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`MERCK
`MAIQFIUAL
`*MEDICAL INFORMATION «
`E
`*3
`
`~
`
`LOME-EDITION?
`
`The world’s most widely used
`medical reference-
`now In everyday language
`
`INTELGENX 1033
`
`

`
`-
`
`
`
`THE
`
`MEECK
`MERCK
`MANUAL
`MANUAL
`
`OF
`
`MEDICAL INFORMATION
`MEDICAL INFORMATION
`
`HOME EDITION
`HGME EEITION
`
`¢“"‘+‘C’
`
`INTELGENX 1033
`
`INTELGENX 1033
`
`

`
`THE
`
`MERCK
`MANUAL
`
`OF
`
`MEDICAL INFORMATION
`
`HOME EDITION
`
`Robert Berkow, M.D., EDITOR-IN-CHIEF
`
`Mark H. Beers, M.D., AssociATE EDITOR
`
`Robert M. Bogin, M.D. , SENIOR ASSISTANT EDITOR and EDITOR, ELECTRONIC VERSIONS
`
`Andrew J. Fletcher, M.B., B.Chir., SENIOR ASSISTANT EDITOR
`
`Editorial Board
`
`Lawrence K. Altman, M.D.
`Susan J. Blumenthal, M.D., M.P.A.
`Philip K. Bondy, M.D.
`Preston V. Dilts, Jr., M.D.
`Douglas A. Drossman, M.D.
`L. Jack Faling, M.D.
`Eugene P. Frenkel, M.D.
`
`Glen 0. Gabbard, M.D.
`Robert A. Hoekelman, M.D.
`Gerald L. Mandell, M.D.
`Edwina A. McConnell, R.N., Ph.D.
`Fred Plum, M.D.
`G . Victor Rossi, Ph.D.
`Paul H. Tanser, M.D., F.R.C.P.(C)
`
`Published by
`
`MERCK RESEARCH LABORATORIES
`
`Division of
`
`Merck & Co. ·1 IC.
`Whiteho•.:;e Scation, N.J.
`
`1997
`
`INTELGENX 1033
`
`

`
`Edit orial and Production Staff
`
`Executive Editor
`S enior Staff Editor
`Senior Staff Editor
`
`Keryn A.G . Lane
`William J. Kelly
`Susan T. Schindler
`
`Design Director
`Illustrator
`Indexer
`Production Editor
`Textbook Production Coordinator
`Medical Textbook Coordinator
`Executive Assistant
`
`Lynn Foulk
`Michael Reingold
`Ann Cassar
`Debra G. S hare
`Diane C . Zenker
`Dorothy A. Bailey
`Diane C . B obrin
`
`Publisher
`Advertising and P romotional Supervisor
`
`Gary Z elko
`Pamela J . Barnes
`
`Library of Congress Catalog Number 96-080494
`
`!SBN 0911910-87-5
`
`First Printing-July 1997
`Second Printing-October 1997
`T hird Printing-March 1998
`
`Copyright© 1997 by Merck & Co., Inc.
`
`All rights reserved. No part of this book may be reproduced or used in any form
`or by any means, electronic or mechanical, including photocopying, or by any
`information storage and retrieval system, without permission in writing from the
`Publisher. Inquiries should be addressed to T he Merck Manuals Department,
`P.O. Box 4, Merck & Co., West Point, PA 19486.
`
`Printed in the United States of America
`
`INTELGENX 1033
`
`

`
`Special Note to Readers
`The authors, reviewers, editors, and publisher have made extensive
`efforts to ensure that treatment information is accurate and conforms
`to the standards accepted at the time of publication. However, con(cid:173)
`stant changes in information resulting from continuing research and
`clinical experience, reasonable differences in opinions among author(cid:173)
`ities, unique aspects of individual situations, and the possibility of
`human error in preparing such an extensive text require that the
`reader exercise judgment when making decisions and consult and
`compare information from other sources. In particular, the reader is
`advised to discuss information obtained in this book with a doctor,
`pharmacist, nurse, or other health care practitioner.
`
`INTELGENX 1033
`
`

