InternalMed_Harrison

InternalMed_Harrison. Bayes’ rule, while illustrative as presented above, provides an unrealistically simple solution to most problems a clinician faces. Predictions based on multivariable statistical models, however, can more accurately address these more complex problems by accounting for specific patient characteristics. In particular, these models explicitly account for multiple possibly overlapping pieces of patient-specific information and assign a relative weight to each on the basis of its unique contribution to the prediction in question. For example, a logistic regression model to predict the probability of CAD considers all the relevant independent factors from the clinical examination and diagnostic testing and their significance instead of the limited data that clinicians can manage in their heads or with Bayes’ rule. However, despite this strength, prediction models are usually too complex computationally to use without a calculator or computer (although this limitation may be overcome once


InternalMed_Harrison

InternalMed_Harrison. or with Bayes’ rule. However, despite this strength, prediction models are usually too complex computationally to use without a calculator or computer (although this limitation may be overcome once medicine is practiced from a fully computerized platform).


InternalMed_Harrison

InternalMed_Harrison. To date, only a handful of prediction models have been validated properly (for example, Wells criteria for pulmonary embolism) (Table 3-2). The importance of independent validation in a population separate from the one used to develop the model cannot be overstated. An unvalidated prediction model should be viewed with the skepticism appropriate for any new drug or medical device that has not had rigorous clinical trial testing. When statistical models have been compared directly with expert clinicians, they have been found to be more consistent, as would be expected, but not significantly more accurate. Their biggest promise, then, may be in helping less-experienced clinicians identify critical discriminating patient characteristics and become more accurate in their predictions.


InternalMed_Harrison

InternalMed_Harrison. Over the last 40 years, many attempts have been made to develop computer systems to aid clinical decision-making and patient management. Conceptually attractive because computers offer ready access to the vast information available to today’s physicians, they may also support management decisions by making accurate predictions of outcome, simulating the whole decision process, or providing algorithmic guidance. Computer-based predictions using Bayesian or statistical regression models inform a clinical decision but do not actually reach a “conclusion” or “recommendation.” Artificial intelligence systems attempt to simulate or replace human reasoning with a computer-based analogue. To date, such approaches have achieved only limited success. Reminder or protocol-directed systems do not make predictions but use existing algorithms, such as guidelines, to guide clinical practice. In general, however, decision support systems have had little impact on practice. Reminder systems, although


InternalMed_Harrison

InternalMed_Harrison. predictions but use existing algorithms, such as guidelines, to guide clinical practice. In general, however, decision support systems have had little impact on practice. Reminder systems, although not yet in widespread use, have shown the most promise, particularly in correcting drug dosing and promoting adherence to guidelines. Checklists, as used by pilots for example, have garnered recent support as an approach to avoid or reduce errors.


InternalMed_Harrison

InternalMed_Harrison. Compared with the decision support methods discussed above, decision analysis represents a prescriptive approach to decision making in the face of uncertainty. Its principal application is risk, abundant uncertainty, trade-offs in the outcomes emphasizing a role for preferences, or absence of evidence due to an idiosyncratic feature. For a public health example, Fig. 3-3 displays a decision tree to evaluate strategies for screening for HIV infection. Infected individuals who are unaware of their illness cause up to of the initial diagnosis because of delayed diagnosis. Early identification offers the opportunity to prevent progression to AIDS through CD4 count and viral load monitoring and combination antiretroviral therapy and to reduce spread by reducing risky injection or sexual behaviors.


InternalMed_Harrison

InternalMed_Harrison. In 2003, the Centers for Disease Control and Prevention (CDC) proposed that routine universal HIV testing should be incorporated into standard adult medical care and, in part, cited a decision analysis model comparing HIV screening with usual care. Assuming a 1% prevalence of unidentified HIV infection in the population, routine screening of a cohort of 43-year-old men and women increased life expectancy by 5.5 days and lifetime costs by $194 per person screened, yielding an incremental cost-effectiveness ratio for screening versus usual care of $15,078 per quality-adjusted life-year (the additional cost to society to increase population health by 1 year of perfect health). Factors that influenced the results included assumptions about the effectiveness of behavior modification on subsequent sexual behavior, the benefits of early therapy for HIV infection, and the prevalence and incidence of HIV infection in the population targeted. This model, which required over 75 separate data


InternalMed_Harrison

InternalMed_Harrison. sexual behavior, the benefits of early therapy for HIV infection, and the prevalence and incidence of HIV infection in the population targeted. This model, which required over 75 separate data points, provided novel insights into a public health problem in the absence of a randomized clinical trial and helped weigh the pros and cons of such a health policy recommendation. Although such models have been developed for selected clinical problems, their benefit and application to individual real-time clinical management have yet to be demonstrated.


