Goodman and Gilman Manual of Pharmacology and Therapeutics

Section I
General Principles

chapter 2
Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination

The absorption, distribution, metabolism (biotransformation), and elimination of drugs (ADME) are the processes of pharmacokinetics (Figure 2–1). Understanding and employing pharmacokinetic principles can increase the probability of therapeutic success and reduce the occurrence of adverse drug effects in the body.

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Figure 2-1 The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. Possible distribution and binding of metabolites in relation to their potential actions at receptors are not depicted.

PHYSICOCHEMICAL FACTORS IN TRANSFER OF DRUGS ACROSS MEMBRANES

The absorption, distribution, metabolism, excretion, and action of a drug involve its passage across cell membranes. Mechanisms by which drugs cross membranes and the physicochemical properties of molecules and membranes that influence this transfer are critical to understanding the disposition of drugs in the human body. The characteristics of a drug that predict its movement and availability at sites of action are its molecular size and structural features, degree of ionization, relative lipid solubility of its ionized and nonionized forms, and its binding to serum and tissue proteins. Although barriers to drug movement may be a single layer of cells (e.g., intestinal epithelium) or several layers of cells and associated extracellular protein (e.g., skin), the plasma membrane represents the common barrier to drug distribution.

The plasma membrane consists of a bilayer of amphipathic lipids with their hydrocarbon chains oriented inward to the center of the bilayer to form a continuous hydrophobic phase, with their hydrophilic heads oriented outward. Individual lipid molecules in the bilayer vary according to the particular membrane and can move laterally and organize themselves with cholesterol (e.g., sphingolipids), endowing the membrane with fluidity, flexibility, organization, high electrical resistance, and relative impermeability to highly polar molecules. Membrane proteins embedded in the bilayer serve as structural anchors, receptors, ion channels, or transporters to transduce electrical or chemical signaling pathways and provide selective targets for drug actions. Membranes are highly ordered and compartmented. Membrane proteins may be associated with caveolin and sequestered within caveolae, excluded from caveolae, or be organized in signaling domains rich in cholesterol and sphingolipid not containing caveolin or other scaffolding proteins (i.e., lipid rafts). Cell membranes are relatively permeable to water either by diffusion or by flow resulting from hydrostatic or osmotic differences across the membrane, and bulk flow of water can carry with it small drug molecules (<200 Da). Paracellular passage through intercellular gaps is sufficiently large that transfer across capillary endothelium is generally limited by blood flow (Figure 2–2). Capillaries of the central nervous system (CNS) and a variety of epithelial tissues have tight junctions. Bulk-flow transfer is limited when the molecular mass of the solute exceeds 100-200 Da. Accordingly, most large lipophilic drugs must pass through the cell membrane itself (see Figure 2–2) by passive and active processes.

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Figure 2-2 The variety of ways drugs move across cellular barriers in their passage throughout the body. See details in Figure 5-4.

PASSIVE MEMBRANE TRANSPORT. In passive transport, the drug molecule usually penetrates by diffusion along a concentration gradient by virtue of its solubility in the lipid bilayer. Such transfer is directly proportional to the magnitude of the concentration gradient across the membrane, to the lipid-water partition coefficient of the drug, and to the membrane surface area exposed to the drug. At steady state, the concentration of the unbound drug is the same on both sides of the membrane if the drug is a nonelectrolyte. For ionic compounds, the steady-state concentrations depend on the electrochemical gradient for the ion and on differences in pH across the membrane, which will influence the state of ionization of the molecule disparately on either side of the membrane and can effectively trap drug on one side of the membrane.

WEAK ELECTROLYTES AND THE INFLUENCE OF pH. Many drugs are weak acids or bases that are present in solution as both the lipid-soluble and diffusible nonionized form, and the relatively lipid-insoluble nondiffusible ionized species. The transmembrane distribution of a weak electrolyte is influenced by its pKa and the pH gradient across the membrane. The pKa is the pH at which half the drug (weak acid or base electrolyte) is in its ionized form. The ratio of nonionized to ionized drug at any pH may be calculated from the Henderson-Hasselbalch equation:

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Equation 2–1 relates the pH of the medium around the drug and the drug’s acid dissociation constant (pKa) to the ratio of the protonated (HA or BH+) and unprotonated (A or B) forms, where HA ↔ A + H+ (Ka = [A][H+]/[HA]) describes the dissociation of an acid, and BH+ ↔ B + H+ (Ka = [B][H+]/[BH+]) describes the dissociation of the protonated form of a base. At steady state, an acidic drug will accumulate on the more basic side of the membrane and a basic drug on the more acidic side. This phenomenon, known as ion trapping, is an important process in drug distribution (Figure 2–3).

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Figure 2-3 Influence of pH on the distribution of a weak acid (pKa = 4.4) between plasma and gastric juice separated by a lipid barrier. Dissociation of the weak acid in plasma (pH 7.4) and gastric acid (pH 1.4). The uncharged form, HA, equilibrates across the membrane. Blue numbers in brackets show relative concentrations of HA and A, as calculated from Equation 2-1.

CARRIER-MEDIATED MEMBRANE TRANSPORT. Active transport and facilitated diffusion are carrier-mediated processes. Pharmacologically important transporters may mediate either drug uptake or efflux and often facilitate vectorial transport across polarized cells. An important efflux transporter is the P-glycoprotein encoded by the multidrug resistance-1 (MDR1) gene (see Table 5–4). P-glycoprotein localized in the enterocyte limits the absorption of some orally administered drugs because it exports compounds into the lumen of the GI tract subsequent to their absorption. The P-glycoprotein also can confer resistance to some cancer chemotherapeutic agents (see Chapters 6063). Transporters and their roles in drug action are presented in detail in Chapter 5.

DRUG ABSORPTION, BIOAVAILABILITY, AND ROUTES OF ADMINISTRATION

Absorption is the movement of a drug from its site of administration into the central compartment (see Figure 2–1). For solid dosage forms, absorption first requires dissolution of the tablet or capsule, thus liberating the drug. The clinician is concerned primarily with bioavailability rather than absorption. Bioavailability describes the fractional extent to which a dose of drug reaches its site of action or a biological fluid from which the drug has access to its site of action.

For example, a drug given orally must be absorbed first from the GI tract, but net absorption may be limited by the characteristics of the dosage form, the drug’s physicochemical properties, by intestinal metabolism, and by export into the intestinal lumen. The absorbed drug then passes through the liver, where metabolism and biliary excretion may occur before the drug enters the systemic circulation. Accordingly, a fraction of the administered and absorbed dose of drug will be inactivated or diverted in the intestine and liver before it can reach the general circulation and be distributed to its sites of action. If the metabolic or excretory capacity of the liver and the intestine for the drug is large, bioavailability will be reduced substantially (first-pass effect). This decrease in availability is a function of the anatomical site from which absorption takes place; other anatomical, physiological, and pathological factors can influence bioavailability (described later), and the choice of the route of drug administration must be based on an understanding of these conditions.