`
`......
`
`Is
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`:e
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`s-
`al
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`at
`1g
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`SECTION 2
`
`Drugs
`
`23
`
`5. Overview of Drugs
`
`6 Drug Administration,
`Distribution, and Elimination
`
`1. Pharmacodynamics
`Selectivity of Drug Action • Affinity and Intrinsic
`Activity • Potency and Efficacy • Tolerance • Drug
`Design and Development
`
`a. Factors Affecting Drug
`Response
`Genetics • Drug Interactions • Drug-Disease
`Interactions • Placebos
`
`9. Drugs and Aging
`
`23
`
`28
`
`31
`
`34
`
`39
`
`11 . Compliance With Drug
`Treatment
`Results of Noncompliance • Compliance Among
`Children • Compliance Among the Elderly • Ways to
`Improve Compliance
`
`46
`
`12. Generic Drugs
`Patent Protection • Evaluation and Approval
`Procedures • Comparing Generic and T rade-Name
`Drugs • Choosing a Generic Drug • Generic
`Nonprescription Drugs
`
`48
`
`13. Over-the-Counter Drugs
`Historical Background • Safety Considerations •
`Analgesics and Anti-inflammatory Drugs • Cold
`Remedies • Diet Aids • Antacids and Indigestion
`Aids • Motion Sickness Drugs • Sleep Aids • Special
`Precautions
`
`53
`
`1 0. Adverse Drug Reactions
`42
`Types of Adverse Reactions • Severity of Adverse
`Reactions • Benefits Versus Risks • Risk Factors •
`Drug Allergies • Overdose Toxicity
`
`CHAPTER 5
`
`Overview of Drugs
`
`People in every civilization in recorded history
`have used drugs of plant and animal origin to
`prevent and treat disease. The quest for sub(cid:173)
`stances to combat sickness and to alter mood and
`consciousness is nearly as basic as the search for
`food and shelter. Many drugs obtained from
`Plants and animals are still highly valued, but
`most drugs used in modern medicine are the
`~roducts of advances in synthetic organic chem(cid:173)
`Istry and biotechnology made since the end of
`World War II.
`
`Under United States law, a drug is any sub(cid:173)
`stance (ot her than a food or device) intended for
`use in the diagnosis, cure, relief, treatment, or
`prevention of disease, or intended to affect the
`structure or function of the body. Oral contra(cid:173)
`ceptives are examples of drugs that affect the
`structure or function of the body, as opposed to
`altering a disease process. Although this compre(cid:173)
`hensive definition is important for legal purposes,
`it isn't practical for everyday use. A simple but
`workable definition of a drug is any chemical that
`affects the body and its processes.
`
`INTELGENX 1033
`
`

`
`24
`
`Drugs
`
`Traditional Cures, Modern Uses
`
`Drug
`
`Source
`
`Conditio
`Treated
`
`Digitalis
`
`Purple foxglove
`
`Heart failure
`
`Quinine
`
`Cinchona bark
`
`Malaria
`
`Vinca
`alkaloids
`
`Insulin
`
`Periwinkle plant
`
`Cancer
`
`Pig, cow, and
`genetically
`engineered
`human insulin
`
`Diabetes
`
`Urokinase Cultures of human
`kidney cells
`
`Blood clots
`
`Opium
`
`Poppy plant
`
`Pain
`
`Prescription and
`No nprescription Drugs
`By law, drugs are divided into two categories:
`prescription drugs and nonprescription drugs.
`Prescription drugs-t hose considered safe for
`use only under medical supervision-may be
`dispensed only with a written prescription
`from a licensed professional (for example, a phy(cid:173)
`sician, dentist, or veterin arian). Nonprescription
`drugs-those considered safe for use without
`medical supervision-are sold over the counter
`without a prescription. In the United States, the
`Food and Drug Administration (FDA) is the gov(cid:173)
`ernme t agency that decides which drugs require
`a prescription and which may be sold over the
`counter.
`After many years of use under prescription reg(cid:173)
`ulation, drugs with excellent safety records may
`be approved by the FDA for over-the-counter
`sale.A The pain-relieving drug ibuprofen is one
`former prescription drug now available over the
`
`A see box, page 54
`
`• see page48
`
`counter. Often, the amount of active ingredient in
`each tablet, capsule, or caplet of a drug approved
`for over-the-counter sale is.substantially lower
`than the amount in a dose of the drug available
`by prescription.
`In the United States, the inventor or discoverer
`of a new drug is given a patent t hat grants the
`person exclusive rights t o the drug formula for 17
`years, although usually many of those years have
`already passed by the time the drug is approved
`for sale. While the patent is in effect, the drug is
`a proprietary drug. A generic (nonproprietary)
`drug is not protected by patent. Aft er the patent
`expires, the drug can be legally marketed under
`the generic name by any FDA-approved manufac(cid:173)
`turer or vendor, but the original holder of the
`copyright still controls the rights to the drug's
`trade name.• Generic versions are usually sold at
`lower prices than the original drug.
`
`Drug Names
`
`Some understanding of how drugs are named
`can help in deciphering drug product labels.
`Every proprietary d r ug has at least three names(cid:173)
`a chemical name, a generic (nonproprietary)
`name, and a trade (proprietary or brand) name.
`The chemical name describes the atomic or
`molecular structure of the drug. Although the
`chemical name describes and identifies the prod(cid:173)
`uct precisely, it's usually too complex and cum(cid:173)
`bersome for general use, except in the case of
`some simple, inorganic drugs such as sodium
`bicarbonate.
`In the United States, the generic name is as(cid:173)
`signed by an official body-the United States
`Adopted Names (USAN) Council. The trade name
`is chosen by the pharmaceutical company that
`manufactures it. The company tries to choose a
`unique name that's short and easy to remember
`so doctors will prescribe it and consumers will
`look fo r it by name. For this reason, trade names
`sometimes link the drug to its intended use, tor
`example, Diabinese for diabetes and Flexeril tor
`muscle cramps.
`The FDA requires that generic versions of drugs
`have the same active ingredients as the original
`and that they be absorbed into the body at the
`same rate. The manufacturer of a generic versioJl
`may or may not decide to give the drug its oWJl
`trade name, depending on whether it thinks itS
`"branded" version will sell better.
`
`r
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`INTELGENX 1033
`
`