InternalMed_Harrison

InternalMed_Harrison. High-quality medical care begins with accurate diagnosis. Recently, diagnostic errors have been re-envisioned: the old view was that they were caused by a lack of sufficient skill of an individual clinician; the new view is that they represent a quality of care patient-safety problem traceable to breakdowns in the health care system. Whether this conceptual shift will lead to new ways to improve diagnosis is uncertain. An annual rate of diagnostic errors of 10–15%, possibly leading to 40,000 deaths in the United States, is commonly cited, but these figures are imprecise.


InternalMed_Harrison

InternalMed_Harrison. Solutions to the “diagnostic errors as a system of care problem” have focused on system-level approaches, such as decision support and other tools integrated into electronic medical records. The use of checklists has been proposed as a means of reducing some of the cognitive errors discussed earlier in the chapter, such as premature closure. Although checklists have been shown to be useful in certain medical contexts, such as operating rooms and intensive care units, their value in preventing diagnostic errors that lead to patient adverse events remains to be shown.


InternalMed_Harrison

InternalMed_Harrison. Clinical medicine is defined traditionally as a practice combining medical knowledge (including scientific evidence), intuition, and judgment in the care of patients (Chap. 1). EBM updates this construct by placing much greater emphasis on the processes by which clinicians gain knowledge of the most up-to-date and relevant clinical research 20,000 new cases of HIV infection annually FIgURE 3-3 Basic structure of decision model used to evaluate strategies for screen-in the United States, and about 40% of HIV-ing for HIV in the general population. HAART, highly active antiretroviral therapy. positive patients progress to AIDS within a year (Provided courtesy of G. Sanders, with permission.) to determine for themselves whether medical interventions alter the disease course and improve the length or quality of life. The meaning of practicing EBM becomes clearer through an examination of its four key steps: 1. Formulating the management question to be answered 2.


InternalMed_Harrison

InternalMed_Harrison. Formulating the management question to be answered 2. Searching the literature and online databases for applicable research data 3. Appraising the evidence gathered with regard to its validity and relevance 4. Integrating this appraisal with knowledge about the unique aspects of the patient (including the patient’s preferences about the possible outcomes) The process of searching the world’s research literature and appraising the quality and relevance of studies thus identified can be quite time-consuming and requires skills and training that most clinicians do not possess. Thus, identifying recent systematic overviews of the problem in question (Table 3-3) may offer the best starting point for most EBM searches.


InternalMed_Harrison

InternalMed_Harrison. Generally, the EBM tools listed in Table 3-3 provide access to research information in one of two forms. The first, primary research reports, is the original peer-reviewed research work that is published in medical journals and accessible through MEDLINE in abstract form. However, without training in using MEDLINE, quickly and efficiently locating reports that are on point in a huge sea of irrelevant or unhelpful citations may be difficult, and important studies could also be missed. The second form, systematic reviews, is the highest level of evidence in the hierarchy because it comprehensively summarizes the available evidence on a particular topic up to a certain date. To avoid the potential biases in review articles, predefined explicit search strategies and inclusion and exclusion criteria are used to find all of the relevant scientific research and grade its quality. The prototype for this kind of resource is the Cochrane Database of Systematic Reviews. When appropriate, a


InternalMed_Harrison

InternalMed_Harrison. criteria are used to find all of the relevant scientific research and grade its quality. The prototype for this kind of resource is the Cochrane Database of Systematic Reviews. When appropriate, a meta-analysis quantitatively summarizes the systematic review findings. The next two sections explicate the major types of clinical research reports available in the literature and the process of aggregating those data into meta-analyses.


InternalMed_Harrison

InternalMed_Harrison. SoURCES oF EVIdENCE: CLINICAL TRIALS ANd REgISTRIES The notion of learning from observation of patients is as old as medicine itself. Over the last 50 years, physicians’ understanding of how best to turn raw observation into useful evidence has evolved considerably. Case reports, personal anecdotal experience, and small single-center case series are now recognized as having severe limitations in validity and generalizability, and although they may generate hypotheses or be the first reports of adverse events, they have no role in formulating modern standards of practice. The major tools used to develop reliable evidence consist of the randomized clinical trial and the large observational registry. A registry or database typically is focused on a disease or syndrome (e.g., cancer, CAD, heart failure), a clinical procedure (e.g., bone marrow transplantation, coronary revascularization), or an administrative process (e.g., claims data used for billing and reimbursement).


