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Basic & Clinical Pharmacology, 14th Edition Bertram G. Katzung
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53. Clinical Pharmacology of the Antihelminthic Drugs 444
54. Cancer Chemotherapy 450
55. Immunopharmacology 463
part IX
TOXICOLOGY 477
56. Environmental & Occupational Toxicology 477
57. Heavy Metals 483
58. Management of the Poisoned Patient 489
part X
SPECIAL TOPICS 497
59. Drugs Used in Gastrointestinal Disorders 497
60. Dietary Supplements & Herbal Medications 507
61. Important Drug Interactions & Their Mechanisms 512
Appendix I. Strategies for Improving Test Performance 519
Appendix II. Key Words for Key Drugs 522
Appendix III. Examination 1 535
Appendix IV. Examination 2 551
Index 567
Preface
This book is designed to help students review pharmacology and to prepare for both regular course examinations and board examinations. The twelfth edition has been revised to make such preparation as active and efficient as possible. As with earlier editions, rigorous standards of accuracy and currency have been maintained in keeping with the book’s status as the companion to the Basic & Clinical Pharmacology textbook. This review book divides pharmacology into the topics used in most courses and textbooks. Major introductory chapters (eg, autonomic pharmacology and CNS pharmacology) are included for integration with relevant physiology and biochemistry. The chapter-based approach facilitates use of this book in conjunction with course notes or a larger text. We recommend several strategies to make reviewing more effective (Appendix I contains a summary of learning and test-taking strategies that most students find useful).
First, each chapter has a short discussion of the major concepts that underlie its basic principles or the specific drug group, accompanied by explanatory figures and tables. The figures are in full color and some are new to this edition. Students are advised to read the text thoroughly before they attempt to answer the study questions at the end of each chapter. If a concept is found to be difficult or confusing, the student is advised to consult a regular textbook such as Basic & Clinical Pharmacology, 14th edition.
Second, each drug-oriented chapter opens with an Overview that organizes the group of drugs visually in diagrammatic form. We recommend that students practice reproducing the overview diagram from memory.
Third, a list of High-Yield Terms to Learn and their definitions is near the front of most chapters. Make sure that you are able to define those terms.
Fourth, many chapters include a Skill Keeper question that prompts the student to review previous material and to see links between related topics. We suggest that students try to answer Skill Keeper questions on their own before checking the answers that are provided at the end of the chapter.
Fifth, each of the sixty-one chapters contains up to ten sample questions followed by a set of answers with explanations. For most effective learning, you should take each set of sample questions as if it were a real examination. After you have answered every question, work through the answers. When you
are analyzing the answers, make sure that you understand why each choice is either correct or incorrect.
Sixth, each chapter includes a Checklist of focused tasks that you should be able to do once you have finished the chapter.
Seventh, most chapters end with a Summary Table that lists the most important drugs and includes key information concerning their mechanisms of action, effects, clinical uses, pharmacokinetics, drug interactions, and toxicities.
Eighth, when preparing for a comprehensive examination, you should review the strategies described in Appendix I if you have not already done so. Then review the list of drugs in Appendix II: Key Words for Key Drugs. Students are also advised to check this appendix as they work through the chapters so they can begin to identify drugs out of the context of a chapter that reviews a restricted set of drugs.
Ninth, after you have worked your way through most or all of the chapters and have a good grasp of the Key Drugs, you should take the comprehensive examinations, each of 100 questions, presented in Appendices III and IV. These examinations are followed by a list of answers, each with a short explanation or rationale underlying the correct choice and the numbers of the chapters in which more information can be found if needed. We recommend that you take an entire examination or a block of questions as if it were a real examination: commit to answers for the whole set before you check the answers. As you work through the answers, make sure that you understand why each answer is either correct or incorrect. If you need to, return to the relevant chapters(s) to review the text that covers key concepts and facts that form the basis for the question.
We recommend that this book be used with a regular text. Basic & Clinical Pharmacology, 14th edition (McGraw-Hill, 2018), follows the chapter sequence used here. However, this review book is designed to complement any standard medical pharmacology text. The student who completes and understands Pharmacology: Examination & Board Review will greatly improve his or her performance and will have an excellent command of pharmacology.
Because it was developed in parallel with the textbook Basic & Clinical Pharmacology, this review book represents the authors’ interpretations of chapters written by contributors to
that text. We are grateful to those contributors, to our other faculty colleagues, and to our students, who have taught us most of what we know about teaching.
Bertram G. KKatzung, MD, PhD
Marieke Kruidering-Hall, PhD
Anthony J. Trevor, PhD
We very much appreciate the invaluable contributions to this text afforded by the editorial team of Peter Boyle and Michael Weitz. The authors also thank Katharine Katzung for her excellent copyediting and proofreading contributions to this edition.
PART I BASIC PRINCIPLES
CHAPTER
Introduction
Pharmacology is the body of knowledge concerned with the action of chemicals on biologic systems. Medical pharmacology is the area of pharmacology concerned with the use of chemicals in the prevention, diagnosis, and treatment of disease, especially in humans. Toxicology is the area of pharmacology concerned with the undesirable effects of chemicals on biologic systems. Pharmacokinetics describes the effects of the body on
drugs, eg, absorption, metabolism, excretion, etc. Pharmacodynamics denotes the actions of the drug on the body, such as mechanism of action and therapeutic and toxic effects. The first part of this chapter reviews the basic principles of pharmacokinetics and pharmacodynamics that will be applied in subsequent chapters. The second part of the chapter reviews the discovery and development of new drugs and the regulation of drugs.
■ I. THE NATURE OF DRUGS
Drugs in common use include inorganic ions, nonpeptide organic molecules, small peptides and proteins, nucleic acids, lipids, and carbohydrates. Some are found in plants or animals, and others are partially or completely synthetic. Many drugs found in nature are alkaloids, which are molecules that have a basic (alkaline) pH in solution, usually as a result of amine groups in their structure. Many biologically important endogenous molecules and exogenous drugs are optically active; that is, they contain one or more asymmetric centers and can exist as enantiomers. The enantiomers of optically active drugs usually differ, sometimes more than 1000-fold, in their affinity for biologic receptor sites. Furthermore, such enantiomers may be metabolized at different rates in the body, with important clinical consequences.
A. Size and Molecular Weight
Drugs vary in size from molecular weight (MW) 7 (lithium) to over MW 50,000 (thrombolytic enzymes, antibodies, other proteins). Most drugs, however, have MWs between 100 and 1000. Drugs smaller than MW 100 are rarely sufficiently selective in their actions, whereas drugs much larger than MW 1000 are often poorly absorbed and poorly distributed in the body. Most protein drugs (“biologicals”) are commercially produced in cell, bacteria, or yeast cultures using recombinant DNA technology.
B. Drug-Receptor Bonds
Drugs bind to receptors with a variety of chemical bonds. These include very strong covalent bonds (which usually result in irreversible action), somewhat weaker reversible electrostatic bonds
High-Yield Terms to Learn (continued)
Drugs
Drug receptors
(eg, between a cation and an anion), and much weaker interactions (eg, hydrogen, van der Waals, and hydrophobic bonds).
PHARMACODYNAMIC PRINCIPLES
A. Receptors
Drug actions are mediated through the effects of drug ligand molecules on drug receptors in the body. Most receptors are large regulatory molecules that influence important biochemical processes (eg, enzymes involved in glucose metabolism) or physiologic processes (eg, ion channel receptors, neurotransmitter reuptake transporters, and ion transporters).
If drug-receptor binding results in activation of the receptor molecule, the drug is termed an agonist; if inhibition results, the drug is considered an antagonist. Some drugs mimic agonist molecules by inhibiting metabolic enzymes, eg, acetylcholinesterase inhibitors. As suggested in Figure 1–1, a receptor molecule may have several binding sites. Quantitation of the effects of drugreceptor interaction as a function of dose (or concentration) yields dose-response curves that provide information about the nature of the drug-receptor interaction. Dose-response phenomena are discussed in more detail in Chapter 2. A few drugs are enzymes themselves (eg, thrombolytic enzymes, pancreatic enzymes). These drugs do not act on endogenous receptors but on substrate molecules.
B. Receptor and Inert Binding Sites
Because most ligand molecules are much smaller than their receptor molecules (discussed in the text that follows), specific regions
Substances that act on biologic systems at the chemical (molecular) level and alter their functions
The molecular components of the body with which drugs interact to bring about their effects
Distribution phase The phase of drug movement from the site of administration into the tissues
Elimination phase
Endocytosis, exocytosis
Permeation
Pharmacodynamics
Pharmacokinetics
Transporter
Mutagenic
Carcinogenic
Teratogenic
The phase of drug inactivation or removal from the body by metabolism or excretion
Endocytosis: Absorption of material across a cell membrane by enclosing it in cell membrane material and pulling it into the cell, where it can be processed or released. Exocytosis: Expulsion of material from vesicles in the cell into the extracellular space
Movement of a molecule (eg, drug) through the biologic medium
The actions of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic actions
The actions of the body on the drug, including absorption, distribution, metabolism, and elimination. Elimination of a drug may be achieved by metabolism or by excretion. Biodisposition is a term sometimes used to describe the processes of metabolism and excretion
A specialized molecule, usually a protein, that carries a drug, transmitter, or other molecule across a membrane in which it is not permeable, eg, Na+/K+ ATPase, serotonin reuptake transporter, etc
An effect on the inheritable characteristics of a cell or organism—a mutation in the DNA; usually tested in microorganisms with the Ames test
An effect of inducing malignant characteristics
An effect on the in utero development of an organism resulting in abnormal structure or function; not generally heritable
High-Yield Terms to Learn (continued)
Placebo
Single-blind study
Double-blind study
IND
NDA
Phases 1, 2, and 3 of clinical trials
Positive control
Orphan drugs
An inactive “dummy” medication made up to resemble the active investigational formulation as much as possible but lacking therapeutic effect
A clinical trial in which the investigators—but not the subjects—know which subjects are receiving active drug and which are receiving placebos
A clinical trial in which neither the subjects nor the investigators know which subjects are receiving placebos; the code is held by a third party
Investigational New Drug Exemption; an application for FDA approval to carry out new drug trials in humans; requires animal data
New Drug Application; seeks FDA approval to market a new drug for ordinary clinical use; requires data from clinical trials as well as preclinical (animal) data
Three parts of a clinical trial that are usually carried out before submitting an NDA to the FDA; adaptive trials, combined two or more phases
A known standard therapy, to be used in addition to placebo, to evaluate the superiority or inferiority of a new drug in relation to the other drugs available
Drugs developed for diseases in which the expected number of patients is small. Some countries bestow certain commercial advantages on companies that develop drugs for uncommon diseases
FIGURE 1–1 Potential mechanisms of drug interaction with a receptor. Possible effects resulting from these interactions are diagrammed in the dose-response curves at the right. The traditional agonist (drug A)-receptor binding process results in the dose-response curve denoted “A alone.” B is a pharmacologic antagonist drug that competes with the agonist for binding to the receptor site. The dose-response curve produced by increasing doses of A in the presence of a fixed concentration of B is indicated by the curve “A + B.” Drugs C and D act at different sites on the receptor molecule; they are allosteric activators or inhibitors. Note that allosteric inhibitors do not compete with the agonist drug for binding to the receptor, and they may bind reversibly or irreversibly. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 1–3.)
of receptor molecules provide the local areas responsible for drug binding. Such areas are termed receptor sites or recognition sites. In addition, drugs bind to some nonregulatory molecules in the body without producing a discernible effect. Such binding sites are termed inert binding sites. In some compartments of the body (eg, the plasma), inert binding sites play an important role in buffering the concentration of a drug because bound drug does not contribute directly to the concentration gradient that drives diffusion. Albumin and orosomucoid (α1-acid glycoprotein) are 2 important plasma proteins with significant drug-binding capacity.
PHARMACOKINETIC PRINCIPLES
To produce useful therapeutic effects, most drugs must be absorbed, distributed, and eliminated. Pharmacokinetic principles make rational dosing possible by quantifying these processes.
The Movement of Drugs in the Body
To reach its receptors and bring about a biologic effect, a drug molecule (eg, a benzodiazepine sedative) must travel from the site of administration (eg, the gastrointestinal tract) to the site of action (eg, the brain).
A. Permeation
Permeation is the movement of drug molecules into and within the biologic environment. It involves several processes, the most important of which include the following:
1. Aqueous diffusion—Aqueous diffusion is the movement of molecules through the watery extracellular and intracellular spaces. The membranes of most capillaries have small water-filled pores that permit the aqueous diffusion of molecules up to the size of small proteins between the blood and the extravascular space. This is a passive process governed by Fick’s law (see later discussion). The capillaries in the brain, testes, and some other organs lack aqueous pores, and these tissues are less exposed to some drugs.
2. Lipid diffusion—Lipid diffusion is the passive movement of molecules through lipid bilayer cell membranes and other lipid barriers. Like aqueous diffusion, this process is governed by Fick’s law.
3. Transport by special carriers—Drugs that do not readily diffuse through membranes may be transported across barriers by mechanisms that carry similar endogenous substances. A very large number of such transporter molecules have been identified, and many of these are important in the movement of drugs or as targets of drug action. Unlike aqueous and lipid diffusion, carrier transport is not governed by Fick’s law and has a maximum capacity, ie, is saturable. Important examples are transporters for ions (eg, Na+/K+ ATPase), for neurotransmitters (eg, transporters for serotonin, norepinephrine), for metabolites (eg, glucose, amino acids), and for foreign molecules (xenobiotics) such as anticancer drugs.
After release, amine neurotransmitters (dopamine, norepinephrine, and serotonin) and some other transmitters are recycled
into nerve endings by selective transport molecules. Selective inhibitors for these transporters often have clinical value; for example, several antidepressants act by inhibiting the transport of amine neurotransmitters back into the nerve endings from which they have been released or into nearby cells.
