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Pharmacology_Katzung. Quantal dose-effect curves may also be used to generate information regarding the margin of safety to be expected from a particular drug used to produce a specified effect. One measure, which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect, is the therapeutic index. In animal studies, the therapeutic index is usually defined as the ratio of the TD50 to the ED50 for some therapeutically relevant effect. The precision possible in animal experiments may make it useful to use such a therapeutic index to estimate the potential benefit of a drug in humans. Of course, the therapeutic index of a drug in humans is almost never known with real precision; instead, drug trials and accumulated clinical experience often reveal a range of usually effective doses and a different (but sometimes overlapping) range of possibly toxic doses. The range between the minimum toxic dose and the minimum therapeutic dose is called the therapeutic window


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Pharmacology_Katzung. effective doses and a different (but sometimes overlapping) range of possibly toxic doses. The range between the minimum toxic dose and the minimum therapeutic dose is called the therapeutic window and is of greater practical value in choosing the dose for a patient. The clinically acceptable risk of toxicity depends critically on the severity of the disease being treated. For example, the dose range that provides relief from an ordinary headache in the majority of patients should be very much lower than the dose range that produces serious toxicity, even if the toxicity occurs in a small minority of patients. However, for treatment of a lethal disease such as Hodgkin’s lymphoma, the acceptable difference between therapeutic and toxic doses may be smaller.


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Pharmacology_Katzung. Finally, note that the quantal dose-effect curve and the graded dose-response curve summarize somewhat different sets of information, although both appear sigmoid in shape on a semilogarithmic plot (compare Figures 2–15 and 2–16). Critical information required for making rational therapeutic decisions can be obtained from each type of curve. Both curves provide information regarding the potency and selectivity of drugs; the graded dose-response curve indicates the maximal efficacy of a drug, and the quantal dose-effect curve indicates the potential variability of responsiveness among individuals.


Pharmacology_Katzung

Pharmacology_Katzung. Individuals may vary considerably in their response to a drug; indeed, a single individual may respond differently to the same drug at different times during the course of treatment. Occasionally, individuals exhibit an unusual or idiosyncratic drug response, one that is infrequently observed in most patients. The idiosyncratic responses are usually caused by genetic differences in metabolism of the drug or by immunologic mechanisms, including allergic reactions.


Pharmacology_Katzung

Pharmacology_Katzung. Quantitative variations in drug response are, in general, more common and more clinically important. An individual patient is hyporeactive or hyperreactive to a drug in that the intensity of effect of a given dose of drug is diminished or increased compared with the effect seen in most individuals. (Note: The term hypersensitivity usually refers to allergic or other immunologic responses to drugs.) With some drugs, the intensity of response to a given dose may change during the course of therapy; in these cases, responsiveness usually decreases as a consequence of continued drug administration, producing a state of relative tolerance to the drug’s effects. When responsiveness diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis.


Pharmacology_Katzung

Pharmacology_Katzung. Even before administering the first dose of a drug, the prescriber should consider factors that may help in predicting the direction and extent of possible variations in responsiveness. These include the propensity of a particular drug to produce tolerance or tachyphylaxis as well as the effects of age, sex, body size, disease state, genetic factors, and simultaneous administration of other drugs. Four general mechanisms may contribute to variation in drug responsiveness among patients or within an individual patient at different times. A. Alteration in Concentration of Drug That Reaches the Receptor


Pharmacology_Katzung

Pharmacology_Katzung. As described in Chapter 3, patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood. By altering the concentration of drug that reaches relevant receptors, such pharmacokinetic differences may alter the clinical response. Some differences can be predicted on the basis of age, weight, sex, disease state, and liver and kidney function, and by testing specifically for genetic differences that may result from inheritance of a functionally distinctive complement of drug-metabolizing enzymes (see Chapters 4 and 5). Another important mechanism influencing drug availability is active transport of drug from the cytoplasm, mediated by a family of membrane transporters encoded by the so-called multidrug resistance (MDR) genes. For example, up-regulation of MDR gene-encoded transporter expression is a major mechanism by which tumor cells develop resistance to anti-cancer drugs.


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Pharmacology_Katzung. B. Variation in Concentration of an Endogenous Receptor Ligand This mechanism contributes greatly to variability in responses to pharmacologic antagonists. Thus, propranolol, a β-adrenoceptor antagonist, markedly slows the heart rate of a patient whose endogenous catecholamines are elevated (as in pheochromocytoma) but does not affect the resting heart rate of a well-trained marathon runner. A partial agonist may exhibit even more dramatically different responses: Saralasin, a weak partial agonist at angiotensin II receptors, lowers blood pressure in patients with hypertension caused by increased angiotensin II production and raises blood pressure in patients who produce normal amounts of angiotensin. C. Alterations in Number or Function of Receptors


Pharmacology_Katzung

Pharmacology_Katzung. C. Alterations in Number or Function of Receptors Experimental studies have documented changes in drug response caused by increases or decreases in the number of receptor sites or by alterations in the efficiency of coupling of receptors to distal effector mechanisms. In some cases, the change in receptor number is caused by other hormones; for example, thyroid hormones increase both the number of β adrenoceptors in rat heart muscle and cardiac sensitivity to catecholamines. Similar changes probably contribute to the tachycardia of thyrotoxicosis in patients and may account for the usefulness of propranolol, a β-adrenoceptor antagonist, in ameliorating symptoms of this disease.


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Pharmacology_Katzung. In other cases, the agonist ligand itself induces a decrease in the number (eg, down-regulation) or coupling efficiency (eg, desensitization) of its receptors. These mechanisms (discussed previously under Signaling Mechanisms & Drug Action) may contribute to two clinically important phenomena: first, tachyphylaxis or tolerance to the effects of some drugs (eg, biogenic amines and their congeners), and second, the “overshoot” phenomena that follow withdrawal of certain drugs. These phenomena can occur with either agonists or antagonists. An antagonist may increase the number of receptors in a critical cell or tissue by preventing down-regulation caused by an endogenous agonist. When the antagonist is withdrawn, the elevated number of receptors can produce an exaggerated response to physiologic concentrations of agonist. Potentially disastrous withdrawal symptoms can result for the opposite reason when administration of an agonist drug is discontinued. In this situation, the number of


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Pharmacology_Katzung. concentrations of agonist. Potentially disastrous withdrawal symptoms can result for the opposite reason when administration of an agonist drug is discontinued. In this situation, the number of receptors, which has been decreased by drug-induced down-regulation, is too low for endogenous agonist to produce effective stimulation. For example, the withdrawal of clonidine (a drug whose α2-adrenoceptor agonist activity reduces blood pressure) can produce hypertensive crisis, probably because the drug down-regulates α2 adrenoceptors (see Chapter 11).


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Pharmacology_Katzung. The study of genetic factors determining drug response is called pharmacogenetics, and the use of gene sequencing or expression profile data to tailor therapies specific to an individual patient is called personalized or precision medicine. For example, somatic mutations affecting the tyrosine kinase domain of the epidermal growth factor receptor in lung cancers can confer enhanced sensitivity to kinase inhibitors such as gefitinib. This effect enhances the antineoplastic effect of the drug, and because the somatic mutation is specific to the tumor and not present in the host, the therapeutic index of these drugs can be significantly enhanced in patients whose tumors harbor such mutations. Genetic analysis can also predict drug resistance during treatment or identify new targets for therapy based on rapid mutation of the tumor in the patient. D. Changes in Components of Response Distal to the Receptor


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Pharmacology_Katzung. D. Changes in Components of Response Distal to the Receptor Although a drug initiates its actions by binding to receptors, the response observed in a patient depends on the functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ systems. Clinically, changes in these postreceptor processes represent the largest and most important class of mechanisms that cause variation in responsiveness to drug therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Before initiating therapy with a drug, the prescriber should be aware of patient characteristics that may limit the clinical response. These characteristics include the age and general health of the patient and—most importantly—the severity and pathophysiologic mechanism of the disease. The most important potential cause of failure to achieve a satisfactory response is that the diagnosis is wrong or physiologically incomplete. Drug therapy is most successful when it is accurately directed at the pathophysiologic mechanism responsible for the disease.


Pharmacology_Katzung

Pharmacology_Katzung. When the diagnosis is correct and the drug is appropriate, an unsatisfactory therapeutic response can often be traced to compensatory mechanisms in the patient that respond to and oppose the beneficial effects of the drug. Compensatory increases in sympathetic nervous tone and fluid retention by the kidney, for example, can contribute to tolerance to antihypertensive effects of a vasodilator drug. In such cases, additional drugs may be required to achieve a useful therapeutic result. Clinical Selectivity: Beneficial versus Toxic Effects of Drugs


Pharmacology_Katzung

Pharmacology_Katzung. Clinical Selectivity: Beneficial versus Toxic Effects of Drugs Although we classify drugs according to their principal actions, it is clear that no drug causes only a single, specific effect. Why is this so? It is exceedingly unlikely that any kind of drug molecule will bind to only a single type of receptor molecule, if only because the number of potential receptors in every patient is astronomically large. Even if the chemical structure of a drug allowed it to bind to only one kind of receptor, the biochemical processes controlled by such receptors would take place in many cell types and would be coupled to many other biochemical functions; as a result, the patient and the prescriber would probably perceive more than one drug effect. Accordingly, drugs are only selective—rather than specific—in their actions, because they bind to one or a few types of receptor more tightly than to others and because these receptors control discrete processes that result in distinct effects.


Pharmacology_Katzung

Pharmacology_Katzung. It is only because of their selectivity that drugs are useful in clinical medicine. Selectivity can be measured by comparing binding affinities of a drug to different receptors or by comparing ED50s for different effects of a drug in vivo. In drug development and in clinical medicine, selectivity is usually considered by separating effects into two categories: beneficial or therapeutic effects versus toxic or adverse effects. Pharmaceutical advertisements and prescribers occasionally use the term side effect, implying that the effect in question is insignificant or occurs via a pathway that is to one side of the principal action of the drug; such implications are frequently erroneous. A. Beneficial and Toxic Effects Mediated by the Same Receptor-Effector Mechanism Much of the serious drug toxicity in clinical practice represents a direct pharmacologic extension of the therapeutic actions of the drug.


