Case Study

A 26-year-old man is brought by friends to the emergency department of the city hospital because he has been behaving strangely for several days. A known user of methamphetamine, he has not eaten or slept in 48 hours. He threatened to shoot one of his friends because he believes his friend is plotting against him. On admission, the man is extremely agitated, appears to be underweight, and is unable to give a coherent history. He has to be restrained to prevent him from walking out of the emergency department and into traffic on the street. His blood pressure is 160/100 mm Hg, heart rate 100, temperature 39°C, and respirations 30/min. His arms show evidence of numerous intravenous injections. The remainder of his physical examination is unremarkable. After evaluation, the man is given a sedative, fluids, a diuretic, and ammonium chloride parenterally. What is the purpose of the ammonium chloride?

Introduction to Pharmacology: Introduction

Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. These substances may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient. Such deliberate therapeutic applications may be considered the proper role of medical pharmacology, which is often defined as the science of substances used to prevent, diagnose, and treat disease. Toxicology is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems (Figure 1–1).

The History of Pharmacology

Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal materials. Early written records from China and Egypt and the traditions of India list remedies of many types, including a few that are still recognized as useful drugs today. Most, however, were worthless or actually harmful. In the 1500 years or so preceding the present, there were sporadic attempts to introduce rational methods into medicine, but none was successful owing to the dominance of systems of thought that purported to explain all of biology and disease without the need for experimentation and observation. These schools promulgated bizarre notions such as the idea that disease was caused by excesses of bile or blood in the body, that wounds could be healed by applying a salve to the weapon that caused the wound, and so on.

Around the end of the 17th century, and following the example of the physical sciences, reliance on observation and experimentation began to replace theorizing in medicine. As the value of these methods in the study of disease became clear, physicians in Great Britain and on the Continent began to apply them to the effects of traditional drugs used in their own practices. Thus, materia medica—the science of drug preparation and the medical use of drugs—began to develop as the precursor to pharmacology. However, any real understanding of the mechanisms of action of drugs was prevented by the absence of methods for purifying active agents from the crude materials that were available and—even more—by the lack of methods for testing hypotheses about the nature of drug actions.

In the late 18th and early 19th centuries, François Magendie, and later his student Claude Bernard, began to develop the methods of experimental physiology and pharmacology. Advances in chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid the foundation needed for understanding how drugs work at the organ and tissue levels. Paradoxically, real advances in basic pharmacology during this time were accompanied by an outburst of unscientific claims by manufacturers and marketers of worthless "patent medicines." Not until the concepts of rational therapeutics, especially that of the controlled clinical trial, were reintroduced into medicine—only about 60 years ago—did it become possible to accurately evaluate therapeutic claims.

Around the same time, a major expansion of research efforts in all areas of biology began. As new concepts and new techniques were introduced, information accumulated about drug action and the biologic substrate of that action, the drug receptor. During the last half-century, many fundamentally new drug groups and new members of old groups were introduced. The last three decades have seen an even more rapid growth of information and understanding of the molecular basis for drug action. The molecular mechanisms of action of many drugs have now been identified, and numerous receptors have been isolated, structurally characterized, and cloned. In fact, the use of receptor identification methods (described in Chapter 2) has led to the discovery of many orphan receptors—receptors for which no ligand has been discovered and whose function can only be surmised. Studies of the local molecular environment of receptors have shown that receptors and effectors do not function in isolation; they are strongly influenced by companion regulatory proteins. Pharmacogenomics—the relation of the individual's genetic makeup to his or her response to specific drugs—is close to becoming a practical area of therapy (see Pharmacology & Genetics). Decoding of the genomes of many species—from bacteria to humans—has led to the recognition of unsuspected relationships between receptor families and the ways that receptor proteins have evolved. Much of this progress is summarized in this book.