4. Endocytosis—Endocytosis occurs through binding of the molecule to specialized components (receptors) on cell membranes, with subsequent internalization by infolding of that area of the membrane. The contents of the resulting intracellular vesicle are subsequently released into the cytoplasm of the cell. Endocytosis permits very large or very lipid-insoluble chemicals to enter cells. For example, large molecules such as proteins may cross cell membranes by endocytosis. Smaller, polar substances such as vitamin B12 and iron combine with special proteins (B12 with intrinsic factor and iron with transferrin), and the complexes enter cells by this mechanism. Because the substance to be transported must combine with a membrane receptor, endocytotic transport can be quite selective. Exocytosis is the reverse process, that is, the expulsion of material that is membrane-encapsulated inside the cell out of the cell. Most neurotransmitters are released by exocytosis.
B. Fick’s Law of Diffusion
Fick’s law predicts the rate of movement of molecules across a barrier. The concentration gradient (C1 – C2) and permeability coefficient for the drug and the area and thickness of the barrier membrane are used to compute the rate as follows:
Thus, drug absorption into the blood is faster within organs with large surface areas, such as the small intestine, than from organs with smaller absorbing areas (the stomach). Furthermore, drug absorption is faster from organs with thin membrane barriers (eg, the lung) than from those with thick barriers (eg, the skin).
C. Water and Lipid Solubility of Drugs
1. Solubility—The aqueous solubility of a drug is often a function of the electrostatic charge (degree of ionization, polarity) of the molecule, because water molecules behave as dipoles and are attracted to charged drug molecules, forming an aqueous shell around them. Conversely, the lipid solubility of a molecule is inversely proportional to its charge.
Many drugs are weak bases or weak acids. For such molecules, the pH of the medium determines the fraction of molecules charged (ionized) versus uncharged (nonionized). If the pKa of the drug and the pH of the medium are known, the fraction of molecules in the ionized state can be predicted by means of the Henderson-Hasselbalch equation:
“Protonated” means associated with a proton (a hydrogen ion); this form of the equation applies to both acids and bases.
2. Ionization of weak acids and bases—Weak bases are ionized—and therefore more polar and more water-soluble—when they are protonated. Weak acids are not ionized—and so are less water-soluble—when they are protonated.
The following equations summarize these points:
protonated weak base (charged, more water-soluble)
protonated weak acid (uncharged, more lipid-soluble)
Unprotonated weak base (uncharged, more lipid-soluble)
Unprotonated weak acid (charged, more water-soluble)
The Henderson-Hasselbalch relationship is clinically important when it is necessary to estimate or alter the partition of drugs between compartments of differing pH. For example, most drugs are freely filtered at the glomerulus, but lipid-soluble drugs can be rapidly reabsorbed from the tubular urine. If a patient takes an overdose of a weak acid drug, for example, aspirin, the excretion of this drug is faster in alkaline urine. This is because a drug that is a weak acid dissociates to its charged, polar form in alkaline solution, and this form cannot readily diffuse from the renal tubule back into the blood; that is, the drug is trapped in the tubule. Conversely, excretion of a weak base (eg, pyrimethamine, amphetamine) is faster in acidic urine (Figure 1–2).
Absorption of Drugs
A. Routes of Administration
Drugs usually enter the body at sites remote from the target tissue or organ and thus require transport by the circulation to the intended site of action. To enter the bloodstream, a drug must be absorbed from its site of administration (unless the drug has been injected directly into the vascular compartment). The rate and efficiency of absorption differ depending on a drug’s route of administration as well as the drug’s physicochemical properties. In fact, for some drugs, the amount absorbed may be only a small fraction of the dose administered when given by certain routes. The amount absorbed into the systemic circulation divided by the amount of drug administered constitutes its bioavailability by that route. Common routes of administration and some of their features are listed in Table 1–1.
B. Blood Flow
Blood flow influences absorption from intramuscular and subcutaneous sites and, in shock, from the gastrointestinal tract as well. High blood flow maintains a high concentration gradient between the drug depot and the blood and thus facilitates absorption.
C. Concentration
The concentration of drug at the site of administration is important in determining the concentration gradient relative to the blood as noted previously. As indicated by Fick’s law (Equation 1), the
FIGURE 1–2 The Henderson-Hasselbalch principle applied to drug excretion in the urine. Because the nonionized, uncharged form diffuses readily across the lipid barriers of the nephron, this form may reach equal concentrations in the blood and urine; in contrast, the ionized form does not diffuse as readily. Protonation occurs within the blood and the urine according to the Henderson-Hasselbalch equation. Pyrimethamine, a weak base of pKa 7.0, is used in this example. At blood pH, only 0.4 μmol of the protonated species will be present for each 1.0 μmol of the unprotonated form. The total concentration in the blood will thus be 1.4 μmol/L if the concentration of the unprotonated form is 1.0 μmol/L. In the urine at pH 6.0, 10 μmol of the nondiffusible ionized form will be present for each 1.0 μmol of the unprotonated, diffusible form. Therefore, the total urine concentration (11 μmol/L) may be almost 8 times higher than the blood concentration.
concentration gradient is a major determinant of the rate of absorption. Drug concentration in the vehicle is particularly important in the absorption of drugs applied topically.
Distribution of Drugs
A. Determinants of Distribution
1. Size of the organ—The size of the organ determines the concentration gradient between blood and the organ. For example, skeletal muscle can take up a large amount of drug because the concentration in the muscle tissue remains low (and the bloodtissue gradient high) even after relatively large amounts of drug have been transferred; this occurs because skeletal muscle is a very large organ. In contrast, because the brain is smaller, distribution of a smaller amount of drug into it will raise the tissue concentration and reduce to zero the blood-tissue concentration gradient, preventing further uptake of drug unless it is actively transported.
2. Blood flow—Blood flow to the tissue is an important determinant of the rate of uptake of drug, although blood flow may not affect the amount of drug in the tissue at equilibrium. As a result, well-perfused tissues (eg, brain, heart, kidneys, and splanchnic
TABLE 1–1 Common routes of drug administration.
Oral (swallowed) Offers maximal convenience; absorption is often slower. Subject to the first-pass effect, in which a significant amount of the agent is metabolized in the gut wall, portal circulation, and liver before it reaches the systemic circulation. Bioavailability may be limited by the first pass effect.
Buccal and sublingual (not swallowed)
Direct absorption into the systemic venous circulation, bypassing the hepatic portal circuit and first-pass metabolism.
Intravenous Instantaneous and complete absorption (by definition, bioavailability is 100%). Potentially more dangerous.
Intramuscular Often faster and more complete (higher bioavailability) than with oral administration. Large volumes may be given if the drug is not too irritating. First-pass metabolism is avoided.
Subcutaneous Slower absorption than the intramuscular route. First-pass metabolism is avoided.
Rectal (suppository) The rectal route offers partial avoidance of the first-pass effect. Larger amounts of drug and drugs with unpleasant taste are better administered rectally than by the buccal or sublingual routes.
Inhalation Route offers delivery closest to respiratory tissues (eg, for asthma). Usually very rapid absorption (eg, for anesthetic gases).
Topical The topical route includes application to the skin or to the mucous membrane of the eye, ear, nose, throat, airway, or vagina for local effect.
Transdermal The transdermal route utilizes application to the skin for systemic effect. Absorption usually occurs very slowly (because of the thickness of the skin), but the first-pass effect is avoided.
organs) usually achieve high tissue concentrations sooner than poorly perfused tissues (eg, fat, bone).
3. Solubility—The solubility of a drug in tissue influences the concentration of the drug in the extracellular fluid surrounding the blood vessels. If the drug is very soluble in the cells, the concentration in the perivascular extracellular space will be lower and diffusion from the vessel into the extravascular tissue space will be facilitated. For example, some organs (such as the brain) have a high lipid content and thus dissolve a high concentration of lipidsoluble agents rapidly.
4. Binding—Binding of a drug to macromolecules in the blood or a tissue compartment tends to increase the drug’s concentration in that compartment. For example, warfarin is strongly bound to plasma albumin, which restricts warfarin’s diffusion out of the vascular compartment. Conversely, chloroquine is strongly bound
TABLE 1–2 Average values for some physical volumes within the adult human body.
to extravascular tissue proteins, which results in a marked reduction in the plasma concentration of chloroquine.
B. Apparent Volume of Distribution and Physical Volumes
The apparent volume of distribution (Vd) is an important pharmacokinetic parameter that reflects the above determinants of the distribution of a drug in the body. Vd relates the amount of drug in the body to the concentration in the plasma (Chapter 3). In contrast, the physical volumes of various body compartments are less important in pharmacokinetics (Table 1–2). However, obesity alters the ratios of total body water to body weight and fat to total body weight, and this may be important when using highly lipid-soluble drugs. A simple approximate rule for the aqueous compartments of the normal body is as follows: 40% of total body weight is intracellular water and 20% is extracellular water; thus, water constitutes approximately 60% of body weight.
Metabolism of Drugs
Drug disposition is a term sometimes used to refer to metabolism and elimination of drugs. Some authorities use disposition to denote distribution as well as metabolism and elimination. Metabolism of a drug sometimes terminates its action, but other effects of drug metabolism are also important. Some drugs when given orally are metabolized before they enter the systemic circulation. This first-pass metabolism was referred to in Table 1–1 as one cause of low bioavailability. Drug metabolism occurs primarily in the liver and is discussed in greater detail in Chapter 4.
A. Drug Metabolism as a Mechanism of Activation or Termination of Drug Action
The action of many drugs (eg, sympathomimetics, phenothiazines) is terminated before they are excreted because they are metabolized to biologically inactive derivatives. Conversion to an inactive metabolite is a form of elimination. In contrast, prodrugs (eg, levodopa, minoxidil) are inactive as administered and must be metabolized in the body to become active. Many drugs are active as administered and have active metabolites as well (eg, morphine, some benzodiazepines).
B. Drug Elimination Without Metabolism
Some drugs (eg, lithium, many others) are not modified by the body; they continue to act until they are excreted.
FIGURE 1–3 Comparison of first-order and zero-order elimination. For drugs with first-order kinetics (left), rate of elimination (units per hour) is proportional to concentration; this is the more common process. In the case of zero-order elimination (right), the rate is constant and independent of concentration.
Elimination of Drugs
Along with the dosage, the rate of elimination following the last dose (disappearance of the active molecules from the site of action, the bloodstream, and the body) determines the duration of action for many drugs. Therefore, knowledge of the time course of concentration in plasma is one factor used in predicting the intensity and duration of effect for most drugs. Note: Drug elimination is not the same as drug excretion: A drug may be eliminated by metabolism long before the modified molecules are excreted from the body. For most drugs and their metabolites, excretion is primarily by way of the kidney. Volatile anesthetic gases, a major exception, are excreted primarily by the lungs. For drugs with active metabolites (eg, diazepam), elimination of the parent molecule by metabolism is not synonymous with termination of action. For drugs that are not metabolized, excretion is the mode of elimination. A small number of drugs combine irreversibly with their receptors, so that disappearance from the bloodstream is not equivalent to cessation of drug action: These drugs may have a very prolonged action. For example, phenoxybenzamine, an irreversible inhibitor of α adrenoceptors, is eliminated from the bloodstream in less than 1 h after administration. The drug’s action, however, lasts for 48 h, the time required for turnover of the receptors.
A. First-Order Elimination
The term first-order elimination indicates that the rate of elimination is proportional to the concentration (ie, the higher the concentration, the greater the amount of drug eliminated per unit time). The result is that the drug’s concentration in plasma decreases exponentially with time (Figure 1–3, left). Drugs with first-order elimination have a characteristic half-life of elimination that is constant regardless of the amount of drug in the body. The concentration of such a drug in the blood will decrease by 50% for every half-life. Most drugs in clinical use demonstrate first-order kinetics.
B. Zero-Order Elimination
The term zero-order elimination implies that the rate of elimination is constant regardless of concentration (Figure 1–3, right).
This occurs with drugs that saturate their elimination mechanisms at concentrations of clinical interest. As a result, the concentrations of these drugs in plasma decrease in a linear fashion over time. Such drugs do not have a constant half-life. This is typical of ethanol (over most of its plasma concentration range) and of phenytoin and aspirin at high therapeutic or toxic concentrations.
Pharmacokinetic Models
A. Multicompartment Distribution
After absorption into the circulation, many drugs undergo an early distribution phase followed by a slower elimination phase. Mathematically, this behavior can be simulated by means of a “two-compartment model” as shown in Figure 1–4. The two compartments consist of the blood and the extravascular tissues. (Note that each phase is associated with a characteristic half-life: t1/2α for the first phase, t1/2β for the second phase. Note also that when concentration is plotted on a logarithmic axis, the elimination phase for a first-order drug is a straight line.)
B. Other Distribution Models
A few drugs behave as if they were distributed to only 1 compartment (eg, if they are restricted to the vascular compartment). Others have more complex distributions that require more than 2 compartments for construction of accurate mathematical models.
■ II. DRUG DEVELOPMENT & REGULATION
The sale and use of drugs are regulated in most countries by governmental agencies. In the United States, regulation is by the Food and Drug Administration (FDA). New drugs are developed in industrial or academic laboratories. Before a new drug can be approved for regular therapeutic use in humans, a series of animal and experimental human studies (clinical trials) must be carried out.
FIGURE 1–4 Serum concentration-time curve after administration of a drug as an intravenous bolus. This drug follows first-order kinetics and appears to occupy 2 compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination half-life (t1/2β) can be extracted graphically as shown by measuring the time between any 2 plasma concentration points on the elimination phase that differ by twofold. (See Chapter 3 for additional details.)