Pharmacology_Katzung

Pharmacology_Katzung. Much of the serious drug toxicity in clinical practice represents a direct pharmacologic extension of the therapeutic actions of the drug. In some of these cases (eg, bleeding caused by anticoagulant therapy; hypoglycemic coma due to insulin), toxicity may be avoided by judicious management of the dose of drug administered, guided by careful monitoring of effect (measurements of blood coagulation or serum glucose) and aided by ancillary measures (avoiding tissue trauma that may lead to hemorrhage; regulation of carbohydrate intake). In still other cases, the toxicity may be avoided by not administering the drug at all, if the therapeutic indication is weak or if other therapy is available.


Pharmacology_Katzung

Pharmacology_Katzung. In certain situations, a drug is clearly necessary and beneficial but produces unacceptable toxicity when given in doses that produce optimal benefit. In such situations, it may be necessary to add another drug to the treatment regimen. In treating hypertension, for example, administration of a second drug often allows the prescriber to reduce the dose and toxicity of the first drug (see Chapter 11). B. Beneficial and Toxic Effects Mediated by Identical Receptors but in Different Tissues or by Different Effector Pathways Many drugs produce both their desired effects and adverse effects by acting on a single receptor type in different tissues. Examples discussed in this book include digitalis glycosides, which act by inhibiting Na+/K+-ATPase in cell membranes; methotrexate, which inhibits the enzyme dihydrofolate reductase; and glucocorticoid hormones.


Pharmacology_Katzung

Pharmacology_Katzung. Three therapeutic strategies are used to avoid or mitigate this sort of toxicity. First, the drug should always be administered at the lowest dose that produces acceptable benefit. Second, adjunctive drugs that act through different receptor mechanisms and produce different toxicities may allow lowering the dose of the first drug, thus limiting its toxicity (eg, use of other immunosuppressive agents added to glucocorticoids in treating inflammatory disorders). Third, selectivity of the drug’s actions may be increased by manipulating the concentrations of drug available to receptors in different parts of the body, for example, by aerosol administration of a glucocorticoid to the bronchi in asthma. C. Beneficial and Toxic Effects Mediated by Different Types of Receptors


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Pharmacology_Katzung. C. Beneficial and Toxic Effects Mediated by Different Types of Receptors Therapeutic advantages resulting from new chemical entities with improved receptor selectivity were mentioned earlier in this chapter and are described in detail in later chapters. Many receptors, such as catecholamines, histamine, acetylcholine, and corticosteroids, and their associated therapeutic uses were discovered by analyzing effects of the physiologic chemical signals. This approach continues to be fruitful. For example, mis-expression of microRNAs (miRNAs), small RNAs that regulate protein expression by binding to protein-coding (messenger) RNAs, was linked recently to Duchenne muscular dystrophy. Current preclinical investigations include the utility of RNA-based therapy for this and other diseases.


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Pharmacology_Katzung. Other drugs were discovered by exploiting therapeutic or toxic effects of chemically similar agents observed in a clinical context. Examples include quinidine, the sulfonylureas, thiazide diuretics, tricyclic antidepressants, opioid drugs, and phenothiazine anti-psychotics. Often such agents turn out to interact with receptors for endogenous substances (eg, opioids and phenothiazines for endogenous opioid and dopamine receptors, respectively). This approach is evolving toward understanding the structural details of how chemically similar agents differ in binding to receptors. For example, X-ray crystallography of β1 and β2 adrenoceptors shows that their orthosteric binding sites are identical; drugs discriminate between subtypes based on differences in traversing a divergent “vestibule” to access the orthosteric site. Many GPCRs have such passages, revealing a new basis for improving the selectivity of GPCR-targeted drugs.


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Pharmacology_Katzung. Thus, the propensity of drugs to bind to different classes of receptor sites is not only a potentially vexing problem in treating patients, but it also presents a continuing challenge to pharmacology and an opportunity for developing new and more useful drugs.


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Pharmacology_Katzung. Brodlie M et al: Targeted therapies to improve CFTR function in cystic fibrosis. Genome Med 2015;7:101. Catterall WA, Swanson TM: Structural basis for pharmacology of voltage-gated sodium and calcium channels. Mol Pharm 2015;88:141. Christopoulos A: Advances in G protein-coupled receptor allostery: From function to structure. Mol Pharmacol 2014;86:463. Dar AC, Shokat KM: The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Ann Rev Biochem 2011;80:7069. Davies MA, Samuels Y: Analysis of the genome to personalize therapy for melanoma. Oncogene 2010;29:5545. Di Fiore PP, von Zastrow M: Endocytosis, signaling, and beyond. Cold Spring Harb Perspect Biol 2014;6:a016865. Esseltine JL, Scott JD: AKAP signaling complexes: Pointing towards the next generation of therapeutic targets? Trends Pharmacol Sci 2013;34:648. Gouaux E, MacKinnon R: Principles of selective ion transport in channels and pumps. Science 2005;310:1461.


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Pharmacology_Katzung. Gouaux E, MacKinnon R: Principles of selective ion transport in channels and pumps. Science 2005;310:1461. Homan KT, Tesmer JJ: Structural insights into G protein-coupled receptor kinase function. Curr Opin Cell Biol 2014;27:25. Huang Y et al: Molecular basis for multimerization in the activation of the epidermal growth factor receptor. Elife 2016;5:e14107. Kang DS, Tian X, Benovic JL: Role of β-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Curr Opin Cell Biol 2014;27:63. Kenakin T, Williams M: Defining and characterizing drug/compound function. Biochem Pharmacol 2014;87:40. Kho C, Lee A, Hajjar RJ: Altered sarcoplasmic reticulum calcium cycling: Targets for heart failure therapy. Nat Rev Cardiol 2012;9:717. Kobilka BK: Structural insights into adrenergic receptor function and pharmacology. Trends Pharmacol Sci 2011;32:213.


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Pharmacology_Katzung. Kobilka BK: Structural insights into adrenergic receptor function and pharmacology. Trends Pharmacol Sci 2011;32:213. Liu N et al: microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice. J Clin Invest 2012;122:2054. Olson EN: MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease. Sci Transl Med 2014;6:239ps3. Park HW, Tantisira KG, Weiss ST: Pharmacogenomics in asthma therapy: Where are we and where do we go? Annu Rev Pharmacol Toxicol 2015;55:129. Quon BS, Rowe SM: New and emerging targeted therapies for cystic fibrosis. Br Med J 2016;352:i859. Rosell R, Bivona TG, Karachaliou N: Genetics and biomarkers in personalisation of lung cancer treatment. Lancet 2013;382:720. Sprang SR: Activation of G proteins by GTP and the mechanism of Gα-catalyzed GTP hydrolysis. Biopolymers 2016;105:449.


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Pharmacology_Katzung. Sprang SR: Activation of G proteins by GTP and the mechanism of Gα-catalyzed GTP hydrolysis. Biopolymers 2016;105:449. Thorner J et al: Signal transduction: From the atomic age to the post-genomic era. Cold Spring Harb Perspect Biol 2014;6:a022913. Wisler JW et al: Recent developments in biased agonism. Curr Opin Cell Biol 2014;27:18.


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Pharmacology_Katzung. Propranolol, a β-adrenoceptor antagonist, is a useful antihy-pertensive agent because it reduces cardiac output and prob-ably vascular resistance as well. However, it also prevents β-adrenoceptor–induced bronchodilation and therefore may precipitate bronchoconstriction in susceptible individuals. Calcium channel blockers such as verapamil also reduce blood pressure but, because they act on a different target, rarely cause bronchoconstriction or prevent bronchodila-tion. An alternative approach in this patient would be to use a more highly selective adrenoceptor antagonist drug (such as metoprolol) that binds preferentially to the β1 subtype, which is a major βadrenoceptor in the heart, and has a lower affinity (ie, higher Kd) for binding the β2 subtype that mediates bronchodilation. Selection of the most appropriate drug or drug group for one condition requires awareness of the other conditions a patient may have and the receptor selectivity of the drug groups available.


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Pharmacology_Katzung. Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action Nicholas H. G. Holford, MB, ChB, FRACP is 1 ng/mL. Tablets of digoxin are available that contain 62.5 micrograms (mcg) and 250 mcg. What maintenance dose would you recommend? An 85-year-old, 60-kg woman with a serum creatinine of 1.8 mg/dL has atrial fibrillation. A decision has been made to use digoxin to control the rapid heart rate. The target con-centration of digoxin for the treatment of atrial fibrillation


Pharmacology_Katzung

Pharmacology_Katzung. The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects. When a medicine has been selected for a patient, the clinician must determine the dose that most closely achieves this goal. A rational approach to this objective combines the principles of pharmacokinetics with pharmacodynamics to clarify the dose-effect relationship (Figure 3–1). Pharmacodynamics governs the concentration-effect part of the interaction, whereas pharmacokinetics deals with the dose-concentration part (Holford & Sheiner, 1981). The pharmacokinetic processes of absorption, distribution, and elimination determine how rapidly and for how long the drug will appear at the target organ. The pharmacodynamic concepts of maximum response and sensitivity determine the magnitude of the effect at a particular concentration (see Emax and C50, Chapter 2; C50 is also known as EC50).


Pharmacology_Katzung

Pharmacology_Katzung. Figure 3–1 illustrates a fundamental hypothesis of pharmacology, namely, that a relationship exists between a beneficial or toxic effect of a drug and the concentration of the drug. This hypothesis has been documented for many drugs, as indicated by the Target Concentration and Toxic Concentration columns in Table 3–1. The apparent lack of such a relationship for some drugs does not weaken the basic hypothesis but points to the need to consider the time course of concentration at the actual site of pharmacologic effect (see below).


