, Access Provided by:
Basic & Clinical Pharmacology, 15e
Chapter 1: Introduction: The Nature of Drugs & Drug Development & Regulation
Bertram G. Katzung
CASE STUDY
CASE STUDY
A 78-year-old woman is brought to the hospital because of suspected aspirin overdose*. She has taken aspirin for joint pain for many years without
incident, but during the past year, she has exhibited signs of cognitive decline. Her caregiver finds her confused, hyperventilating, and vomiting. The
caregiver finds an empty bottle of aspirin tablets and calls 9-1-1. In the emergency department, samples of venous and arterial blood are obtained
while the airway, breathing, and circulation are evaluated. An intravenous (IV) drip is started, and gastrointestinal decontamination is begun. After
blood gas results are reported, sodium bicarbonate is administered via the IV. What is the purpose of the sodium bicarbonate?
Pharmacology can be defined as the study of substances that interact with living systems through chemical processes. These interactions usually
occur by binding of the substance to regulatory molecules and activating or inhibiting normal body processes. These substances may be chemicals
administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites
infecting the patient. Such deliberate therapeutic applications may be considered the proper role of medical pharmacology, which is often defined
as the science of substances used to prevent, diagnose, and treat disease. Toxicology is the branch of pharmacology that deals with the undesirable
effects of chemicals on living systems, from individual cells to humans to complex ecosystems (Figure 1–1). The nature of drugs—their physical
properties and their interactions with biological systems—is discussed in part I of this chapter.
FIGURE 1–1
Major areas of study in pharmacology. The actions of chemicals can be divided into two large domains. The first (left side) is that of medical
pharmacology and toxicology, which is aimed at understanding the actions of drugs as chemicals on individual organisms, especially humans and
domestic animals. Both beneficial and toxic effects are included. Pharmacokinetics deals with the absorption, distribution, and elimination of drugs.
Pharmacodynamics concerns the actions of the chemical on the organism. The second domain (right side) is that of environmental toxicology, which is
concerned with the effects of chemicals on all organisms and their survival in groups and as species.
Downloaded 2021728 7:13 P Your IP is 178.238.11.245
Chapter 1: Introduction: The Nature of Drugs &; Drug Development &; Regulation, Bertram G. Katzung Page
©2021 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
,pharmacology and toxicology, which is aimed at understanding the actions of drugs as chemicals on individual organisms, especially humansAccessand
Provided by:
domestic animals. Both beneficial and toxic effects are included. Pharmacokinetics deals with the absorption, distribution, and elimination of drugs.
Pharmacodynamics concerns the actions of the chemical on the organism. The second domain (right side) is that of environmental toxicology, which is
concerned with the effects of chemicals on all organisms and their survival in groups and as species.
New drugs are added every year; they are needed for several reasons including: (1) increasing resistance by bacteria and other parasites; (2) discovery
of new target processes in diseases that have not been adequately treated; and (3) recognition of new diseases. Furthermore, a dramatic increase has
occurred in the number of large molecule drugs (especially antibodies) approved during the last two decades. The development of new drugs and their
regulation by government agencies are discussed in part II.
*The author thanks Barry Berkowitz, PhD, for contributions to the second part of this chapter in previous editions.
THE HISTORY OF PHARMACOLOGY
Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal materials. Early written records list remedies of
many types, including a few that are still recognized as useful drugs today. Most, however, were worthless or actually harmful. Beginning about 1500
years ago, sporadic attempts were made to introduce rational methods into medicine, but none was successful owing to the dominance of systems of
thought (“schools”) that purported to explain all of biology and disease without the need for experimentation and observation. These schools
promulgated bizarre notions such as the idea that disease was caused by excesses of bile or blood in the body, that wounds could be healed by
applying a salve to the weapon that caused the wound, and so on.