ORAL (ENTERAL) VERSUS PARENTERAL ADMINISTRATION. Some characteristics of the major routes employed for systemic drug effect are compared in Table 2–1.

Table 2–1

Some Characteristics of Common Routes of Drug Administrationa

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Oral ingestion is the most common method of drug administration. It also is the safest, most convenient, and most economical. Its disadvantages include limited absorption of some drugs because of their physical characteristics (e.g., low water solubility or poor membrane permeability), emesis as a result of irritation to the GI mucosa, destruction of some drugs by digestive enzymes or low gastric pH, irregularities in absorption or propulsion in the presence of food or other drugs, and the need for cooperation on the part of the patient. In addition, drugs in the GI tract may be metabolized by the enzymes of the intestinal flora, mucosa, or liver before they gain access to the general circulation.

Parenteral injection of drugs has distinct advantages over oral administration. In some instances, parenteral administration is essential for the drug to be delivered in its active form, as in the case of monoclonal antibodies. Availability usually is more rapid, extensive, and predictable when a drug is given by injection; the effective dose can be delivered more accurately. In emergency therapy and when a patient is unconscious, uncooperative, or unable to retain anything given by mouth, parenteral therapy may be necessary. Parenteral administration also has its disadvantages: asepsis must be maintained, especially when drugs are given over time (e.g., intravenous or intrathecal administration); pain may accompany the injection; and it is sometimes difficult for patients to perform the injections themselves if self-medication is necessary.

ORAL ADMINISTRATION. Absorption from the GI tract is governed by factors such as surface area for absorption, blood flow to the site of absorption, the physical state of the drug (solution, suspension, or solid dosage form), its water solubility, and the drug’s concentration at the site of absorption. For drugs given in solid form, the rate of dissolution may limit their absorption. Because most drug absorption from the GI tract occurs by passive diffusion, absorption is favored when the drug is in the nonionized, more lipophilic form. Based on the pH-partition concept (Figure 2–3), one would predict that drugs that are weak acids would be better absorbed from the stomach (pH 1-2) than from the upper intestine (pH 3-6), and vice versa for weak bases. However the epithelium of the stomach is lined with a thick mucus layer, and its surface area is small; by contrast, the villi of the upper intestine provide an extremely large surface area (~200 m2). Accordingly, the rate of absorption of a drug from the intestine will be greater than that from the stomach even if the drug is predominantly ionized in the intestine and largely nonionized in the stomach. Thus, any factor that accelerates gastric emptying will generally increase the rate of drug absorption, whereas any factor that delays gastric emptying is expected to have the opposite effect. Gastric emptying rate is influenced by numerous factors, including the caloric content of food; volume, osmolality, temperature, and pH of ingested fluid; diurnal and interindividual variation; metabolic state (rest or exercise); and the ambient temperature. Gastric emptying is influenced in women by the effects of estrogen (i.e., compared to men, it is slower for premenopausal women and those taking estrogen replacement therapy).

Drugs that are destroyed by gastric secretions and low pH or that cause gastric irritation sometimes are administered in dosage forms with an enteric coating that prevents dissolution in the acidic gastric contents. Enteric coatings are useful for drugs such as aspirin, which can cause gastric irritation, and for presenting a drug such as mesalamine to sites of action in the ileum and colon (see Figure 47–4).

Controlled-Release Preparations. The rate of absorption of a drug administered as a tablet or other solid oral dosage form is partly dependent on its rate of dissolution in GI fluids. This is the basis forcontrolled-release, extended-release, sustained-release, and prolonged-action pharmaceutical preparations that are designed to produce slow, uniform absorption of the drug for 8 h or longer. Potential advantages of such preparations are reduction in the frequency of administration compared with conventional dosage forms (often with improved compliance by the patient), maintenance of a therapeutic effect overnight, and decreased incidence and/or intensity of undesired effects (by dampening of the peaks in drug concentration) and nontherapeutic blood levels of the drug (by elimination of troughs in concentration) that often occur after administration of immediate-release dosage forms. Controlled-release dosage forms are most appropriate for drugs with short half-lives (t1/2 <4 h) or in selected patient groups such as those receiving antiepileptics.

Sublingual Administration. Venous drainage from the mouth is to the superior vena cava, bypassing the portal circulation and thereby protecting the drug from rapid intestinal and hepatic first-pass metabolism. For example, nitroglycerin (see Chapter 27) is effective when retained sublingually because it is nonionic and has very high lipid solubility.

TRANSDERMAL ABSORPTION. Absorption of drugs able to penetrate the intact skin is dependent on the surface area over which they are applied and their lipid solubility (see Chapter 65). Systemic absorption of drugs occurs much more readily through abraded, burned, or denuded skin. Toxic effects result from absorption through the skin of highly lipid-soluble substances (e.g., a lipid-soluble insecticide in an organic solvent). Absorption through the skin can be enhanced by suspending the drug in an oily vehicle and rubbing the resulting preparation into the skin. Hydration of the skin with an occlusive dressing may be used to facilitate absorption. Controlled-release topical patches have become increasingly available, including nicotine for tobacco-smoking withdrawal, scopolamine for motion sickness, nitroglycerin for angina pectoris, testosterone and estrogen for replacement therapy, various estrogens and progestins for birth control, and fentanyl for pain relief.

RECTAL ADMINISTRATION. Approximately 50% of the drug that is absorbed from the rectum will bypass the liver; thus reducing hepatic first-pass metabolism. However, rectal absorption can be irregular and incomplete, and certain drugs can cause irritation of the rectal mucosa.

PARENTERAL INJECTION. The major routes of parenteral administration are intravenous, subcutaneous, and intramuscular. Absorption from subcutaneous and intramuscular sites occurs by simple diffusion along the gradient from drug depot to plasma. The rate is limited by the area of the absorbing capillary membranes and by the solubility of the substance in the interstitial fluid. Relatively large aqueous channels in the endothelial membrane account for the indiscriminate diffusion of molecules regardless of their lipid solubility. Larger molecules, such as proteins, slowly gain access to the circulation by way of lymphatic channels. Drugs administered into the systemic circulation by any route, excluding the intraarterial route, are subject to possible first-pass elimination in the lung prior to distribution to the rest of the body. The lungs also serve as a filter for particulate matter that may be given intravenously and provide a route of elimination for volatile substances.

Intravenous. Factors limiting absorption are circumvented by intravenous injection of drugs in aqueous solution because bioavailability is complete and rapid. Also, drug delivery is controlled and achieved with an accuracy and immediacy not possible by any other procedure. Certain irritating solutions can be given only in this manner because the drug, when injected slowly, is greatly diluted by the blood.