InternalMed_Harrison

InternalMed_Harrison. By definition, in observational data, the investigator does not control patient care. Carefully collected prospective observational data, however, can achieve a level of evidence quality approaching that of major clinical trial data. At the other end of the spectrum, data collected retrospectively (e.g., chart review) are limited in form and content to what previous observers recorded, which may not include the specific research data being sought, e.g., claims data. Advantages of observational data include the inclusion of a broader population as encountered in practice than is typically represented in clinical trials because of their restrictive inclusion and exclusion criteria. In addition, observational data provide primary evidence for research questions when a randomized trial cannot be performed. For example, it would be difficult to randomize patients to test diagnostic or therapeutic strategies that are unproven but widely accepted in practice, and it would be unethical to


InternalMed_Harrison

InternalMed_Harrison. be performed. For example, it would be difficult to randomize patients to test diagnostic or therapeutic strategies that are unproven but widely accepted in practice, and it would be unethical to randomize based on sex, racial/ethnic group, socioeconomic status, or country of residence or to randomize patients to a potentially harmful intervention, such as smoking or deliberately overeating to develop obesity.


InternalMed_Harrison

InternalMed_Harrison. A well-done prospective observational study of a particular management strategy differs from a well-done randomized clinical trial most importantly by its lack of protection from treatment selection bias. The use of observational data to compare diagnostic or therapeutic strategies assumes that sufficient uncertainty exists in clinical practice to ensure that similar patients will be managed differently by different physicians. In short, the analysis assumes that a sufficient element of randomness (in the sense of disorder rather than in the formal statistical sense) exists in clinical management. In such cases, statistical models attempt to adjust for important imbalances to “level the playing field” so that a fair comparison among treatment options can be made. When management is clearly not random (e.g., all eligible left main CAD patients are referred for coronary bypass surgery), the problem may be too confounded (biased) for statistical correction, and observational data may not


InternalMed_Harrison

InternalMed_Harrison. not random (e.g., all eligible left main CAD patients are referred for coronary bypass surgery), the problem may be too confounded (biased) for statistical correction, and observational data may not provide reliable evidence.


InternalMed_Harrison

InternalMed_Harrison. In general, the use of concurrent controls is vastly preferable to that of historical controls. For example, comparison of current surgical management of left main CAD with left main CAD patients treated medically during the 1970s (the last time these patients were routinely treated with medicine alone) would be extremely misleading because “medical therapy” has substantially improved in the interim. MEDLINE National Library of Medicine database with cita-www.nlm.nih.gov Free via Internet. tions back to 1966.


InternalMed_Harrison

InternalMed_Harrison. MEDLINE National Library of Medicine database with cita-www.nlm.nih.gov Free via Internet. tions back to 1966. Randomized controlled clinical trials include the careful prospective design features of the best observational data studies but also include the use of random allocation of treatment. This design provides the best protection against measured and unmeasured confounding due to treatment selection bias (a major aspect of internal validity). However, the randomized trial may not have good external validity (generalizability) if the process of recruitment into the trial resulted in the exclusion of many patients seen in clinical practice.


InternalMed_Harrison

InternalMed_Harrison. Consumers of medical evidence need to be aware that randomized trials vary widely in their quality and applicability to practice. The process of designing such a trial often involves many compromises. For example, trials designed to gain U.S. Food and Drug Administration (FDA) approval for an investigational drug or device must fulfill regulatory requirements that may result in a trial population and design that differs substantially from what practicing clinicians would find most useful.


InternalMed_Harrison

InternalMed_Harrison. The Greek prefix meta signifies something at a later or higher stage of development. Meta-analysis is research that combines and summarizes the available evidence quantitatively. Although occasionally used to examine nonrandomized studies, meta-analysis is used most typically to summarize all randomized trials examining a particular therapy. Ideally, unpublished trials should be identified and included to avoid publication bias (i.e., missing “negative” trials that may not be published). Furthermore, the best meta-analyses obtain and analyze individual patient-level data from all trials rather than working only the summary data in published reports of each trial. Nonetheless, not all published meta-analyses yield reliable evidence for a particular problem, so their methodology should be scrutinized carefully to ensure proper study design and analysis. The results of a well-done meta-analysis are likely to be most persuasive if they include at least several large-scale, properly


InternalMed_Harrison

InternalMed_Harrison. be scrutinized carefully to ensure proper study design and analysis. The results of a well-done meta-analysis are likely to be most persuasive if they include at least several large-scale, properly performed randomized trials. Meta-analysis can especially help detect benefits when individual trials are inadequately powered (e.g., the benefits of streptokinase thrombolytic therapy in acute MI demonstrated by ISIS-2 in 1988 were evident by the early 1970s through meta-analysis). However, in cases in which the available trials are small or poorly done, meta-analysis should not be viewed as a remedy for the deficiency in primary trial data.


