Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

chapter 1. Introduction

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. Pharmacokineticsdescribes the effects of the body on drugs, eg, absorption, excretion, etc. Pharmacodynamics denotes the actions of the drug on the body, such as mechanism of action and therapeutic and toxic effects. This chapter introduces the basic principles of pharmacokinetics and pharmacodynamics that will be applied in subsequent chapters.

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, but many are partially or completely synthetic. 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 their biologic receptor sites. Furthermore, such enantiomers may be metabolized at different rates in the body, with important clinical consequences.

Size and Molecular Weight

Drugs vary in size from molecular weight (MW) 7 (lithium) to over MW 50,000 (thrombolytic enzymes, other proteins). Most drugs, however, have molecular weights 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.

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 electrostatic bonds (eg, between a cation and an anion), and much weaker interactions (eg, hydrogen, van der Waals, and hydrophobic bonds).

High-Yield Terms to Learn

Drugs Substances that act on biologic systems at the chemical (molecular) level and alter their functions

Drug receptors 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 The phase of drug inactivation or removal from the body by metabolism or excretion

Endocytosis, exocytosis 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 released. Exocytosis: Expulsion of material from vesicles in the cell into the extracellular space

Permeation Movement of a molecule (eg, drug) through the biologic medium

Pharmacodynamics The actions of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic actions

Pharmacokinetics 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. Biodispositionis a term sometimes used to describe the processes of metabolism and excretion

Transporter 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

Pharmacodynamic Principles

Receptors and Receptor Sites

Drug actions are mediated through the effects of drug 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, neurotransmitter receptors, neurotransmitter reuptake transporters, and ion transporters).

If drug-receptor binding results in activation of the receptor, the drug is termed an agonist; if inhibition results, the drug is considered an antagonist. As suggested in Figure 1-1, a receptor molecule may have several binding sites. Quantitation of the effects of drug-receptor binding as a function of dose 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 that dissolve blood clots). These drugs do not act on endogenous receptors but on endogenous substrate molecules, such as plasminogen.

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, 11th ed. McGraw-Hill, 2009: Fig. 1-3.)

Inert Binding Sites

Because most drug molecules are much smaller than their receptor molecules (discussed in the text that follows), specific regions of receptor molecules often can be identified that provide the local areas for drug binding. Such areas are termed receptor sites. In addition, drugs bind to other, 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 (1-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).

Permeation

Permeation is the movement of drug molecules into and within the biologic environment. It involves several processes, the most important of which are discussed next.

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.

Lipid Diffusion

Lipid diffusion is the passive movement of molecules through membranes and other lipid structures. Like aqueous diffusion, this process is governed by Fick's law (see later discussion).

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 transporters 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 is capacity-limited. 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 anticancer drugs.

Selective inhibitors for these carriers may 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. After release, such amine neurotransmitters (dopamine, norepinephrine, and serotonin) and some other transmitters are recycled into nerve endings by transport molecules. Probenecid, which inhibits transport of uric acid, penicillin, and other weak acids in the nephron, is used to increase the excretion of uric acid in gout. The family of P-glycoprotein transport molecules, previously identified in malignant cells as one cause of cancer drug resistance, has been identified in the epithelium of the gastrointestinal tract and in the blood-brain barrier.

Endocytosis, Pinocytosis

Endocytosis occurs through binding of the transported 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 membrane-encapsulated material from cells.

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:

This relationship quantifies the observation that drug absorption is faster from 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).

Water and Lipid Solubility of Drugs

Aqueous Diffusion

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.

Lipid Diffusion

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.

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:

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 may be accelerated by alkalinizing the urine, for example, by giving bicarbonate. 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) may be accelerated by acidifying the urine, for example, by administering ammonium chloride (Figure 1-2).

FIGURE 1-2

The Henderson-Hasselbalch principle applied to drug excretion in the urine. Because the nonionized 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 mol of the protonated species will be present for each 1.0 mol of the unprotonated form. The total concentration in the blood will thus be 1.4 mol/L if the concentration of the unprotonated form is 1.0 mol/L. In the urine at pH 6.0, 10 mol of the nondiffusible ionized form will be present for each 1.0 mol of the unprotonated, diffusible, form. Therefore, the total urine concentration (11 mol/L) may be almost 8 times higher than the blood concentration.

Absorption of Drugs

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. 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 include the following:

Oral (Swallowed)

The oral route offers maximum convenience, but absorption may be slower and less complete than when parenteral routes are used. Ingested drugs are 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. Thus, some drugs have low bioavailability when given orally.

Intravenous

The intravenous route offers instantaneous and complete absorption (by definition, bioavailability is 100%). This route is potentially more dangerous, however, because of the high blood levels reached when the dose is large or administration is too rapid.