There are advantages and disadvantages to intravenous administration. Unfavorable reactions can occur because high concentrations of drug may be attained rapidly in plasma and tissues. There are therapeutic circumstances where it is advisable to administer a drug by bolus injection (e.g., tissue plasminogen activator) and other circumstances where slower administration of drug is advisable (e.g., antibiotics). Intravenous administration of drugs warrants close monitoring of the patient’s response; once the drug is injected, there is often no retreat. Repeated intravenous injections depend on the ability to maintain a patent vein. Drugs in an oily vehicle, those that precipitate blood constituents or hemolyze erythrocytes, and drug combinations that cause precipitates to form must not be given by this route.

Subcutaneous. Injection into a subcutaneous site can be done only with drugs that are not irritating to tissue; otherwise, severe pain, necrosis, and tissue sloughing may occur. The rate of absorption following subcutaneous injection of a drug often is sufficiently constant and slow to provide a sustained effect. Moreover, altering the period over which a drug is absorbed may be varied intentionally, as is accomplished with insulin for injection using particle size, protein complexation, and pH. The incorporation of a vasoconstrictor agent in a solution of a drug to be injected subcutaneously also retards absorption. Absorption of drugs implanted under the skin in a solid pellet form occurs slowly over a period of weeks or months; some hormones (e.g., contraceptives) are administered effectively in this manner.

Intramuscular. Drugs in aqueous solution are absorbed rapidly after intramuscular injection depending on the rate of blood flow to the injection site. This may be modulated to some extent by local heating, massage, or exercise. Generally, the rate of absorption following injection of an aqueous preparation into the deltoid or vastus lateralis is faster than when the injection is made into the gluteus maximus. The rate is particularly slower for females after injection into the gluteus maximus. This has been attributed to the different distribution of subcutaneous fat in males and females and because fat is relatively poorly perfused. Slow, constant absorption from the intramuscular site results if the drug is injected in solution in oil or suspended in various other repository (depot) vehicles.

Intraarterial. Occasionally, a drug is injected directly into an artery to localize its effect in a particular tissue or organ, such as in the treatment of liver tumors and head and neck cancers. Diagnostic agents sometimes are administered by this route (e.g., technetium-labeled human serum albumin).

Intrathecal. The blood-brain barrier and the blood-cerebrospinal fluid (CSF) barrier often preclude or slow the entrance of drugs into the CNS. Therefore, when local and rapid effects of drugs on the meninges or cerebrospinal axis are desired, drugs sometimes are injected directly into the spinal subarachnoid space. Brain tumors also may be treated by direct intraventricular drug administration.

PULMONARY ABSORPTION. Gaseous and volatile drugs may be inhaled and absorbed through the pulmonary epithelium and mucous membranes of the respiratory tract. Access to the circulation is rapid by this route because the lung’s surface area is large. In addition, solutions of drugs can be atomized and the fine droplets in air (aerosol) inhaled. Advantages are the almost instantaneous absorption of a drug into the blood, avoidance of hepatic first-pass loss, and in the case of pulmonary disease, local application of the drug at the desired site of action (see Chapters 19 and 36).

TOPICAL APPLICATION

Mucous Membranes. Drugs are applied to the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, and urinary bladder primarily for their local effects.

Eye. Topically applied ophthalmic drugs are used primarily for their local effects (see Chapter 64).

BIOEQUIVALENCE

Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration. Two pharmaceutically equivalent drug products are considered to be bioequivalent when the rates and extents of bioavailability of the active ingredient in the 2 products are not significantly different under suitable test conditions. However, brand name and generic forms of the same drug are not always legally equivalent; law suits that have succeeded against the makers of brand name drugs have failed against the producers of the equivalent generic forms (see recent cases involving Phenergan and generic promethazine). Generic versus brand name prescribing is further discussed in connection with drug nomenclature and the choice of drug name in writing prescription orders (see Appendix I).

DISTRIBUTION OF DRUGS

Following absorption or systemic administration into the bloodstream, a drug distributes into interstitial and intracellular fluids depending on the particular physicochemical properties of the individual drug. Cardiac output, regional blood flow, capillary permeability, and tissue volume determine the rate of delivery and potential amount of drug distributed into tissues. Initially, liver, kidney, brain, and other well-perfused organs receive most of the drug; delivery to muscle, most viscera, skin, and fat is slower. This second distribution phase may require minutes to several hours before the concentration of drug in tissue is in equilibrium with that in blood. The second phase also involves a far larger fraction of body mass (e.g., muscle) than does the initial phase and generally accounts for most of the extravascularly distributed drug. With exceptions such as the brain, diffusion of drug into the interstitial fluid occurs rapidly because of the highly permeable nature of the capillary endothelial membrane. Thus, tissue distribution is determined by the partitioning of drug between blood and the particular tissue.

PLASMA PROTEINS. Many drugs circulate in the bloodstream bound to plasma proteins. Albumin is a major carrier for acidic drugs; α1-acid glycoprotein binds basic drugs. Nonspecific binding to other plasma proteins generally occurs to a much smaller extent. The binding is usually reversible. In addition, certain drugs may bind to proteins that function as specific hormone carrier proteins, such as the binding of estrogen or testosterone to sex hormone–binding globulin or the binding of thyroid hormone to thyroxin-binding globulin.

The fraction of total drug in plasma that is bound is determined by the drug concentration, the affinity of binding sites for the drug, and the number of binding sites. For most drugs, the therapeutic range of plasma concentrations is limited; thus, the extent of binding and the unbound fraction are relatively constant. The extent of plasma protein binding also may be affected by disease-related factors (e.g., hypoalbuminemia). Conditions resulting in the acute-phase reaction response (e.g., cancer, arthritis, myocardial infarction, Crohn disease) lead to elevated levels of α1-acid glycoprotein and enhanced binding of basic drugs. Changes in protein binding caused by disease states and drug-drug interactions are clinically relevant mainly for a small subset of so-called high-clearance drugs of narrow therapeutic index that are administered intravenously, such as lidocaine. When changes in plasma protein binding occur in patients, unbound drug rapidly equilibrates throughout the body and only a transient significant change in unbound plasma concentration will occur. Only drugs that show an almost instantaneous relationship between free plasma concentration and effect (e.g., anti-arrhythmics) will show a measureable effect. Thus, unbound plasma drug concentrations will exhibit significant changes only when either drug input or clearance of unbound drug occurs, as a consequence of metabolism or active transport. A more common problem resulting from competition of drugs for plasma protein-binding sites is misinterpretation of measured concentrations of drugs in plasma because most assays do not distinguish free drug from bound drug.