InternalMed_Harrison

InternalMed_Harrison. Meta-analyses typically focus on summary measures of relative treatment benefit, such as odds ratios or relative risks. Clinicians also should examine what absolute risk reduction (ARR) can be expected from the therapy. A useful summary metric of absolute treatment benefit is the number needed to treat (NNT) to prevent one adverse outcome event (e.g., death, stroke). NNT is simply 1/ARR. For example, if a hypothetical therapy reduced mortality rates over a 5-year follow-up by 33% (the relative treatment benefit) from 12% (control arm) to 8% (treatment arm), the ARR would be 12% – 8% = 4%, and the NNT would be 1/0.04, or 25. Thus, it would be necessary to treat 25 patients for 5 years to prevent 1 death. If the hypothetical treatment was applied to a lower-risk population, say, with a 6% 5-year mortality, the 33% relative treatment benefit would reduce absolute mortality by 2% (from 6% to 4%), and the NNT for the same therapy in this lower-risk group of patients would be 50. Although


InternalMed_Harrison

InternalMed_Harrison. 5-year mortality, the 33% relative treatment benefit would reduce absolute mortality by 2% (from 6% to 4%), and the NNT for the same therapy in this lower-risk group of patients would be 50. Although not always made explicit, comparisons of NNT estimates from different studies should account for the duration of follow-up used to create each estimate.


InternalMed_Harrison

InternalMed_Harrison. According to the 1990 Institute of Medicine definition, clinical practice guidelines are “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.” This definition emphasizes several crucial features of modern guideline development. First, guidelines are created by using the tools of EBM. In particular, the core of the development process is a systematic literature search followed by a review of the relevant peer-reviewed literature. Second, guidelines usually are focused on a clinical disorder (e.g., adult diabetes, stable angina pectoris) or a health care intervention (e.g., cancer screening). Third, the primary objective of guidelines is to improve the quality of medical care by identifying care practices that should be routinely implemented, based on high-quality evidence and high benefit-to-harm ratios for the interventions. Guidelines are intended to “assist” decision-making, not to define


InternalMed_Harrison

InternalMed_Harrison. that should be routinely implemented, based on high-quality evidence and high benefit-to-harm ratios for the interventions. Guidelines are intended to “assist” decision-making, not to define explicitly what decisions should be made in a particular situation, in part because evidence alone is never sufficient for clinical decision-making (e.g., deciding whether to intubate and administer antibiotics for pneumonia in a terminally ill individual, in an individual with dementia, or in an otherwise healthy 30-year-old mother).


InternalMed_Harrison

InternalMed_Harrison. Guidelines are narrative documents constructed by expert panels whose composition often is determined by interested professional organizations. These panels vary in the degree to which they represent all relevant stakeholders. The guideline documents consist of a series of specific management recommendations, a summary indication of the quantity and quality of evidence supporting each recommendation, an assessment of the benefit-to-harm ratio for the recommendation, and a narrative discussion of the recommendations. Many recommendations simply reflect the expert consensus of the guideline panel because literature-based evidence is absent. The final step in guideline construction is peer review, followed by a final revision in response to the critiques provided. To improve the reliability and trustworthiness of guidelines, the Institute of Medicine has made methodologic recommendations for guideline development.


InternalMed_Harrison

InternalMed_Harrison. Guidelines are closely tied to the process of quality improvement in medicine through their identification of evidence-based best practices. Such practices can be used as quality indicators. Examples include the proportion of acute MI patients who receive aspirin upon admission to a hospital and the proportion of heart failure patients with a depressed ejection fraction treated with an ACE inhibitor.