Around the end of the 17th century, concepts based on observation and experimentation began to replace theorizing in physiology and clinical
medicine. As the value of these methods in the study of disease became clear, physicians in Great Britain and on the Continent began to apply them
systematically to the effects of traditional drugs used in their own practices. Thus, materia medica—the science of drug preparation and the medical
uses of drugs—began to develop as the precursor to pharmacology. However, any real understanding of the mechanisms of action of drugs was
prevented by the absence of methods for purifying active agents from the crude materials that were available and—even more—by the lack of methods
for testing hypotheses about the nature of drug actions.
In the late 18th and early 19th centuries, François Magendie and his student Claude Bernard began to develop the methods of experimental
physiology and pharmacology. Advances in chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid the
foundation needed for understanding how drugs work at the organ and cellular levels. Paradoxically, real advances in basic pharmacology during this
time were accompanied by an outburst of unscientific claims by manufacturers and marketers of worthless “patent medicines.” Not until the concepts
Downloaded 2021728 especially
of rational therapeutics, 7:13 P Your
thatIP
ofisthe
178.238.11.245
controlled clinical trial, were reintroduced into medicine—only about 60 years ago—did it become
Chapter 1: Introduction: The Nature of Drugs &; Drug Development &; Regulation, Bertram G. Katzung
possible to adequately evaluate therapeutic claims.
Page
©2021 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Around the 1940s and 1950s, a major expansion of research efforts in all areas of biology began. As new concepts and new techniques were
introduced, information accumulated about drug action and the biologic substrate of that action, the drug receptor. During the last 60 years, many
, for testing hypotheses about the nature of drug actions. Access Provided by:
In the late 18th and early 19th centuries, François Magendie and his student Claude Bernard began to develop the methods of experimental
physiology and pharmacology. Advances in chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid the
foundation needed for understanding how drugs work at the organ and cellular levels. Paradoxically, real advances in basic pharmacology during this
time were accompanied by an outburst of unscientific claims by manufacturers and marketers of worthless “patent medicines.” Not until the concepts
of rational therapeutics, especially that of the controlled clinical trial, were reintroduced into medicine—only about 60 years ago—did it become
possible to adequately evaluate therapeutic claims.
Around the 1940s and 1950s, a major expansion of research efforts in all areas of biology began. As new concepts and new techniques were
introduced, information accumulated about drug action and the biologic substrate of that action, the drug receptor. During the last 60 years, many
fundamentally new drug groups and new members of old groups have been introduced. The last three decades have seen an even more rapid growth
of information and understanding of the molecular basis for drug action. The molecular mechanisms of action of many drugs have now been
identified, and numerous receptors have been isolated, structurally characterized, and cloned. In fact, the use of receptor identification methods
(described in Chapter 2) has led to the discovery of many orphan receptors—receptors for which no ligand has been discovered and whose function
can only be guessed. Studies of the local molecular environment of receptors have shown that receptors and effectors do not function in isolation;
they are strongly influenced by other receptors and by companion regulatory proteins. Most recently, it has become clear that gravitational change,
radiation, and other aspects of space outside the Earth’s environment require the development of space medicine. This has opened another important
area for the future of pharmacology. One result of these discoveries is the confirmation that pharmacology represents an area where anatomy,
biochemistry, genetics, physiology, pathology, clinical medicine, and the environment meet. Many problems that the health practitioner confronts can
now be corrected or mitigated using pharmacologic tools.
Pharmacogenomics—the relation of the individual’s genetic makeup to his or her response to specific drugs—is becoming an important part of
therapeutics (see Chapter 5). Decoding of the genomes of many species—from bacteria to humans—has led to the recognition of unsuspected
relationships between receptor families and the ways that receptor proteins have evolved. Furthermore, discovery of regulatory functions exerted by
the neighbors of chromosomes and the noncoding regions of DNA on the expression of exons has opened a new area of possible manipulation of the
genes—epigenetics—that control pharmacologic responses.