Intramuscular

Absorption from an intramuscular injection site is often faster and more complete (higher bioavailability) than with oral administration. Large volumes (eg, >5 mL into each buttock) may be given if the drug is not too irritating. First-pass metabolism is avoided, but anticoagulants such as heparin cannot be given by this route because they may cause bleeding (hematomas) in the muscle.

Subcutaneous

The subcutaneous route offers slower absorption than the intramuscular route. Large-volume bolus doses are less feasible, but heparin does not cause hematomas when administered by this route. First-pass metabolism is avoided.

Buccal and Sublingual

The sublingual route (under the tongue) permits direct absorption into the systemic venous circulation, bypassing the hepatic portal circuit and first-pass metabolism. This process may be fast or slow, depending on the physical formulation of the product. The buccal route (in the pouch between the gums and cheek) offers the same features as the sublingual route.

Rectal (Suppository)

The rectal route offers partial avoidance of the first-pass effect. First-pass avoidance is not as complete as with the sublingual route because suppositories tend to migrate upward in the rectum and absorption from this higher location is partially into the portal circulation. Larger amounts of drug and drugs with unpleasant tastes are better administered rectally than by the buccal or sublingual routes. Rectal administration is often used in patients who are vomiting. Some drugs administered rectally may cause significant irritation.

Inhalation

In the case of respiratory diseases, the inhalation route offers delivery closest to the target tissue. This route often results in rapid absorption because of the large and thin alveolar surface area. Inhalation is particularly convenient for drugs that are gases at room temperature (eg, nitrous oxide, nitric oxide) or easily volatilized (many general anesthetics).

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. The rate of absorption varies with the area of application and the drug's formulation but is usually slower than any of the routes listed previously.

Transdermal

The transdermal route involves 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.

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 drug depot-to-blood concentration gradient and thus facilitates absorption.

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 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 for dermatologic conditions.

Distribution of Drugs

Determinants of Distribution

The distribution of drugs to the tissues depends on the following:

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 blood-tissue 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.

Blood Flow

Blood flow to the tissue is an important determinant of the rate of uptake, 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 organs) usually achieve high tissue concentrations sooner than poorly perfused tissues (eg, fat, bone). If the drug is rapidly eliminated, the concentration in poorly perfused tissues may never rise significantly.

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 (including the brain) have a high lipid content and thus dissolve a high concentration of lipid-soluble agents. As a result, a very lipid-soluble anesthetic will transfer out of the blood and into the brain tissue more rapidly and to a greater extent than a drug with low lipid solubility.

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 to extravascular tissue proteins, which results in a marked reduction in the plasma concentration of chloroquine.

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 1-1). 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.

TABLE 1-1 Average values for some physical volumes within the adult human body.

Metabolism of Drugs

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 previously as one cause of low bioavailability. Drug metabolism occurs primarily in the liver and is discussed in greater detail in Chapter 4.

Drug Metabolism as a Mechanism of 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 a metabolite is a form of elimination.

Drug Metabolism as a Mechanism of Drug Activation

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, some benzodiazepines).

Drug Elimination Without Metabolism

Some drugs (eg, lithium, many others) are not modified by the body; they continue to act until they are excreted.

Elimination of Drugs

Along with the dosage, the rate of elimination following the last dose (disappearance of the active molecules from the bloodstream or body) determines the duration of action for most drugs. Therefore, knowledge of the time course of concentration in plasma is important 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 metabolites, excretion is primarily by way of the kidney. 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 adrenoceptors, is eliminated from the bloodstream in less than 1 h after administration. The drug's action, however, lasts for 48 h.

First-Order Elimination

The term first-order elimination implies 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.

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.

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. 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

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 "2-compartment model" as shown in Figure 1-4. The 2 compartments consist of the blood and the extravascular tissues. (Note that each phase is associated with a characteristic half-life: t 1/2 for the first phase, t 1/2 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.)

FIGURE 1-4

Serum concentration-time curve after administration of chlordiazepoxide as an intravenous bolus. The experimental data are plotted on a semilogarithmic scale as filled circles. 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 (t 1/2) 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.)

(Modified and reproduced, with permission, from Greenblatt DJ, Koch-Weser J: Drug therapy: Clinical pharmacokinetics. N Engl J Med 1975;293:702. Copyright © 1975 Massachusetts Medical Society. All rights reserved.)

Other Distribution Models

A few drugs behave as if they are 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.

Checklist

When you complete this chapter, you should be able to:

 Define and describe the terms receptor and receptor site.

 Distinguish between a competitive inhibitor and an allosteric inhibitor.

 Predict the relative ease of permeation of a weak acid or base from a knowledge of its pKa, 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.

Chapter 1 Summary Table


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