Binding of a drug to plasma proteins limits its concentration in tissues and at its site of action because only unbound drug is in equilibrium across membranes. Accordingly, after distribution equilibrium is achieved, the concentration of active, unbound drug in intracellular water is the same as that in plasma except when carrier-mediated transport is involved. Binding of a drug to plasma protein also limits the drug’s glomerular filtration. Drug transport and metabolism also are limited by binding to plasma proteins, except when these are especially efficient, and drug clearance, calculated on the basis of unbound drug, exceeds organ plasma flow.

TISSUE BINDING. Many drugs accumulate in tissues at higher concentrations than those in the extracellular fluids and blood. Tissue binding of drugs usually occurs with cellular constituents such as proteins, phospholipids, or nuclear proteins and generally is reversible. A large fraction of drug in the body may be bound in this fashion and serve as a reservoir that prolongs drug action in that same tissue or at a distant site reached through the circulation. Such tissue binding and accumulation also can produce local toxicity.

FAT AS A RESERVOIR. Many lipid-soluble drugs are stored by physical solution in the neutral fat. In obese persons, the fat content of the body may be as high as 50%, and even in lean individuals, fat constitutes 10% of body weight; hence, fat may serve as a reservoir for lipid-soluble drugs. Fat is a rather stable reservoir because it has a relatively low blood flow.

BONE. The tetracycline antibiotics (and other divalent metal-ion chelating agents) and heavy metals may accumulate in bone by adsorption onto the bone crystal surface and eventual incorporation into the crystal lattice. Bone can become a reservoir for the slow release of toxic agents such as lead or radium; their effects thus can persist long after exposure has ceased. Local destruction of the bone medulla also may lead to reduced blood flow and prolongation of the reservoir effect because the toxic agent becomes sealed off from the circulation; this may further enhance the direct local damage to the bone. A vicious cycle results, whereby the greater the exposure to the toxic agent, the slower is its rate of elimination. The adsorption of drug onto the bone crystal surface and incorporation into the crystal lattice have therapeutic advantages for the treatment of osteoporosis.

REDISTRIBUTION. Termination of drug effect after withdrawal of a drug usually is by metabolism and excretion but also may result from redistribution of the drug from its site of action into other tissues or sites. Redistribution is a factor in terminating drug effect primarily when a highly lipid-soluble drug that acts on the brain or cardiovascular system is administered rapidly by intravenous injection or inhalation, such as intravenous anesthetic thiopental, a highly lipid-soluble drug. Because blood flow to the brain is so high, thiopental reaches its maximal concentration in brain within a minute of its intravenous injection. After injection is concluded, the plasma and brain concentrations decrease as thiopental redistributes to other tissues, such as muscle. The concentration of the drug in brain follows that of the plasma because there is little binding of the drug to brain constituents. Thus, both the onset and termination of thiopental anesthesia are rapid and both are related directly to the concentration of drug in the brain.

CNS AND CEREBROSPINAL FLUID. The brain capillary endothelial cells have continuous tight junctions; therefore, drug penetration into the brain depends on transcellular rather than paracellular transport. The unique characteristics of brain capillary endothelial cells and pericapillary glial cells constitute the blood-brain barrier. At the choroid plexus, a similar blood-CSF barrier is present, formed by epithelial cells that are joined by tight junctions. The lipid solubility of the nonionized and unbound species of a drug is therefore an important determinant of its uptake by the brain; the more lipophilic a drug, the more likely it is to cross the blood-brain barrier. Pharmaceutical chemists have used this fact to regulate the extent to which drugs penetrate into the CNS (e.g., compare first- and second-generation antihistamines; see Chapter 32). In general, the blood-brain barrier’s function is well maintained; however, meningeal and encephalic inflammation increase local permeability. Drugs may also be imported to and exported from the CNS by specific transporters (see Chapter 5).

PLACENTAL TRANSFER OF DRUGS. The transfer of drugs across the placenta is of critical importance because drugs may cause anomalies in the developing fetus. Lipid solubility, extent of plasma binding, and degree of ionization of weak acids and bases are important general determinants in drug transfer across the placenta. The fetal plasma is slightly more acidic than that of the mother (pH 7.0-7.2 versus 7.4), so that ion trapping of basic drugs occurs. The view that the placenta is an absolute barrier to drugs is inaccurate, in part because a number of influx transporters are also present. The fetus is to some extent exposed to all drugs taken by the mother.

EXCRETION OF DRUGS

Drugs are eliminated from the body either unchanged or as metabolites. Excretory organs, the lung excluded, eliminate polar compounds more efficiently than substances with high lipid solubility. Lipid-soluble drugs thus are not readily eliminated until they are metabolized to more polar compounds. The kidney is the most important organ for excreting drugs and their metabolites. Renal excretion of unchanged drug is a major route of elimination for 25-30% of drugs administered to humans. Substances excreted in the feces are principally unabsorbed orally ingested drugs or drug metabolites excreted either in the bile or secreted directly into the intestinal tract and not reabsorbed. Excretion of drugs in breast milk is important not because of the amounts eliminated, but because the excreted drugs may affect the nursing infant. Excretion from the lung is important mainly for the elimination of anesthetic gases (see Chapter 19).

RENAL EXCRETION. Excretion of drugs and metabolites in the urine involves 3 distinct processes: glomerular filtration, active tubular secretion, and passive tubular reabsorption. Changes in overall renal function generally affect all 3 processes to a similar extent. In neonates, renal function is low compared with body mass but matures rapidly within the first few months after birth. During adulthood, there is a slow decline in renal function, ~1% per year, so that in elderly patients a substantial degree of functional impairment may be present.

The amount of drug entering the tubular lumen by filtration depends on the glomerular filtration rate and the extent of plasma binding of the drug; only unbound drug is filtered. In the proximal renal tubule, active, carrier-mediated tubular secretion also may add drug to the tubular fluid (see Chapter 5). Membrane transporters, mainly located in the distal renal tubule, also are responsible for any active reabsorption of drug from the tubular lumen back into the systemic circulation; however, in the proximal and distal tubules, the nonionized forms of weak acids and bases undergo net passive reabsorption. The concentration gradient for back diffusion is created by the reabsorption of water with Na+ and other inorganic ions. Because the tubular cells are less permeable to the ionized forms of weak electrolytes, passive reabsorption of these substances depends on the pH. When the tubular urine is made more alkaline, weak acids are largely ionized and thus are excreted more rapidly and to a greater extent; conversely, acidification of the urine will reduce fractional ionization and excretion of weak acids. Alkalinization and acidification of the urine have the opposite effects on the excretion of weak bases. In the treatment of drug poisoning, the excretion of some drugs can be hastened by appropriate alkalinization or acidification of the urine.