The discovery that small segments of RNA can interfere with protein synthesis with extreme selectivity has led to investigation of small interfering
RNAs (siRNAs) and micro-RNAs (miRNAs) as therapeutic agents. Similarly, short nucleotide chains called antisense oligonucleotides (ANOs),
synthesized to be complementary to natural RNA or DNA, can interfere with the readout of genes and the transcription of RNA. Finally, new, efficient
methods of DNA editing have made possible the modification of genes that encode proteins that are critical to immunologic functions, including
anticancer receptors on T-cells. These developments have led to a dramatic increase in large molecule therapeutics in the last 20 years (Table 1–1).
TABLE 1–1
Development of large molecule therapeutic agents as a fraction of all new drug approvals, 2000–2017.
Year Total New Drug Approvals New Protein Drugs (∼% of new drug approvals) New MABs (∼% of new drug approvals)
2000 63 3 (5%) 1 (2%)
2008 34 5 (15%) 1 (3%)
2010 49 8 (16%) 4 (8%)
2015 69 13 (19%) 9 (13%)
2017 63 10 (16%) 9 (14%)
MABs, monoclonal antibodies.
Unfortunately, the medication-consuming public is still exposed to vast amounts of inaccurate or unscientific information regarding the
pharmacologic effects of chemicals. This results in the irrational use of innumerable expensive, ineffective, and sometimes harmful remedies and the
growth of a huge “alternative health care” industry. Furthermore, manipulation of the legislative process in the United States has allowed many
substances promoted for health—but not promoted specifically as “drugs”—to avoid meeting the Food and Drug Administration (FDA) standards
described in the second part of this chapter. Conversely, lack of understanding of basic scientific principles in biology and statistics and the absence of
Downloaded 2021728 7:13 P Your IP is 178.238.11.245
critical thinking about public health issues have led to rejection of medical science, including vaccines, by a segment of the public and to a common
Chapter 1: Introduction: The Nature of Drugs &; Drug Development &; Regulation, Bertram G. Katzung Page
tendency
©2021 McGrawto assume
Hill.that all adverse
All Rights drug effects
Reserved. Termsareofthe
Useresult of malpractice.
• Privacy Policy • Notice • Accessibility
General principles that the student should remember are (1) that all substances can under certain circumstances be toxic; (2) that the chemicals in
Basic & Clinical Pharmacology, 15e
Chapter 1: Introduction: The Nature of Drugs & Drug Development & Regulation
Bertram G. Katzung
CASE STUDY
CASE STUDY
A 78-year-old woman is brought to the hospital because of suspected aspirin overdose*. She has taken aspirin for joint pain for many years without
incident, but during the past year, she has exhibited signs of cognitive decline. Her caregiver finds her confused, hyperventilating, and vomiting. The
caregiver finds an empty bottle of aspirin tablets and calls 9-1-1. In the emergency department, samples of venous and arterial blood are obtained
while the airway, breathing, and circulation are evaluated. An intravenous (IV) drip is started, and gastrointestinal decontamination is begun. After
blood gas results are reported, sodium bicarbonate is administered via the IV. What is the purpose of the sodium bicarbonate?
Pharmacology can be defined as the study of substances that interact with living systems through chemical processes. These interactions usually
occur by binding of the substance to regulatory molecules and activating or inhibiting normal body processes. These substances may be chemicals
administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites
infecting the patient. Such deliberate therapeutic applications may be considered the proper role of medical pharmacology, which is often defined
as the science of substances used to prevent, diagnose, and treat disease. Toxicology is the branch of pharmacology that deals with the undesirable
effects of chemicals on living systems, from individual cells to humans to complex ecosystems (Figure 1–1). The nature of drugs—their physical
properties and their interactions with biological systems—is discussed in part I of this chapter.
FIGURE 1–1
Major areas of study in pharmacology. The actions of chemicals can be divided into two large domains. The first (left side) is that of medical
pharmacology and toxicology, which is aimed at understanding the actions of drugs as chemicals on individual organisms, especially humans and
domestic animals. Both beneficial and toxic effects are included. Pharmacokinetics deals with the absorption, distribution, and elimination of drugs.
Pharmacodynamics concerns the actions of the chemical on the organism. The second domain (right side) is that of environmental toxicology, which is
concerned with the effects of chemicals on all organisms and their survival in groups and as species.