New drugs may emerge from a variety of sources. Some are the result of identification of a new target for a disease. Rational molecular design or screening is then used to find a molecule that selectively alters the function of the target. New drugs may result from the screening of hundreds of compounds against model diseases in animals. In contrast, many so-called “me-too” drugs are the result of simple chemical alteration of the pharmacokinetic properties of an original prototype agent.
SAFETY & EFFICACY
Because society expects prescription drugs to be safe and effective, governments regulate the development and marketing of new drugs. Current regulations in the USA require evidence of relative safety (derived from acute and subacute toxicity testing in animals) and probable therapeutic action (from the pharmacologic profile in animals) before human testing is permitted. Some information about the pharmacokinetics of a compound is also required before clinical evaluation is begun. Chronic toxicity test results are generally not required, but testing must be underway before human studies are started. The development of a new drug and its pathway through various levels of testing and regulation are illustrated in Figure 1–5. The cost of development of a new drug, including false starts and discarded molecules, may be
greater than $500 million although the true cost is often hidden by the manufacturer.
ANIMAL TESTING
The animal testing of a specific drug that is required before human studies can begin is a function of its proposed use and the urgency of the application. Thus, a drug proposed for occasional topical use requires less extensive testing than one destined for chronic systemic administration.
Because of the urgent need, anticancer drugs and some antiviral drugs require less evidence of safety than do drugs used in treatment of less threatening diseases. Urgently needed drugs are often investigated and approved on an accelerated schedule.
A. Acute Toxicity
Acute toxicity studies are required for all new drugs. These studies involve administration of incrementing doses of the agent up to the lethal level in at least 2 species (eg, 1 rodent and 1 nonrodent).
B. Subacute and Chronic Toxicity
Subacute and chronic toxicity testing is required for most agents, especially those intended for chronic use. Doses are selected based on the results of acute tests. Tests are usually conducted
In vitro studies
Biologic products
Animal testing Clinical testing Marketing
(Is it safe phar macokinetics?)
20–100 subjects
Phase 1 Phase 2
Lead compound Efficacy, selectivity, mechanism
Chemical synthesis
Years (average)
100–200 patients
(Does it work in patients?)
Phase 3
(Does it work, double blind?)
1000–6000 patients
Drug metabolism, safety assessment
IND (Investigational New Drug)
Generics become available
Phase 4
(Postmarketing surveillance)
NDA (New Drug Application)
(Patent expires 20 years after filing of application)
FIGURE 1–5 The development and testing process required to bring a new drug to market in the United States. Some requirements may be different for drugs used in life-threatening diseases. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 5–1.)
for 2–4 weeks (subacute) and 6–24 months (chronic), in at least 2 species.
TYPES OF ANIMAL TESTS
A. Pharmacologic Profile
The pharmacologic profile is a description of all the pharmacologic effects of a drug (eg, effects on cardiovascular function, gastrointestinal activity, respiration, hepatic and renal function, endocrine function, CNS). Both graded and quantal dose-response data are gathered.
B. Reproductive Toxicity
Reproductive toxicity testing involves the study of the fertility effects of the candidate drug and its teratogenic and mutagenic toxicity. Until 2015, the FDA had used a 5-level (A, B, C, D, X) minimally descriptive scale to summarize information regarding the safety of drugs in pregnancy (Table 1–3). For drugs submitted after June 2015, the letter scale has been abolished in favor of a narrative description of the safety or hazards of each drug, and separate categories are established for pregnancy, lactation, and for males and females of reproductive potential. The new system is designated the Pregnancy and Lactation Labeling Rule (PLLR) and is set forth at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/Labeling/ucm093307.htm. New labeling for drugs approved after 2001 will be phased in. Teratogenesis can be defined as the induction of developmental defects in the somatic tissues of the fetus (eg, by exposure of the fetus to a chemical, infection, or radiation). Teratogenesis is studied by treating pregnant female animals of at least 2 species at selected times during early pregnancy when organogenesis is known to take place and by later examining the fetuses or neonates for abnormalities. Examples
TABLE 1–3 FDA ratings of drug safety in pregnancy.*
Category Description
A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote
B
Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters)
C Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only when the potential benefit justifies the potential risk to the fetus
D There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective)
X Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant
*Because of lack of definitive evidence for many drugs, many experts consider the A through X ranking system to be too simplistic and inaccurate; they prefer more detailed narrative descriptions of evidence available for each drug in question. See Pregnancy and Lactation Labeling Rule, text.
of drugs known to have teratogenic effects include thalidomide, isotretinoin, valproic acid, ethanol, glucocorticoids, warfarin, lithium, and androgens. Mutagenesis denotes induction of changes in the genetic material of animals of any age and therefore induction of heritable abnormalities. The Ames test, the standard in vitro test for mutagenicity, uses a special strain of salmonella bacteria whose growth depends on specific nutrients in the culture medium. Loss of this dependence as a result of exposure to the test drug signals a mutation. Many carcinogens (eg, aflatoxin, cancer chemotherapeutic drugs, and other agents that bind to DNA) have mutagenic effects and test positive in the Ames test. The dominant lethal test is an in vivo mutagenicity test carried out in mice. Male animals are exposed to the test substance before mating. Abnormalities in the results of subsequent mating (eg, loss of embryos, deformed fetuses) signal a mutation in the male’s germ cells.
C. Carcinogenesis
Carcinogenesis is the induction of malignant characteristics in cells. Carcinogenicity is difficult and expensive to study, and the Ames test is often used to screen chemicals because there is a moderately high degree of correlation between mutagenicity in the Ames test and carcinogenicity in some animal tests, as previously noted. Agents with known carcinogenic effects include coal tar, aflatoxin, dimethylnitrosamine and other nitrosamines, urethane, vinyl chloride, and the polycyclic aromatic hydrocarbons in tobacco smoke (eg, benzo[a]pyrene) and other tobacco products.
CLINICAL TRIALS
Human testing of new drugs in the United States requires approval by institutional committees that monitor the ethical (informed consent, patient safety) and scientific aspects (study design, statistical power) of the proposed tests. Such testing also requires the prior approval by the FDA of an Investigational New Drug (IND) Exemption application, which is submitted by the developer to the FDA (Figure 1–5). The IND includes all the preclinical data collected up to the time of submission and the detailed proposal for clinical trials. The major clinical testing process is usually divided into 3 phases that are carried out to provide information for a New Drug Application (NDA). The NDA includes all the results of preclinical and clinical testing and constitutes the request for FDA approval of general marketing of the new agent for prescription use. A fourth phase of study (the surveillance phase) follows NDA approval. In particularly lethal conditions, the FDA may permit carefully monitored treatment of patients before phases 2 and 3 are completed.
A. Phase 1
A phase 1 trial consists of careful evaluation of the dose-response relationship and the pharmacokinetics of the new drug in a small number of normal human volunteers (eg, 20–100). An exception is the phase 1 trials of cancer chemotherapeutic agents and
other highly toxic drugs; these are carried out by administering the agents to volunteer patients with the target disease. In phase 1 studies, the acute effects of the agent are studied over a broad range of dosages, starting with one that produces no detectable effect and progressing to one that produces either a significant physiologic response or a very minor toxic effect.
B. Phase 2
A phase 2 trial involves evaluation of a drug in a moderate number of sick patients (eg, 100–200) with the target disease. A placebo or positive control drug is included in a single-blind or double-blind design. The study is carried out under very carefully controlled conditions, and patients are closely monitored, often in a hospital research ward. The goal is to determine whether the agent has the desired efficacy (ie, produces adequate therapeutic response) at doses that are tolerated by sick patients. Detailed data are collected regarding the pharmacokinetics and pharmacodynamics of the drug in this patient population.
C. Phase 3
A phase 3 trial usually involves many patients (eg, 1000–6000 or more, in many centers) and many clinicians who are using the drug in the manner proposed for its ultimate general use (eg, in outpatients). Such studies usually include placebo and positive controls in a double-blind crossover design. The goals are to explore further, under the conditions of the proposed clinical use, the spectrum of beneficial actions of the new drug, to compare it with placebo (negative control) and older therapy (positive control), and to discover toxicities, if any, that occur so infrequently as to be undetectable in phase 2 studies. Very large amounts of data are collected and these studies are usually very expensive. Unfortunately, relatively few phase 3 trials include the current standard of care as a positive control.
If the drug successfully completes phase 3, an NDA is submitted to the FDA. If the NDA is approved, the drug can be marketed and phase 4 begins.
D. Phase 4
Phase 4 represents the postmarketing surveillance phase of evaluation, in which it is hoped that toxicities that occur very infrequently will be detected and reported early enough to prevent major therapeutic disasters. Manufacturers are required to inform the FDA at regular intervals of all reported untoward drug reactions. Unlike the first 3 phases, phase 4 has not been rigidly regulated by the FDA in the past. Because so many drugs have been found to be unacceptably toxic only after they have been marketed, there is considerable current interest in making phase 4 surveillance more consistent, effective, and informative.
E. Adaptive Clinical Trials
Because the traditional 3-phase clinical trials are often prolonged and expensive, a newer type of clinical trial is currently under development. Adaptive trials are aimed at combining 2 or more of the traditional phases and altering conditions, dosage, and targets as the trial progresses, based on data being collected.
DRUG PATENTS & GENERIC DRUGS
A patent application is usually submitted around the time that a new drug enters animal testing (Figure 1–5). In the United States, approval of the patent and completion of the NDA approval process give the originator the right to market the drug without competition from other firms for a period of 10–14 years from the NDA approval date. After expiration of the patent, any company may apply to the FDA for permission to market a generic version of the same drug if they demonstrate that their generic drug molecule is bioequivalent (ie, meets certain requirements for content, purity, and bioavailability) to the original product.
DRUG LEGISLATION
Many laws regulating drugs in the United States were passed during the 20th century. Refer to Table 1–4 for a partial list of this legislation.
ORPHAN DRUGS
An orphan drug is a drug for a rare disease (in the United States, defined as one affecting fewer than 200,000 people). The study of such agents has often been neglected because profits from the sales of an effective agent for an uncommon ailment might not pay the costs of development. In the United States, current legislation provides for tax relief and other incentives designed to encourage the development of orphan drugs.
TABLE 1–4 Selected legislation pertaining to drugs in the United States.
Law
Pure Food and Drug Act of 1906
Harrison Narcotics Act of 1914
Food, Drug, and Cosmetics Act of 1938
Kefauver-Harris Amendment (1962)
Dietary Supplement and Health Education Act (1994)
Purpose and Effect
Prohibited mislabeling and adulteration of foods and drugs (but no requirement for efficacy or safety)
Established regulations for the use of opium, opioids, and cocaine (marijuana added in 1937)
Required that new drugs be tested for safety as well as purity
Required proof of efficacy as well as safety for new drugs
Amended the Food, Drug, and Cosmetics Act of 1938 to establish standards for dietary supplements but prohibited the FDA from applying drug efficacy and safety standards to supplements
QUESTIONS
1. A 3-year-old is brought to the emergency department having just ingested a large overdose of chlorpropamide, an oral antidiabetic drug. Chlorpropamide is a weak acid with a pK a of 5.0. It is capable of entering most tissues. On physical examination, the heart rate is 110/min, blood pressure 90/50 mm Hg, and respiratory rate 30/min. Which of the following statements about this case of chlorpropamide overdose is most correct?
(A) Urinary excretion would be accelerated by administration of NH4Cl, an acidifying agent
(B) Urinary excretion would be accelerated by giving NaHCO3, an alkalinizing agent
(C) Less of the drug would be ionized at blood pH than at stomach pH
(D) Absorption of the drug would be slower from the stomach than from the small intestine
2. Botulinum toxin is a large protein molecule. Its action on cholinergic transmission depends on an intracellular action within nerve endings. Which one of the following processes is best suited for permeation of very large protein molecules into cells?
(A) Aqueous diffusion
(B) Endocytosis
(C) First-pass effect
(D) Lipid diffusion
(E) Special carrier transport
3. A 12-year-old child has bacterial pharyngitis and is to receive an oral antibiotic. She complains of a sore throat and pain on swallowing. The tympanic membranes are slightly reddened bilaterally, but she does not complain of earache. Blood pressure is 105/70 mm Hg, heart rate 100/min, temperature 37.8°C (100.1°F). Ampicillin is a weak organic acid with a pKa of 2.5. What percentage of a given dose will be in the lipidsoluble form in the duodenum at a pH of 4.5?
(A) About 1%
(B) About 10%
(C) About 50%
(D) About 90%
(E) About 99%
4. Ampicillin is eliminated by first-order kinetics. Which of the following statements best describes the process by which the plasma concentration of this drug declines?
(A) There is only 1 metabolic path for drug elimination
(B) The half-life is the same regardless of the plasma concentration
(C) The drug is largely metabolized in the liver after oral administration and has low bioavailability
(D) The rate of elimination is proportional to the rate of administration at all times
(E) The drug is distributed to only 1 compartment outside the vascular system
5. The pharmacokinetics of a new drug are under study in a phase 1 clinical trial. Which statement about the distribution of drugs to specific tissues is most correct?