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Pharmacology_Katzung. Knowing the relationship between dose, drug concentration, and effects allows the clinician to take into account the various pathologic and physiologic features of a particular patient that make him or her different from the average individual in responding to a drug. The importance of pharmacokinetics and pharmacodynamics in patient care thus rests upon the improvement in therapeutic benefit and reduction in toxicity that can be achieved by application of these principles. The “standard” dose of a drug is based on trials in healthy volunteers and patients with average ability to absorb, distribute, and eliminate the drug (see Clinical Trials: The IND & NDA Drug in tissues of distribution


Pharmacology_Katzung

Pharmacology_Katzung. Drug in tissues of distribution FIGURE 3–1 The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components. Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing. The three primary processes of pharmacokinetics are input, distribution, and elimination.


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Pharmacology_Katzung. in Chapter 1). This dose will not be suitable for every patient. Several physiologic processes (eg, body size, maturation of organ function in infants) and pathologic processes (eg, heart failure, renal failure) dictate dosage adjustment in individual patients. These processes modify specific pharmacokinetic parameters. The two basic parameters are clearance, the measure of the ability of the body to eliminate the drug; and volume of distribution, the measure of the apparent space in the body available to contain the drug. These parameters are illustrated schematically in Figure 3–2 where the volume of the beakers into which the drugs diffuse represents the volume of distribution, and the size of the outflow “drain” in Figures 3–2B and 3–2D represents the clearance. Volume of Distribution Volume of distribution (V) relates the amount of drug in the body to the concentration of drug (C) in blood or plasma:


Pharmacology_Katzung

Pharmacology_Katzung. Volume of Distribution Volume of distribution (V) relates the amount of drug in the body to the concentration of drug (C) in blood or plasma: The volume of distribution may be defined with respect to blood, plasma, or water (unbound drug), depending on the concentration used in equation (1) (C = Cb, Cp, or Cu).


Pharmacology_Katzung

Pharmacology_Katzung. That the V calculated from equation (1) is an apparent volume may be appreciated by comparing the volumes of distribution of drugs such as digoxin or chloroquine (Table 3–1) with some of the physical volumes of the body (Table 3–2). Volume of distribution can vastly exceed any physical volume in the body because it is the volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or water. Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than in the vascular compartment, ie, they are not homogeneously distributed. Drugs that are completely retained within the vascular compartment, on the other hand, would have a minimum possible volume of distribution equal to the blood component in which they are distributed, eg, 0.04 L/kg body weight or 2.8 L/70 kg (Table 3–2) for a drug that is restricted to the plasma compartment.


Pharmacology_Katzung

Pharmacology_Katzung. Drug clearance principles are similar to the clearance concepts of renal physiology. Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration (C): Clearance, like volume of distribution, may be defined with respect to blood (CLb), plasma (CLp), or unbound in water (CLu), depending on where and how the concentration is measured. It is important to note the additive character of clearance. Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. Dividing the rate of elimination at each organ by the concentration of drug presented to it yields the respective clearance at that organ. CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action TABLE 3–1 Pharmacokinetic and pharmacodynamic parameters for selected drugs in adults. (See Holford et al, 2013, for parameters in neonates and children.)


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Pharmacology_Katzung. TABLE 3–1 Pharmacokinetic and pharmacodynamic parameters for selected drugs in adults. (See Holford et al, 2013, for parameters in neonates and children.) TABLE 3–1 Pharmacokinetic and pharmacodynamic parameters for selected drugs in adults. (See Holford et al, 2013, for parameters in neonates and children.) (Continued) 1Assuming creatinine clearance 100 mL/min/70 kg. 2Convert to mL/min by multiplying the number given by 16.6. 3Average steady-state concentration. 4Target area under the concentration-time curve after a single dose. 5Can be estimated from measured C using CL = Vmax/(Km + C); Vmax = 415 mg/d, Km = 5 mg/L. See text. 6Varies because of concentration-dependent clearance. 7Bound in whole blood (%). 8Based on whole blood standardized to hematocrit 45%. CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action TABLE 3–2 Physical volumes (in L/kg body weight) of some body compartments into which drugs may be distributed.


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Pharmacology_Katzung. TABLE 3–2 Physical volumes (in L/kg body weight) of some body compartments into which drugs may be distributed. Compartment and Volume Examples of Drugs Total body water Small water-soluble molecules: eg, ethanol Blood 0 Time (0.6 L/kg1) Extracellular water Larger water-soluble molecules: eg, (0.2 L/kg) gentamicin Plasma (0.04 L/kg) Large protein molecules: eg, antibodies Fat (0.2-0.35 L/kg) Highly lipid-soluble molecules: eg, diazepam Bone (0.07 L/kg) Certain ions: eg, lead, fluoride 1An average figure. Total body water in a young lean person might be 0.7 L/kg; in an obese person, 0.5 L/kg. Added together, these separate clearances equal total systemic clearance: “Other” tissues of elimination could include the lungs and additional sites of metabolism, eg, blood or muscle.


Pharmacology_Katzung

Pharmacology_Katzung. Added together, these separate clearances equal total systemic clearance: “Other” tissues of elimination could include the lungs and additional sites of metabolism, eg, blood or muscle. The two major sites of drug elimination are the kidneys and the liver. Clearance of unchanged drug in the urine represents renal clearance. Within the liver, drug elimination occurs via biotransformation of parent drug to one or more metabolites, or excretion of unchanged drug into the bile, or both. The pathways of biotransformation are discussed in Chapter 4. For most drugs, clearance is constant over the concentration range encountered in clinical settings, ie, elimination is not saturable, and the rate of drug elimination is directly proportional to concentration (rearranging equation [2]):


Pharmacology_Katzung

Pharmacology_Katzung. This is usually referred to as first-order elimination. When clearance is first-order, it can be estimated by calculating the area under the curve (AUC) of the time-concentration profile after a dose. Clearance is calculated from the dose divided by the AUC. Note that this is a convenient form of calculation—not the definition of clearance. A. Capacity-Limited Elimination For drugs that exhibit capacity-limited elimination (eg, phenytoin, ethanol), clearance will vary depending on the


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 3–2 Models of drug distribution and elimination. The effect of adding drug to the blood by rapid intravenous injection is represented by expelling a known amount of the agent into a beaker. The time course of the amount of drug in the beaker is shown in the graphs at the right. In the first example (A), there is no movement of drug out of the beaker, so the graph shows only a steep rise to a maximum followed by a plateau. In the second example (B), a route of elimination is present, and the graph shows a slow decay after a sharp rise to a maximum. Because the amount of agent in the beaker falls, the “pressure” driving the elimination process also falls, and the slope of the curve decreases. This is an exponential decay curve. In the third model (C), drug placed in the first compartment (“blood”) equilibrates rapidly with the second compartment (“extravascular volume”) and the amount of drug in “blood” declines exponentially to a new steady state. The fourth model (D)


Pharmacology_Katzung

Pharmacology_Katzung. compartment (“blood”) equilibrates rapidly with the second compartment (“extravascular volume”) and the amount of drug in “blood” declines exponentially to a new steady state. The fourth model (D) illustrates a more realistic combination of elimination mechanism and extravascular equilibration. The resulting graph shows an early distribution phase followed by the slower elimination phase. Note that the volume of fluid remains constant because of a fluid input at the same rate as elimination in (B) and (D).


Pharmacology_Katzung

Pharmacology_Katzung. concentration of drug that is achieved (Table 3–1). Capacity-limited elimination is also known as mixed-order, saturable, doseor concentration-dependent, nonlinear, and Michaelis-Menten elimination. Most drug elimination pathways will become saturated if the dose and therefore the concentration are high enough. When blood flow to an organ does not limit elimination (see below), the relation between elimination rate and concentration (C) is expressed mathematically in equation (5):


Pharmacology_Katzung

Pharmacology_Katzung. The maximum elimination capacity is Vmax, and Km is the drug concentration at which the rate of elimination is 50% of Vmax. At concentrations that are high relative to the Km, the elimination rate is almost independent of concentration—a state of “pseudozero order” elimination. If dosing rate exceeds elimination capacity, steady state cannot be achieved: The concentration will keep on rising as long as dosing continues. This pattern of capacity-limited elimination is important for three drugs in common use: ethanol, phenytoin, and aspirin. Clearance has no real meaning for drugs with capacity-limited elimination, and AUC should not be used to calculate clearance of such drugs. B. Flow-Dependent Elimination


Pharmacology_Katzung

Pharmacology_Katzung. B. Flow-Dependent Elimination In contrast to capacity-limited drug elimination, some drugs are cleared very readily by the organ of elimination, so that at any clinically realistic concentration of the drug, most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through it. The elimination of these drugs will thus depend primarily on the rate of drug delivery to the organ of elimination. Such drugs (see Table 4–7) can be called “high-extraction” drugs since they are almost completely extracted from the blood by the organ. Blood flow to the organ is the main determinant of drug delivery, but plasma protein binding and blood cell partitioning may also be important for extensively bound drugs that are highly extracted.


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Pharmacology_Katzung. Half-life (t1/2) is the time required to change the amount of drug in the body by one-half during elimination (or during a constant infusion). In the simplest case—and the most useful in designing drug dosage regimens—the body may be considered as a single compartment (as illustrated in Figure 3–2B) of a size equal to the volume of distribution (V). The time course of drug in the body will depend on both the volume of distribution and the clearance: Because drug elimination can be described by an exponential process, the time taken for a twofold decrease can be shown to be proportional to the natural logarithm of 2. The constant 0.7 in equation (6) is an approximation to the natural logarithm of 2.


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Pharmacology_Katzung. FIGURE 3–3 The time course of drug accumulation and elimination. Solid line: Plasma concentrations reflecting drug accumulation during a constant-rate infusion of a drug. Fifty percent of the steady-state concentration is reached after one half-life, 75% after two half-lives, and over 90% after four half-lives. Dashed line: Plasma concentrations reflecting drug elimination after a constant-rate infusion of a drug had reached steady state. Fifty percent of the drug is lost after one half-life, 75% after two half-lives, etc. The “rule of thumb” that four half-lives must elapse after starting a drug-dosing regimen before full effects will be seen is based on the approach of the accumulation curve to over 90% of the final steady-state concentration.


Pharmacology_Katzung

Pharmacology_Katzung. Half-life is useful because it indicates the time required to attain 50% of steady state—or to decay 50% from steady-state conditions—after a change in the rate of drug administration. Figure 3–3 shows the time course of drug accumulation during a constant-rate drug infusion and the time course of drug elimination after stopping an infusion that has reached steady state.