The extension of scientific principles into everyday therapeutics is still going on, although the medication-consuming public is still exposed to vast amounts of inaccurate, incomplete, or unscientific information regarding the pharmacologic effects of chemicals. This has resulted in the irrational use of innumerable expensive, ineffective, and sometimes harmful remedies and the growth of a huge "alternative health care" industry. Unfortunately, manipulation of the legislative process in the United States has allowed many substances promoted for health—but not promoted specifically as "drugs"—to avoid meeting the Food and Drug Administration standards described in Chapter 5. Conversely, lack of understanding of basic scientific principles in biology and statistics and the absence of critical thinking about public health issues have led to rejection of medical science by a segment of the public and to a common tendency to assume that all adverse drug effects are the result of malpractice.

Two general principles that the student should remember are (1) that all substances can under certain circumstances be toxic, and the chemicals in botanicals (herbs and plant extracts) are no different from chemicals in manufactured drugs except for the proportion of impurities; and, (2) that all dietary supplements and all therapies promoted as health-enhancing should meet the same standards of efficacy and safety as conventional drugs and medical therapies. That is, there should be no artificial separation between scientific medicine and "alternative" or "complementary" medicine.

Pharmacology & the Pharmaceutical Industry

Much of the recent progress in the application of drugs to disease problems can be ascribed to the pharmaceutical industry and specifically to "big pharma," the multibillion-dollar corporations that specialize in drug discovery and development. These entities deserve great credit for making possible many of the therapeutic advances that we employ today. As described in Chapter 5, these companies are uniquely skilled in exploiting discoveries from academic and governmental laboratories and translating these basic findings into commercially successful therapeutic breakthroughs.

Such breakthroughs come at a price, however, and the escalating cost of drugs has become a significant contributor to the inflationary increase in the cost of health care. Development of new drugs is enormously expensive, and to survive and prosper, big pharma must pay the costs of drug development and marketing and return a profit to its shareholders. Today, considerable controversy surrounds drug pricing. Critics claim that the costs of development and marketing are grossly inflated by marketing procedures, which may consume as much as 25% or more of a company's budget in advertising and other promotional efforts. Furthermore, profit margins for big pharma have historically exceeded all other industries by a significant factor. Finally, pricing schedules for many drugs vary dramatically from country to country and even within countries, where large organizations can negotiate favorable prices and small ones cannot. Some countries have already addressed these inequities, and it seems likely that all countries will have to do so during the next few decades.

General Principles of Pharmacology

The Nature of Drugs

In the most general sense, a drug may be defined as any substance that brings about a change in biologic function through its chemical actions. In most cases, the drug molecule interacts as an agonist  (activator) or antagonist  (inhibitor) with a specific molecule in the biologic system that plays a regulatory role. This molecule is called a receptor . The nature of receptors is discussed more fully in Chapter 2. In a very small number of cases, drugs known as chemical antagonists  may interact directly with other drugs, whereas a few drugs (osmotic agents) interact almost exclusively with water molecules. Drugs may be synthesized within the body (eg, hormones ) or may be chemicals not synthesized in the body (ie, xenobiotics,  from the Greek xenos,  meaning "stranger"). Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus (1493–1541) famously stated that "the dose makes the poison," meaning that any substance can be harmful if taken in the wrong dosage. Toxins are usually defined as poisons of biologic origin, ie, synthesized by plants or animals, in contrast to inorganic poisons such as lead and arsenic.

To interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a location distant from its intended site of action, eg, a pill given orally to relieve a headache. Therefore, a useful drug must have the necessary properties to be transported from its site of administration to its site of action. Finally, a practical drug should be inactivated or excreted from the body at a reasonable rate so that its actions will be of appropriate duration.

The Physical Nature of Drugs

Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide). These factors often determine the best route of administration. The most common routes of administration are described in Chapter 3. The various classes of organic compounds—carbohydrates, proteins, lipids, and their constituents—are all represented in pharmacology.

A number of useful or dangerous drugs are inorganic elements, eg, lithium, iron, and heavy metals. Many organic drugs are weak acids or bases. This fact has important implications for the way they are handled by the body, because pH differences in the various compartments of the body may alter the degree of ionization of such drugs (see text that follows).