(A) Distribution to an organ is independent of blood flow
(B) Distribution of a lipid-soluble drug will be to adipose tissue initially
(C) Distribution into a tissue depends on the unbound drug concentration gradient between blood and the tissue
(D) Distribution is increased for drugs that are strongly bound to plasma proteins
(E) Distribution has no effect on the half-life of the drug
6. The pharmacokinetic process or property that distinguishes the elimination of ethanol and high doses of phenytoin and aspirin from the elimination of most other drugs is called
(A) Distribution
(B) Excretion
(C) First-pass effect
(D) First-order elimination
(E) Zero-order elimination
7. Which of the following statements about animal testing of potential new therapeutic agents is most correct?
(A) Requires at least 3 years to discover late toxicities
(B) Requires at least 1 primate species (eg, rhesus monkey)
(C) Requires the submission of histopathologic slides and specimens to the FDA for evaluation by government scientists
(D) Has good predictability for drug allergy-type reactions (E) May be abbreviated in the case of some very toxic agents used in cancer
8. The “dominant lethal” test involves the treatment of a male adult animal with a chemical before mating; the pregnant female is later examined for fetal death and abnormalities. The dominant lethal test therefore is a test of
(A) Teratogenicity
(B) Mutagenicity
(C) Carcinogenicity
(D) Sperm viability
9. In a phase 1 clinical trial, “Novexum,” a new drug, was administered intravenously to 25 volunteers, and blood samples were taken for several hours. Several inactive metabolites were found as well as declining concentrations of Novexum. A graph was prepared as shown below, with the Novexum plasma levels plotted on a logarithmic ordinate and time on a linear abscissa. It was concluded that the drug has first-order kinetics. From this graph, what is the best estimate of the elimination half-life of Novexum?
(A) 0.5 h
(B) 1 h
(C) 3 h
(D) 4 h
(E) 7 h
(h)
10. A large pharmaceutical company has conducted extensive animal testing of a new drug for the treatment of advanced prostate cancer. The chief of research and development recommends that the company now submit an IND application in order to start clinical trials. Which of the following statements is most correct regarding clinical trials of new drugs?
(A) Phase 1 involves the study of a small number of normal volunteers by highly trained clinical pharmacologists
(B) Phase 2 involves the use of the new drug in a large number of patients (1000–5000) who have the disease to be treated under conditions of proposed use (eg, outpatients)
(C) Chronic animal toxicity studies must be complete and reported in the IND
(D) Phase 4 involves the detailed study of toxic effects that have been discovered in phase 3
(E) Phase 2 requires the use of a positive control (a known effective drug) and a placebo
11. Which of the following would probably not be included in an optimal phase 3 clinical trial of a new analgesic drug for mild pain?
(A) A negative control (placebo)
(B) A positive control (current standard analgesic therapy)
(C) Double-blind protocol (in which neither the patient nor immediate observers of the patient know which agent is active)
(D) A group of 1000–5000 subjects with a clinical condition requiring analgesia
(E) Prior submission of an NDA (new drug application) to the FDA
12. The Ames test is frequently carried out before clinical trials are begun. The Ames test is a method that detects
(A) Carcinogenesis in primates
(B) Carcinogenesis in rodents
(C) Mutagenesis in bacteria
(D) Teratogenesis in any mammalian species
(E) Teratogenesis in primates
13. Which of the following statements about new drug development is most correct?
(A) If the need is great, drugs that test positive for teratogenicity, mutagenicity, or carcinogenicity can be tested in humans but the IND must specify safety measures to be taken
(B) Food supplements and herbal (botanical) remedies must be shown to be effective for the target condition before marketing is approved by the FDA
(C) All new drugs must be studied in at least 1 primate species before NDA submission
(D) Orphan drugs are drugs that are no longer produced by the original manufacturer
(E) Phase 4 (surveillance) is the most rigidly regulated phase of clinical drug trials
14. Which statement about the development of new drugs is most correct?
(A) Because they may cause anaphylaxis, proteins cannot be used as drugs
(B) Most drugs fall between 100 and 1000 in molecular weight
(C) Drugs for systemic action that are to be administered orally should be highly water soluble and insoluble in lipids
(D) Water solubility is minimal in highly polarized (charged) drug molecules
ANSWERS
1. Questions that deal with acid-base (Henderson-Hasselbalch) manipulations are common on examinations. Since absorption involves permeation across lipid membranes, we can in theory treat an overdose by decreasing absorption from the gut and reabsorption from the tubular urine by making the drug less lipid-soluble. Ionization attracts water molecules and decreases lipid solubility. Chlorpropamide is a weak acid, which means that it is less ionized when protonated, ie, at acid pH. Choice C suggests that the drug would be less ionized at pH 7.4 than at pH 2.0, which is clearly wrong for weak acids. Choice D says (in effect) that the more ionized form is absorbed faster, which is incorrect. A and B are opposites because NH4Cl is an acidifying salt and sodium bicarbonate an alkalinizing one. (From the point of view of test strategy, opposites in a list of answers always deserve careful attention.) Because an alkaline environment favors ionization of a weak acid, we should give bicarbonate. The answer is B. Note that clinical management of overdose involves many other considerations in addition to trapping the drug in urine; manipulation of urine pH may be contraindicated for other reasons.
2. Endocytosis is an important mechanism for transport of very large molecules across membranes. Aqueous diffusion is not involved in transport across the lipid barrier of cell membranes. Lipid diffusion and special carrier transport are common for smaller molecules. The first-pass effect has nothing to do with the mechanisms of permeation; rather, it denotes drug metabolism or excretion before absorption into the systemic circulation. The answer is B.
3. U.S. Medical Licensing Examination (USMLE)-type questions often contain a lengthy clinical description in the stem. One can often determine the relevance of the clinical data by scanning the last sentence in the stem and the list
of answers, see Appendix I. In this question, the emphasis is clearly on pharmacokinetic principles. Ampicillin is an acid, so it is more ionized at alkaline pH and less ionized at acidic pH. The Henderson-Hasselbalch equation predicts that the ratio changes from 50/50 at the pH equal to the pKa to 1/10 (protonated/unprotonated) at 1 pH unit more alkaline than the pKa and 1/100 at 2 pH units more alkaline. For acids, the protonated form is the nonionized, more lipid-soluble form. The answer is A.
4. “First-order” means that the elimination rate is proportional to the concentration perfusing the organ of elimination. The half-life is a constant. The rate of elimination is proportional to the rate of administration only at steady state. The order of elimination is independent of the number of compartments into which a drug distributes. The answer is B.
5. This is a straightforward question of pharmacokinetic distribution concepts. Choice B is incorrect because distribution depends on blood flow as well as solubility in the tissue; thus most drugs will initially distribute to high blood flow tissues and only later to larger, low-flow tissues, even if they are more soluble in them. From the list of determinants of drug distribution given on pages 5–6, choice C is correct.
6. The excretion of most drugs follows first-order kinetics. However, ethanol and, in higher doses, aspirin and phenytoin follow zero-order kinetics; that is, their elimination rates are constant regardless of blood concentration. The answer is E.
7. Drugs proposed for short-term use may not require longterm chronic testing. For some drugs, no primates are used; for other agents, only 1 species is used. The data from the tests, not the evidence itself, must be submitted to the FDA. Prediction of human drug allergy from animal testing is useful but not definitive (see answer 12). Testing may be abbreviated for drugs for which there is urgent need; the answer is E.
8. The description of the test indicates that a chromosomal change (passed from father to fetus) is the toxicity detected. This is a mutation. The answer is B.
9. Drugs with first-order kinetics have constant half-lives, and when the log of the concentration in a body compartment is plotted versus time, a straight line results. The half-life is defined as the time required for the concentration to decrease by 50%. As shown in the graph, the concentration of Novexum decreased from 16 units at 1 h to 8 units at 4 h and 4 units at 7 h; therefore, the half-life is 7 h minus 4 h or 3 h. The answer is C.
10. Except for known toxic drugs (eg, cytotoxic cancer chemotherapy drugs), phase 1 is carried out in 25–50 normal volunteers. Phase 2 is carried out in several hundred closely monitored patients with the disease. Results of chronic toxicity studies in animals are required in the NDA and are usually underway at the time of IND submission. However, they do not have to be completed and reported in the IND. Phase 4 is the general surveillance phase that follows marketing of the new drug. It is not targeted at specific effects. Positive controls and placebos are not a rigid requirement of any phase of clinical trials, although placebos are often used in phase 2 and phase 3 studies. The answer is A.
11. The first 4 items (A–D) are correct; they would be included. An NDA cannot be acted upon until the first 3 phases of clinical trials have been completed. (The IND must be approved before clinical trials can be conducted.) The answer is E.
12. The Ames test is carried out in Salmonella and detects mutations in the bacterial DNA. Because mutagenic potential is associated with carcinogenic risk for many chemicals, a positive Ames test is often used to suggest that a particular agent may be a carcinogen. However, the test itself only detects mutations. The answer is C.
13. Food supplements and botanicals are much more loosely regulated than conventional drugs; they are not required to be shown effective before marketing. Primates are not required in any phase of new drug testing, although they are sometimes used. (Note the trigger word “all” in choice (C); answers claiming “all…” are almost always wrong.) Orphan drugs are those for which the anticipated patient population is smaller than 200,000 patients in the United States. Phase 4
CHECKLIST
When you complete this chapter, you should be able to:
❑ Define and describe the terms receptor and receptor site
surveillance is the most loosely regulated phase of clinical trials. Many drugs in current clinical use test positive for teratogenicity, mutagenicity, or carcinogenicity. Such drugs are usually labeled with warnings about these toxicities and, in the case of teratogenicity, are labeled as contraindicated in pregnancy. The answer is A.
14. Many peptide and protein drugs, eg, insulin, antibodies, are in use; if identical or sufficiently similar to the human molecules, anaphylaxis is uncommon. Most drugs do fall between 100 and 1000 in molecular weight. Drugs for systemic use should be at least minimally water soluble (so they do not precipitate in the intestine) and lipid soluble (so they can cross lipid barriers). Charged molecules attract a shell of water molecules, making them more water soluble. The answer is B.
❑ Distinguish between a competitive inhibitor and an allosteric inhibitor.
❑ Predict the relative ease of permeation of a weak acid or base from knowledge of its pK a, the pH of the medium, and the Henderson-Hasselbalch equation.
❑ List and discuss the common routes of drug administration and excretion.
❑ Draw graphs of the blood level versus time for drugs subject to zero-order elimination and for drugs subject to first-order elimination. Label the axes appropriately.
❑ Describe the major animal and clinical studies carried out in drug development.
❑ Describe the purpose of the Investigational New Drug (IND) Exemption and the New Drug Application (NDA).
❑ Define carcinogenesis, mutagenesis, and teratogenesis.
❑ Describe the difference between the FDA regulations for ordinary drugs and those for botanical remedies.
CHAPTER 1 Summary Table
(Continued)
Major Concept Description
Nature of drugs
Drug permeation
Rate of diffusion
Drug trapping
Drugs are chemicals that modify body functions. They may be ions, carbohydrates, lipids, or proteins. They vary in size from lithium (MW 7) to proteins (MW ≥ 50,000)
Most drugs are administered at a site distant from their target tissue. To reach the target, they must permeate through both lipid and aqueous pathways. Movement of drugs occurs by means of aqueous diffusion, lipid diffusion, transport by special carriers, or by exocytosis and endocytosis
Aqueous diffusion and lipid diffusion are predicted by Fick’s law and are directly proportional to concentration gradient, area, and permeability coefficient and inversely proportional to the length or thickness of the diffusion path
Because the permeability coefficient of a weak base or weak acid varies with the pH according to the HendersonHasselbalch equation, drugs may be trapped in a cellular compartment in which the pH is such as to reduce their solubility in the barriers surrounding the compartment
Continued )
CHAPTER 1 Summary Table (Continued)
Major Concept Description
Routes of administration
Drug distribution
Drug elimination
Elimination kinetics
Drug safety and efficacy
Preclinical drug testing
Clinical drug trials
Drugs are usually administered by one of the following routes of administration: oral, buccal, sublingual, topical, transdermal, intravenous, subcutaneous, intramuscular, rectal, or by inhalation
After absorption, drugs are distributed to different parts of the body depending on concentration gradient, blood flow, solubility, and binding in the tissue
Drugs are eliminated by reducing their concentration or amount in the body. This occurs when the drug is inactivated by metabolism or excreted from the body
The rate of elimination of drugs may be zero order (ie, constant regardless of concentration) or first order (ie, proportional to the concentration)
Standards of safety and efficacy for drugs developed slowly during the 20th century and are still incomplete. Because of heavy lobbying by manufacturers, these standards are still not applied to nutritional supplements and many so-called botanical or herbal medications. A few of the relevant US laws are listed in Table 1–4
All new drugs undergo extensive preclinical testing in isolated tissue preparations and cell cultures, isolated animal organ preparations, and intact animals. Experiments are carried out to determine the full range of toxic and therapeutic effects. See Figure 1–5
In the USA, all new drugs proposed for use in humans must undergo a series of tests in humans. These tests are regulated by the FDA and may be accelerated or prolonged depending on the perceived clinical need and possible toxicities. The trials are often divided into 3 phases before marketing is allowed. See Figure 1–5
Pharmacodynamics
Pharmacodynamics deals with the effects of drugs on biologic systems, whereas pharmacokinetics (Chapter 3) deals with actions of the biologic system on the drug. The principles
of pharmacodynamics apply to all biologic systems, from isolated receptors in the test tube to patients with specific diseases.
Pharmacodynamics
Receptors, effectors
Dose -response cur ves, spare receptors
Agonists, par tial agonists, biased agonists, antagonists, inverse agonists
Signaling mechanisms
Receptor regulation
RECEPTORS
Receptors are the specific molecules in a biologic system with which drugs interact to produce changes in the function of the system. Receptors must be selective in their ligand-binding characteristics (so as to respond to appropriate chemical signals and not to meaningless ones). Receptors must also be modifiable when they bind a drug molecule (so as to bring about a change in function). Many receptors have been identified, purified, chemically characterized, and cloned. Most are proteins; a few are other macromolecules such as DNA. Some authorities consider enzymes as a separate category; for the purposes of this book, enzymes that are affected by drugs are considered receptors. The receptor site (also known as the recognition site) for a drug is the specific binding region of the receptor macromolecule and has a relatively high and selective affinity for the drug molecule. The interaction of a drug with its receptor is the fundamental event that initiates the action of the drug, and many drugs are classified on the basis of their primary receptor affinity.
