Chapter 3. Principles of Clinical Pharmacology

Chapter 3 Chapter 3. Principles of Clinical Pharmacology Principles of Clinical Pharmacology: Introduction Indications for Drug Therapy Principles of Pharmacokinetics Bioavailability First-Order Distribution and Elimination Drug Distribution Plasma Protein Binding Clearance Active Drug Metabolites Principles of Pharmacodynamics Principles of Dose Selection Concentration of Drugs in Plasma As a Guide to Therapy Determination of Maintenance Dose Effects of Disease on Drug Concentration and Response Renal Disease Liver Disease Heart Failure and Shock Drug Use in the Elderly Genetic Determinants of the Response to Drugs Principles of Genetic Variation and Human Traits Genetically Determined Drug Disposition and Variable Effects Variability in the Molecular Targets with Which Drugs Interact Polymorphisms That Modulate the Biologic Context Within Which the Drug-Target Interactions Occur Prospects for Incorporating Genetic Information into Clinical Practice Interactions between Drugs Pharmacokinetic Interactions Causing Diminished Drug Delivery to Target Sites Drug Interactions Not Mediated by Changes in Drug Disposition Adverse Reactions to Drugs Epidemiology Etiology Toxicity Unrelated to a Drug's Primary Pharmacologic Activity Diagnosis and Treatment of Adverse Drug Reactions Summary Acknowledgment Further Reading Principles of Clinical Pharmacology: Introduction Drugs are the cornerstone of modern therapeutics. Nevertheless, it is well recognized among physicians and among the lay community that the outcome of drug therapy varies widely among individuals. While this variability has been perceived as an unpredictable, and therefore inevitable, accompaniment of drug therapy, this is not the case. The goal of this chapter is to describe the principles of clinical pharmacology that can be used for the safe and optimal use of available and new drugs. Drugs interact with specific target molecules to produce their beneficial and adverse effects. The chain of events between administration of a drug and production of these effects in the body can be divided into two important components, both of which contribute to variability in drug actions. The first component comprises the processes that determine drug delivery to, and removal from, molecular targets. The resultant description of the relationship between drug concentration and time is termed pharmacokinetics. The second component of variability in drug action comprises the processes that determine variability in drug actions despite equivalent drug delivery to effector drug sites. This description of the relationship between drug concentration and effect is termed pharmacodynamics. As discussed further below, pharmacodynamic variability can arise as a result of variability in function of the target molecule itself or of variability in the broad biologic context in which the drug-target interaction occurs to achieve drug effects. Two important goals of the discipline of clinical pharmacology are (1) to provide a description of conditions under which drug actions vary among human subjects; and (2) to determine mechanisms underlying this variability, with the goal of improving therapy with available drugs as well as pointing to new drug mechanisms that may be effective in the treatment of human disease. The first steps in the discipline were empirical descriptions of the influence of disease X on drug action Y or of individuals or families with unusual sensitivities to adverse drug effects. These important descriptive findings are now being replaced by an understanding of the molecular mechanisms underlying variability in drug actions. Thus, the effects of disease, drug coadministration, or familial factors in modulating drug action can now be reinterpreted as variability in expression or function of specific genes whose products determine pharmacokinetics and pharmacodynamics. Nevertheless, it is the personal interaction of the patient with the physician or other health care provider that first identifies unusual variability in drug actions; maintained alertness to unusual drug responses continues to be a key component of improving drug safety. Unusual drug responses, segregating in families, have been recognized for decades and initially defined the field of pharmacogenetics. Now, with an increasing appreciation of common polymorphisms across the human genome, comes the opportunity to reinterpret descriptive mechanisms of variability in drug action as a consequence of specific DNA polymorphisms, or sets of DNA polymorphisms, among individuals. This approach defines the nascent field of pharmacogenomics, which may hold the opportunity of allowing practitioners to integrate a molecular understanding of the basis of disease with an individual's genomic makeup to prescribe personalized, highly effective, and safe therapies. Indications for Drug Therapy It is self-evident that the benefits of drug therapy should outweigh the risks. Benefits