Pharmacology_Katzung

Pharmacology_Katzung. Disease states can affect both of the physiologically related primary pharmacokinetic parameters: volume of distribution and clearance. A change in half-life will not necessarily reflect a change in drug elimination. For example, patients with chronic renal failure have both decreased renal clearance of digoxin and a decreased volume of distribution; the increase in digoxin half-life is not as great as might be expected based on the change in renal function. The decrease in volume of distribution is due to the decreased renal and skeletal muscle mass and consequent decreased tissue binding of digoxin to Na+/K+-ATPase. Many drugs will exhibit multicompartment pharmacokinetics (as illustrated in Figures 3–2C and 3–2D). Under these conditions, the “half-life” reflecting drug accumulation, as given in Table 3–1, will be greater than that calculated from equation (6).


Pharmacology_Katzung

Pharmacology_Katzung. Whenever drug doses are repeated, the drug will accumulate in the body until dosing stops. This is because it takes an infinite time (in theory) to eliminate all of a given dose. In practical terms, this means that if the dosing interval is shorter than four half-lives, accumulation will be detectable. Accumulation is inversely proportional to the fraction of the dose lost in each dosing interval. The fraction lost is 1 minus the fraction remaining just before the next dose. The fraction remaining can be predicted from the dosing interval and the Plasma concentration(% of steady state) CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action half-life. A convenient index of accumulation is the accumula tion factor:


Pharmacology_Katzung

Pharmacology_Katzung. CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action half-life. A convenient index of accumulation is the accumula tion factor: For a drug given once every half-life, the accumulation factor is 1/0.5, or 2. The accumulation factor predicts the ratio of the steady-state concentration to that seen at the same time following the first dose. Thus, the peak concentrations after intermittent doses at steady state will be equal to the peak concentration after the first dose multiplied by the accumulation factor.


Pharmacology_Katzung

Pharmacology_Katzung. Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route (Table 3–3). The area under the blood concentration-time curve (AUC) is proportional to the dose and the extent of bioavailability for a drug if its elimination is first-order (Figure 3–4). For an intravenous dose, bioavailability is assumed to be equal to unity. For a drug administered orally, bioavailability may be less than 100% for two main reasons—incomplete extent of absorption across the gut wall and first-pass elimination by the liver (see below). A. Extent of Absorption After oral administration, a drug may be incompletely absorbed, eg, only 70% of a dose of digoxin reaches the systemic circulation. TABLE 3–3 Routes of administration, bioavailability, and general characteristics. A:Drug rapidly and completely available B:Only half of availability of A but rate equal to A C:Drug completely available but rate only half of A


Pharmacology_Katzung

Pharmacology_Katzung. A:Drug rapidly and completely available B:Only half of availability of A but rate equal to A C:Drug completely available but rate only half of A FIGURE 3–4 Blood concentration-time curves illustrating how changes in the rate of absorption and extent of bioavailability can influence both the duration of action and the effectiveness of the same total dose of a drug administered in three different formulations. The dashed line indicates the target concentration (TC) of the drug in the blood.


Pharmacology_Katzung

Pharmacology_Katzung. This is mainly due to lack of absorption from the gut. Other drugs are either too hydrophilic (eg, atenolol) or too lipophilic (eg, acyclovir) to be absorbed easily, and their low bioavailability is also due to incomplete absorption. If too hydrophilic, the drug cannot cross the lipid cell membrane; if too lipophilic, the drug is not soluble enough to cross the water layer adjacent to the cell. Drugs may not be absorbed because of a reverse transporter associated with P-glycoprotein. This process actively pumps drug out of gut wall cells back into the gut lumen. Inhibition of P-glycoprotein and gut wall metabolism, eg, by grapefruit juice, may be associated with substantially increased drug absorption. B. First-Pass Elimination


Pharmacology_Katzung

Pharmacology_Katzung. B. First-Pass Elimination Following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug can be metabolized in the gut wall (eg, by the CYP3A4 enzyme system) or even in the portal blood, but most commonly it is the liver that is responsible for metabolism before the drug reaches the systemic circulation. In addition, the liver can excrete the drug into the bile. Any of these sites can contribute to this reduction in bioavailability, and the overall process is known as first-pass elimination. The effect of first-pass hepatic elimination on bioavailability is expressed as the extraction ratio (ER): where Q is hepatic blood flow, normally about 90 L/h in a person weighing 70 kg. The systemic bioavailability of the drug (F) can be predicted from the extent of absorption (f) and the extraction ratio (ER):


Pharmacology_Katzung

Pharmacology_Katzung. The systemic bioavailability of the drug (F) can be predicted from the extent of absorption (f) and the extraction ratio (ER): A drug such as morphine is almost completely absorbed (f = 1), so that loss in the gut is negligible. However, the hepatic extraction ratio for morphine is morphine clearance (60 L/h/70 kg) divided by hepatic blood flow (90 L/h/70 kg) or 0.67. Its oral bioavailability (1 – ER) is therefore expected to be about 33%, which is close to the observed value (Table 3–1). Rate of Absorption


Pharmacology_Katzung

Pharmacology_Katzung. The distinction between rate and extent of absorption is shown in Figure 3–4. The rate of absorption is determined by the site of administration and the drug formulation. Both the rate of absorption and the extent of input can influence the clinical effectiveness of a drug. For the three different dosage forms depicted in Figure 3–4, differences in the intensity of clinical effect are expected. Dosage form B would require twice the dose to attain blood concentrations equivalent to those of dosage form A. Differences in rate of absorption may become important for drugs given as a single dose, such as a hypnotic used to induce sleep. In this case, drug from dosage form A would reach its target concentration earlier than drug from dosage form C; concentrations from A would also reach a higher level and remain above the target concentration for a longer period. In a multiple dosing regimen, dosage forms A and C would yield the same average blood level concentrations, although dosage form


Pharmacology_Katzung

Pharmacology_Katzung. level and remain above the target concentration for a longer period. In a multiple dosing regimen, dosage forms A and C would yield the same average blood level concentrations, although dosage form A would show somewhat greater maximum and lower minimum concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanism of drug absorption is said to be zero-order when the rate is independent of the amount of drug remaining in the gut, eg, when it is determined by the rate of gastric emptying or by a controlled-release drug formulation. In contrast, when the dose is dissolved in gastrointestinal fluids, the rate of absorption is usually proportional to the gastrointestinal fluid concentration and is said to be first-order. Extraction Ratio & the First-Pass Effect


Pharmacology_Katzung

Pharmacology_Katzung. Extraction Ratio & the First-Pass Effect Systemic clearance is not affected by bioavailability. However, clearance can markedly affect the extent of availability because it determines the extraction ratio (equation [8a]). Of course, therapeutic blood concentrations may still be reached by the oral route of administration if larger doses are given. However, in this case, the concentrations of the drug metabolites will be increased compared with those that would occur following intravenous administration. Lidocaine and verapamil are both used to treat cardiac arrhythmias and have bioavailability less than 40%, but lidocaine is never given orally because its metabolites are believed to contribute to central nervous system toxicity. Other drugs that are highly extracted by the liver include morphine (see above), isoniazid, propranolol, and several tricyclic antidepressants (Table 3–1).


Pharmacology_Katzung

Pharmacology_Katzung. Drugs with high extraction ratios will show marked variations in bioavailability between subjects because of differences in hepatic function and blood flow. These differences can explain some of the variation in drug concentrations that occurs among individuals given similar doses. For drugs that are highly extracted by the liver, bypassing hepatic sites of elimination (eg, in hepatic cirrhosis with portosystemic shunting) will result in substantial increases in drug availability, whereas for drugs that are poorly extracted by the liver (for which the difference between entering and exiting drug concentration is small), shunting of blood past the liver will cause little change in availability. Drugs in Table 3–1 that are poorly extracted by the liver include warfarin, diazepam, phenytoin, theophylline, tolbutamide, and chlorpropamide. Alternative Routes of Administration & the First-Pass Effect


Pharmacology_Katzung

Pharmacology_Katzung. Alternative Routes of Administration & the First-Pass Effect There are several reasons for different routes of administration used in clinical medicine (Table 3–3)—for convenience (eg, oral), to maximize concentration at the site of action and minimize it elsewhere (eg, topical), to prolong the duration of drug absorption (eg, transdermal), or to avoid the first-pass effect (sublingual or rectal).


Pharmacology_Katzung

Pharmacology_Katzung. The hepatic first-pass effect can be avoided to a great extent by use of sublingual tablets and transdermal preparations and to a lesser extent by use of rectal suppositories. Sublingual absorption provides direct access to systemic—not portal—veins. The transdermal route offers the same advantage. Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena cava, thus bypassing the liver. However, suppositories tend to move upward in the rectum into a region where veins that lead to the liver predominate. Thus, only about 50% of a rectal dose can be assumed to bypass the liver. Although drugs administered by inhalation bypass the hepatic first-pass effect, the lung may also serve as a site of first-pass loss by excretion and possibly metabolism for drugs administered by nongastrointestinal (“parenteral”) routes.


Pharmacology_Katzung

Pharmacology_Katzung. The principles of pharmacokinetics (discussed in this chapter) and those of pharmacodynamics (discussed in Chapter 2 and Holford & Sheiner, 1981) provide a framework for understanding the time course of drug effect. In the simplest case, drug effects are directly related to plasma concentrations, but this does not necessarily mean that effects simply parallel the time course of concentrations. Because the relationship between drug concentration and effect is not linear (recall the Emax model described in Chapter 2), the effect will not usually be linearly proportional to the concentration.