EFFECTORS
Effectors are molecules that translate the drug-receptor interaction into a change in cellular activity. The best examples of effectors are enzymes such as adenylyl cyclase. Some receptors are also effectors in that a
single molecule may incorporate both the drug-binding site and the effector mechanism. For example, a tyrosine kinase effector enzyme is part of the insulin receptor molecule, and a sodium-potassium channel is the effector part of the nicotinic acetylcholine receptor.
GRADED DOSE-RESPONSE RELATIONSHIPS
When the response of a particular receptor-effector system is measured against increasing concentrations of a drug, the graph of the response versus the drug concentration or dose is called a graded dose-response curve (Figure 2–1A). Plotting the same data on a logarithmic concentration axis usually results in a sigmoid curve, which simplifies the mathematical manipulation of the doseresponse data (Figure 2–1B). The efficacy (Emax) and potency (EC50 or ED50) parameters are derived from these data. The smaller the EC50 (or ED50), the greater the potency of the drug.
It is possible to measure the percentage of receptors bound by a drug, and by plotting this percentage against the log of the concentration of the drug, a dose-binding graph similar to the
High-Yield Terms to Learn
Receptor
Inert binding molecule or site
Receptor site
Spare receptor
Effector
Agonist
Biased agonist
Pharmacologic antagonist
Competitive antagonist
Irreversible antagonist
Physiologic antagonist
Chemical antagonist
Allosteric agonist, antagonist
Partial agonist
Constitutive activity
Inverse agonist
Graded dose-response curve
Quantal dose-response curve
EC50, ED50, TD50, etc
Kd
Efficacy, maximal efficacy
Potency
A molecule to which a drug binds to bring about a change in function of the biologic system
A molecule to which a drug may bind without changing any function
Specific region of the receptor molecule to which the drug binds
Receptor that does not bind drug when the drug concentration is sufficient to produce maximal effect; present if Kd > EC50
Component of a system that accomplishes the biologic effect after the receptor is activated by an agonist; often a channel, transporter, or enzyme molecule, may be part of the receptor molecule
A drug that activates its receptor upon binding
An agonist that activates the same receptor as other drugs in its group but also causes additional downstream effects that are not seen with other agonists in the group
A drug that binds to the receptor without activating it and thereby prevents activation by an agonist
A pharmacologic antagonist that can be overcome by increasing the concentration of agonist
A pharmacologic antagonist that cannot be overcome by increasing agonist concentration
A drug that counters the effects of another by binding to a different receptor and causing opposing effects
A drug that counters the effects of another by binding the agonist drug (not the receptor)
A drug that binds to a receptor molecule without interfering with normal agonist binding but alters the response to the normal agonist
A drug that binds to its receptor but produces a smaller effect (Emax) at full dosage than a full agonist
Activity of a receptor-effector system in the absence of an agonist ligand
A drug that binds to the non-active state of receptor molecules and decreases constitutive activity (see text)
A graph of the increasing response to increasing drug concentration or dose
A graph of the increasing fraction of a population that shows a specified response at progressively increasing doses
In graded dose-response curves, the concentration or dose that causes 50% of the maximal effect or toxicity. In quantal dose-response curves, the concentration or dose that causes a specified response in 50% of the population under study
The concentration of drug that binds 50% of the receptors in the system
The largest effect that can be achieved with a particular drug, regardless of dose, Emax
The amount or concentration of drug required to produce a specified effect, usually EC50 or ED50
FIGURE 2–1
Graded dose-response and dose-binding graphs. (In isolated tissue preparations, concentration is usually used as the measure of dose.) A. Relation between drug dose or concentration (abscissa) and drug effect (ordinate). When the dose axis is linear, a hyperbolic curve is commonly obtained. B. Same data, logarithmic dose axis. The dose or concentration at which effect is half-maximal is denoted EC50, whereas the maximal effect is Emax. C. If the percentage of receptors that bind drug is plotted against drug concentration, a similar curve is obtained, and the concentration at which 50% of the receptors are bound is denoted Kd, and the maximal number of receptors bound is termed Bmax.
dose-response curve is obtained (Figure 2–1C). The concentration of drug required to bind 50% of the receptor sites is denoted by the dissociation constant (Kd) and is a useful measure of the affinity of a drug molecule for its binding site on the receptor molecule. The smaller the Kd, the greater the affinity of the drug for its receptor. If the number of binding sites on each receptor molecule is known, it is possible to determine the total number of receptors in the system from the Bmax
QUANTAL DOSE-RESPONSE RELATIONSHIPS
When the minimum dose required to produce a specified response is determined in each member of a population, the quantal doseresponse relationship is defined (Figure 2–2). For example, a blood pressure-lowering drug might be studied by measuring the dose required to lower the mean arterial pressure by 20 mm Hg in 100 hypertensive patients. When plotted as the percentage of the population that shows this response at each dose versus the log of the dose administered, a cumulative quantal dose-response curve, usually sigmoid in shape, is obtained. The median effective dose (ED50), median toxic dose (TD50), and (in animals) median lethal dose (LD50) are derived from experiments carried out in this manner. Because the magnitude of the specified effect is arbitrarily determined, the ED50 determined by quantal dose-response measurements has no direct relation to the ED50
determined from graded dose-response curves. Unlike the graded dose-response determination, no attempt is made to determine the maximal effect of the drug. Quantal dose-response data provide information about the variation in sensitivity to the drug in a given population, and if the variation is small, the curve is steep.
EFFICACY
Efficacy—often called maximal efficacy—is the greatest effect (Emax) an agonist can produce if the dose is taken to the highest tolerated level. Efficacy is determined mainly by the nature of the drug and the receptor and its associated effector system. It can be measured with a graded dose-response curve (Figure 2–1) but not with a quantal dose-response curve. By definition, partial agonists have lower maximal efficacy than full agonists (see later discussion).
POTENCY
Potency denotes the amount of drug needed to produce a specified effect. In graded dose-response measurements, the effect usually chosen is 50% of the maximal effect and the concentration or dose causing this effect is called the EC50 or ED50 (Figure 2–1A and B). Potency is determined mainly by the affinity of the receptor for the drug and the number of receptors available. In quantal doseresponse measurements, ED50, TD50, and LD50 are also potency variables (median effective, median toxic, and median lethal doses, respectively, in the population studied). Thus, a measure of potency can be specified using either graded or quantal dose-response curves (eg, Figures 2–1 and 2–2, respectively), but the numbers obtained are not identical and they have different meanings.
SPARE RECEPTORS
FIGURE 2–2 Quantal dose-response plots from a study of the therapeutic and lethal effects of a new drug in mice. Shaded boxes (and the accompanying bell-shaped curves) indicate the frequency distribution of doses of drug required to produce a specified effect, that is, the percentage of animals that required a particular dose to exhibit the effect. The open boxes (and corresponding sigmoidal curves) indicate the cumulative frequency distribution of responses, which are lognormally distributed. (Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 2–16.)
Spare receptors are said to exist if the maximal drug response (Emax) is obtained at less than 100% occupation of the receptors (Bmax). In practice, the determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the concentration for 50% of maximal binding (Kd). If the EC50 is less than the Kd, spare receptors are said to exist (Figure 2–3). This might result from 1 of 2 mechanisms. First, the duration of the effector activation may be much greater than the duration of the drug-receptor interaction. Second, the actual number of receptors may exceed the number of effector molecules available. The presence of spare receptors increases sensitivity to the agonist because the likelihood of a drug-receptor interaction increases in proportion to the number of receptors available. (For contrast, the system depicted in Figure 2–1, panels B and C, does not have spare receptors, since the EC50 and the Kd are equal.)
Current concepts of drug-receptor interactions consider the receptor to have at least 2 states—active and inactive. In the absence of ligand, a receptor might be fully active or completely inactive; alternatively,
FIGURE 2–3 In a system with spare receptors, the EC50 is lower than the Kd, indicating that to achieve 50% of maximal effect, less than 50% of the receptors must be activated. Explanations for this phenomenon are discussed in the text.
an equilibrium state might exist with some receptors in the activated state and most in the inactive state (Ra + Ri; Figure 2–4). Many receptor systems exhibit some activity in the absence of ligand, suggesting that some fraction of the receptor pool is always in the activated state. Activity in the absence of ligand is called constitutive activity. A full agonist is a drug capable of fully activating the effector system when it binds to the receptors. In the model system illustrated in Figure 2–4, a full agonist has high affinity for the activated receptor conformation, and sufficiently high concentrations result in all the receptors achieving the activated state (Ra – Da). A partial agonist produces less than the full effect, even when it has saturated the receptors (Ra–Dpa + Ri–Dpa), presumably by combining with both receptor conformations, but favoring the active state. In the presence of a full agonist, a partial agonist acts as an inhibitor. In this model, neutral antagonists bind with equal affinity to the Ri and Ra states, preventing binding by an agonist and preventing any deviation from the level of constitutive activity. In contrast, inverse agonists have a higher affinity for the inactive Ri state than for Ra and decrease or abolish any constitutive activity. Biased agonism denotes the ability of some agonists in a group (eg, β-adrenoceptor ligands) to produce somewhat different (biased) downstream effects despite activating the same receptors. The mechanism of this effect is not understood but may involve changes induced in the conformation of the receptor that differ with different agonists.
ANTAGONISTS
A. Competitive and Irreversible Pharmacologic Antagonists
Competitive antagonists are drugs that bind to, or very close to, the agonist receptor site in a reversible way without activating the effector system for that receptor. Neutral antagonists bind the receptor without shifting the ratio of Ra to Ri (Figure 2–4). In the presence of a competitive antagonist, the dose-response
FIGURE 2–4 Upper: One model of drug-receptor interactions. The receptor is able to assume 2 conformations, Ri and Ra. In the Ri state, it is inactive and produces no effect, even when combined with a drug (D) molecule. In the Ra state, it activates its effectors and an effect is recorded, even in the absence of ligand. In the absence of drug, the equilibrium between Ri and Ra determines the degree of constitutive activity. Lower: A full agonist drug (Da) has a much higher affinity for the Ra than for the Ri receptor conformation, and a maximal effect is produced at sufficiently high drug concentration. A partial agonist drug (Dpa) has somewhat greater affinity for the Ra than for the Ri conformation and produces less effect, even at saturating concentrations. A neutral antagonist (Dant) binds with equal affinity to both receptor conformations and prevents binding of agonist. An inverse agonist (Di) binds much more avidly to the Ri receptor conformation, prevents conversion to the Ra state, and reduces constitutive activity. (Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 1–4.)
curve for an agonist is shifted to higher doses (ie, horizontally to the right on the dose axis), but the same maximal effect is reached (Figure 2–5A). The agonist, if given in a high enough concentration, can displace the antagonist and fully activate the receptors. In contrast, an irreversible antagonist causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present (Figure 2–5B). Unlike the effects of a competitive antagonist, the effects of an irreversible antagonist cannot be overcome by adding more agonist. Competitive antagonists increase the ED50; irreversible antagonists do not (unless spare receptors are present). A noncompetitive antagonist that acts at an allosteric site on the receptor (see Figure 1–1) may bind reversibly or irreversibly; a noncompetitive antagonist that acts at the receptor site binds irreversibly.
Agonist plus irreversible antagonist
Agonist dose (log scale)
FIGURE 2–5 Agonist dose-response curves in the presence of competitive and irreversible antagonists. Note the use of a logarithmic scale for drug concentration. A. A competitive antagonist has an effect illustrated by the shift of the agonist curve to the right. B. An irreversible (or noncompetitive) antagonist shifts the agonist curve downward.
B. Physiologic Antagonists
A physiologic antagonist binds to a different receptor molecule, producing an effect opposite to that produced by the drug it antagonizes. Thus, it differs from a pharmacologic antagonist, which interacts with the same receptor as the drug it inhibits. Typical examples of physiologic antagonists are the antagonism of the bronchoconstrictor action of histamine by epinephrine’s bronchodilator action and glucagon’s antagonism of the hypoglycemic action of insulin.
C. Chemical Antagonists
A chemical antagonist interacts directly with the drug being antagonized to remove it or to prevent it from binding to its target. A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur). Common examples of chemical antagonists are dimercaprol, a chelator of lead and some other toxic metals, and pralidoxime, which combines avidly with the phosphorus in organophosphate cholinesterase inhibitors.
SKILL KEEPER: ALLOSTERIC ANTAGONISTS
(SEE CHAPTER 1)
Describe the difference between a pharmacologic antagonist and an allosteric inhibitor. How could you differentiate these two experimentally?
THERAPEUTIC INDEX & THERAPEUTIC WINDOW
The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, determined from quantal dose-response curves. The therapeutic index represents an estimate of the safety of a drug, because
a very safe drug might be expected to have a very large toxic dose and a much smaller effective dose. For example, in Figure 2–2, the ED50 is approximately 3 mg, and the LD50 is approximately 150 mg. The therapeutic index is therefore approximately 150/3, or 50, in mice. Obviously, a full range of toxic doses cannot be ethically studied in humans. Furthermore, factors such as the varying slopes of dose-response curves make this estimate a poor safety index even in animals.
The therapeutic window, a more clinically useful index of safety, describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose. For example, if the average minimum therapeutic plasma concentration of theophylline is 8 mg/L and toxic effects are observed at 18 mg/L, the therapeutic window is 8–18 mg/L. Both the therapeutic index and the therapeutic window depend on the specific therapeutic and toxic effects used in the determination.