`
`What's in a Name?
`
`N-( 4-hydroxyphenyl) acetamide
`
`----Chemical Name
`----
`t ----
`---
`
`?-chloro-1 ,3-dihydro-1-methyl-5-phenyi-2H-1 ,4-benzodiazepin-2-one
`
`4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone
`
`oL-threo-2-(methylamino )-phenylpropan-1-ol
`
`N"-cyano-N-methyi-N' -[2-[[(5-methyl-1 H-imidazol-4-yl)
`methyl]thio]ethyl]guanidine
`
`i
`
`)
`
`r
`:-
`e
`'s
`lt
`
`25
`
`Generic Name
`
`acetaminophen
`
`diazepam
`
`haloperidol
`
`pseudoephedrine
`hydrochloride
`
`Trade
`Name
`
`Tylenol
`
`Valium
`
`Haldol
`
`Sudafed
`
`cimetidine
`
`Tagamet
`
`Drug Dynamics and Kinetics
`
`Two primary medical considerations influence
`drug selection and use: pharmacodynamics
`(what the drug does to the body) and pharma(cid:173)
`cokinetics (what the body does to the drug). In
`addition to what the drug does (for example, re(cid:173)
`lieve pain, lower blood pressure, reduce plasma
`cholesterol level), pharmacodynamics describes
`where (the site) and how (the mechanism) a drug
`acts on the body. Although what a drug does is
`readily apparent, the precise site and mechanism
`of action may not be understood until years after
`the drug has proved its worth many times over.
`For example, opium and morphine have been
`used for centuries to relieve pain and distress,
`but the brain structures and brain chemistry in(cid:173)
`volved in the pain relief and euphoria they pro(cid:173)
`duce were discovered only recently.
`For a drug to work, it has to get to the place in
`the body where the problem lies, and that's why
`the science of pharmacokinetics is important.
`Enough of the drug has to stay at the !;ite of action
`until the drug does its job, but not so much that
`it produces severe side effects or toxic reactions.
`Every doctor knows that selecting the right dose
`is a tricky balancing act.
`Many drugs get to their site of action through
`the bloodstream. How much time these drugs
`need to work and how long their effects last often
`depend on how fast they get into the blood(cid:173)
`stream, how much of them gets into the blood-
`
`stream, how fast they leave the bloodstream, how
`efficiently they're broken down (metabolized) by
`the liver, and how quickly they're eliminated by
`the kidneys and intestines . .A
`
`Drug Action
`
`Much of the mystery surrounding drug action
`can be cleared up by recognizing that drugs affect
`only the rate at which biologic functions proceed;
`they do not change the basic nature of existing
`processes or create new functions. For example,
`drugs can speed up or slow down the biochemical
`reactions that cause muscles to contract, kidney
`cells to regulate the volume of water and salts
`retained or eliminated by the body, glands to se(cid:173)
`crete substances (such as mucus, gastric acid, or
`insulin), and nerves to transmit messages. How
`well the drug works generally depends on how
`well the targeted processes respond.
`Drugs can alter the rate of existing biologic
`processes. For example, some antiepileptic drugs
`reduce seizures by sending the brain an order to
`slow down production of certain brain chemicals.
`However, drugs can't restore systems already
`damaged beyond repair. This fundamental limi(cid:173)
`tation of drug action underlies much of the cur(cid:173)
`rent frustration in trying to treat tissue-destroy-
`
`A see page28
`
`!d
`s.
`
`y)
`
`or
`:1e
`)d(cid:173)
`m(cid:173)
`of
`tm
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`:es
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`1at
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`Nill
`1es
`for
`for
`
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`the
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`>WO
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`
`tn
`
`INTELGENX 1033
`
`