fall into two broad categories: those designed to alleviate a symptom, and those designed to prolong useful life. An increasing emphasis on the principles of evidence-based medicine and techniques such as large clinical trials and meta-analyses have defined benefits of drug therapy in specific patient subgroups. Establishing the balance between risk and benefit is not always simple: for example, therapies that provide symptomatic benefits but shorten life may be entertained in patients with serious and highly symptomatic diseases such as heart failure or cancer. These decisions illustrate the continuing highly personal nature of the relationship between the prescriber and the patient. Some adverse effects are so common, and so readily associated with drug therapy, that they are identified very early during clinical use of a drug. On the other hand, serious adverse effects may be sufficiently uncommon that they escape detection for many years after a drug begins to be widely used. The issue of how to identify rare but serious adverse effects (that can profoundly affect the benefit-risk perception in an individual patient) has not been satisfactorily resolved. Potential approaches range from an increased understanding of the molecular and genetic basis of variability in drug actions to expanded postmarketing surveillance mechanisms. None of these have been completely effective, so practitioners must be continuously vigilant to the possibility that unusual symptoms may be related to specific drugs, or combinations of drugs, that their patients receive. Beneficial and adverse reactions to drug therapy can be described by a series of dose-response relations (Fig. 3-1). Well-tolerated drugs demonstrate a wide margin, termed the therapeutic ratio, therapeutic index, or therapeutic window, between the doses required to produce a therapeutic effect and those producing toxicity. In cases where there is a similar relationship between plasma drug concentration and effects, monitoring plasma concentrations can be a highly effective aid in managing drug therapy, by enabling concentrations to be maintained above the minimum required to produce an effect and below the concentration range likely to produce toxicity. Such monitoring has been most widely used to guide therapy with specific agents, such as certain antiarrhythmics, anticonvulsants, and antibiotics. Many of the principles in clinical pharmacology and examples outlined below—that can be applied broadly to therapeutics—have been developed in these arenas. Figure 3-1  The concept of a therapeutic ratio. Each panel illustrates the relationship between increasing dose and cumulative probability of a desired or adverse drug effect. Top. A drug with a wide therapeutic ratio, i.e., a wide separation of the two curves. Bottom. A drug with a narrow therapeutic ratio; here, the likelihood of adverse effects at therapeutic doses is increased because the curves are not well separated. Further, a steep dose-response curve for adverse effects is especially undesirable, as it implies that even small dosage increments may sharply increase the likelihood of toxicity. When there is a definable relationship between drug concentration (usually measured in plasma) and desirable and adverse effect curves, concentration may be substituted on the abscissa. Note that not all patients necessarily demonstrate a therapeutic response (or adverse effect) at any dose, and that some effects (notably some adverse effects) may occur in a dose-independent fashion. Principles of Pharmacokinetics The processes of absorption, distribution, metabolism, and elimination—collectively termed drug disposition—determine the concentration of drug delivered to target effector molecules. Mathematical analysis of these processes can define specific, and clinically useful, parameters that describe drug disposition. This approach allows prediction of how factors such as disease, concomitant drug therapy, or genetic variants affect these parameters, and how dosages therefore should be adjusted. In this way, the chances of undertreatment due to low drug concentrations or adverse effects due to high drug concentrations can be minimized. Bioavailability When a drug is administered intravenously, each drug molecule is by definition available to the systemic circulation. However, drugs are often administered by other routes, such as orally, subcutaneously, intramuscularly, rectally, sublingually, or directly into desired sites of action. With these other routes, the amount of drug actually entering the systemic circulation may be less than with the intravenous route. The fraction of drug available to the systemic circulation by other routes is termed bioavailability. Bioavailability may be <100% for two reasons: (1) absorption is reduced, or (2) the drug undergoes metabolism or elimination prior to entering the systemic circulation. Bioavailability (F) is defined as the area under the time-concentration curve (AUC) after a drug