SIGNALING MECHANISMS
Once an agonist drug has bound to its receptor, some effector mechanism is activated. The receptor-effector system may be an enzyme in the intracellular space (eg, cyclooxygenase, a target of nonsteroidal anti-inflammatory drugs) or in the membrane or extracellular space (eg, acetylcholinesterase). Neurotransmitter reuptake transporters (eg, the serotonin transporter, SERT; and the dopamine transporter, DAT) are receptors for many drugs, eg, antidepressants and cocaine. Most antiarrhythmic drugs target voltage-activated ion channels in the membrane for sodium, potassium, or calcium. For the largest group of drug-receptor interactions, the drug is present in the extracellular space, whereas the effector mechanism resides inside the cell and modifies some intracellular process. These classic drug-receptor interactions involve signaling across the membrane. Five major types of transmembrane-signaling mechanisms for receptor-effector systems have been defined (Figure 2–6, Table 2–1).
FIGURE 2–6 Signaling mechanisms for drug effects. Five major cross-membrane signaling mechanisms are recognized: (1) transmembrane diffusion of the drug to bind to an intracellular receptor; (2) transmembrane enzyme receptors, whose outer domain provides the receptor function and inner domain provides the effector mechanism converting A to B; (3) transmembrane receptors that, after activation by an appropriate ligand, activate separate cytoplasmic tyrosine kinase molecules (JAKs), which phosphorylate STAT molecules that regulate transcription (Y, tyrosine; P, phosphate); (4) transmembrane channels that are gated open or closed by the binding of a drug to the receptor site; and (5) G protein-coupled receptors, which use a coupling protein to activate a separate effector molecule. (Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 2–5.)
RECEPTOR REGULATION
Receptors are dynamically regulated in number, location, and interaction with other molecules. Changes can occur over short times (seconds to minutes) and longer periods (days).
Frequent or continuous exposure to agonists often results in short-term diminution of the response, sometimes called tachyphylaxis. Several mechanisms are responsible for this phenomenon.
TABLE 2–1 Types of transmembrane signaling
receptors.
First, intracellular molecules may block access of a G protein to the activated receptor molecule. For example, the molecule β-arrestin has been shown to bind to an intracellular loop of the β adrenoceptor when the receptor is continuously activated. Beta-arrestin prevents access of the Gs-coupling protein and thus desensitizes the tissue to further β-agonist activation within minutes. Removal of the β agonist results in removal of β arrestin and restoration of the full response after a few minutes or hours.
Receptor Type
Intracellular, often steroid receptor-like
Membrane-spanning receptoreffector enzymes
Membrane receptors that bind intracellular tyrosine kinase enzymes (JAK-STAT receptors)
Ligand-activated or modulated membrane ion channels
G-protein-coupled receptors (GPCRs)
Description
Steroids, vitamin D, nitric oxide, and a few other highly membrane-permeant agents cross the membrane and activate intracellular receptors. The effector molecule may be part of the receptor or separate.
Insulin, epidermal growth factor, and similar agents bind to the extracellular domain of molecules that incorporate tyrosine kinase enzyme activity in their intracellular domains. Most of these receptors dimerize upon activation.
Many cytokines activate receptor molecules that bind separate intracellular tyrosine kinase enzymes (Janus kinases, JAKs) that activate transcription regulators (signal transducers and activators of transcription, STATs) that migrate to the nucleus to bring about the final effect.
Certain Na+/K+ channels are activated by drugs: acetylcholine activates nicotinic Na+/K+ channels, serotonin activates 5-HT3 Na+/K+ channels. Benzodiazepines, barbiturates, and several other sedative hypnotics allosterically modulate GABA-activated Cl– channels; sympathomimetics modulate voltage-activated Ca2+ channels, other drugs modulate voltage-activated K+ channels.
GPCRs consist of 7 transmembrane (7-TM) domains and when activated by extracellular ligands, bind trimeric G proteins at the inner membrane surface and cause the release of activated Gα and Gβγ units. These activated units, in turn, modulate cytoplasmic effectors. The effectors commonly synthesize or release second messengers such as cAMP, IP3, and DAG. GPCRs are the most common type of receptors in the body.
Second, agonist-bound receptors may be internalized by endocytosis, removing them from further exposure to extracellular molecules. The internalized receptor molecule may then be either reinserted into the membrane (eg, morphine receptors) or degraded (eg, β adrenoceptors, epidermal growth factor receptors). In some cases, a cyclic internalization-reinsertion process may actually be necessary for normal functioning of the receptoreffector system.
Third, continuous activation of the receptor-effector system may lead to depletion of some essential substrate required for downstream effects. For example, depletion of endogenous thiol cofactors may be responsible for tolerance to nitroglycerin. In some cases, repletion of the missing substrate (eg, by administration of glutathione) can reverse the tolerance.
Long-term reductions in receptor number (downregulation) may occur in response to continuous exposure to agonists. The opposite change (upregulation) may occur when receptor activation is blocked for prolonged periods (usually several days) by pharmacologic antagonists or by denervation.
QUESTIONS
1. A 55-year-old man is seen in the clinic with hypertension of 150/95 mm Hg (millimeters of mercury). His personal medical history and physical examination are otherwise unremarkable but his family history is positive for early deaths due to cardiovascular disease. A decision is made to treat his hypertension, starting with a calcium channel blocker. Blocker A in a dose of 5 mg produces the same decrease in blood pressure as 500 mg of blocker B. Which of the following predictions is most accurate?
(A) Blocker A will be more efficacious than blocker B
(B) Blocker A will be about 100 times more potent than blocker B
(C) Toxicity of blocker A will be less than that of blocker B
(D) Blocker A will have a wider therapeutic window than blocker B
(E) Blocker A will have a longer half-life than blocker B
2. Graded and quantal dose-response curves are being used for evaluation of a new analgesic drug in the animal laboratory and in clinical trials. Which of the following statements best describes graded dose-response curves?
(A) More precisely quantitated than quantal dose-response curves
(B) Obtainable from isolated tissue preparations but not from the study of intact subjects
(C) Used to determine the maximal efficacy of the drug
(D) Used to determine the therapeutic index of the drug
(E) Used to determine the variation in sensitivity of subjects to the drug
3. Prior to clinical trials in patients with heart failure, an animal study was carried out to compare two new positive inotropic drugs (A and B) to a current standard agent (C). The results of cardiac output measurements are shown in the graph below.
Increase in cardiac output
Log dose
Which of the following statements is correct?
(A) Drug A is most effective
(B) Drug B is least potent
(C) Drug C is most potent
(D) Drug B is more potent than drug C and more effective than drug A
(E) Drug A is more potent than drug B and more effective than drug C
4. A study was carried out in isolated intestinal smooth muscle preparations to determine the action of a new drug “novamine,” which in separate studies bound to the same receptors as acetylcholine, an agonist. In the absence of other drugs, acetylcholine caused contraction of the muscle. Novamine alone caused relaxation of the preparation. In the presence of a low concentration of novamine, the EC50 of acetylcholine was unchanged, but the Emax was reduced. In the presence of a high concentration of novamine, extremely high concentrations of acetylcholine had no effect. Which of the following expressions best describes novamine?
(A) A chemical antagonist
(B) An irreversible antagonist
(C) A partial agonist
(D) A physiologic antagonist
(E) A spare receptor agonist
5. Beta adrenoceptors in the heart regulate cardiac rate and contractile strength. Several studies have indicated that in humans and experimental animals, about 90% of β adrenoceptors in the heart are spare receptors. Which of the following statements about spare receptors is most correct?
(A) Spare receptors, in the absence of drug, are sequestered in the cytoplasm
(B) Spare receptors may be detected by finding that the drug-receptor interaction lasts longer than the intracellular effect
(C) Spare receptors influence the maximal efficacy of the drug-receptor system
(D) Spare receptors activate the effector machinery of the cell without the need for a drug
(E) Spare receptors may be detected by finding that the EC50 is smaller than the Kd for the agonist
A B C
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come to the house, for fear of infection. I have therefore written to Dr. Lickemwell, asking him to keep you for the holidays. If Ned gets better soon, your mamma and I may, perhaps, come and see you.
“I know that this will be a great disappointment to you, but disappointments are things none of us can help meeting in this world, and we must just try to bear them cheerfully, and make the best of them.
“I am sure Dr. and Mrs. Lickemwell will do all they can to make you enjoy your holidays, and I hope that your not being able to come home may turn out to be not such a great misfortune after all. I enclose you five shillings as a Christmas present.
“I have no time to write more. Mamma cannot write at all, she is so anxious about Ned, but she sends her love to you. And, hoping you are quite well, I am, your affectionate
“P .”
Just fancy my feelings when I had read this letter! It was so sudden and unexpected, that at first I could scarcely believe it to be true. But there was the well-known handwriting, and the words were plain enough. When I had read it over twice, I put the letter into my pocket, and, seeking out a solitary corner of the playground, had a good cry. Need I be ashamed of it? I was only twelve years old, and you may judge for yourselves how great the disappointment was.
For two or three days I was very dull and miserable. The pleasure with which I had looked forward to the holidays was all gone, and the glee of the other boys made me feel quite angry. But it takes a great deal to depress a boy’s spirits for any length of time, and I soon began to get over my disappointment, and to console myself with the first maxim of philosophy, “What must be, must be.” Perhaps the five shillings contributed more than the philosophy to reconcile me to my lot.
But when the breaking-up day came, I felt my misfortune very keenly. The Doctor had been in the habit of making us a farewell speech on these occasions, which had always appeared to me very appropriate, but now I thought his jesting tone singularly out of place. “I have to bid you good-bye for a few weeks,” he said, “and, in doing so, I need not say how sorry I am to part with you. Of course teaching you, and caning you, and scolding you, is the greatest pleasure I have in the world. Of course I don’t like holidays. Of course you give me very little trouble, and I am very angry with your parents for taking that trouble off my shoulders for a few weeks. But that we may not forget each other during the holidays, I suppose I must give out some work for you to do while you are away.”
Dr. Lickemwell always said this at the beginning of the holidays, but the boys, who understood very well the merry twinkle in his eye, always met the proposal by a laughing shout of “No, no; oh, no, Sir! No holiday task.” “What!” cried the Doctor, pretending to be very much astonished. “No holiday task! Well, I think that I understand your feelings. You haven’t the heart to do any work away from me and my cane. It is very gratifying to me to find that we are such favourites. So let it be, then. And now all I have to do is to hope that you will get home safely, and spend a merry Christmas.”
At this the boys leaped up and gave three tremendous cheers for the Doctor, and then most of them rushed off to make their final preparations for departure. I could not bear to see the coaches full of happy faces roll off, so I betook myself to my retreat in the playground, and remained there alone till the dinner bell rang, when I returned to the house and joined my companions in misery.
There were five of us who, from various reasons, were to pass the holidays at school. First, Jack and Willy Somers. These two brothers generally spent their holidays at the house of an aunt, but she was ill, and could not receive them this time. Jack was certainly the very worst boy to be near a sick bed, always chattering, and shouting, and racketing about. Unless his aunt was a very different person from most single ladies I have known, I can’t understand how she ever managed to put up with him; indeed, I believe they had frequent squabbles, in consequence of a propensity of Jack’s for climbing on
the outside of the staircase, and a habit he had of tying a tin kettle to the tail of her favourite cat, and other amusements, which the good lady did not at all approve of. Willy was a small boy, about nine years old, and all I can remember of him is that he had curly hair, great red cheeks, and a funny little lump in the place where other people have noses. Then there was Arthur Howard, a quiet, gentle boy, who had neither father nor mother, nor aunt to go to, and spent all his holidays at the school, poor fellow. And the last was Edwin Saunders, whose parents were in India, where he gave us to understand that he was soon to follow them, and reside in a palace surrounded with palmtrees, with about a dozen white elephants, and rather more than a hundred native servants at his disposal. This picture of oriental luxury rather dazzled us, and we looked to Saunders as a person of consequence, but I have since had reason to believe that he was exaggerating his expectations, inasmuch as I afterwards found him residing in a small house in a country town with his father, who had retired from the army on half pay.
Being left alone, then, in the great school-house, which seemed so strangely silent and empty, we five resolved to make the best of it. And we got on pretty well after all. We had no lessons to learn, and almost nobody to look after us, and could roam about all day where we liked. So we chattered, and played, and read story books out of the school library, and enjoyed our freedom. If it had only come on hard frost, we wouldn’t have minded staying at school a bit, for there was a splendid pond for skating just at the back of Upton House.
On the third day we were all sitting round the fire in the schoolroom, after dinner, when Willy Somers, who had been meditating deeply, uttered the following remarkable piece of information:—
“To-morrow’s Christmas Day.”
“Well, we all know that,” said his brother. “Can’t you think of something new and original to tell us, Willy?”
“I was thinking—I was wondering if Lickemwell would give us a plum pudding.”
“Catch him,” said Saunders, who was of a cynical disposition, and had no great faith in human nature. “He’ll have one himself, but we’ll get nothing better than that everlasting stick jaw. If I was in India, what a splendid pudding I should have!”
“‘If ifs and ands were pots and pans,’” quoted Jack, and then stopped, leaving us to meditate over this unfinished sentiment.
We were all silent for a few minutes, thinking of the same subject, the glories of the Christmas dinner which the other boys would enjoy. And the more we thought of it, the less we liked the cheerless prospect which was before us. I am afraid we were a set of greedy little fellows.
Suddenly, as I turned over my five shillings, or what was left of them, in my trousers’ pocket, a bright idea came into my mind.
“Why shouldn’t we get up a Christmas dinner for ourselves? I mean, buy a lot of things, and cook them at the school-room fire, and have a regular spread.”
“Oh, that would be jolly!” cried little Willy. “I have three shillings and sixpence. That would buy—let me see—forty-two apple tarts. No; I think I would rather buy eighty-four sponge biscuits.”
“Buy your grandmother!” said Jack, contemptuously. “If we go in for the thing at all, we must do it in regular style—get a goose or a turkey, or something of that sort. It’s not a bad idea. What do you say, Saunders?”