Pharmacology_Katzung

Pharmacology_Katzung. Consider the effect of an angiotensin-converting enzyme (ACE) inhibitor, such as enalapril, on ACE. After an oral dose of 20 mg, the peak plasma concentration at 2.5 hours is about 64 ng/mL. The half-life that explains ACE inhibition is about 4 hours. Enalapril is usually given once a day, so more than five of these half-lives will elapse from the time of peak concentration to the end of the dosing interval. The concentration of enalapril explaining the effect and the corresponding extent of ACE inhibition are shown in Figure 3–5. The extent of inhibition of ACE is calculated using the Emax model, where Emax, the maximum CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action


Pharmacology_Katzung

Pharmacology_Katzung. CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action FIGURE 3–5 Time course (hours) of angiotensin-converting enzyme (ACE) inhibitor concentrations and effects. The blue line shows the plasma enalapril concentrations in nanograms per milliliter after a single oral dose. The red line indicates the percentage inhibition of its target, ACE. Note the different shapes of the concentration-time course (exponentially decreasing) and the effect-time course (linearly decreasing in its central portion). extent of inhibition, is 100% and the C50, the concentration of enalapril associated with 50% of maximum effect, is 5 ng/mL.


Pharmacology_Katzung

Pharmacology_Katzung. extent of inhibition, is 100% and the C50, the concentration of enalapril associated with 50% of maximum effect, is 5 ng/mL. Note that plasma concentrations of enalapril change by a factor of eight over the first 12 hours (three half-lives) after the peak, but ACE inhibition has only decreased by about 30%. Because the concentrations over this time are so high in relation to the C50, the effect on ACE is almost constant. After 24 hours, ACE is still about 25% inhibited. This explains why a drug with a short half-life can be given once a day and still maintain its effect throughout the day. The key factor is a high initial concentration in relation to the C50. Even though the plasma concentration at 24 hours is only about 1% of its peak, this low concentration is still around half the C50. Once-a-day dosing is common for drugs with minimal adverse effects related to peak concentrations that act on enzymes (eg, ACE inhibitors) or compete at receptors (eg, propranolol).


Pharmacology_Katzung

Pharmacology_Katzung. When concentrations are in the range between four times and one fourth of the C50, the time course of effect is essentially a linear function of time. It takes four half-lives for concentrations to drop from an effect of 80% to 20% of Emax—15% of the effect is lost every half-life over this concentration range. At concentrations below one fourth the C50, the effect becomes almost directly proportional to concentration, and the time course of drug effect will follow the exponential decline of concentration. It is only when the concentration is low in relation to the C50 that the concept of a “half-life of drug effect” has any meaning.


Pharmacology_Katzung

Pharmacology_Katzung. Changes in drug effects are often delayed in relation to changes in plasma concentration. This delay may reflect the time required for the drug to distribute from plasma to the site of action. This will be the case for almost all drugs. The delay due to distribution is a pharmacokinetic phenomenon that can account for delays of a few minutes. This distributional process can account for the short delay of effects after rapid intravenous injection of central nervous system (CNS)–active agents such as thiopental. Some drugs bind tightly to receptors, and it is the half-life of dissociation that determines the delay in effect, eg, for digoxin. Note that it is the dissociation process that controls the time to receptor equilibrium. This is exactly the same principle as the elimination process controlling the time to accumulate to steady state with a constant rate infusion (see Figure 3–3).


Pharmacology_Katzung

Pharmacology_Katzung. A common reason for more delayed drug effects—especially those that take many hours or even days to occur—is the slow turnover of a physiologic substance that is involved in the expression of the drug effect. For example, warfarin works as an anticoagulant by inhibiting vitamin K epoxide reductase (VKOR) in the liver. This action of warfarin occurs rapidly, and inhibition of the enzyme is closely related to plasma concentrations of warfarin. The clinical effect of warfarin, eg, on the international normalized ratio (INR), reflects a decrease in the concentration of the prothrombin complex of clotting factors. Inhibition of VKOR decreases the synthesis of these clotting factors, but the complex has a long half-life (about 14 hours), and it is this half-life that determines how long it takes for the concentration of clotting factors to reach a new steady state and for a drug effect to reflect the average warfarin plasma concentration.


Pharmacology_Katzung

Pharmacology_Katzung. Some drug effects are more obviously related to a cumulative action than to a rapidly reversible one. The renal toxicity of aminoglycoside antibiotics (eg, gentamicin) is greater when administered as a constant infusion than with intermittent dosing. It is the accumulation of aminoglycoside in the renal cortex that is thought to cause renal damage. Even though both dosing schemes produce the same average steady-state concentration, the intermittent dosing scheme produces much higher peak concentrations, which saturate an uptake mechanism into the cortex; thus, total aminoglycoside accumulation is less. The difference in toxicity is a predictable consequence of the different patterns of concentration and the saturable uptake mechanism.


Pharmacology_Katzung

Pharmacology_Katzung. The effect of many drugs used to treat cancer also reflects a cumulative action—eg, the extent of binding of a drug to DNA is proportional to drug concentration and is usually irreversible. The effect on tumor growth is therefore a consequence of cumulative exposure to the drug. Measures of cumulative exposure, such as AUC, provide a means to individualize treatment.


Pharmacology_Katzung

Pharmacology_Katzung. A rational dosage regimen is based on the assumption that there is a target concentration that will produce the desired therapeutic effect. By considering the pharmacokinetic factors that determine the dose-concentration relationship, it is possible to individualize the dose regimen to achieve the target concentration. The effective concentration ranges shown in Table 3–1 are a guide to the concentrations measured when patients are being effectively treated. The initial target concentration should usually be chosen from the lower end of this range. In some cases, the target concentration will also depend on the specific therapeutic objective—eg, the control of atrial fibrillation by digoxin may require a target concentration of 2 ng/mL, while heart failure is usually adequately managed with a target concentration of 1 ng/mL.


Pharmacology_Katzung

Pharmacology_Katzung. In most clinical situations, drugs are administered in such a way as to maintain a steady state of drug in the body, ie, just enough drug is given in each dose to replace the drug eliminated since the preceding dose. Thus, calculation of the appropriate maintenance dose is a primary goal. Clearance is the most important pharmacokinetic term to be considered in defining a rational steady-state drug dosage regimen. At steady state, the dosing rate (“rate in”) must equal the rate of elimination (“rate out”). Substitution of the target concentration (TC) for concentration (C) in equation (4) predicts the maintenance dosing rate: Thus, if the desired target concentration is known, the clearance in that patient will determine the dosing rate. If the drug is given by a route that has a bioavailability less than 100%, then the dosing rate predicted by equation (9) must be modified. For oral dosing:


Pharmacology_Katzung

Pharmacology_Katzung. If intermittent doses are given, the maintenance dose is calculated from: (See Box: Example: Maintenance Dose Calculations.) Note that the steady-state concentration achieved by continuous infusion or the average concentration following intermittent dosing depends only on clearance. The volume of distribution and the half-life need not be known in order to determine the average plasma concentration expected from a given dosing rate or to predict the dosing rate for a desired target concentration. Figure 3–6 shows that at different dosing intervals, the concentration-time curves will have different maximum and minimum values even though the average concentration will always be 10 mg/L.


Pharmacology_Katzung

Pharmacology_Katzung. Estimates of dosing rate and average steady-state concentrations, which may be calculated using clearance, are independent of any specific pharmacokinetic model. In contrast, the determination of maximum and minimum steady-state concentrations requires further assumptions about the pharmacokinetic model. The accumulation factor (equation [7]) assumes that the drug follows a one-compartment model (Figure 3–2B), and the peak concentration prediction assumes that the absorption rate is much faster than the elimination rate. For the calculation of estimated maximum and minimum concentrations in a clinical situation, these assumptions are usually reasonable.


Pharmacology_Katzung

Pharmacology_Katzung. When the time to reach steady state is appreciable, as it is for drugs with long half-lives, it may be desirable to administer a loading dose that promptly raises the concentration of drug in plasma to the target concentration. In theory, only the amount of the loading dose need be computed—not the rate of its administration—and, to a first approximation, this is so. The volume of distribution is the proportionality factor that relates the total amount of drug in the body to the concentration; if a loading dose is to achieve the target concentration, then from equation (1):


Pharmacology_Katzung

Pharmacology_Katzung. A target plasma theophylline concentration of 10 mg/L is desired to relieve acute bronchial asthma in a patient. If the patient is a nonsmoker and otherwise normal except for asthma, we may use the mean clearance given in Table 3–1, ie, 2.8 L/h/70 kg. Since the drug will be given as an intravenous infusion, F = 1. Dosing rate = CL × TC = 2.8 L/h/70 kg × 10 mg/L = 28 mg/h/70 kg Therefore, in this patient, the infusion rate would be 28 mg/h/ 70 kg. If the asthma attack is relieved, the clinician might want to maintain this plasma level using oral theophylline, which might be given every 12 hours using an extended-release formulation to approximate a continuous intravenous infusion. According to Table 3–1, Foral is 0.96. When the dosing interval is 12 hours, the size of each maintenance dose would be: Maintenance dose = Dosing Rate/F × Dosing interval = 28 mg/h/0.96 × 12 h = 350 mg A tablet or capsule size close to the ideal dose of 350 mg would then be prescribed at 12-hour intervals.


Pharmacology_Katzung

Pharmacology_Katzung. would be: Maintenance dose = Dosing Rate/F × Dosing interval = 28 mg/h/0.96 × 12 h = 350 mg A tablet or capsule size close to the ideal dose of 350 mg would then be prescribed at 12-hour intervals. If an 8-hour dosing interval was used, the ideal dose would be 233 mg; and if the drug was given once a day, the dose would be 700 mg. In practice, F could be omitted from the calculation since it is so close to 1.


Pharmacology_Katzung

Pharmacology_Katzung. CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action FIGURE 3–6 Relationship between frequency of dosing and maximum and minimum plasma concentrations when a steady-state theophylline plasma level of 10 mg/L is desired. The smoothly rising black line shows the plasma concentration achieved with an intravenous infusion of 28 mg/h. The doses for 8-hour administration (orange line) are 224 mg; for 24-hour administration (blue line), 672 mg. In each of the three cases, the mean steady-state plasma concentration is 10 mg/L. For the theophylline example given in the box, Example: Maintenance Dose Calculations, the loading dose would be 350 mg (35 L × 10 mg/L) for a 70-kg person. For most drugs, the loading dose can be given as a single dose by the chosen route of administration.