dose, divided by AUC after the same dose intravenously (Fig. 3-2A). Figure 3-2  Idealized time-plasma concentration curves after a single dose of drug. A. The time course of drug concentration after an instantaneous intravenous (IV) bolus or an oral dose in the one-compartment model shown. The area under the time-concentration curve is clearly less with the oral drug than the IV, indicating incomplete bioavailability. Note that despite this incomplete bioavailability, concentration after the oral dose can be higher than after the IV dose at some time points. The inset shows that the decline of concentrations over time is linear on a log-linear plot, characteristic of first-order elimination, and that oral and IV drug have the same elimination (parallel) time course. B. The decline of central compartment concentration when drug is both distributed to and from a peripheral compartment and eliminated from the central compartment. The rapid initial decline of concentration reflects not drug elimination but distribution. Absorption Drug administration by nonintravenous routes often involves an absorption process characterized by the plasma level increasing to a maximum value at some time after administration and then declining as the rate of drug elimination exceeds the rate of absorption (Fig. 3-2A). Thus, the peak concentration is lower and occurs later than after the same dose given by rapid intravenous injection. The extent of absorption may be reduced because a drug is incompletely released from its dosage form, undergoes destruction at its site of administration, or has physicochemical properties such as insolubility that prevent complete absorption from its site of administration. The rate of absorption can be an important consideration for determining a dosage regimen, especially for drugs with a narrow therapeutic ratio. If absorption is too rapid, then the resulting high concentration may cause adverse effects not observed with a more slowly absorbed formulation. At the other extreme, slow absorption is deliberately designed into "slow-release" or "sustained-release" drug formulations in order to minimize variation in plasma concentrations during the interval between doses, because the drug's rate of elimination is offset by an equivalent rate of absorption controlled by formulation factors (Fig. 3-3). Figure 3-3  Concentration excursions between doses at steady state as a function of dosing frequency. With less frequent dosing (blue), excursions are larger; this is acceptable for a wide therapeutic ratio drug (Fig. 3-1). For narrower therapeutic ratio drugs, more frequent dosing (red) may be necessary to avoid toxicity and maintain efficacy. Another approach is use of a sustained-release formulation (black) that in theory results in very small excursions even with infrequent dosing. Presystemic Metabolism or Elimination When a drug is administered orally, it must transverse the intestinal epithelium, the portal venous system, and the liver prior to entering the systemic circulation (Fig. 3-4). At each of these sites, drug availability may be reduced; this mechanism of reduction of systemic availability is termed presystemic elimination, or first-pass elimination, and its efficiency assessed as extraction ratio. Uptake into the enterocyte is a combination of passive and active processes, the latter mediated by specific drug uptake transport molecules. Once a drug enters the enterocyte, it may undergo metabolism, be transported into the portal vein, or undergo excretion back into the intestinal lumen. Both excretion into the intestinal lumen and metabolism decrease systemic bioavailability. Once a drug passes this enterocyte barrier, it may also undergo uptake (again often by specific uptake transporters such as the organic cation transporter or organic anion transporter) into the hepatocyte, where bioavailability can be further limited by metabolism or excretion into the bile. Figure 3-4  Mechanism of presystemic clearance. After drug enters the enterocyte, it can undergo metabolism, excretion into the intestinal lumen, or transport into the portal vein. Similarly, the hepatocyte may accomplish metabolism and biliary excretion prior to the entry of drug and metabolites to the systemic circulation. [Adapted by permission from DM Roden, in DP Zipes, J Jalife (eds): Cardiac Electrophysiology: From Cell to Bedside, 4th ed. Philadelphia, Saunders, 2003. Copyright 2003 with permission from Elsevier.] The drug transport molecule that has been most widely studied is P-glycoprotein, the product of the normal expression of the MDR1 gene. P-glycoprotein is expressed on the apical aspect of the enterocyte and on the canalicular aspect of the hepatocyte (Fig. 3-4); in both locations, it serves as an efflux pump, thus limiting availability of drug to the systemic circulation. Most drug metabolism takes place in the liver, although the enzymes accomplishing drug metabolism may be expressed, and hence drug metabolism may take place, in