“I say it’s a splendid idea,” said Saunders, who hadn’t any money, and therefore felt free to pronounce a very decided opinion on the matter.
“But the Doctor won’t allow us to be cooking things in the schoolroom,” objected Howard.
“Then we’ll allow ourselves,” said Jack. “No fear of the Doctor shoving his nose into the business. He’ll be too busy guzzling in the parlour with Mrs. L. and the young Licks.”
“Oh, we can easily manage it,” said I. “I have about half-a-crown.”
“At all events, if we are to do it, we must look sharp about it,” said Jack. “We must buy the things this afternoon. All the shops will be shut to-morrow.”
Without further discussion Jack and I settled that the thing should be. Saunders and Howard held back, being rather afraid of the Doctor; but, as they were not to furnish the funds, their opinion was not regarded.
Our first step was to form ourselves into a committee of ways and means, of which Jack, who was one of those fellows that always take the lead in everything, elected himself president, secretary, and treasurer. Our joint funds were found to amount to about ten shillings, but as we didn’t care to spend all our money, Jack, Willy, and I, agreed to give two shillings a-piece, which we thought would be enough to furnish a sumptuous feast. Saunders contributed half of a cake, which somebody had sent him. Greedy fellow! he had already eaten up the other half, without saying a word to any of us. Howard gave nothing, but nobody grudged him his share in the matter, for we all knew that he would have been generous enough, if he had had anything to give.
Of course the great question was what to buy with our money. Willy was very anxious to have a turkey, but that was out of the question, so it was settled that a duck should be got instead, which Jack assured us could be bought for half-a-crown, and could be easily roasted at the school-room fire. Then sixpence was to be spent on potatoes, tenpence on apple tarts, two for each of us, the same sum on sweet biscuits, and the rest, it was unanimously voted, should be applied to the purchase of chocolate drops, by way of dessert. As soon as this bill of fare was decided upon, we sallied forth in a body to make our purchases, and succeeded in bringing back the articles, duck and all, without being observed, and locking them up in an empty desk in the school-room.
Next day, you may be sure, we were in a state of great excitement. I am sure no family in England could have been looking forward to their Christmas dinner with more pleasing anticipations than we five. As soon as church was done we hastened home, and sat down with
no great relish to our ordinary school dinner It seemed lucky for us that we had something better in view, for all that was on the table was a dish of potatoes and some scraps of cold mutton. Neither the Doctor nor Mrs. Lickemwell made their appearance; only one of the maids was in attendance, and to her Jack began to grumble, more for the sake of grumbling than because he cared particularly what he had for dinner on that day.
“I say, Sally,” said he, “this is a low shame. Is this all the grub we’re to get?”
I may here remark that, by time-honoured custom, all the maids at Upton House were called Sally by the boys, who further distinguished them, with a lofty disregard for the rules of gender, as Sally Primus, Sally Secundus, and so forth. They didn’t use to like it at first, but they soon got accustomed to it, I dare say.
“That’s all you are to get just now,” said Sally. “There’s a great deal of cooking going on to-day.”
“Mother L. might have given us a plum pudding, at least. We’ll all be starved,” said Jack, winking at us.
Sally vouchsafed no further answer, but disappeared with the dish cover, leaving us to the enjoyment of the cold mutton, which disappeared very fast. We were too full of the thoughts of our own banquet to waste more time on the discussion of Mrs. Lickemwell’s stinginess, as we thought it.
Before Sally came back we had hidden away as many plates and knives as we thought she would not miss, and, when she had cleared away and left the room, we at once commenced operations, trusting to good luck that we would not be interrupted.
Jack and I undertook the important business of roasting the duck. We first carefully plucked it and buried the feathers, and then tied a string to one of its legs, and took turns at spinning it round before the fire, with such satisfactory results that in about an hour and a half it was pronounced ready for eating, one side being by that time burnt quite black. To Willy and Howard was entrusted the task of roasting the potatoes, which they accomplished much to their own
satisfaction, though a critical observer might have objected that they burned to cinders a good many more than they cooked. Saunders, for his part, engaged to manufacture a wonderful cake of bread crumbs, slices of raw potato, and salt butter, which compound, I may here remark, was unanimously pronounced to be an utter failure.
Everything being thus ready, it was agreed to take the viands up to one of the bedrooms, and spend the rest of the afternoon there, in the enjoyment of them. This was done, and we were preparing to abandon ourselves to festivity, when a heavy tread was heard in the passage, and Jack exclaimed in a loud whisper—“Look out! Here’s the Doctor, or Porbury.” In a moment a counterpane was flung over the tempting array of tarts and so forth, spread out on one of the beds. Saunders hastily sat down on the dish containing the potatoes, thereby mashing them for us very well, as Jack afterwards remarked. The roast duck was not so easily disposed of, but Jack’s presence of mind did not forsake him. He hastily squeezed it into the pocket of his greatcoat, which he had just put on, as there was no fire in the bedroom. Scarcely was all this done, than the door opened, and in walked Mr. Porbury, the only one of the assistant masters who had remained for the Christmas holidays.
How lucky it wasn’t the Doctor! we thought Porbury was a heavy, slow fellow, with spectacles, whom we boys rather looked down upon, I am sorry to say, because it was so easy to “humbug him.”
“What are you doing here?” asked Mr. Porbury.
“Nothing, sir,” said Saunders, who was in agony lest he should have to rise and reveal the potatoes.
This seemed to satisfy Mr. Porbury, and he was going out again, when he suddenly stopped, and began to snuff about him suspiciously.
“H’m. Dear me! Isn’t there a very curious smell in this room, boys?”
“Smell, sir?” said Jack, innocently, though all the while guiltily conscious of the roast duck in his pocket.
“Yes; a smell of burning, I think. Surely there is something on fire. Dear me, I hope not.”
“Perhaps it is in some of the other rooms, sir,” suggested Jack, hoping that he would go to look, and thus give us an opportunity of getting rid of the unlucky duck.
“Perhaps it is,” said Mr. Porbury. “Will you come round with me to the other rooms, and we will see.”
There was nothing for it but to obey, and with a comical look at us Jack followed him out of the room. His presence of mind quite forsook him here. He should have taken off his great coat, and left it behind. But he did not think of that, and so, as Mr. Porbury was making his tour of inspection, he, curiously enough, noticed the same smell in every room they entered.
You may be sure we waited in great anxiety for Jack’s return. In a few minutes he rushed back into the room, choking with laughter, and, flinging himself on his bed, began to relieve his feelings by kicking up his heels, and writhing about convulsively. “Oh, dear! oh, dear! What a joke! I never saw anything like it. Oh! I say, you fellows, hold me together, or I’ll split with laughing. Oh, dear!”
“What’s the matter? Did he twig the duck?” we inquired, anxiously.
“Not a bit of him,” shouted Jack, drawing it forth from his pocket in triumph. “Every room we went into he snuffed about, and said, ‘very curious; there’s the same smell here.’ At length he thought it must be coming from the kitchen—oh, dear! I shall never get over it;” and Jack rolled about, and screamed, till the tears ran down his cheeks, and he could laugh no longer. Only, for the next half hour or so, he was always threatening to burst out into another explosion, and exclaiming, “Well, I can’t help it. To think how neatly Porbury was taken in. What a splendid joke!”
Not having such a keen sense of the ludicrous as Jack, our mirth was not so boisterous, but we were greatly relieved to find that our duck was safe. It was thought prudent, however, to put off the feast for a little, in case we should again be interrupted. But at the end of half-an-hour our impatience overcame our prudence.
“The Doctor has a dinner-party to-day, so he’s safe not to come near us,” said Jack. “And Porbury’s sure to be at it. He wasn’t at our dinner, you know.”
So we set to work at once upon the duck, which Jack divided by tearing off the legs and wings, and giving one to each of us. The body he kept to himself, and I think he had the best of the bargain. But Jack, as I said before, was one of those fellows who manage to get the best of everything for themselves. I remember we thought him very generous when he cut off a piece of the breast with his pocket knife, and gave it to Howard, to whose lot had fallen the wing that had been burned in the process of cooking.
The duck was pronounced excellent; the only fault was that there seemed to be so little on it after all; and when it and the potatoes were finished, and the bones licked clean, we turned our attention to the less substantial portion of the entertainment. Didn’t we make short work of the apple tarts and Saunders’ cake, washing them down with lemonade, made out of two lemons and some sugar, which we had coaxed out of the housekeeper! All the while we were talking and laughing, as well as eating as fast as we could, and agreeing that it was the jolliest Christmas dinner we had ever had.
The fun, indeed, began to grow fast and furious. At a very early stage of the proceedings Jack had volunteered a song, and now, inspired by the potent liquor I have just mentioned, he had mounted on a chair, and was bellowing, at the pitch of his voice, a song which some youthful genius had composed, as a sort of national anthem for the school. I only remember the first verse, which was—
“In Upton House’s wintry clime, We now must work at our books for a time, Or, if we don’t, we’ll catch toko, Which is what Mr. Patrick did upon the musical instrument bestow,
So early in the morning, So early in the morning, So early in the morning, Before the break of day.”
The remarkable feature of this melody was, that every verse was sung to a different air, and with a different chorus, in which we all joined lustily, and made such a din, that this time we never heard footsteps creaking along the passage, as we might have done if we had been less noisy.
But in the middle of the song the door of the room was flung open, and in stalked—the Doctor.
He cast one sharp glance at the bed, on which was spread out our feast, and another at us. We looked at one another, and then, though we were in a great fright, couldn’t help smiling, the whole thing was so ludicrous. Jack, standing on a chair, with his back turned to the door, flourishing the backbone of the duck in one hand, and a halfeaten tart in the other, had just begun a new verse—
“Old Lickemwell, he is a—”
But here, suddenly perceiving from our silence that something had gone wrong, Jack turned round, and, when he saw the Doctor, stopped short, and got down from the chair, looking foolish enough. We were all looking foolish, I dare say, but we couldn’t help laughing, and the Doctor looked as if he, too, was inclined to smile, though he was trying to look stern.
“Well,” he said at length, and then there was a portentous silence. When Dr. Lickemwell said “well,” in a peculiarly dry, meaning way which he had, we generally understood that matters were going to turn out anything but well for us. “This is how Mr. Porbury felt a smell of burning. Ah!”
Then the Doctor looked at us again, and we felt particularly uncomfortable.
“I suppose you are the ringleader in this, Somers?”
“Yes, sir,” said Jack, modestly.
“Come with me,” said the Doctor, motioning to Jack to follow him out of the room.
Jack obeyed, trying to wink at us as he went, to show that he didn’t care for what was going to happen. But it was rather an unhappy wink.
The rest of us waited in great suspense for about ten minutes, wondering what would be done to Jack, and if we ourselves would escape punishment. A sudden damper had been cast on our mirth. We all knew the Doctor’s cane too well to feel happy while we were expecting to have an interview with it
At length the Doctor came back, and made us a speech:—
“I am very sorry to find, boys, that you have been resorting to deception of this kind. If you had known something which I wished to be a surprise for you, I don’t think you would have cared to take all this trouble on the sly. Come here with me, all of you.”
We followed him, looking at each other in surprise, and quite unable to make out what he meant. Was he angry with us? Was he going to punish us? Was he taking us to his study, which was to Upton House what the torture-chamber was to the Tower of London! No; he led the way past the study door, and over the hall, and into his private dining-room, at the door of which we all hung back, like a brood of chickens, reluctant to follow into the pond the duck that has hatched them.
“Come along,” said the Doctor, encouraging us; and, taking courage to venture inside, we saw the table spread out for dinner, and the sideboard loaded with apples, oranges, and nuts.
“We are just going to dine,” said the Doctor, in the same grave voice, but with a merry twinkle in his eye. “Mrs. Lickemwell and I had intended to ask you to take your Christmas dinner with us—it is a pity we did not issue our invitation sooner. However, if you think you could eat a little bit, although you have dined, perhaps you will sit down and join us. You see Somers has kindly consented to favour us with his company.”
We looked at the Doctor, and at the table, and at each other, in perfect amazement. Was the Doctor speaking seriously? We felt quite uncomfortable. But there was that cool fish, Jack Somers,
sitting at the head of the table, beside Mrs. Lickemwell, making himself agreeable, and grinning at us like a porpoise. Seeing our perplexity, the Doctor burst into a laugh, and cried out—
“Poor fellows! Did you really think we weren’t going to give you a Christmas dinner? We meant it to be a surprise, but perhaps I should have told you, and then we shouldn’t have had you wasting your money on bad pastry, and bothering Mr. Porbury with your culinary operations. Well, we’ll say no more about it, but sit down and see if you can’t find room for another dinner.”
Then the Doctor laughed louder than before, and Mrs. Lickemwell laughed, and Jack laughed, and we all laughed, and finally we sat down, and Sally Primus, and Sally Secundus, appeared with a splendid turkey, and a roast joint of beef, at the sight of which we discovered that the duck and the apple tarts had been mere trifles that had only whetted our appetites.
In short, we had a splendid dinner, and glorious fun afterwards. The young Lickemwells were all there in their best bibs and tuckers, and some other boys and girls came in to tea, and we had a snapdragon, and a Christmas tree, and charades, and no end of games. And, when we had said good night, and gone back to the schoolroom to gather up the remnants of our own despised feast, which were now preserved for another time, we agreed that the Doctor was a much jollier fellow than we had ever before thought him, and that we were great fools for having wasted our money. And that is the story of our Christmas dinner, the only one, I am glad to say, I ever ate at school, for Ned got all right again very soon, and, as he came to school himself next half, took good care not to catch any more scarlet fevers about Christmas time.
A WILD YULE E’EN.
By C .