Pharmacology_Katzung

Pharmacology_Katzung. Up to this point, we have ignored the fact that some drugs follow more complex multicompartment pharmacokinetics, eg, the distribution process illustrated by the two-compartment model in Figure 3–2. This is justified in the great majority of cases. However, in some cases the distribution phase may not be ignored, particularly in connection with the calculation of loading doses. If the rate of absorption is rapid relative to distribution (this is always true for rapid intravenous administration), the concentration of drug in plasma that results from an appropriate loading dose—calculated using the apparent volume of distribution—can initially be considerably higher than desired. Severe toxicity may occur, albeit transiently. This may be particularly important, eg, in the administration of antiarrhythmic drugs such as lidocaine, where an almost immediate toxic response may occur. Thus, while the estimation of the amount of a loading dose may be quite correct, the rate of administration


Pharmacology_Katzung

Pharmacology_Katzung. antiarrhythmic drugs such as lidocaine, where an almost immediate toxic response may occur. Thus, while the estimation of the amount of a loading dose may be quite correct, the rate of administration can sometimes be crucial in preventing excessive drug concentrations, and slow administration of an intravenous drug (over minutes rather than seconds) is almost always prudent practice.


Pharmacology_Katzung

Pharmacology_Katzung. When intermittent doses are given, the loading dose calculated from equation (12) will only reach the average steady-state concentration and will not match the peak steady-state concentration (Figure 3–6). To match the peak steady-state concentration, the loading dose can be calculated from equation (13): TARGET CONCENTRATION INTERVENTION: APPLICATION OF PHARMACOKINETICS & PHARMACODYNAMICS TO DOSE INDIVIDUALIZATION


Pharmacology_Katzung

Pharmacology_Katzung. TARGET CONCENTRATION INTERVENTION: APPLICATION OF PHARMACOKINETICS & PHARMACODYNAMICS TO DOSE INDIVIDUALIZATION The basic principles outlined above can be applied to the interpretation of clinical drug concentration measurements on the basis of three major pharmacokinetic variables: absorption, clearance, and volume of distribution (and the derived variable, half-life). In addition, it may be necessary to consider two pharmacodynamic variables: maximum effect attainable in the target tissue and the sensitivity of the tissue to the drug. Diseases may modify all of these parameters, and the ability to predict the effect of disease states on pharmacokinetic parameters is important in properly adjusting dosage in such cases. (See Box: The Target Concentration Strategy.) A. Input The amount of drug that enters the body depends on the patient’s adherence to the prescribed regimen and on the rate and extent of transfer from the site of administration to the blood.


Pharmacology_Katzung

Pharmacology_Katzung. A. Input The amount of drug that enters the body depends on the patient’s adherence to the prescribed regimen and on the rate and extent of transfer from the site of administration to the blood. C. Volume of Distribution The apparent volume of distribution reflects a balance between Recognition of the essential role of concentration in linking pharmacokinetics and pharmacodynamics leads naturally to the target concentration strategy. Pharmacodynamic principles can be used to predict the concentration required to achieve a particular degree of therapeutic effect. This target concentration can then be achieved by using pharmacokinetic principles to arrive at a suitable dosing regimen (Holford, 1999). The target concentration strategy is a process for optimizing the dose in an individual on the basis of a measured surrogate response such as drug concentration: 1. Choose the target concentration, TC. 2.


Pharmacology_Katzung

Pharmacology_Katzung. Choose the target concentration, TC. 2. Predict volume of distribution (V) and clearance (CL) based on standard population values (eg, Table 3–1) with adjustments for factors such as weight and renal function. 3. Give a loading dose or maintenance dose calculated from TC, V, and CL. 4. Measure the patient’s response and drug concentration. 5. Revise V and/or CL based on the measured concentration. 6. Repeat steps 3–5, adjusting the predicted dose to achieve TC.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Measure the patient’s response and drug concentration. 5. Revise V and/or CL based on the measured concentration. 6. Repeat steps 3–5, adjusting the predicted dose to achieve TC. Overdosage and underdosage relative to the prescribed dosage—both aspects of failure of adherence—can frequently be detected by concentration measurements when gross deviations from expected values are obtained. If adherence is found to be adequate, absorption abnormalities in the small bowel may be the cause of abnormally low concentrations. Variations in the extent of bioavailability are rarely caused by irregularities in the manufacture of the particular drug formulation. More commonly, variations in bioavailability are due to metabolism during absorption. B. Clearance


Pharmacology_Katzung

Pharmacology_Katzung. B. Clearance Abnormal clearance may be anticipated when there is major impairment of the function of the kidney, liver, or heart. Creatinine clearance is a useful quantitative indicator of renal function. Conversely, drug clearance may be a useful indicator of the functional consequences of heart, kidney, or liver failure, often with greater precision than clinical findings or other laboratory tests. For example, when renal function is changing rapidly, estimation of the clearance of aminoglycoside antibiotics may be a more accurate indicator of glomerular filtration than serum creatinine.


Pharmacology_Katzung

Pharmacology_Katzung. Hepatic disease has been shown to reduce the clearance and prolong the half-life of many drugs. However, for many other drugs known to be eliminated by hepatic processes, no changes in clearance or half-life have been noted with similar hepatic disease. This reflects the fact that hepatic disease does not always affect the hepatic intrinsic clearance. At present, there is no reliable marker of hepatic drug-metabolizing function that can be used to predict changes in liver clearance in a manner analogous to the use of creatinine clearance as a marker of renal drug clearance.


Pharmacology_Katzung

Pharmacology_Katzung. binding to tissues, which decreases plasma concentration and makes the apparent volume larger, and binding to plasma proteins, which increases plasma concentration and makes the apparent volume smaller. Changes in either tissue or plasma binding can change the apparent volume of distribution determined from plasma concentration measurements. Older people have a relative decrease in skeletal muscle mass and tend to have a smaller apparent volume of distribution of digoxin (which binds to muscle proteins). The volume of distribution may be overestimated in obese patients if based on body weight and the drug does not enter fatty tissues well, as is the case with digoxin. In contrast, theophylline has a volume of distribution similar to that of total body water. Adipose tissue has almost as much water in it as other tissues, so that the apparent total volume of distribution of theophylline is proportional to body weight even in obese patients.


Pharmacology_Katzung

Pharmacology_Katzung. Abnormal accumulation of fluid—edema, ascites, pleural effusion—can markedly increase the volume of distribution of drugs such as gentamicin that are hydrophilic and have small volumes of distribution. D. Half-Life The differences between clearance and half-life are important in defining the underlying mechanisms for the effect of a disease state on drug disposition. For example, the half-life of diazepam increases with patient age. When clearance is related to age, it is found that clearance of this drug does not change with age. The increasing half-life for diazepam actually results from changes in the volume of distribution with age; the metabolic processes responsible for eliminating the drug are fairly constant. A. Maximum Effect All pharmacologic responses must have a maximum effect (Emax). No matter how high the drug concentration goes, a point will be reached beyond which no further increment in response is achieved.


Pharmacology_Katzung

Pharmacology_Katzung. All pharmacologic responses must have a maximum effect (Emax). No matter how high the drug concentration goes, a point will be reached beyond which no further increment in response is achieved. If increasing the dose in a particular patient does not lead to a further clinical response, it is possible that the maximum effect has been reached. Recognition of maximum effect is helpful in avoiding ineffectual increases of dose with the attendant risk of toxicity. B. Sensitivity The sensitivity of the target organ to drug concentration is reflected by the concentration required to produce 50% of maximum effect, the C50. Diminished sensitivity to the drug can be detected by measuring drug concentrations that are usually associated with therapeutic response in a patient who has not responded. This may be a result of abnormal physiology—eg, hyperkalemia diminishes responsiveness to digoxin—or drug antagonism—eg, calcium channel blockers impair the inotropic response to digoxin.


Pharmacology_Katzung

Pharmacology_Katzung. Increased sensitivity to a drug is usually signaled by exaggerated responses to small or moderate doses. The pharmacodynamic nature of this sensitivity can be confirmed by measuring drug concentrations that are low in relation to the observed effect. CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action Clearance is the single most important factor determining drug concentrations. The interpretation of measurements of drug concentrations depends on a clear understanding of three factors that may influence clearance: the dose, the organ blood flow, and the intrinsic function of the liver or kidneys. Each of these factors should be considered when interpreting clearance estimated from a drug concentration measurement.


Pharmacology_Katzung

Pharmacology_Katzung. It must also be recognized that changes in protein binding may lead the unwary to believe there is a change in clearance when in fact drug elimination is not altered (see Box: Plasma Protein Binding: Is It Important?). Factors affecting protein binding include the following: 1. Albumin concentration: Drugs such as phenytoin, salicylates, and disopyramide are extensively bound to plasma albumin. Albumin levels are low in many disease states, resulting in lower total drug concentrations. 2. Alpha1-acid glycoprotein concentration: α1-Acid glycoprotein is an important binding protein with binding sites for drugs such as quinidine, lidocaine, and propranolol. It is increased in acute inflammatory disorders and causes major changes in total plasma concentration of these drugs even though drug elimination is unchanged. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Capacity-limited protein binding: The binding of drugs to plasma proteins is capacity-limited. Therapeutic concentrations of salicylates and prednisolone show concentration-dependent protein binding. Because unbound drug concentration is determined by dosing rate and clearance—which is not altered, in the case of these low-extraction-ratio drugs, by protein binding—increases in dosing rate will cause corresponding changes in the pharmacodynamically important unbound concentration. In contrast, total drug concentration will increase less rapidly than the dosing rate would suggest as protein binding approaches saturation at higher concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Binding to red blood cells: Drugs such as cyclosporine and tacrolimus bind extensively inside red blood cells. Typically, whole blood concentrations are measured, and they are about 50 times higher than plasma concentration. A decrease in red blood cell concentration (reflected in the hematocrit) will cause whole blood concentration to fall without a change in pharmacologically active concentrations. Standardization of concentrations to a standard hematocrit helps to interpret the concentration-effect relationship. An accurate dosing history is essential if one is to obtain maximum value from a drug concentration measurement. In fact, if the dosing history is unknown or incomplete, a drug concentration measurement loses all predictive value. Timing of Samples for Concentration Measurement


Pharmacology_Katzung

Pharmacology_Katzung. Timing of Samples for Concentration Measurement Information about the rate and extent of drug absorption in a particular patient is rarely of great clinical importance. Absorption usually occurs during the first 2 hours after a drug dose and varies according to food intake, posture, and activity. Therefore, it is important to avoid drawing blood until absorption is complete (about 2 hours after an oral dose). Attempts to measure peak concentrations early after oral dosing are usually unsuccessful and compromise the validity of the measurement, because one cannot be certain that absorption is complete. Plasma Protein Binding: Is It Important?