InternalMed_Harrison

InternalMed_Harrison. In this era of EBM, it is tempting to think that all the difficult decisions practitioners face have been or soon will be solved and digested into practice guidelines and computerized reminders. However, EBM provides practitioners with an ideal rather than a finished set of tools with which to manage patients. Moreover, even with such evidence, it is always worth remembering that the response to therapy of the “average” patient represented by the summary clinical trial outcomes may not be what can be expected for the specific patient sitting in front of a physician in the clinic or hospital. In addition, meta-analyses cannot generate evidence when there are no adequate randomized trials, and most of what clinicians confront in practice will never be thoroughly tested in a randomized trial. For the foreseeable future, excellent clinical reasoning skills, experience supplemented by well-designed quantitative tools, and a keen appreciation for the role of individual patient preferences


InternalMed_Harrison

InternalMed_Harrison. For the foreseeable future, excellent clinical reasoning skills, experience supplemented by well-designed quantitative tools, and a keen appreciation for the role of individual patient preferences in their health care will continue to be of paramount importance in the practice of clinical medicine.


InternalMed_Harrison

Katrina Armstrong, Gary J. Martin

InternalMed_Harrison. Katrina Armstrong, Gary J. Martin


InternalMed_Harrison

InternalMed_Harrison. A primary goal of health care is to prevent disease or detect it early enough that intervention will be more effective. Tremendous progress has been made toward this goal over the last 50 years. Screening tests are available for many common diseases and encompass biochemical (e.g., cholesterol, glucose), physiologic (e.g., blood pressure, growth curves), radiologic (e.g., mammogram, bone densitometry), and cytologic (e.g., Pap smear) approaches. Effective preventive interventions have resulted in dramatic declines in mortality from many diseases, particularly infections. Preventive interventions include counseling about risk behaviors, vaccinations, medications, and, in some relatively uncommon settings, surgery. Preventive services (including screening tests, preventive interventions, and counseling) are different than other medical interventions because they are proactively administered to healthy individuals instead of in response to a symptom, sign, or diagnosis. Thus, the


InternalMed_Harrison

InternalMed_Harrison. and counseling) are different than other medical interventions because they are proactively administered to healthy individuals instead of in response to a symptom, sign, or diagnosis. Thus, the decision to recommend a screening test or preventive intervention requires a particularly high bar of evidence that testing and intervention are both practical and effective.


InternalMed_Harrison

InternalMed_Harrison. must be extremely low risk to have an acceptable benefit-to-harm ratio, the ability to target individuals who are more likely to develop disease could enable the application of a wider set of potential approaches and increase efficiency. Currently, there are many types of data that can predict disease incidence in an asymptomatic individual. Genomic data have received the most attention to date, at least in part because mutations in high-penetrance genes have clear implications for preventive care (Chap. 84). Women with mutations in either BRCA1 or BRCA2, the two major breast cancer susceptibility genes identified to date, have a markedly increased risk (5to 20-fold) of breast and ovarian cancer. Screening and prevention recommendations include prophylactic oophorectomy and breast magnetic resonance imaging (MRI), both of which are considered to incur too much harm for women at average cancer risk. Some women opt for prophylactic mastectomy to dramatically reduce their breast cancer


InternalMed_Harrison

InternalMed_Harrison. resonance imaging (MRI), both of which are considered to incur too much harm for women at average cancer risk. Some women opt for prophylactic mastectomy to dramatically reduce their breast cancer risk. Although the proportion of common disease explained by high-penetrance genes appears to be relatively small (5–10% of most diseases), mutations in rare, moderate-penetrance genes, and variants in low-penetrance genes, also contribute to the prediction of disease risk. The advent of affordable whole exome/whole genome sequencing is likely to speed the dissemination of these tests into clinical practice and may transform the delivery of preventive care.


InternalMed_Harrison

InternalMed_Harrison. Other forms of “omic” data also have the potential to provide important predictive information, including proteomics and metabolomics. These fields are earlier in development and have yet to move into clinical practice. Imaging and other clinical data may also be integrated into a risk-stratified paradigm as evidence grows about the predictive ability of these data and the feasibility of their collection. Of course, all of these data may also be helpful in predicting the risk of harms from screening or prevention, such as the risk of a false-positive mammogram. To the degree that this information can be incorporated into personalized screening and prevention strategies, it could also improve delivery and efficiency.


InternalMed_Harrison

InternalMed_Harrison. In addition to advances in risk prediction, there are several other factors that are likely to promote the importance of screening and prevention in the near term. New imaging modalities are being developed that promise to detect changes at the cellular and subcellular levels, greatly increasing the probability that early detection improves outcomes. The rapidly growing understanding of the biologic pathways underlying initiation and progression of many common diseases has the potential to transform the development of preventive interventions, including chemoprevention. Furthermore, screening and prevention offer the promise of both improving health and sparing the costs of disease treatment, an issue that has gained national attention with the continued growth in health care costs.