There are mad northern breezes howling over the heather, and there are savage blinding showers of snow, which fall in stinging bits and cover up the little dells, leaving only those same wind-waked heathtops uncovered. There are loud-voiced tempestuous waves and anger-tossed foam, which lift themselves wildly up, as if in their insolent pride they would mingle with the low-lying clouds. There are grey gaunt cliffs frowning over the black water, and there are bare dreary-looking hills, with here and there a solitary cottage, standing unsheltered by tree or wall. It is not a pleasant scene, although, for some folks, it may have a weird beauty of its own. This snow is not like the gentle feathery flakes which robe your naked Christmas boughs in a robe of heavenly white. These gales are not the softtoned breezes which bear to your expectant ears the sound of Christmas bells. These champing surges are not the light-footed friends who come to greet you with a smile and a word of seasonable cheer. Ah, no! but surely those fierce combating elements are fit attendants on the Yule of our sea-king sires.
“Mother, this is Yule e’en,” said little Tronda Henderson, looking wistfully up in her mother’s face.
“Well, what if it is, bairn? we can have no Yule fun, you know,” and Doya cast a glance at her husband, who was sitting by the uncurtained window. It was a look which said much: it was a look of reproach, of enquiry, of fear, of love; and the children, who sat beside Doya, crept nearer to her chair and kept silence when they saw that look. But Bartle did not notice either the woman or children. He was a sullen, discontented man, who evaded, as lazy ne’er-dowells will always do, the poor man’s honest lot—a life of labour. He was the scion of a good old house, which had fallen into poverty and
decay
Being too idle and too proud to work for a living, Bartle had left Shetland in his early manhood and had betaken himself to the wild unfettered life of an Australian digger. Years went past, and he came back in his prime and married an orphan cousin, to whom he had been engaged since his youth. He came back a reserved and selfish man, with a shadow on his brow and a strange mystery about even his everyday life. Bartle took up his abode in the half-ruined home of his boyhood, and became a subject of curiosity and conjecture to the whole island. His wife was a lady born, yet it was known that she did all the work of the house, keeping no servant; and the public also discovered that she “knitted and ’broidered and sewed” for a livelihood, just as any poor man’s spouse might do. They did not mingle with their neighbours, but rather shunned the society of high and low. Bartle had no live stock or banked money; he did no work, either mental or physical, and although he always wore the dress of a sailor, he never soiled his fingers with a fishingline or other marine implements. He always had plenty of silver, nay, even gold, in hand for his own personal wants, yet Doya’s deft fingers provided for herself and the three children. Once Bartle had offered half-a-crown to his wife, when he chanced to overhear the little ones cry for breakfast, but she gave it back with such a gesture of horror and disgust as deterred him from ever repeating the act. And so they jogged on for many years, living in the same house utterly independent of one another, each going their own way—the mother keeping Rassmie, Hermann, and Tronda by her, and the father shrouded in the same mystery which had hitherto encompassed him.
On this same dark Yule even, Bartle looked out of window, moodily unconcerned for those within. He looked on a dismal scene. Between the cottage and the sea there stretched a piece of rough stony ground, which hardly allowed a weed to find refuge on it. This meagre morsel of mother earth terminated in a reef of dangerous crags, which were quite covered at high water, but, when the tide was out, extended high and dry between the island and a large grass-crowned skerry, which lay a short distance from the mainland. You could not picture to yourself a more barbarous coast.
The grey of night had come down, and only the outlines of the landscape, with here and there a foam-wreath curling about the rocks, could be descried by the looker out. Evidently such an imperfect view was not to Bartle’s liking, for very soon he got up, donned his seaman’s hat of waterproof, and without a word left the house. It was not pleasant out in that shivering cold, and the sullen man was not a good companion, but he had scarcely quitted the cottage ere he was followed by his sons. They were fine manly boys of twelve and fourteen, on whose honest faces lurked no resemblance to the hard features of their father It seemed that they followed Bartle with reluctance, but certainly with a purpose, and he was not long in observing them. Turning round, he addressed the boys savagely, with a “What do you want? where are you bound for, you young rascals?”
They hesitated some time, and then Rassmie, as the oldest, replied, “Mother told us to go after you in case you might want help or a messenger, for she guessed you were going to look after the ship we saw locking the land this afternoon.”
These were simple enough words, but they roused Bartle’s passion in an instant, and, catching Rassmie by the collar, he would have flung the poor boy to the ground, had not Hermann thrown himself on his father’s arm, and so prevented the blow from falling On his beloved brother. “You young scoundrels,” shouted Bartle, shaking them from him; “what do you mean by dogging me like this, as if I were a madman who required a keeper, or—”
“A sinner who needs a Saviour,” said the meek voice of Doya, who had come to the spot. “Don’t be angry with me, Bartle; don’t hurt the poor boys, they are too young and innocent to dream of what I know is true, or to suspect the real motive of your going from home at this late and stormy hour Oh, Bartle! it is years since I spoke to you thus —listen to me. Let me lead you home again, or let us rouse the neighbours, that your already red hand may be held from further crime.”
I may not repeat to you all the profane abuse with which Bartle Henderson replied to the timid entreaties of his wife, while the boys
stood by, too terrified to move or speak. When he had exhausted his powers of swearing (and they were not by any means limited), and had ordered his wife and children to return to the house, Bartle took his way along the rough beach with a rapid stride and a lowering look on his face that it was not good to see. Doya gazed after the figure of her husband until it was lost in the obscurity of nightfall. Her face was very pale, and sad, and spiritless. She scarcely knew what instinct had told her to follow Bartle and speak words which she had never ventured to address to him since the early days of their married life, when first she came to know the dark mystery of his means of livelihood.
The courage which had prompted her appeal had died out before his fierce outburst of anger, and after telling the boys not to go near their father again, the poor woman returned to her lonely dwelling. Ah! not all lonely, for little deformed Tronda was waiting there for her mother’s return. The tiny lassie had raked the fire together and swept the hearth, as well as her feeble hands could, and the bright face which she lifted to Doya’s shed light, warm as sunshine, on the leaden heart of her parent. “Mother, mother, how came you to be so forgetful as to leave me here alone on Yule e’en, and after day set?” A sweet ringing laugh followed Tronda’s words, and Doya caught its infection and smiled upon the bonnie-featured, crooked-backed child, whose infirmities had not prevented her from being (as the “one ewe lamb” always is) the most useful and most beloved member of the family.
“Ah, bairn! I was indeed forgetful, but I have been so short a time away, that I cannot think the fairies have had leisure left them in which to do mischief to you.”
“Don’t be too sure, mother; I did hear a noise of something hopping about by the churn, and may be you won’t get any butter tomorrow; and are you quite sure I am just the same as when you left me? You know this,” touching her own twisted side, “came of my being left on Yule e’en by myself.” Tronda spoke jestingly, of course, but her light words carried a sad pang to the mother’s heart.
Folding her arms about the little thin figure, Doya said, whisperingly, “If the fairies took my child that night, or if they brought this life-trouble to her, I dare not repine, for who could be to us what loving, patient, unselfish, sickly Tronda is?”
Tronda knew that there were serious thoughts expressed in those words of pleasantry, so she let the Yule joke pass by, and nestling closer to the loving bosom above her, the child asked: “Tell me how it really happened, dear mother; I want so much to know, for although it’s all nonsense about the fairies or trows hurting me, still—I should —like to—know.”
“How old is my little girl?” Doya answered. “Let me see, thirteen past in September, and not so large as most bairns are at ten; but more than thirteen, aye, more than twenty, in mind and feeling. I have never spoken of my sorrows to any one, but I think my daughter can be my sympathizing friend, so she shall hear it all. It was just ten years ago, on that awful stormy Yule even, of which you have heard folks talk. I was happy then, for your father was kind, my little ones were healthy and beautiful, and I had never looked upon sin in its darker aspects. My little Tronda shall know all the story On that wild Yule even I had put you and Rassmie to bed, and was hushing Hermann on my knee, when I was startled by hearing a succession of shrieks, which seemed borne to my ear on the wings of an exultant storm fiend. With the baby in my arms, I ran to the door and looked out into the mirkness—just such a night as this,” and Doya shivered, even by the glowing fire; “a tempest of wind, bright gleaming moonlight, and flying clouds. Again and again that dreadful cry arose, and, forgetful of everything, I flew down the slope and stood upon the beach. It was covered with bits of wreck—tables, chairs, trunks, hammocks. Near these, up to his waist in the roaring sea, I found your father. Above us, on the height, gleamed a gigantic fire of peat, and among the surf, close beside me, floated unresistingly the blood-stained form of a sailor—”
“Oh! mother, don’t tell me more of that. I know, I know; it is all plain now!”
“Yes,” Doya said, in a dreamy apathetic tone; “it’s all plain; you know now what I knew then. Hours afterwards I returned to the house, with Hermann still innocently sleeping on my bosom, and I discovered that in my absence you had waked up, and finding yourself alone, had tried to get out of bed, and in so doing had fallen against something on the floor, where I found you lying helpless and almost unconscious. It was not trows—no, Tronda; on that Yule e’en it was not trows that came to injure you—it was a fiend—your own flesh and blood!”
The poor feeble girl shrank away in meek terror from the sudden fierceness of Doya’s words and gesture. She had never seen her gentle, patient mother in that mood before, but it passed away, and a long painful silence fell upon them both.
Loudly and hoarsely roared the winter gales around the cottage. Sometimes their stormy voices rose defiantly above the boom of the breaking wave. Sometimes they clamoured fiercely against the chafing surge, whose anger they had awakened. Oftentimes they moaned and mourned among the heather, or hurled the “drifting veil” of snow before their impatient pinions deep into some dimpled valley; and you might well have deemed that evil spirits were wandering unfettered over the world, for the sweet Christmas heralds could not have bent their bright brows to earth in such a fearful hour. But still, musing and silent, sat Doya Henderson and her deformed child; and the minutes passed into hours, and both were so engrossed with dismal thoughts and forebodings that they never seemed to miss the presence of Rassmie and Hermann. But the same dark demon to whom power had been given over land and sea and human heart—that same “foul fiend” was reigning to-night as then; and again was brought to Doya’s ear the wail of bitterest mortal agony. You might almost have thought that she expected it, for when that awful cry rang out on the night air, Doya did not start or look surprised, her face just paled, and she dropped on her knees beside Tronda, whose trembling figure had sought that attitude which instinct teaches us to adopt when we turn to God in our hours of helplessness and woe.
“Pray, mother; pray!” cried the girl. “Pray for father; oh! let it be for him more than all.”
Earnest, though broken, were the supplications which rose from those grieving hearts; but their “woman’s heavenly part” was interrupted by the hasty entrance of Rassmie and Hermann, who rushed to their mother, with white and horror-stricken faces.
“We saw it all; oh, mother, we saw it!” they panted forth. “The peat stack had been lighted, and the ship had come on the rocks, lured by the false signals. She went down at once, and then—then we saw father among the crags. Some one floated on shore; and oh, how could he? he—father! struck at the swimming man with his knife, and there was a great cry, and blood among the white surf. Mother, mother! what shall we do? Father saw us beside him there; his face was awful, and oh, there may come others, for he was waiting, when we fled to you!”
Tronda had stood up when her brothers came, and as soon as their hurried tale was told, she spoke calmly and with resolution: “We must all go to father. It is not for us to give him to the hand of justice, but we dare not stand still and see murder committed. Come, mother; come, boys; father must be guided by us now,” and the small decrepit figure and pinched puny face looked noble and beautiful when the spirit spoke so boldly and undauntedly.
In obedience to a mind stronger than their own, the others followed Tronda from the house—from the house, down the slope, over the stony beach, under the moonlight, against the gale, to the scene of the shipwreck. There they found no living thing. There were broken spars and floating débris of various kinds, and there was a helpless human corpse, but that was all. In vain did Rassmie and Hermann search among the crags, in the hope of finding their father concealed there. In vain did Doya call upon his name; and at last they were obliged to believe that fear had compelled Bartle to fly. He had felt that he was safe from discovery while only Doya knew of his crimes, but he could not be so certain of the boys, whose eyes had actually been on him while he committed murder.
They all lingered on the beach for some time, but no one came from either land or sea, and at last the storm compelled them to seek the shelter of their home. You may believe it was a sad, sad night in that lone dwelling, and although the gale calmed down, and the snow lay still and fair when the daylight gleamed upon it, there was no hushing the inward storm. A very dark picture of sin had been presented to young pure spirits, and it was little wonder that their innocent hearts quivered and bled before the remembrance of that dreadful scene.
Morning—Yule morning—with its merry breakfast by candlelight, frothing bowl of “whipcull,” and sweetest of short-cakes for the rich; its “burstin” and rarely-tasted bacon, with jolly drams of whiskey, for the cottagers; and its fun and mystic spells, and football and evening dance, and olden tale and Norland song for both high and low. Morning—Yule morning—brought the discovery to all in the neighbourhood of the disastrous shipwreck on the island. Doya and her children sat in the house and saw the gathering crowd hurry to and fro upon the beach. They saw when the poor sailor’s body was found wounded, as the simple islanders supposed, by their own cruel crags; and all the day long the wife and family of the wrecker watched and waited, but no one came to them. The corpse was conveyed to an uninhabited dwelling close by, and decently buried next day; and Doya fell mechanically into all her accustomed duties. Curious people wondered what had become of Bartle, and somehow a story got about that he had deserted his wife, because she had taunted him with having taken her from a life of ease to one of hard and humble work. Those who believed such a tale had surely observed little of Doya’s meek contented acceptance of her lowlier lot; but she was quite willing that the inquisitive neighbours should accept that solution of Bartle’s conduct. That he had fled from his home and family she knew was true, but the reason, ah! how different from what was supposed.
The events of that most eventful Yule e’en had worked a great change in Rassmie and Hermann. They were sharp enough lads, and had made a pretty shrewd guess that their father gained his livelihood by rescuing from the deep its unlawful prey, but that he