Pharmacology_Katzung

Pharmacology_Katzung. Plasma protein binding is often mentioned as a factor play-ing a role in pharmacokinetics, pharmacodynamics, and drug interactions. However, there are no clinically relevant examples of changes in drug disposition or effects that can be clearly ascribed to changes in plasma protein binding (Benet & Hoener, 2002). The idea that if a drug is displaced from plasma proteins it would increase the unbound drug concentration and increase the drug effect and, perhaps, produce toxicity seems a simple and obvious mechanism. Unfortunately, this simple theory, which is appropriate for a test tube, does not work in the body, which is an open system capable of eliminating unbound drug. First, a seemingly dramatic change in the unbound fraction from 1% to 10% releases less than 5% of the total amount of drug in the body into the unbound pool because less than one third of the drug in the body is bound to plasma proteins even in the most extreme cases, eg, warfarin. Drug displaced from plasma protein


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Pharmacology_Katzung. drug in the body into the unbound pool because less than one third of the drug in the body is bound to plasma proteins even in the most extreme cases, eg, warfarin. Drug displaced from plasma protein will of course distribute throughout the volume of distribution, so that a 5% increase in the amount of unbound drug in the body produces at most a 5% increase in pharmaco-logically active unbound drug at the site of action. Second, when the amount of unbound drug in plasma increases, the rate of elimination will increase (if unbound clearance is unchanged), and after four half-lives the unbound concentration will return to its previous steady-state value. When drug interactions associated with protein binding displacement and clinically important effects have been studied, it has been found that the displacing drug is also an inhibitor of clearance, and it is the change in clearance of the unbound drug that is the relevant mechanism explaining the interaction. The clinical importance of


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Pharmacology_Katzung. that the displacing drug is also an inhibitor of clearance, and it is the change in clearance of the unbound drug that is the relevant mechanism explaining the interaction. The clinical importance of plasma protein binding is only to help interpretation of measured drug concentrations. When plasma proteins are lower than normal, total drug con-centrations will be lower but unbound concentrations will not be affected.


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Pharmacology_Katzung. Some drugs, such as digoxin and lithium, take several hours to distribute to tissues. Digoxin samples should be taken at least 6 hours after the last dose and lithium just before the next dose (usually 24 hours after the last dose). Aminoglycosides distribute quite rapidly, but it is still prudent to wait 1 hour after giving the dose before taking a sample. Clearance is readily estimated from the dosing rate and mean steady-state concentration. Blood samples should be appropriately timed to estimate steady-state concentration. Provided steady state has been approached (at least three half-lives of constant dosing), a sample obtained near the midpoint of the dosing interval will usually be close to the mean steady-state concentration. Initial Predictions of Volume of Distribution & Clearance A. Volume of Distribution


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Pharmacology_Katzung. Initial Predictions of Volume of Distribution & Clearance A. Volume of Distribution Volume of distribution is commonly calculated for a particular patient using body weight (70-kg body weight is assumed for the values in Table 3–1). If a patient is obese, drugs that do not readily penetrate fat (eg, gentamicin, digoxin, tacrolimus, gemcitabine) should have their volumes calculated from fat-free mass (FFM) as shown below. Total body weight (WT) is in kilograms and height


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Pharmacology_Katzung. Patients with edema, ascites, or pleural effusions offer a larger volume of distribution to the aminoglycoside antibiotics (eg, gentamicin) than is predicted by body weight. In such patients, the weight should be corrected as follows: Subtract an estimate of the weight of the excess fluid accumulation from the measured weight. Use the resultant “normal” body weight to calculate the normal volume of distribution. Finally, this normal volume should be increased by 1 L for each estimated kilogram of excess fluid. This correction is important because of the relatively small volumes of distribution of these water-soluble drugs. B. Clearance Drugs cleared by the renal route often require adjustment of clearance in proportion to renal function. This can be conveniently estimated from the creatinine clearance, calculated from a single serum creatinine measurement and the predicted creatinine production rate.


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Pharmacology_Katzung. The predicted creatinine production rate in women is 85% of the calculated value because they have a smaller muscle mass per kilogram, and it is muscle mass that determines creatinine production. Muscle mass as a fraction of body weight decreases with age, which is why age appears in the Cockcroft-Gault equation. * The decrease of renal function with age is independent of the decrease in creatinine production. Because of the difficulty of obtaining complete urine collections, creatinine clearance calculated in this way is at least as reliable as estimates based on urine collections. The fat-free mass (equation [14]) should be considered rather than total body weight for obese patients, and correction should be made for muscle wasting in severely ill patients. Revising Individual Estimates of Volume of Distribution & Clearance


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Pharmacology_Katzung. Revising Individual Estimates of Volume of Distribution & Clearance The commonsense approach to the interpretation of drug concentrations compares predictions of pharmacokinetic parameters and expected concentrations to measured values. If measured concentrations differ by more than 20% from predicted values, revised estimates of V or CL for that patient should be calculated using equation (1) or equation (2). If the change calculated is more than a 100% increase or 50% decrease in either V or CL, the assumptions made about the timing of the sample and the dosing history should be critically examined.


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Pharmacology_Katzung. For example, if a patient is taking 0.25 mg of digoxin a day, a clinician may expect the digoxin concentration to be about 1 ng/ mL. This is based on typical values for bioavailability of 70% and total clearance of about 7 L/h (CLrenal 4 L/h, CLnonrenal 3 L/h). If the patient has heart failure, the nonrenal (hepatic) clearance might be halved because of hepatic congestion and hypoxia, so the expected clearance would become 5.5 L/h. The concentration is then expected to be about 1.3 ng/mL. Suppose that the concentration actually measured is 2 ng/mL. Common sense would suggest halving the daily dose to achieve a target concentration of 1 ng/mL. This approach implies a revised clearance of 3.5 L/h. The smaller clearance compared with the expected value of 5.5 L/h may reflect additional renal functional impairment due to heart failure.


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Pharmacology_Katzung. This technique will often be misleading if steady state has not been reached. At least a week of regular dosing (four half-lives) must elapse before the implicit method will be reliable. Benet LZ, Hoener B: Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002;71:115. Holford NHG: Pharmacokinetic and pharmacodynamic principles, 2013. http:// holford.fmhs.auckland.ac.nz/teaching/pharmacometrics/advanced.php. Holford NHG: Target concentration intervention: Beyond Y2K. Br J Clin Pharmacol 1999;48:9. Holford N, Heo YA, Anderson B: A pharmacokinetic standard for babies and adults. J Pharm Sci 2013;102:2941. Holford NHG, Sheiner LB: Understanding the dose-effect relationship. Clin Pharmacokinet 1981;6:429. * The Cockcroft-Gault equation is given in Chapter 60. CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action


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Pharmacology_Katzung. Pharmacokinet 1981;6:429. * The Cockcroft-Gault equation is given in Chapter 60. CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action Sixty-seven percent of total standard digoxin clearance is renal, so the standard renal clearance is 0.67 × 9 L/h = 6 L/h/70 kg with creatinine clearance of 100 mL/min and nonrenal clearance is (1 0.67) × 9 L/h = 3 L/h/70 kg (see Table 3–1 for standard pharmacokinetic parameters). Her predicted creatinine clearance is 22 mL/min (Cockcroft and Gault), so for digoxin, her renal clearance is 6 × 22/100 × 60/70 = 1.1 L/h, nonrenal clearance 2.7 × 60/70 = 2.6 L/h, and total clearance 3.7 L/h. The parenteral maintenance dose rate is 1 mcg/L × 3.7 L/h = 3.7 mcg/h. Once-a-day oral dosing with bioavailability of 0.7 would require a daily maintenance dose of 3.7/0.7 × 24 = 127 mcg/day. A practical dose would be two 62.5 mcg tablets per day. Maria Almira Correia, PhD


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Pharmacology_Katzung. A 40-year-old woman presents to the emergency department of her local hospital somewhat disoriented, complaining of midsternal chest pain, abdominal pain, shaking, and vomiting for 2 days. She admits to having taken a “handful” of Lorcet (hydrocodone/acetaminophen, an opioid/nonopioid analgesic combination), Soma (carisoprodol, a centrally acting muscle relaxant), and Cymbalta (duloxetine HCl, an antidepressant/ antifibromyalgia agent) 2 days earlier. On physical examina-tion, the sclera of her eyes shows yellow discoloration. Labora-tory analyses of blood drawn within an hour of her admission reveal abnormal liver function as indicated by the increased indices: alkaline phosphatase 302 (41–133),* alanine amino-transferase (ALT) 351 (7–56),* aspartate aminotransferase (AST) 1045 (0–35),* bilirubin 3.33 mg/dL (0.1–1.2),* and pro-thrombin time of 19.8 seconds (11–15).* In addition, plasma bicarbonate is reduced, and she has ~45% reduced glomerular filtration rate from the normal value


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Pharmacology_Katzung. bilirubin 3.33 mg/dL (0.1–1.2),* and pro-thrombin time of 19.8 seconds (11–15).* In addition, plasma bicarbonate is reduced, and she has ~45% reduced glomerular filtration rate from the normal value at her age, elevated serum creatinine and blood urea nitrogen, markedly reduced blood glucose of 35 mg/dL, and a plasma acetaminophen concentra-tion of 75 mcg/mL (10–20).*Her serum titer is significantly positive for hepatitis C virus (HCV). Given these data, how would you proceed with the management of this case? *Normal values are in parentheses.