Drug Size

The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (eg, alteplase [tPA], a protein of MW 59,050). However, most drugs have molecular weights between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for specificity of action. To have a good "fit" to only one type of receptor, a drug molecule must be sufficiently unique in shape, charge, and other properties, to prevent its binding to other receptors. To achieve such selective binding, it appears that a molecule should in most cases be at least 100 MW units in size. The upper limit in molecular weight is determined primarily by the requirement that drugs must be able to move within the body (eg, from the site of administration to the site of action). Drugs much larger than MW 1000 do not diffuse readily between compartments of the body (see Permeation, in following text). Therefore, very large drugs (usually proteins) must often be administered directly into the compartment where they have their effect. In the case of alteplase, a clot-dissolving enzyme, the drug is administered directly into the vascular compartment by intravenous or intra-arterial infusion.

Drug Reactivity and Drug-Receptor Bonds

Drugs interact with receptors by means of chemical forces or bonds. These are of three major types: covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not reversible under biologic conditions. Thus, the covalent bond formed between the acetyl group of aspirin and cyclooxygenase, its enzyme target in platelets, is not readily broken. The platelet aggregation–blocking effect of aspirin lasts long after free acetylsalicylic acid has disappeared from the bloodstream (about 15 minutes) and is reversed only by the synthesis of new enzyme in new platelets, a process that takes several days. Other examples of highly reactive, covalent bond-forming drugs are the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the tumor.

Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena. Electrostatic bonds are weaker than covalent bonds.

Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor "pockets."

The specific nature of a particular drug-receptor bond is of less practical importance than the fact that drugs that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of very strong bonds. This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such a precise fit for a particular drug structure. Thus, if we wished to design a highly selective short-acting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose molecules that form weaker bonds.

A few substances that are almost completely inert in the chemical sense nevertheless have significant pharmacologic effects. For example, xenon, an "inert" gas, has anesthetic effects at elevated pressures.

Drug Shape

The shape of a drug molecule must be such as to permit binding to its receptor site via the bonds just described. Optimally, the drug's shape is complementary to that of the receptor site in the same way that a key is complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so common in biology that more than half of all useful drugs are chiral molecules; that is, they can exist as enantiomeric pairs. Drugs with two asymmetric centers have four diastereomers, eg, ephedrine, a sympathomimetic drug. In most cases, one of these enantiomers is much more potent than its mirror image enantiomer, reflecting a better fit to the receptor molecule. If one imagines the receptor site to be like a glove into which the drug molecule must fit to bring about its effect, it is clear why a "left-oriented" drug is more effective in binding to a left-hand receptor than its "right-oriented" enantiomer.

The more active enantiomer at one type of receptor site may not be more active at another receptor type, eg, a type that may be responsible for some other effect. For example, carvedilol, a drug that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Figure 1–2, Table 1–1). One of these enantiomers, the (S)(–) isomer, is a potent -receptor blocker. The (R)(+) isomer is 100-fold weaker at the receptor. However, the isomers are approximately equipotent as -receptor blockers. Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent anesthetic and is less toxic than the (–) enantiomer. Unfortunately, the drug is still used as the racemic mixture.

Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer may be quite different from that of the other. Similarly, drug transporters may be stereoselective.

Unfortunately, most studies of clinical efficacy and drug elimination in humans have been carried out with racemic mixtures of drugs rather than with the separate enantiomers. At present, only a small percentage of the chiral drugs used clinically are marketed as the active isomer—the rest are available only as racemic mixtures. As a result, many patients are receiving drug doses of which 50% or more is less active, inactive, or actively toxic. Some drugs are currently available in both the racemic and the pure, active isomer forms. Unfortunately, the hope that administration of the pure, active enantiomer would decrease adverse effects relative to those produced by racemic formulations has not been firmly supported. However, there is increasing interest at both the scientific and the regulatory levels in making more chiral drugs available as their active enantiomers.