`
`26
`
`Drugs
`
`ing or degenerative diseases such as heart failure ,
`arthritis , muscular dystro phy, multiple sclerosis,
`and Alzheimer's disease.
`
`Response to Drugs
`
`Everyone responds to drugs differently. A large
`person generally needs more of a drug than a
`smaller person needs for t he same effect. New(cid:173)
`born babies and elderly people metabolize drugs
`more slowly than children and young adults do.
`People with kidney or liver disease have a harder
`time getting rid of drugs once t hey've entered the
`body.
`A standard or average dose is determined for
`every new drug on t h e basis of laboratory testing
`in anim als and trials in humans. But the concept
`of an average dose is like "one s ize fits all" in
`clothing: It fits a range of individuals well enough,
`but it fits almost no one perfectly.
`
`Adverse Reactions
`
`In the early 1900s, the German scientist Paul
`Ehrlich described an ideal drug as a "magic bul(cid:173)
`let"; such a drug would be aimed precisely at a
`disease site and wouldn't harm healthy tissues.
`Although many new drugs are more selective than
`their predecessors, the perfect drug doesn't yet
`exist. Most drugs fall short of the precision envi(cid:173)
`sioned by Ehrlich. Although they work against
`diseases, they also have some undesired effects.
`Unwanted drug effects are called side e ffects or
`adverse reactions. If drugs had cruise control,
`they could automatically maintain a desired level
`of action. For example, they could maintain a nor(cid:173)
`mal blood pressure in someone with high blood
`pressure or a normal blood sugar level in some(cid:173)
`one with diabetes. However, mos drugs can't
`maintain a specific level of action. Rather, a drug
`may produce too strong an effect, causing low
`blood pressure in a person being treated for high
`blood pressure or a low blood sugar level in a
`person with diabetes. Nevertheless, with good
`communication between a patient and doctor,
`
`A see box, page 41
`
`unwanted effects can often be reduced or avoided.
`The patient tells the doctor how the drug is affect(cid:173)
`ing him, and t he doctor adjusts the dosage.
`A drug may affect several functions, even
`though it's targeted at only one. For example, anti(cid:173)
`histamines can help relieve allergy symptoms
`such as a stuffy nose, watery eyes, and s neezing.
`But becau'ie most antihistamines affect t he ner(cid:173)
`vous system, they can also cause sleepiness, con(cid:173)
`fusion, blurred vision, dry mouth, constipation,
`and problems with urination. A
`Whether a particular drug action is called a side
`effect or a desired effect depends on why t he drug
`is being taken. For instance, antihistamines are
`the usual active ingredient in over-the-counter
`sleep aids. When they're taken for this purpose,
`their ability to produce sleepiness is a beneficial
`effect rather than an annoying side effec t.
`
`Effectiveness and Safety
`
`The two goals of drug development are effec(cid:173)
`tiveness (efficacy) and safety. Since all drugs can
`harm as well as help, safety is relative. The wider
`t he margin of safety (therapeutic window)-
`t he
`spread between the usual effective dose and a
`dose that produces severe or life-threatening side
`effects-t he more useful the drug. If a drug's usual
`effective dose is also toxic, doctors aren't willing
`to use the drug except in serious situations in
`which there's no safer alternative.
`The best drugs are both effective and, for the
`most part, safe. Penicillin is such a drug. Except
`in people who are allergic to it, penicillin is vir(cid:173)
`tually nontoxic, even in large doses. On the other
`hand, barbiturates, which were commonly used
`as sleep aids, can interfere with breat hing, disturb
`the heart rhythm, and even cause death if taken
`in excess. Newer sleep aids such as triazolam and
`emazepam have better safety margins.
`Some drugs must be used despite their having
`a very narrow margin of safety. For example, war(cid:173)
`farin, which is taken to prevent blood clotting, can
`cause bleeding. People who take warfarin need
`frequent checkups to see whet her the drug is
`having too much or too little effect on blood clot(cid:173)
`ting.
`Clozapine is another example. This drug often
`helps people with schizophrenia when all other
`
`INTELGENX 1033
`
`