BILIARY AND FECAL EXCRETION. Transporters present in the canalicular membrane of the hepatocyte (see Chapter 5) actively secrete drugs and metabolites into bile. P-gp and BCRP (breast cancer resistance protein, or ABCG2) transport a plethora of amphipathic lipid-soluble drugs, whereas MRP2 is mainly involved in the secretion of conjugated metabolites of drugs (e.g., glutathione conjugates, glucuronides, and some sulfates). Ultimately, drugs and metabolites present in bile are released into the GI tract during the digestive process. Subsequently, drugs and metabolites can be reabsorbed into the body from the intestine, which, in the case of conjugated metabolites, such as glucuronides, may require their enzymatic hydrolysis by the intestinal microflora. Such enterohepatic recycling, if extensive, may prolong significantly the presence of a drug (or toxin) and its effects within the body prior to elimination by other pathways. For this reason, drugs may be given orally to bind substances excreted in the bile.

EXCRETION BY OTHER ROUTES. Excretion of drugs into sweat, saliva, and tears is quantitatively unimportant. Elimination by these routes depends mainly on diffusion of the nonionized lipid-soluble form of drugs through the epithelial cells of the glands and on the pH. The same principles apply to excretion of drugs in breast milk. Because milk is more acidic than plasma, basic compounds may be slightly concentrated in this fluid; conversely, the concentration of acidic compounds in the milk is lower than in plasma. Nonelectrolytes (e.g., ethanol and urea) readily enter breast milk and reach the same concentration as in plasma, independent of the pH of the milk. Thus, the administration of drugs to breast-feeding women carries the general caution that the suckling infant will be exposed to some extent to the medication and/or its metabolites. In certain cases, such as treatment with the β-blocker atenolol, the infant may be exposed to significant amounts of drug. Although excretion into hair and skin is quantitatively unimportant, sensitive methods of detection of drugs in these tissues have forensic significance.

METABOLISM OF DRUGS

The majority of therapeutic agents are lipophilic compounds filtered through the glomerulus and reabsorbed into the systemic circulation during passage through the renal tubules. The metabolism of drugs and other xenobiotics into more hydrophilic metabolites is essential for their elimination from the body, as well as for termination of their biological and pharmacological activity. In general, biotransformation reactions generate more polar, inactive metabolites that are readily excreted from the body. However, in some cases, metabolites with potent biological activity or toxic properties are generated. Many of the enzyme systems that transform drugs to inactive metabolites also generate biologically active metabolites of endogenous compounds, as in steroid biosynthesis.

The enzyme systems involved in the biotransformation of drugs are localized primarily in the liver. Other organs with significant drug metabolizing capacity include the GI tract, kidneys, and lungs.Prodrugs are pharmacologically inactive compounds designed to maximize the amount of the active species that reaches its site of action. Inactive prodrugs are converted rapidly to biologically active metabolites often by the hydrolysis of an ester or amide linkage (see Chapter 6 for details of drug metabolism).

CLINICAL PHARMACOKINETICS

Clinical pharmacokinetics rely on a relationship between the pharmacological effects of a drug and an accessible concentration of the drug (e.g., in blood or plasma). In most cases, the concentration of drug at its sites of action will be related to the concentration of drug in the systemic circulation (see Figure 2–1). The pharmacological effect that results may be the clinical effect desired, or an adverse or toxic effect. The 4 most important parameters governing drug disposition are bioavailability, the fraction of drug absorbed as such into the systemic circulation; volume of distribution, a measure of the apparent space in the body available to contain the drug based on how much is given versus what is found in the systemic circulation; clearance, a measure of the body’s efficiency in eliminating drug from the systemic circulation; and elimination t1/2, a measure of the rate of removal of drug from the systemic circulation.

For some drugs, no clear or simple relationship has been found between pharmacological effect and concentration in plasma, whereas for other drugs, routine measurement of drug concentration is impractical as part of therapeutic monitoring.

CLEARANCE

Clearance is the most important concept to consider when designing a rational regimen for long-term drug administration. The clinician usually wants to maintain steady-state concentrations of a drug within a therapeutic window or range associated with therapeutic efficacy and a minimum of toxicity for a given agent. Assuming complete bioavailability, the steady-state concentration of drug in the body will be achieved when the rate of drug elimination equals the rate of drug administration (Equation 2–2). Thus:

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where CL is clearance of drug from the systemic circulation and Css is the steady-state concentration of drug. If the desired steady-state concentration of drug in plasma or blood is known, the rate of clearance of drug by the patient will dictate the rate at which the drug should be administered.

Metabolizing enzymes and transporters usually are not saturated, and thus the absolute rate of elimination of the drug is essentially a linear function of its concentration in plasma (first-order kinetics), where a constant fraction of drug in the body is eliminated per unit of time. If mechanisms for elimination of a given drug become saturated, the kinetics approach zero order (the case for ethanol), in which a constant amount of drug is eliminated per unit of time. With first-order kinetics, clearance (CL) will vary with the concentration of drug, often according to Equation 2–3:

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where Km represents the concentration at which half the maximal rate of elimination is reached (in units of mass/volume) and vm is equal to the maximal rate of elimination (in units of mass/time). Thus, clearance is derived in units of volume/time. This equation is analogous to the Michaelis-Menten equation for enzyme kinetics.

Clearance of a drug is its rate of elimination by all routes normalized to the concentration of drug C in some biological fluid where measurement can be made:

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Thus, when clearance is constant, the rate of drug elimination is directly proportional to drug concentration. Clearance indicates the volume of biological fluid such as blood or plasma from which drug would have to be completely removed to account for the clearance per unit of body weight (e.g., mL/min per kg). Clearance can be defined further as blood clearance (CLb), plasma clearance (CLp), or clearance based on the concentration of unbound drug (CLu), depending on the measurement made (CbCp, or Cu). Clearance of drug by several organs is additive. Elimination of drug from the systemic circulation may occur as a result of processes that occur in the kidney, liver, and other organs. Division of the rate of elimination by each organ by a concentration of drug (e.g., plasma concentration) will yield the respective clearance by that organ. Added together, these separate clearances will equal systemic clearance:

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Systemic clearance may be determined at steady state by using Equation 2–2. For a single dose of a drug with complete bioavailability and first-order kinetics of elimination, systemic clearance may be determined from mass balance and the integration of Equation 2–4 over time:

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AUC is the total area under the curve that describes the measured concentration of drug in the systemic circulation as a function of time (from zero to infinity), as in Figure 2–6.

Examples. The plasma clearance for the antibiotic cephalexin is 4.3 mL/min/kg, with 90% of the drug excreted unchanged in the urine. For a 70-kg man, the clearance from plasma would be 301 mL/min, with renal clearance accounting for 90% of this elimination. In other words, the kidney is able to excrete cephalexin at a rate such that the drug is completely removed (cleared) from ~270 mL of plasma every minute (renal clearance = 90% of total clearance). Because clearance usually is assumed to remain constant in a medically stable patient (e.g., no acute decline in kidney function), the rate of elimination of cephalexin will depend on the concentration of drug in the plasma (see Equation 2–4).