Rational Drug Design

Rational design of drugs implies the ability to predict the appropriate molecular structure of a drug on the basis of information about its biologic receptor. Until recently, no receptor was known in sufficient detail to permit such drug design. Instead, drugs were developed through random testing of chemicals or modification of drugs already known to have some effect (see Chapter 5). However, the characterization of many receptors during the past three decades has changed this picture. A few drugs now in use were developed through molecular design based on a knowledge of the three-dimensional structure of the receptor site. Computer programs are now available that can iteratively optimize drug structures to fit known receptors. As more becomes known about receptor structure, rational drug design will become more common.

Receptor Nomenclature

The spectacular success of newer, more efficient ways to identify and characterize receptors (see Chapter 2) has resulted in a variety of differing systems for naming them. This in turn has led to a number of suggestions regarding more rational methods of naming receptors. The interested reader is referred for details to the efforts of the International Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature and Drug Classification (reported in various issues of Pharmacological Reviews) and to Alexander SPH, Mathie A, Peters JA: Guide to receptors and channels. Br J Pharmacol 2006;147(Suppl 3):S1–S180. The chapters in this book mainly use these sources for naming receptors.

Drug-Body Interactions

The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamic processes (Figure 1–1); the principles of pharmacodynamics are presented in greater detail in Chapter 2. These properties determine the group in which the drug is classified, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease. The actions of the body on the drug are called pharmacokinetic processes and are described in Chapters 3 and 4. Pharmacokinetic processes govern the absorption, distribution, and elimination of drugs and are of great practical importance in the choice and administration of a particular drug for a particular patient, eg, a patient with impaired renal function. The following paragraphs provide a brief introduction to pharmacodynamics and pharmacokinetics.

Pharmacodynamic Principles

Most drugs must bind to a receptor to bring about an effect. However, at the cellular level, drug binding is only the first in what is often a complex sequence of steps:

       Drug (D) + receptor-effector (R)drug-receptor-effector complexeffect

       D + Rdrug-receptor complexeffector moleculeeffect

       D + RD-R complexactivation of coupling molecule effector moleculeeffect

       Inhibition of metabolism of endogenous activatorincreased activatorincreased effect

Note that the final change in function is accomplished by an effector mechanism. The effector may be part of the receptor molecule or may be a separate molecule. A very large number of receptors communicate with their effectors through coupling molecules, as described in Chapter 2.

Types of Drug-Receptor Interactions

Agonist  drugs bind to and activate  the receptor in some fashion, which directly or indirectly brings about the effect (Figure 1–3A). Receptor activation involves a change in conformation in the cases that have been studied at the molecular structure level. Some receptors incorporate effector machinery in the same molecule, so that drug binding brings about the effect directly, eg, opening of an ion channel or activation of enzyme activity. Other receptors are linked through one or more intervening coupling molecules to a separate effector molecule. The five major types of drug-receptor-effector coupling systems are discussed in Chapter 2. Pharmacologic antagonist drugs, by binding to a receptor, compete with and prevent binding by other molecules. For example, acetylcholine receptor blockers such as atropine are antagonists because they prevent access of acetylcholine and similar agonist drugs to the acetylcholine receptor site and they stabilize the receptor in its inactive state (or some state other than the acetylcholine-activated state). These agents reduce the effects of acetylcholine and similar molecules in the body (Figure 1–3B) but their action can be overcome by increasing the dosage of agonist. Some antagonists bind very tightly to the receptor site in an irreversible or pseudoirreversible fashion and cannot be displaced by increasing the agonist concentration. Drugs that bind to the same receptor molecule but do not prevent binding of the agonist are said to act allosterically and may enhance (Figure 1–3C) or inhibit (Figure 1–3D) the action of the agonist molecule. Allosteric inhibition is not overcome by increasing the dose of agonist.

Agonists that Inhibit Their Binding Molecules

Some drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action of an endogenous agonist. For example, acetylcholinesterase inhibitors, by slowing the destruction of endogenous acetylcholine, cause cholinomimetic effects that closely resemble the actions of cholinoceptor agonist molecules even though cholinesterase inhibitors do not bind or only incidentally bind to cholinoceptors (see Chapter 7, Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs). Because they amplify the effects of physiologically released agonist ligands, their effects are sometimes more selective and less toxic than those of exogenous agonists.