multiple other sites, including kidney, intestinal epithelium, lung, and plasma. Drug metabolism is generally conceptualized as "phase I," which generally results in more polar metabolites that are more readily excreted, and "phase II," during which specific endogenous compounds are conjugated to the drugs or their metabolites, again to enhance polarity and thus excretion. The major process during phase I is drug oxidation, generally accomplished by members of the cytochrome P450 (CYP) monooxygenase superfamily. CYPs that are especially important for drug metabolism (Table 3-1) include CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP1A2, and CYP2E1, and each drug may be a substrate for one or more of these enzymes. The enzymes that accomplish phase II reactions include glucuronyl-, acetyl-, sulfo- and methyltransferases. Drug metabolites may exert important pharmacologic activity, as discussed further below. Table 3–1. Molecular Pathways Mediating Drug Dispositiona Molecule Substratesc   Inhibitorsc   CYP3A Calcium channel blockers; antiarrhythmics (lidocaine, quinidine, mexiletine); HMG-CoA reductase inhibitors ("statins"; see text); cyclosporine, tacrolimus; indinavir, saquinavir, ritonavir Amiodarone; ketoconazole; itraconazole; erythromycin, clarithromycin; ritonavir CYP2D6b   Timolol, metoprolol, carvedilol; phenformin; codeine; propafenone, flecainide; tricyclic antidepressants; fluoxetine, paroxetine Quinidine (even at ultralow doses); tricyclic antidepressants; fluoxetine, paroxetine CYP2C9b   Warfarin; phenytoin; glipizide; losartan Amiodarone; fluconazole; phenytoin CYP2C19b   Omeprazole; mephenytoin   Thiopurine S-methyltransferaseb   6-Mercaptopurine, azathioprine   N-acetyl transferaseb   Isoniazid; procainamide; hydralazine; some sulfonamides   UGT1A1b   Irinotecan   Pseudocholinesteraseb   Succinylcholine   P-glycoprotein Digoxin; HIV protease inhibitors; many CYP3A substrates Quinidine; amiodarone; verapamil; cyclosporine; itraconazole; erythromycin aA listing of CYP substrates, inhibitors, and inducers is maintained at http://medicine.iupui.edu/flockhart/clinlist.htm _blank " http://medicine.iupui.edu/flockhart/clinlist.htm. bClinically important genetics variants described. Clinical Implications of Altered Bioavailability Some drugs undergo near-complete presystemic metabolism and thus cannot be administered orally. Lidocaine is an example; the drug is well absorbed but undergoes near-complete extraction in the liver, so only lidocaine metabolites (which may be toxic) appear in the systemic circulation following administration of the parent drug. Similarly, nitroglycerin cannot be used orally because it is completely extracted prior to reaching the systemic circulation. The drug is therefore used by the sublingual or transdermal routes, which bypass presystemic metabolism. Other drugs undergo very extensive presystemic metabolism but can still be administered by the oral route, using much higher doses than those required intravenously. Thus, a typical intravenous dose of verapamil would be 1 to 5 mg, compared to the usual single oral dose of 40 to 120 mg. Even small variations in the presystemic elimination of very highly extracted drugs such as propranolol or verapamil can cause large interindividual variations in systemic availability and effect. Oral amiodarone is 35 to 50% bioavailable because of poor solubility. Therefore, prolonged administration of usual oral doses by the intravenous route would be inappropriate. Administration of low-dose aspirin can result in exposure of cyclooxygenase in platelets in the portal vein to the drug, but systemic sparing because of first-pass deacylation in the liver. This is an example of presystemic metabolism being exploited to therapeutic advantage. First-Order Distribution and Elimination Most pharmacokinetic processes are first order; i.e., the rate of the process depends on the amount of drug present. In the simplest pharmacokinetic model (Fig. 3-2A), a drug bolus is administered instantaneously to a central compartment, from which drug elimination occurs as a first-order process. The first-order (concentration-dependent) nature of drug elimination leads directly to the relationship describing drug concentration (C) at any time (t) following the bolus: where Vc is the volume of the compartment into which drug is delivered and t1/2 is elimination half-life. As a consequence of this relationship, a plot of the logarithm of concentration vs time is a straight line (Fig. 3-2A, inset). Half-life is the time required for 50% of a first-order process to be complete. Thus, 50% of drug elimination is accomplished after one drug elimination half-life; 75% after two; 87.5% after three, etc. In practice, first-order processes such as elimination are near-complete after four to five half-lives. In some cases, drug is removed from the central compartment not only by elimination but also by distribution into peripheral compartments. In this case, the plot of plasm