The β adrenergic receptor antagonist propranolol is cleared from the blood at a rate of 16 mL/min/kg (or 1120 mL/min in a 70-kg man), almost exclusively by the liver. Thus, the liver is able to remove the amount of propranolol contained in 1120 mL of blood in 1 min. Even though the liver is the dominant organ for elimination, the plasma clearance of some drugs exceeds the rate of blood flow to this organ. Often this is so because the drug partitions readily into red blood cells (RBCs) and the rate of drug delivered to the eliminating organ is considerably higher than expected from measurement of its concentration in plasma. The parent text has a more extended presentation of clearance in Chapter 2 and Appendix II.

HEPATIC CLEARANCE. For a drug that is removed efficiently from the blood by hepatic processes (metabolism and/or excretion of drug into the bile), the concentration of drug in the blood leaving the liver will be low, the extraction ratio will approach unity, and the clearance of the drug from blood will become limited by hepatic blood flow. Drugs that are cleared efficiently by the liver (e.g., drugs with systemic clearances >6 mL/min/kg, such as diltiazem, imipramine, lidocaine, morphine, and propranolol) are restricted in their rate of elimination not by intrahepatic processes but by the rate at which they can be transported in the blood to the liver.

RENAL CLEARANCE. Renal clearance of a drug results in its appearance in the urine. The rate of filtration of a drug depends on the volume of fluid that is filtered in the glomerulus and the unbound concentration of drug in plasma, because drug bound to protein is not filtered. The rate of secretion of drug by the kidney will depend on the drug’s intrinsic clearance by the transporters involved in active secretion as affected by the drug’s binding to plasma proteins, the degree of saturation of these transporters, and the rate of delivery of the drug to the secretory site. In addition, processes involved in drug reabsorption from the tubular fluid must be considered. These factors are altered in renal disease.

DISTRIBUTION

VOLUME OF DISTRIBUTION. The volume of distribution (V) relates the amount of drug in the body to the concentration of drug (C) in the blood or plasma depending on the fluid measured. This volume does not necessarily refer to an identifiable physiological volume but rather to the fluid volume that would be required to contain all of the drug in the body at the same concentration measured in the blood or plasma:

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A drug’s volume of distribution therefore reflects the extent to which it is present in extravascular tissues and not in the plasma. View V as an imaginary volume, because for many drugs V exceeds the known volume of any and all body compartments. For example, the value of V for the highly lipophilic antimalarial chloroquine is some 15,000 L, yet the plasma volume of a typical 70-kg man is 3 L, blood volume is ~5.5 L, extracellular fluid volume outside the plasma is 12 L, and the volume of total-body water is ~42 L.

Many drugs exhibit volumes of distribution far in excess of these values. For example, if 500 μg of the cardiac glycoside digoxin were in the body of a 70-kg subject, a plasma concentration of ~0.75 ng/mL would be observed. Dividing the amount of drug in the body by the plasma concentration yields a volume of distribution for digoxin of ~667 L, or a value ~15 times greater than the total-body volume of a 70-kg man. In fact, digoxin distributes preferentially to muscle and adipose tissue and to its specific receptors (Na+, K+-ATPase), leaving a very small amount of drug in the plasma to be measured. For drugs that are bound extensively to plasma proteins but are not bound to tissue components, the volume of distribution will approach that of the plasma volume because drug bound to plasma protein is measurable in the assay of most drugs. In contrast, certain drugs have high volumes of distribution even though most of the drug in the circulation is bound to albumin because these drugs are also sequestered elsewhere.

The volume of distribution may vary widely depending on the relative degrees of binding to high-affinity receptor sites, plasma and tissue proteins, the partition coefficient of the drug in fat, and accumulation in poorly perfused tissues. The volume of distribution for a given drug can differ according to patient’s age, gender, body composition, and presence of disease. Total-body water of infants younger than 1 year of age, for example, is 75% to 80% of body weight, whereas that of adult males is 60% and that of females is 55%.

The volume of distribution defined in Equation 2–7 considers the body as a single homogeneous compartment. In this one-compartment model, all drug administration occurs directly into the central compartment, and distribution of drug is instantaneous throughout the volume (V). Clearance of drug from this compartment occurs in a first-order fashion, as defined in Equation 2–4; that is, the amount of drug eliminated per unit of time depends on the amount (concentration) of drug in the body compartment. Figure 2–4A and Equation 2–8 describe the decline of plasma concentration with time for a drug introduced into this central compartment:

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Figure 2–4 Plasma concentration-time curves following intravenous administration of a drug (500 mg) to a 70-kg patientA. Drug concentrations are measured in plasma at 2-hour intervals following drug administration. The semilogarithmic plot of plasma concentration (Cp) versus time suggests that the drug is eliminated from a single compartment by a first-order process (see Equation 2–8) with a t1/2 of 4 h (k = 0.693/t1/2 = 0.173 hr–1). The volume of distribution (V) may be determined from the value of Cp obtained by extrapolation to 0-time. Volume of distribution (see Equation 2–7) for the one-compartment model is 31.3 L, or 0.45 L/Kg images. The clearance for this drug is 90 mL/min; for a one-compartment model, CL = kVB. Sampling before 2 h indicates that in fact the drug follows multiexponential kinetics. The terminal disposition t1/2 is 4 h, clearance is 84 mL/min (see Equation 2–6), Varea is 29 L (see Equation 2–8), and Vss is 26.8 L. The initial or “central” distribution volume for the drug images is 16.1 L. The example indicates that multicompartment kinetics may be overlooked when sampling at early times is neglected. In this particular case, there is only a 10% error in the estimate of clearance when the multicompartment characteristics are ignored. For many drugs, multicompartment kinetics may be observed for significant periods of time, and failure to consider the distribution phase can lead to significant errors in estimates of clearance and in predictions of the appropriate dosage. Also, the difference between the “central” distribution volume and other terms reflecting wider distribution is important in deciding a loading dose strategy.

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where k is the rate constant for elimination that reflects the fraction of drug removed from the compartment per unit of time. This rate constant is inversely related to the t1/2 of the drug [kt1/2 = ln 2 = 0.693]. The idealized one-compartment model does not describe the entire time course of the plasma concentration. That is, certain tissue reservoirs can be distinguished from the central compartment, and the drug concentration appears to decay in a manner that can be described by multiple exponential terms (Figure 2–4B).