Agonists, Partial Agonists, and Inverse Agonists

Figure 1–4 describes a useful model of drug-receptor interaction. As indicated, the receptor can exist in the inactive, nonfunctional form (R_i) and in the activated form (R_a). Thermodynamic considerations indicate that even in the absence of any agonist, some of the receptor pool must exist in the R_a form some of the time and may produce the same physiologic effect as agonist-induced activity. This effect, occurring in the absence of agonist, is termed constitutive activity. Agonists are those drugs that have a much higher affinity for the R_a configuration and stabilize it, so that a large percentage of the total pool resides in the R_a–D fraction and a large effect is produced. The recognition of constitutive activity may depend on the receptor density, the concentration of coupling molecules (if a coupled system), and the number of effectors in the system.

Many agonist drugs, when administered at concentrations sufficient to saturate the receptor pool, can activate their receptor-effector systems to the maximum extent of which the system is capable; that is, they cause a shift of almost all of the receptor pool to the R_a–D pool. Such drugs are termed full agonists. Other drugs, called partial agonists, bind to the same receptors and activate them in the same way but do not evoke as great a response, no matter how high the concentration. In the model in Figure 1–4, partial agonists do not stabilize the R_a configuration as fully as full agonists, so that a significant fraction of receptors exists in the R_i–D pool. Such drugs are said to have low intrinsic efficacy. Thus, pindolol, a -adrenoceptor partial agonist, may act either as an agonist (if no full agonist is present) or as an antagonist (if a full agonist such as epinephrine is present). (See Chapter 2.) Intrinsic efficacy is independent of affinity for the receptor.

In the same model, conventional antagonist action can be explained as fixing the fractions of drug-bound R_i and R_a in the same relative amounts as in the absence of any drug. In this situation, no change will be observed, so the drug will appear to be without effect. However, the presence of the antagonist at the receptor site will block access of agonists to the receptor and prevent the usual agonist effect. Such blocking action can be termed neutral antagonism.

What will happen if a drug has a much stronger affinity for the R_i than for the R_a state and stabilizes a large fraction in the R_i–D pool? Such a drug would reduce any constitutive activity, thus resulting in effects that are the opposite of the effects produced by conventional agonists at that receptor. These drugs have been termed inverse agonists (Figure 1–4). One of the best documented examples of such a system is the -aminobutyric acid (GABA_A) receptor-effector (a chloride channel) in the nervous system. This receptor is activated by the endogenous transmitter GABA and causes inhibition of postsynaptic cells. Conventional exogenous agonists such as benzodiazepines also facilitate the receptor-effector system and cause GABA-like inhibition with sedation as the therapeutic result. This inhibition can be blocked by conventional neutral antagonists such as flumazenil. In addition, inverse agonists have been found that cause anxiety and agitation, the inverse of sedation (see Chapter 22). Similar inverse agonists have been found for -adrenoceptors, histamine H₁ and H₂ receptors, and several other receptor systems.

Duration of Drug Action

Termination of drug action is a result of one of several processes. In some cases, the effect lasts only as long as the drug occupies the receptor, and dissociation of drug from the receptor automatically terminates the effect. In many cases, however, the action may persist after the drug has dissociated because, for example, some coupling molecule is still present in activated form. In the case of drugs that bind covalently to the receptor site, the effect may persist until the drug-receptor complex is destroyed and new receptors or enzymes are synthesized, as described previously for aspirin. In addition, many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when agonist molecules continue to be present for long periods. (See Chapter 2 for additional details.)

Receptors and Inert Binding Sites

To function as a receptor, an endogenous molecule must first be selective  in choosing ligands (drug molecules) to bind; and second, it must change its function  upon binding in such a way that the function of the biologic system (cell, tissue, etc) is altered. The selectivity characteristic is required to avoid constant activation of the receptor by promiscuous binding of many different ligands. The ability to change function is clearly necessary if the ligand is to cause a pharmacologic effect. The body contains a vast array of molecules that are capable of binding drugs, however, and not all of these endogenous molecules are regulatory molecules. Binding of a drug to a nonregulatory molecule such as plasma albumin will result in no detectable change in the function of the biologic system, so this endogenous molecule can be called an inert binding site. Such binding is not completely without significance, however, because it affects the distribution of drug within the body and determines the amount of free drug in the circulation. Both of these factors are of pharmacokinetic importance (see also Chapter 3).

