seeking to Evaluate its Cost of Capital - Essay Example The Capital Asset Pricing Model was devised by William Sharpe to calculate as well as explain â€Å"†¦the expected rate of return on an asset †¦ (that) †¦can be written as the risk-free rate of interest plus the asset’s normalized covariance with the market times the difference between markets expected the rate of return and the risk-free rate† (Milne, 1995, pp. 5-6). Under financial theory CAPM is a model that shows assets returns concerning principle in conjunction with econometric models (Milne, 1995, pp. 5-6), and is represented by the following formula (Burton, 1998, pp. 21-22): CAPM is calculated using the beta as it provides a measurement of a stock's volatility in terms of its movement comparison with the overall stock market (Burton, 1998, pp. 21-22). The above means that when a company’s share price moves in tandem with the market, with the beta of a stock is represented by 1 and a 15% movement indicated as 1.5 (Burton, 1998, pp. 21-22). Foster (1986, p. 337) provides a summary of the two assumptions present in the Capital Asset Pricing Model as represented by â€Å"1. Two statistics, the mean and variance, are sufficient to describe investor preferences over the distribution of future returns on a portfolio. 2. Investors prefer higher expected returns to lower expected returns for a given level of portfolio variance, and prefer lower variance to higher variance of portfolio returns for a given level of expected returns". Corporate finance managers utilize CAPM to determine the estimated discount rate that is connected to a project under consideration (Ferran, 1999, p. 12). In conjunction with the foregoing, CAPM is used as a means to measure the systematic risk present in equity investment projects (Megginson, 1997, Pp. 107-123).  

Mr Empanada Recommendation Essay Example | Topics and Well Written Essays - 1000 words

Mr Empanada Recommendation - Essay Example This should enable it to sell more as customers will have a variety to choose from. As a retailer, Mr. Empanada should know that retailing is all about constant persuasion, even though a myriad other factors influence-buying behavior. Visual cues influence buying decisions to a great deal, with color being the most significant. In light of this, customers place value on color more than they do on other factors as smell, sound or texture. Color has a great psychological effect on consumers. Diversifying the breakfast menu to include a healthy combo meal will grant clients an opportunity to sample other meals, effectively increasing sales and revenue. This will have a positive impact on the company’s fortunes for a long time. Diversifying the menu will help this organization to attract new customers, and to eat into its competitors’ client base. This is because presently, Mr. Empanada’s competitors have healthy combo meals on their menus. Mr. Empanada should take a cue and expand the menu. Make a Colorful Logo Prior to the era of digital branding and graphic design, businesses took logos as a luxury worth bypassing. During that era, companies placed emphasis on customer loyalty and good rapport. These days, the business environment is high competitive, calling for companies to invest heavily in attractive logos. Customers have an orientation towards color, and this calls upon companies to invest in an eye-catching logo that captures its aspirations in an apt manner. Mr. Empanada needs rebranding. The current economic setting now forces businesses to reinvent and re-evaluate their operations to remain relevant. These include branding and marketing strategies that arrest the imagination of customers. Every effort to rebrand must have a goal. In this case, Mr. Empanada needs to stand out from the crowd by being highly visible. A good logo must remain imbedded in customers mind; elicit discussion, and making competitors notice (Vaid 144). The log o must not make false promises, but must live up to customers expectations. It would be naive to create a logo that promises the best in the market, and then come up with substandard good or services. Customers must feel that the business is venturing into a new environment that promises an improvement on the past. Its current logo has too much green color. Green does not stand out well for a company that serves a variety of foods as some clients may confuse it for a vegetarian joint. This could make it lose out on potential customers who are not vegetarians. A logo is the first thing a potential client sees and remembers. This is why it must stand out and set the tone for the branding strategy (Wheeler & Katz 119). In essence, Mr. Empanada knows that logos are the corporate faces. They display an organization’s special identity, providing critical information through colors, images and fonts. They should make the customer to identify with the organization. They are a shortcu t to advertisements and marketing. Mr. Empanada should invest in a comprehensible but unique logo. While there are many colors to choose from, an organization of Mr. Empanada’s stance should go for colors that target customers identify with. The colors should reflect freshness, a sense of faithful service, trustworthiness, and loyalty. They should for the entire company’s brand identity. An amateurish logo would be a complete turn off to customers. A good logo should blend well with the company’

History of the Democratic Party Essay Example for Free

History of the Democratic Party Essay The Democratic Party is one of the two major political parties in the United States. When this party makes political decisions, the Democratic Party followed a very liberal viewpoint. The Democratic Party is one of the oldest official political parties in the world and it is the oldest official political party in the United States. In 1792, Thomas Jefferson started the Democratic Party to oppose the Federalist Party to fight for the Bill of Rights. The Democratic Party was called the party of the common man. It was probably called this because it supported the normal citizens, like farmers and middle class people. Thomas Jefferson was elected as the first president from the Democratic Party in 1800. Jefferson served as president for two terms for the Democratic Party. Following this, in 1848, the Democratic National Committee was formed by the National Convention. The Democratic National Committee exists, making it the longest standing political organization ever. The Democratic Party is recognized with serving the lower and middle classes by funding government programs such as Welfare and free or low cost medical insurance. This is an opposite belief of the Republican Party who believes in that no one should face a tax increase, especially the rich. Democratic parties typically rule large states such as New York and California. Since these are two states with a high number of electoral votes, the Democratic Party has an advantage in presidential elections, although despite that support, there have still been many Republican presidents voted into office.

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