Downloaded 2021728 7:13 P Your IP is 178.238.11.245
Chapter 1: Introduction: The Nature of Drugs &; Drug Development &; Regulation, Bertram G. Katzung Page
©2021 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
,pharmacology and toxicology, which is aimed at understanding the actions of drugs as chemicals on individual organisms, especially humansAccessand
Provided by:
domestic animals. Both beneficial and toxic effects are included. Pharmacokinetics deals with the absorption, distribution, and elimination of drugs.
Pharmacodynamics concerns the actions of the chemical on the organism. The second domain (right side) is that of environmental toxicology, which is
concerned with the effects of chemicals on all organisms and their survival in groups and as species.
New drugs are added every year; they are needed for several reasons including: (1) increasing resistance by bacteria and other parasites; (2) discovery
of new target processes in diseases that have not been adequately treated; and (3) recognition of new diseases. Furthermore, a dramatic increase has
occurred in the number of large molecule drugs (especially antibodies) approved during the last two decades. The development of new drugs and their
regulation by government agencies are discussed in part II.
*The author thanks Barry Berkowitz, PhD, for contributions to the second part of this chapter in previous editions.
THE HISTORY OF PHARMACOLOGY
Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal materials. Early written records list remedies of
many types, including a few that are still recognized as useful drugs today. Most, however, were worthless or actually harmful. Beginning about 1500
years ago, sporadic attempts were made to introduce rational methods into medicine, but none was successful owing to the dominance of systems of
thought (“schools”) that purported to explain all of biology and disease without the need for experimentation and observation. These schools
promulgated bizarre notions such as the idea that disease was caused by excesses of bile or blood in the body, that wounds could be healed by
applying a salve to the weapon that caused the wound, and so on.
Around the end of the 17th century, concepts based on observation and experimentation began to replace theorizing in physiology and clinical
medicine. As the value of these methods in the study of disease became clear, physicians in Great Britain and on the Continent began to apply them
systematically to the effects of traditional drugs used in their own practices. Thus, materia medica—the science of drug preparation and the medical
uses of drugs—began to develop as the precursor to pharmacology. However, any real understanding of the mechanisms of action of drugs was
prevented by the absence of methods for purifying active agents from the crude materials that were available and—even more—by the lack of methods
for testing hypotheses about the nature of drug actions.
In the late 18th and early 19th centuries, François Magendie and his student Claude Bernard began to develop the methods of experimental
physiology and pharmacology. Advances in chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid the
foundation needed for understanding how drugs work at the organ and cellular levels. Paradoxically, real advances in basic pharmacology during this
time were accompanied by an outburst of unscientific claims by manufacturers and marketers of worthless “patent medicines.” Not until the concepts
Downloaded 2021728 especially
of rational therapeutics, 7:13 P Your
thatIP
ofisthe
178.238.11.245
controlled clinical trial, were reintroduced into medicine—only about 60 years ago—did it become
Chapter 1: Introduction: The Nature of Drugs &; Drug Development &; Regulation, Bertram G. Katzung
possible to adequately evaluate therapeutic claims.
Page
©2021 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Around the 1940s and 1950s, a major expansion of research efforts in all areas of biology began. As new concepts and new techniques were
introduced, information accumulated about drug action and the biologic substrate of that action, the drug receptor. During the last 60 years, many
, for testing hypotheses about the nature of drug actions. Access Provided by:
In the late 18th and early 19th centuries, François Magendie and his student Claude Bernard began to develop the methods of experimental
physiology and pharmacology. Advances in chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid the
foundation needed for understanding how drugs work at the organ and cellular levels. Paradoxically, real advances in basic pharmacology during this
time were accompanied by an outburst of unscientific claims by manufacturers and marketers of worthless “patent medicines.” Not until the concepts
of rational therapeutics, especially that of the controlled clinical trial, were reintroduced into medicine—only about 60 years ago—did it become
possible to adequately evaluate therapeutic claims.