RATE OF DISTRIBUTION. In many cases, groups of tissues with similar perfusion-to-partition ratios all equilibrate at essentially the same rate such that only one apparent phase of distribution is seen (rapid initial decrease in concentration of intravenously injected drug, as in Figure 2–4B). It is as though the drug starts in a “central” volume (see Figure 2–1), which consists of plasma and tissue reservoirs that are in rapid equilibrium, and distributes to a “final” volume, at which point concentrations in plasma decrease in a log-linear fashion with a rate constant of k (see Figure 2–4B). The multicompartment model of drug disposition can be viewed as though the blood and highly perfused lean organs such as heart, brain, liver, lung, and kidneys cluster as a single central compartment, whereas more slowly perfused tissues such as muscle, skin, fat, and bone behave as the final compartment (the tissue compartment).

STEADY STATE. Equation 2–2 (dosing rate = CL · Css) indicates that a steady-state concentration eventually will be achieved when a drug is administered at a constant rate. At this point, drug elimination (the product of clearance and concentration; Equation 2–4) will equal the rate of drug availability. This concept also extends to regular intermittent dosage (e.g., 250 mg of drug every 8 h). During each interdose interval, the concentration of drug rises with absorption and falls by elimination. At steady state, the entire cycle is repeated identically in each interval (Figure 2–5). Equation 2–2 still applies for intermittent dosing, but it now describes the average steady-state drug concentration images during an interdose interval, where F is fractional bioavailability of the dose and T is dosage interval (time). By substitution of infusion rate for F • dose/T, the formula is equivalent to Equation 2–2 and provides the concentration maintained at steady state during continuous intravenous infusion.

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Figure 2-5 Fundamental pharmacokinetic relationships for repeated administration of drugs. The red line is the pattern of drug accumulation during repeated administration of a drug at intervals equal to its elimination half-time when drug absorption is 10 times as rapid as elimination. As the rate of absorption increases, the concentration maxima approach 2 and the minima approach 1 during the steady state. The blue line depicts the pattern during administration of equivalent dosage by continuous intravenous infusion. Curves are based on the one-compartment model. Average drug concentration at steady state images is given by Equation 2-10, where dosing rate is dose per time interval (T), F is fractional bioavailability, and CL is clearance. Substituting infusion rate for F • dose/T provides the concentration maintained at steady state during continuous intravenous infusion.

HALF-LIFE. The t1/2 is the time it takes for the plasma concentration to be reduced by 50%. For a one-compartment model (Figure 2–4A), t1/2 may be determined readily by inspection and used to make decisions about drug dosage. However, as indicated in Figure 2–4B, drug concentrations in plasma often follow a multiexponential pattern of decline, reflecting the changing amount of drug in the body. When using pharmacokinetics to calculate drug dosing in disease, note in Equation 2–9 that t1/2 changes as a function of both clearance and volume of distribution:

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This t1/2 reflects the decline of systemic drug concentrations during a dosing interval at steady-state as depicted in Figure 2–5.

Clearance is the measure of the body’s ability to eliminate a drug; thus, as clearance decreases, owing to a disease process, for example, t1/2 would be expected to increase as long as the volume of distribution remains unchanged. For example, the t1/2 of diazepam increases with increasing age; however, it is not clearance that changes as a function of age but rather the volume of distribution. Similarly, changes in protein binding of a drug may affect its clearance as well as its volume of distribution, leading to unpredictable changes in t1/2 as a function of disease. The t1/2 defined in Equation 2–9 provides an approximation of the time required to reach steady state after a dosage regimen is initiated or changed (e.g., 4 half-lives to reach ~94% of a new steady state) and a means to estimate the appropriate dosing interval.

EXTENT AND RATE OF ABSORPTION

BIOAVAILABILITY. It is important to distinguish between the rate and extent of drug absorption and the amount of drug that ultimately reaches the systemic circulation. This depends not only on the administered dose but also on the fraction of the dose (F) that is absorbed and escapes any first-pass elimination. This fraction is the drug’s bioavailability.

When drugs are administered by a route that is subject to first-pass loss, the equations presented previously that contain the terms dose or dosing rate (see Equations 2–22–6, and 2–8) also must include the bioavailability term F such that the available dose or dosing rate is used. For example, Equation 2–2 is modified to Equation 2–10:

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where the value of F is between 0 and 1. The value of F varies widely for drugs administered by mouth, and successful therapy can still be achieved for some drugs with F values as low as 0.03 (e.g., etidronate and aliskiren).

RATE OF ABSORPTION. Although the rate of drug absorption does not, in general, influence the average steady-state concentration of the drug in plasma, it may still influence drug therapy. If a drug is absorbed rapidly (e.g., a dose given as an intravenous bolus) and has a small “central” volume, the concentration of drug initially will be high. It will then fall as the drug is distributed to its “final” (larger) volume (see Figure 2–4B). If the same drug is absorbed more slowly (e.g., by slow infusion), a significant amount of the drug will be distributed while it is being administered, and peak concentrations will be lower and will occur later. Controlled-release oral preparations are designed to provide a slow and sustained rate of absorption in order to produce smaller fluctuations in the plasma concentration-time profile during the dosage interval compared with more immediate-release formulations. Because the beneficial, nontoxic effects of drugs are based on knowledge of an ideal or desired plasma concentration range, maintaining that range while avoiding large swings between peak and trough concentrations can improve therapeutic outcome.

NONLINEAR PHARMACOKINETICS

Nonlinearity in pharmacokinetics (i.e., changes in such parameters as clearance, volume of distribution, and t1/2 as a function of dose or concentration of drug) is usually caused by saturation of either protein binding, hepatic metabolism, or active renal transport of the drug.

SATURABLE PROTEIN BINDING. As the molar concentration of drug increases, the unbound fraction eventually also must increase (as all binding sites become saturated when drug concentrations in plasma are in the range of tens to hundreds of μg/mL). For a drug that is metabolized by the liver with a low intrinsic clearance-extraction ratio, saturation of plasma-protein binding will cause both V andCL to increase as drug concentrations increase; t1/2 thus may remain constant (see Equation 2–9). For such a drug, Css will not increase linearly as the rate of drug administration is increased. For drugs that are cleared with high intrinsic clearance-extraction ratios, Css can remain linearly proportional to the rate of drug administration. In this case, hepatic clearance will not change, and the increase in V will increase the half-time of disappearance by reducing the fraction of the total drug in the body that is delivered to the liver per unit of time. Most drugs fall between these 2 extremes.