`
`.-
`
`:1
`i(cid:173)
`s
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`1,
`
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`
`the
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`her
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`Alar(cid:173)
`can
`eed
`g is
`::lot·
`
`1ft en
`ther
`
`have failed. But clozapine has a serious side
`drug~· It can decrease the production of white
`effeC d. cells needed to protect against infection.
`bloo se of this risk, people who take clozapine
`Bee au
`t have their blood tested frequently for as
`rnus
`as they take the drug.
`Io~hen people know what to expect from a drug,
`h good and bad, they and their doctors can
`bO:ter judge how well t h e drug is working and
`b~ ther potentially serious problems are devel·
`w .e g Anyone taking a drug shouldn't hesitate to
`opm ·
`ask a doctor, nurse, or pharmacist to explain the
`goals of treatment, the types of adverse drug re-
`tions and other problems that may arise, and
`:~e extent to which they can participate in the
`t eatrnent plan to help ensure the best outcome . .&
`;eople should also keep their health care practi(cid:173)
`tioners well informed about their medical history,
`current medications, and any other relevant in-
`format ion.
`
`Drug Interactions
`
`When two or more drugs are taken in the same
`general time period, they may interact in ways
`that are good or bad. Together they may be more
`effective in treating a problem, or they may in(cid:173)
`crease the number or severity of adverse reac(cid:173)
`tions. Drug interactions may occur between pre(cid:173)
`scription and nonprescription (over-the-counter)
`drugs.• If someone is receiving care from more
`than one doctor, each doctor needs to know all of
`the drugs being taken. Preferably, people should
`obtain all their prescription drugs from the same
`pharmacy, one that maintains a complete drug
`profile for each patient. The pharmacist can then
`check for the possibility of interactions. People
`should also consult their pharmacist when se(cid:173)
`lecting over-the.counter drugs (for example, lax(cid:173)
`atives, antacids, and cough or cold remedies),
`particularly when they're also taking prescription
`drugs.
`Although many people don't consider alcohol
`a drug, it affects body processes and is often re·
`sponsible for drug interactions. Doctors or phar(cid:173)
`macists can provide answers to questions about
`Possible alcohol and drug interactions.
`Drug interactions aren't always bad. For exam(cid:173)
`ple, some drugs used for treating high blood pres(cid:173)
`sure are prescribed in combination to reduce the
`
`27
`
`Let Them Know
`
`To assist health care practitioners in
`developing a safe and effective treatment
`plan, people must be sure that their doctor,
`nurse, or pharmacist has the following
`information:
`• What medical problems they have
`• What drugs (both prescription and
`nonprescription) they have taken in the
`previous few weeks
`• Whether they are allergic to or have had
`an unusual reaction to any drug, food, or
`other substance
`• Whether they have special diets or food
`restrictions
`• Whether they are pregnant or plan to
`become pregnant or are breastfeeding
`
`side effects that could develop if a single drug
`were prescribed at a higher dose"
`
`Drug Abuse
`
`Through the ages, drugs have been enormously
`beneficial in relieving suffering and in preventing
`and treating diseases. However, to some people,
`the word drug means a substance that alters t he
`brain's function in ways considered pleasurable.
`There has always been a dark side to the discov(cid:173)
`ery and use of drugs, especially those that alle(cid:173)
`viate anxiety or alter mood and behavior in ways
`that satisfy people's emotional needs. Drug
`abuse-the excessive and persistent use of mind(cid:173)
`altering substances without medical need-has
`accompanied the appropriate medical use of
`drugs throughout recorded history. Commonly
`abused drugs include alcohol, marijuana, co(cid:173)
`caine, barbiturates, benzodiazepines, methaqua(cid:173)
`lone, heroin and other narcotics, amphetamines,
`LSD (lysergic acid diethylamide), and PCP (phen(cid:173)
`cyclidine}*
`
`.&. see page46
`
`• see pages 36 and 65
`
`* see page 440
`
`INTELGENX 1033