Pharmacokinetic Principles

In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route. In many cases, the active drug molecule is sufficiently lipid-soluble and stable to be given as such. In some cases, however, an inactive precursor chemical that is readily absorbed and distributed must be administered and then converted to the active drug by biologic processes—inside the body. Such a precursor chemical is called a prodrug.

In only a few situations is it possible to apply a drug directly to its target tissue, eg, by topical application of an anti-inflammatory agent to inflamed skin or mucous membrane. Most often, a drug is administered into one body compartment, eg, the gut, and must move to its site of action in another compartment, eg, the brain in the case of an antiseizure medication. This requires that the drug be absorbed into the blood from its site of administration and distributed to its site of action, permeating through the various barriers that separate these compartments. For a drug given orally to produce an effect in the central nervous system, these barriers include the tissues that make up the wall of the intestine, the walls of the capillaries that perfuse the gut, and the blood-brain barrier, the walls of the capillaries that perfuse the brain. Finally, after bringing about its effect, a drug should be eliminated at a reasonable rate by metabolic inactivation, by excretion from the body, or by a combination of these processes.

Permeation

Drug permeation proceeds by several mechanisms. Passive diffusion in an aqueous or lipid medium is common, but active processes play a role in the movement of many drugs, especially those whose molecules are too large to diffuse readily (Figure 1–5).

Aqueous Diffusion

Aqueous diffusion occurs within the larger aqueous compartments of the body (interstitial space, cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as MW 20,000–30,000.^* See Figure 1–5A.

Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the permeating drug, a downhill movement described by Fick's law (see below). Drug molecules that are bound to large plasma proteins (eg, albumin) do not permeate most vascular aqueous pores. If the drug is charged, its flux is also influenced by electrical fields (eg, the membrane potential and—in parts of the nephron—the transtubular potential).

*The capillaries of the brain, the testes, and some other tissues are characterized by the absence of pores that permit aqueous diffusion. They may also contain high concentrations of drug export pumps (MDR pumps; see text). These tissues are therefore protected or "sanctuary" sites from many circulating drugs.

Lipid Diffusion

Lipid diffusion is the most important limiting factor for drug permeation because of the large number of lipid barriers that separate the compartments of the body. Because these lipid barriers separate aqueous compartments, the lipid:aqueous partition coefficient of a drug determines how readily the molecule moves between aqueous and lipid media. In the case of weak acids and weak bases (which gain or lose electrical charge-bearing protons, depending on the pH), the ability to move from aqueous to lipid or vice versa varies with the pH of the medium, because charged molecules attract water molecules. The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbalch equation (see in following text). See Figure 1–5B.

Special Carriers

Special carrier molecules exist for many substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, and glucose. These carriers bring about movement by active transport or facilitated diffusion and, unlike passive diffusion, are selective, saturable, and inhibitable. Because many drugs are or resemble such naturally occurring peptides, amino acids, or sugars, they can use these carriers to cross membranes. See Figure 1–5C.

Many cells also contain less selective membrane carriers that are specialized for expelling foreign molecules. One large family of such transporters binds adenosine triphosphate (ATP) and is called the ABC (ATP-binding cassette) family. This family includes the P-glycoprotein or multidrug-resistance type 1 (MDR1) transporter found in the brain, testes, and other tissues, and in some drug-resistant neoplastic cells, Table 1–2. Similar transport molecules from the ABC family, the multidrug resistance-associated protein (MRP) transporters, play important roles in the excretion of some drugs or their metabolites into urine and bile and in the resistance of some tumors to chemotherapeutic drugs. Several other transporter families have been identified that do not bind ATP but use ion gradients for transport energy. Some of these (the solute carrier [SLC] family) are particularly important in the uptake of neurotransmitters across nerve-ending membranes. The latter carriers are discussed in more detail in Chapter 6.