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Pharmacology_Katzung. Humans are exposed daily to a wide variety of foreign compounds called xenobiotics—substances absorbed across the lungs or skin or, more commonly, ingested either unintentionally as compounds present in food and drink or deliberately as drugs for therapeutic or “recreational” purposes. Exposure to environmental xenobiotics may be inadvertent and accidental or—when they are present as components of air, water, and food—inescapable. Some xenobiotics are innocuous, but many can provoke biologic responses. Such biologic responses often depend on conversion of the absorbed substance into an active metabolite. The discussion that follows is applicable to xenobiotics in general (including drugs) and to some extent to endogenous compounds. WHY IS DRUG BIOTRANSFORMATION NECESSARY?


Pharmacology_Katzung

Pharmacology_Katzung. The mammalian drug biotransformation systems are thought to have first evolved from the need to detoxify and eliminate plant and bacterial bioproducts and toxins, which later extended to drugs and other environmental xenobiotics. Renal excretion plays a pivotal role in terminating the biologic activity of some drugs, particularly those that have small molecular volumes or possess polar characteristics, such as functional groups that are fully ionized at physiologic pH. However, many drugs do not possess such physicochemical properties. Pharmacologically active organic molecules tend to be lipophilic and remain unionized or only partially ionized at physiologic pH; these are readily reabsorbed from the glomerular filtrate in the nephron. Certain lipophilic compounds are often strongly bound to plasma proteins and may not be readily filtered at the glomerulus. Consequently, most drugs would have a prolonged duration of action if termination of their action depended solely on renal


Pharmacology_Katzung

Pharmacology_Katzung. bound to plasma proteins and may not be readily filtered at the glomerulus. Consequently, most drugs would have a prolonged duration of action if termination of their action depended solely on renal excretion.


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Pharmacology_Katzung. An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds.


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Pharmacology_Katzung. Metabolic products are often less pharmacodynamically active than the parent drug and may even be inactive. However, some biotransformation products have enhanced activity or toxic properties. It is noteworthy that the synthesis of endogenous substrates such as steroid hormones, cholesterol, active vitamin D congeners, and bile acids involves many pathways catalyzed by enzymes associated with the metabolism of xenobiotics. Finally, drug-metabolizing enzymes have been exploited in the design of pharmacologically inactive prodrugs that are converted to active molecules in the body. Most metabolic biotransformations occur at some point between absorption of the drug into the circulation and its renal elimination. A few transformations occur in the intestinal lumen or intestinal wall. In general, all of these reactions can be assigned to one of two major categories called phase I and phase II reactions (Figure 4–1).


Pharmacology_Katzung

Pharmacology_Katzung. Phase I reactions usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (–OH, –NH2, –SH). Often these metabolites are inactive, although in some instances activity is only modified or even enhanced. If phase I metabolites are sufficiently polar, they may be readily excreted. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with the newly incorporated functional group to form a highly polar conjugate. Such conjugation or synthetic reactions are the hallmarks of phase II metabolism. A great variety of drugs undergo these sequential biotransformation reactions, although in some instances, the parent drug may already possess a functional group that may form a conjugate directly. For example, the hydrazide moiety of isoniazid is known to form an


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 4–2 Phase II activation of isoniazid (INH) to a hepatotoxic metabolite. N-acetyl conjugate in a phase II reaction. This conjugate is then a substrate for a phase I type reaction, namely, hydrolysis to isonicotinic acid (Figure 4–2). Thus, phase II reactions may actually precede phase I reactions. WHERE DO DRUG BIOTRANSFORMATIONS OCCUR? Although every tissue has some ability to metabolize drugs, the liver is the principal organ of drug metabolism. Other tissues that display considerable activity include the gastrointestinal tract, the lungs, the skin, the kidneys, and the brain. After oral administration, many drugs (eg, isoproterenol, meperidine, pentazocine, morphine) are absorbed intact from the small intestine and transported first FIGURE 4–1 Phase I and phase II reactions, and direct elimination, in drug biodisposition. Phase II reactions may also precede phase I reactions.


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Pharmacology_Katzung. via the portal system to the liver, where they undergo exten-and fractionation of the cell, they re-form into vesicles called sive metabolism. This process is called the first-pass effect (see microsomes. Microsomes retain most of the morphologic and Chapter 3). Some orally administered drugs (eg, clonazepam, functional characteristics of the intact membranes, including chlorpromazine, cyclosporine) are more extensively metabolized the rough and smooth surface features of the rough (ribosomein the intestine than in the liver, while others (eg, midazolam) studded) and smooth (no ribosomes) endoplasmic reticulum. undergo significant (~50%) intestinal metabolism. Thus, intesti-Whereas the rough microsomes tend to be dedicated to protein nal metabolism can contribute to the overall first-pass effect, and synthesis, the smooth microsomes are relatively rich in enzymes individuals with compromised liver function may rely increasingly responsible for oxidative drug metabolism. In particular,


Pharmacology_Katzung

Pharmacology_Katzung. effect, and synthesis, the smooth microsomes are relatively rich in enzymes individuals with compromised liver function may rely increasingly responsible for oxidative drug metabolism. In particular, they on such intestinal metabolism for drug elimination. Compromise contain the important class of enzymes known as the mixed funcof intestinal metabolism of certain drugs (eg, felodipine, cyclo-tion oxidases (MFOs), or monooxygenases. The activity of these sporine A) can also result in significant elevation of their plasma enzymes requires both a reducing agent (nicotinamide adenine levels and clinically relevant drug-drug interactions (DDIs, see dinucleotide phosphate [NADPH]) and molecular oxygen; in a below). First-pass effects may limit the bioavailability of orally typical reaction, one molecule of oxygen is consumed (reduced) administered drugs (eg, lidocaine) so greatly that alternative routes per substrate molecule, with one oxygen atom appearing in the of administration must be


Pharmacology_Katzung

Pharmacology_Katzung. molecule of oxygen is consumed (reduced) administered drugs (eg, lidocaine) so greatly that alternative routes per substrate molecule, with one oxygen atom appearing in the of administration must be used to achieve therapeutically effective product and the other in the form of water. blood levels. Furthermore, the lower gut harbors intestinal micro-In this oxidation-reduction process, two microsomal enzymes organisms that are capable of many biotransformation reactions. play a key role. The first of these is a flavoprotein, NADPH-In addition, drugs may be metabolized by gastric acid (eg, peni-cytochrome P450 oxidoreductase (POR, or CPR). One mole cillin), by digestive enzymes (eg, polypeptides such as insulin), of this enzyme contains 1 mol each of flavin mononucleotide or by enzymes in the wall of the intestine (eg, sympathomimetic (FMN) and flavin adenine dinucleotide (FAD). The second catecholamines). microsomal enzyme is a hemoprotein called cytochrome P450,


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Pharmacology_Katzung. Although drug biotransformation in vivo can occur by spon-which serves as the terminal oxidase. In fact, the microsomal taneous, noncatalyzed chemical reactions, most transformations membrane harbors multiple forms of this hemoprotein, and are catalyzed by specific cellular enzymes. At the subcellular level, this multiplicity is increased by repeated administration of or these enzymes may be located in the endoplasmic reticulum, exposure to exogenous chemicals (see text that follows). The mitochondria, cytosol, lysosomes, or even the nuclear envelope or name cytochrome P450 (abbreviated as P450 or CYP) is derived from the spectral properties of this hemoprotein. In its reduced plasma membrane.


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Pharmacology_Katzung. (ferrous) form, it binds carbon monoxide to give a complex that absorbs light maximally at 450 nm. The relative abundance MICROSOMAL MIXED FUNCTION of P450s, compared with that of the reductase in the liver, OXIDASE SYSTEM & PHASE I REACTIONS contributes to making P450 heme reduction a rate-limiting step in hepatic drug oxidations. Many drug-metabolizing enzymes are located in the lipophilic Microsomal drug oxidations require P450, P450 reductase, endoplasmic reticulum membranes of the liver and other tissues. NADPH, and molecular oxygen. A simplified scheme of the When these lamellar membranes are isolated by homogenization oxidative cycle is presented in Figure 4–3. Briefly, oxidized (Fe+3) FIGURE 4–3 Cytochrome P450 cycle in drug oxidations. e–, electron; RH, parent drug; ROH, oxidized metabolite.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 4–3 Cytochrome P450 cycle in drug oxidations. e–, electron; RH, parent drug; ROH, oxidized metabolite. P450 combines with a drug substrate to form a binary complex (step 1). NADPH donates an electron to the flavoprotein P450 reductase, which in turn reduces the oxidized P450-drug complex (step 2). A second electron is introduced from NADPH via the same P450 reductase, which serves to reduce molecular oxygen and to form an “activated oxygen”–P450–substrate complex (step 3). This complex in turn transfers activated oxygen to the drug substrate to form the oxidized product (step 4).


Pharmacology_Katzung

Pharmacology_Katzung. The potent oxidizing properties of this activated oxygen permit oxidation of a large number of substrates. Substrate specificity is very low for this enzyme complex. High lipid solubility is the only common structural feature of the wide variety of structurally unrelated drugs and chemicals that serve as substrates in this system (Table 4–1). However, compared with many other enzymes including phase II enzymes, P450s are remarkably sluggish catalysts, and their drug biotransformation reactions are slow.


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Pharmacology_Katzung. Gene arrays combined with immunoblotting analyses of microsomal preparations, as well as the use of relatively selective functional markers and selective P450 inhibitors, have identified numerous P450 isoforms (CYP: 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 4A11, and 7) in the human liver. Of these, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 appear to be the most important forms, accounting for approximately 15%, 4%, 1%, 20%, 5%, 10%, and 30%, respectively, of the total human liver P450 content. Together, they are responsible for catalyzing the bulk of the hepatic drug and xenobiotic metabolism (Table 4–2, Figure 4–4).


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Pharmacology_Katzung. It is noteworthy that CYP3A4 alone is responsible for the metabolism of over 50% of the prescription drugs metabolized by the liver. The involvement of individual P450s in the metabolism of a given drug may be screened in vitro by means of selective functional markers, selective chemical P450 inhibitors, and P450 antibodies. In vivo, such screening may be accomplished by means of relatively selective noninvasive markers, which include breath tests or urinary analyses of specific metabolites after administration of a P450-selective substrate probe.