SATURABLE ELIMINATION. In this situation, the Michaelis-Menten equation (see Equation 2–3) usually describes the nonlinearity. All active processes are undoubtedly saturable, but they will appear to be linear if values of drug concentrations encountered in practice are much less than Km. When drug concentrations exceed Km, nonlinear kinetics are observed. The major consequences of saturation of metabolism or transport are the opposite of those for saturation of protein binding. Saturation of protein binding will lead to increased CL because CL increases as drug concentration increases, whereas saturation of metabolism or transport may decrease CL. Saturable metabolism causes oral first-pass metabolism to be less than expected (higher fractional bioavailability), and there is a greater fractional increase in Css than the corresponding fractional increase in the rate of drug administration. The parent text includes a more detailed treatment.

DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS

The intensity of a drug’s effect is related to its concentration above a minimum effective concentration, whereas the duration of the drug’s effect reflects the length of time the drug level is above this value (Figure 2–6). These considerations, in general, apply to both desired and undesired (adverse) drug effects; as a result, a therapeutic window exists that reflects a concentration range that provides efficacy without unacceptable toxicity.

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Figure 2–6 Temporal characteristics of drug effect and relationship to the therapeutic window (e.g., single dose, oral administration). A lag period is present before the plasma drug concentration (Cp) exceeds the minimum effective concentration (MEC) for the desired effect. Following onset of the response, the intensity of the effect increases as the drug continues to be absorbed and distributed. This reaches a peak, after which drug elimination results in a decline in Cp and in the effect’s intensity. Effect disappears when the drug concentration falls below the MEC. The duration of a drug’s action is determined by the time period over which concentrations exceed the MEC. An MEC exists for each adverse response, and if the drug concentration exceeds this, toxicity will result. The therapeutic goal is to obtain and maintain concentrations within the therapeutic window for the desired response with a minimum of toxicity. Drug response below the MEC for the desired effect will be subtherapeutic; above the MEC for an adverse effect, the probability of toxicity will increase. Increasing or decreasing drug dosage shifts the response curve up or down the intensity scale and is used to modulate the drug’s effect. Increasing the dose also prolongs a drug’s duration of action but at the risk of increasing the likelihood of adverse effects. Unless the drug is nontoxic (e.g., penicillins), increasing the dose is not a useful strategy for extending the duration of action. Instead, another dose of drug should be given, timed to maintain concentrations within the therapeutic window. The area under the blood concentration-time curve (area under the curve, or AUC, shaded in red) can be used to calculate the clearance (see Equation 2–6) for first-order elimination. The AUC is also used as a measure of bioavailability (defined as 100% for an intravenously administered drug). Bioavailability will be less than 100% for orally administered drugs, due mainly to incomplete absorption and first-pass metabolism and elimination.

Similar considerations apply after multiple dosing associated with long-term therapy, and they determine the amount and frequency of drug administration to achieve an optimal therapeutic effect. In general, the lower limit of a drug’s therapeutic range is approximately equal to the drug concentration that produces about half the greatest possible therapeutic effect, and the upper limit of the therapeutic range is such that no more than 5-10% of patients will experience a toxic effect. For some drugs, this may mean that the upper limit of the range is no more than twice the lower limit. Of course, these figures can be highly variable, and some patients may benefit greatly from drug concentrations that exceed the therapeutic range, whereas others may suffer significant toxicity at much lower values (e.g., with digoxin).

For a limited number of drugs, some effect of the drug is easily measured (e.g., blood pressure, blood glucose) and can be used to optimize dosage using a trial-and-error approach. Even in an ideal case, certain quantitative issues arise, such as how often to change dosage and by how much. These usually can be settled with simple rules of thumb based on the principles discussed (e.g., change dosage by no more than 50% and no more often than every 3-4 half-lives). Alternatively, some drugs have very little dose-related toxicity, and maximum efficacy usually is desired. In such cases, doses well in excess of the average required will ensure efficacy (if this is possible) and prolong drug action. Such a “maximal dose” strategy typically is used for penicillins. For many drugs, however, the effects are difficult to measure (or the drug is given for prophylaxis), toxicity and lack of efficacy are both potential dangers, or the therapeutic index is narrow. In these circumstances, doses must be titrated carefully, and drug dosage is limited by toxicity rather than efficacy.

MAINTENANCE DOSE

In most clinical situations, drugs are administered in a series of repetitive doses or as a continuous infusion to maintain a steady-state concentration of drug associated with the therapeutic window. Calculation of the appropriate maintenance dosage is a primary goal. To maintain the chosen steady-state or target concentration, the rate of drug administration is adjusted such that the rate of input equals the rate of loss. This relationship is expressed here in terms of the desired target concentration:

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If the clinician chooses the desired concentration of drug in plasma and knows the clearance and bioavailability for that drug in a particular patient, the appropriate dose and dosing interval can be calculated. An example of calculating the maintenance dose for oral digoxin appears in the parent text.

DOSING INTERVAL FOR INTERMITTENT DOSAGE

In general, marked fluctuations in drug concentrations between doses are not desirable. If absorption and distribution were instantaneous, fluctuations in drug concentrations between doses would be governed entirely by the drug’s elimination t1/2. If the dosing interval T were chosen to be equal to the t1/2, then the total fluctuation would be 2-fold; this is often a tolerable variation.

Pharmacodynamic considerations modify this. For some drugs with a narrow therapeutic range, it may be important to estimate the maximal and minimal concentrations that will occur for a particular dosing interval. The minimal steady-state concentration Css,min may be reasonably determined as:

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where k equals 0.693 divided by the clinically relevant plasma t1/2, and T is the dosing interval. The term exp(–kT) is, in fact, the fraction of the last dose (corrected for bioavailability) that remains in the body at the end of a dosing interval. The parent text gives examples employing Equation 2–12.

LOADING DOSE

The loading dose is one or a series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly. The appropriate magnitude for the loading dose is:

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A loading dose may be desirable if the time required to attain steady state by the administration of drug at a constant rate (4 elimination t1/2 values) is long relative to the temporal demands of the condition being treated as is the case for treatment of arrhythmias and cardiac failure. The use of a loading dose also has significant disadvantages. First, the particularly sensitive individual may be exposed abruptly to a toxic concentration of a drug that may take a long time to decrease (i.e., long t1/2). Loading doses tend to be large, and they are often given parenterally and rapidly; this can be particularly dangerous if toxic effects occur as a result of actions of the drug at sites that are in rapid equilibrium with plasma. It is therefore usually advisable to divide the loading dose into a number of smaller fractional doses that are administered over a period of time. Alternatively, the loading dose should be administered as a continuous intravenous infusion over a period of time using computerized infusion pumps. See the parent text for sample calculations.

THERAPEUTIC DRUG MONITORING

The major use of measured concentrations of drugs (at steady state) is to refine the estimate of CL/F for the patient being treated, using Equation 2–10 as rearranged:

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The new estimate of CL/F can be used in Equation 2–11 to adjust the maintenance dose to achieve the desired target concentration. See the parent text for a fuller presentation of details, precautions, and pitfalls associated with therapeutic drug monitoring.