Endocytosis and Exocytosis

A few substances are so large or impermeant that they can enter cells only by endocytosis, the process by which the substance is bound at a cell-surface receptor, engulfed by the cell membrane, and carried into the cell by pinching off of the newly formed vesicle inside the membrane. The substance can then be released inside the cytosol by breakdown of the vesicle membrane, Figure 1–5D. This process is responsible for the transport of vitamin B12, complexed with a binding protein (intrinsic factor) across the wall of the gut into the blood. Similarly, iron is transported into hemoglobin-synthesizing red blood cell precursors in association with the protein transferrin. Specific receptors for the transport proteins must be present for this process to work.

The reverse process (exocytosis) is responsible for the secretion of many substances from cells. For example, many neurotransmitter substances are stored in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the cytoplasm. Appropriate activation of the nerve ending causes fusion of the storage vesicle with the cell membrane and expulsion of its contents into the extracellular space (see Chapter 6).

Fick's Law of Diffusion

The passive flux of molecules down a concentration gradient is given by Fick's law:

where C₁ is the higher concentration, C₂ is the lower concentration, area is the area across which diffusion is occurring, permeability coefficient is a measure of the mobility of the drug molecules in the medium of the diffusion path, and thickness is the thickness (length) of the diffusion path. In the case of lipid diffusion, the lipid:aqueous partition coefficient is a major determinant of mobility of the drug, because it determines how readily the drug enters the lipid membrane from the aqueous medium.

Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch Equation

The electrostatic charge of an ionized molecule attracts water dipoles and results in a polar, relatively water-soluble and lipid-insoluble complex. Because lipid diffusion depends on relatively high lipid solubility, ionization of drugs may markedly reduce their ability to permeate membranes. A very large percentage of the drugs in use are weak acids or weak bases (Table 1–3). For drugs, a weak acid is best defined as a neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen ion). For example, aspirin dissociates as follows:

A drug that is a weak base can be defined as a neutral molecule that can form a cation (a positively charged molecule) by combining with a proton. For example, pyrimethamine, an antimalarial drug, undergoes the following association-dissociation process:

Note that the protonated form of a weak acid is the neutral, more lipid-soluble form, whereas the unprotonated form of a weak base is the neutral form. The law of mass action requires that these reactions move to the left in an acid environment (low pH, excess protons available) and to the right in an alkaline environment. The Henderson-Hasselbalch equation relates the ratio of protonated to unprotonated weak acid or weak base to the molecule's pK_a and the pH of the medium as follows:

This equation applies to both acidic and basic drugs. Inspection confirms that the lower the pH relative to the pK_a, the greater will be the fraction of drug in the protonated form. Because the uncharged form is the more lipid-soluble, more of a weak acid will be in the lipid-soluble form at acid pH, whereas more of a basic drug will be in the lipid-soluble form at alkaline pH.

Application of this principle is made in the manipulation of drug excretion by the kidney. Almost all drugs are filtered at the glomerulus. If a drug is in a lipid-soluble form during its passage down the renal tubule, a significant fraction will be reabsorbed by simple passive diffusion. If the goal is to accelerate excretion of the drug (eg, in a case of drug overdose), it is important to prevent its reabsorption from the tubule. This can often be accomplished by adjusting urine pH to make certain that most of the drug is in the ionized state, as shown in Figure 1–6. As a result of this partitioning effect, the drug is "trapped" in the urine. Thus, weak acids are usually excreted faster in alkaline urine; weak bases are usually excreted faster in acidic urine. Other body fluids in which pH differences from blood pH may cause trapping or reabsorption are the contents of the stomach and small intestine; breast milk; aqueous humor; and vaginal and prostatic secretions (Table 1–4).