Around the 1940s and 1950s, a major expansion of research efforts in all areas of biology began. As new concepts and new techniques were
introduced, information accumulated about drug action and the biologic substrate of that action, the drug receptor. During the last 60 years, many
fundamentally new drug groups and new members of old groups have been introduced. The last three decades have seen an even more rapid growth
of information and understanding of the molecular basis for drug action. The molecular mechanisms of action of many drugs have now been
identified, and numerous receptors have been isolated, structurally characterized, and cloned. In fact, the use of receptor identification methods
(described in Chapter 2) has led to the discovery of many orphan receptors—receptors for which no ligand has been discovered and whose function
can only be guessed. Studies of the local molecular environment of receptors have shown that receptors and effectors do not function in isolation;
they are strongly influenced by other receptors and by companion regulatory proteins. Most recently, it has become clear that gravitational change,
radiation, and other aspects of space outside the Earth’s environment require the development of space medicine. This has opened another important
area for the future of pharmacology. One result of these discoveries is the confirmation that pharmacology represents an area where anatomy,
biochemistry, genetics, physiology, pathology, clinical medicine, and the environment meet. Many problems that the health practitioner confronts can
now be corrected or mitigated using pharmacologic tools.
Pharmacogenomics—the relation of the individual’s genetic makeup to his or her response to specific drugs—is becoming an important part of
therapeutics (see Chapter 5). Decoding of the genomes of many species—from bacteria to humans—has led to the recognition of unsuspected
relationships between receptor families and the ways that receptor proteins have evolved. Furthermore, discovery of regulatory functions exerted by
the neighbors of chromosomes and the noncoding regions of DNA on the expression of exons has opened a new area of possible manipulation of the
genes—epigenetics—that control pharmacologic responses.
The discovery that small segments of RNA can interfere with protein synthesis with extreme selectivity has led to investigation of small interfering
RNAs (siRNAs) and micro-RNAs (miRNAs) as therapeutic agents. Similarly, short nucleotide chains called antisense oligonucleotides (ANOs),
synthesized to be complementary to natural RNA or DNA, can interfere with the readout of genes and the transcription of RNA. Finally, new, efficient
methods of DNA editing have made possible the modification of genes that encode proteins that are critical to immunologic functions, including
anticancer receptors on T-cells. These developments have led to a dramatic increase in large molecule therapeutics in the last 20 years (Table 1–1).
TABLE 1–1
Development of large molecule therapeutic agents as a fraction of all new drug approvals, 2000–2017.
Year Total New Drug Approvals New Protein Drugs (∼% of new drug approvals) New MABs (∼% of new drug approvals)
2000 63 3 (5%) 1 (2%)
2008 34 5 (15%) 1 (3%)
2010 49 8 (16%) 4 (8%)
2015 69 13 (19%) 9 (13%)
2017 63 10 (16%) 9 (14%)
MABs, monoclonal antibodies.
Unfortunately, the medication-consuming public is still exposed to vast amounts of inaccurate or unscientific information regarding the
pharmacologic effects of chemicals. This results in the irrational use of innumerable expensive, ineffective, and sometimes harmful remedies and the
growth of a huge “alternative health care” industry. Furthermore, manipulation of the legislative process in the United States has allowed many
substances promoted for health—but not promoted specifically as “drugs”—to avoid meeting the Food and Drug Administration (FDA) standards
described in the second part of this chapter. Conversely, lack of understanding of basic scientific principles in biology and statistics and the absence of
Downloaded 2021728 7:13 P Your IP is 178.238.11.245
critical thinking about public health issues have led to rejection of medical science, including vaccines, by a segment of the public and to a common
Chapter 1: Introduction: The Nature of Drugs &; Drug Development &; Regulation, Bertram G. Katzung Page
tendency
©2021 McGrawto assume
Hill.that all adverse
All Rights drug effects
Reserved. Termsareofthe
Useresult of malpractice.
• Privacy Policy • Notice • Accessibility
General principles that the student should remember are (1) that all substances can under certain circumstances be toxic; (2) that the chemicals in