In the case study presented at the beginning of this chapter, the patient intravenously self-administered an overdose of methamphetamine, a weak base. This drug is freely filtered at the glomerulus, but can be rapidly reabsorbed in the renal tubule. Administration of ammonium chloride acidifies the urine, converting a larger fraction of the drug to the protonated, charged form, which is poorly reabsorbed and thus more rapidly eliminated.^*

As suggested by Table 1–3, a large number of drugs are weak bases. Most of these bases are amine-containing molecules. The nitrogen of a neutral amine has three atoms associated with it plus a pair of unshared electrons (see the display that follows). The three atoms may consist of one carbon (designated "R") and two hydrogens (a primary amine ), two carbons and one hydrogen (a secondary amine ), or three carbon atoms (a tertiary amine ). Each of these three forms may reversibly bind a proton with the unshared electrons. Some drugs have a fourth carbon-nitrogen bond; these are quaternary amines. However, the quaternary amine is permanently charged and has no unshared electrons with which to reversibly bind a proton. Therefore, primary, secondary, and tertiary amines may undergo reversible protonation and vary their lipid solubility with pH, but quaternary amines are always in the poorly lipid-soluble charged form.

*Not all experts recommend forced diuresis and urinary pH manipulation after methamphetamine overdose because of the risk of renal damage.

Drug Groups

To learn each pertinent fact about each of the many hundreds of drugs mentioned in this book would be an impractical goal and, fortunately, is unnecessary. Almost all the several thousand drugs currently available can be arranged into about 70 groups. Many of the drugs within each group are very similar in pharmacodynamic actions and in their pharmacokinetic properties as well. For most groups, one or more prototype drugs can be identified that typify the most important characteristics of the group. This permits classification of other important drugs in the group as variants of the prototype, so that only the prototype must be learned in detail and, for the remaining drugs, only the differences from the prototype.

Sources of Information

Students who wish to review the field of pharmacology in preparation for an examination are referred to Pharmacology: Examination and Board Review, by Trevor, Katzung, and Masters (McGraw-Hill, 2007). This book provides over 1000 questions and explanations in USMLE format. A short study guide is USMLE Road Map: Pharmacology, by Katzung and Trevor (McGraw-Hill, 2006). Road Map contains numerous tables, figures, mnemonics, and USMLE-type clinical vignettes.

The references at the end of each chapter in this book were selected to provide reviews or classic publications, of information specific to those chapters. More detailed questions relating to basic or clinical research are best answered by referring to the journals covering general pharmacology and clinical specialties. For the student and the physician, three periodicals can be recommended as especially useful sources of current information about drugs: The New England Journal of Medicine, which publishes much original drug-related clinical research as well as frequent reviews of topics in pharmacology; The Medical Letter on Drugs and Therapeutics, which publishes brief critical reviews of new and old therapies, mostly pharmacologic; and Drugs, which publishes extensive reviews of drugs and drug groups.

Other sources of information pertinent to the United States should be mentioned as well. The "package insert" is a summary of information that the manufacturer is required to place in the prescription sales package; Physicians' Desk Reference (PDR) is a compendium of package inserts published annually with supplements twice a year. It is sold in bookstores and given free to licensed physicians. The package insert consists of a brief description of the pharmacology of the product. This brochure contains much practical information, and it is also used as a means of shifting liability for untoward drug reactions from the manufacturer onto the practitioner. Therefore, the manufacturer typically lists every toxic effect ever reported, no matter how rare. Micromedex is an extensive subscription website maintained by the Thomson Corporation (http://clinical.thomsonhealthcare.com/products/physicians/). It provides downloads for personal digital assistant devices, online drug dosage and interaction information, and toxicologic information. A useful and objective quarterly handbook that presents information on drug toxicity and interactions is Drug Interactions: Analysis and Management. Finally, the Food and Drug Administration has an Internet website that carries news regarding recent drug approvals, withdrawals, warnings, etc. It can be accessed at http://www.fda.gov. The MedWatch drug safety program is a free e-mail notification service that provides news of drug warnings and withdrawals. Subscriptions may be obtained at https://service.govdelivery.com/service/user.html?code=USFDA.

References