InternalMed_Harrison

InternalMed_Harrison. This chapter will review the basic principles of screening and prevention in the primary care setting. Recommendations for specific disorders such as cardiovascular disease, diabetes, and cancer are provided in the chapters dedicated to those topics. The basic principles of screening populations for disease were published by the World Health Organization in 1968 (Table 4-1). In general, screening is most effective when applied to relatively common disorders that carry a large disease burden (Table 4-2). The five leading causes of mortality in the United States are heart diseases, malignant neoplasms, accidents, cerebrovascular diseases, and chronic obstructive pulmonary disease. Thus, many screening strategies are targeted at these conditions. From a global health perspective, these conditions are priorities, but malaria, malnutrition, AIDS, tuberculosis, and violence also carry a heavy disease burden (Chap. 2). challenging for some common diseases. For example, although


InternalMed_Harrison

InternalMed_Harrison. challenging for some common diseases. For example, although Alzheimer’s disease is the sixth leading cause of death in the prInCIpLes of sCreenInG The condition should be an important health problem. There should be a treatment for the condition. Facilities for diagnosis and treatment should be available. There should be a latent stage of the disease. There should be a test or examination for the condition. The test should be acceptable to the population. The natural history of the disease should be adequately understood. There should be an agreed policy on whom to treat. The cost of finding a case should be balanced in relation to overall medical expenditure.


InternalMed_Harrison

InternalMed_Harrison. United States, there are no curative treatments and no evidence that early treatment improves outcomes. Lack of facilities for diagnosis and treatment is a particular challenge for developing countries and may change screening strategies, including the development of “see and treat” approaches such as those currently used for cervical cancer screening in some countries. A long latent or preclinical phase where early treatment increases the chance of cure is a hallmark of many cancers; for example, polypectomy prevents progression to colon cancer. Similarly, early identification of hypertension or hyperlipidemia allows therapeutic interventions that reduce the long-term risk of cardiovascular or cerebrovascular events. In contrast, lung cancer screening has historically proven more challenging because most tumors are not curable by the time they can be detected on a chest x-ray. However, the length of the preclinical phase also depends on the level of resolution of the screening test,


InternalMed_Harrison

InternalMed_Harrison. because most tumors are not curable by the time they can be detected on a chest x-ray. However, the length of the preclinical phase also depends on the level of resolution of the screening test, and this situation changed with the development of chest computed tomography (CT). Low-dose chest CT scanning can detect tumors earlier and was recently demonstrated to reduce lung cancer mortality by 20% in individuals who had at least a 30-pack-year history of smoking. The short interval between the ability to detect disease on a screening test and the development of incurable disease also contributes to the limited effectiveness of mammography screening in reducing breast cancer mortality among premenopausal women. Similarly, the early detection of prostate cancer may not lead to a difference in the mortality rate because the disease is often indolent and competing morbidities, such as coronary artery disease, may ultimately cause mortality (Chap. 100). This uncertainty about the natural


InternalMed_Harrison

InternalMed_Harrison. in the mortality rate because the disease is often indolent and competing morbidities, such as coronary artery disease, may ultimately cause mortality (Chap. 100). This uncertainty about the natural history is also reflected in the controversy about treatment of prostate cancer, further contributing to the challenge of screening in this disease. Finally, screening programs can incur significant economic costs that must be considered in the context of the available resources and alternative strategies for improving health outcomes.


InternalMed_Harrison

InternalMed_Harrison. Because screening and preventive interventions are recommended to asymptomatic individuals, they are held to a high standard for demonstrating a favorable risk-benefit ratio before implementation. In general, the principles of evidence-based medicine apply to demonstrating the efficacy of screening tests and preventive interventions, where randomized controlled trials (RCTs) with mortality outcomes are the gold standard. However, because RCTs are often not feasible, observational studies, such as case-control designs, have been used to assess the effectiveness of some interventions such as colorectal cancer screening. For some strategies, such as cervical cancer screening, the only data available are ecologic data demonstrating dramatic declines in mortality. Chapter 4 Screening and Prevention of Disease


InternalMed_Harrison

InternalMed_Harrison. Irrespective of the study design used to assess the effectiveness of screening, it is critical that disease incidence or mortality is the primary endpoint rather than length of disease survival. This is important because lead time bias and length time bias can create the appearance of an improvement in disease survival from a screening test when there is no actual effect. Lead time bias occurs because screening identifies a case before it would have presented clinically, thereby creating the perception that a patient lived longer after diagnosis simply by moving the date of diagnosis earlier rather than the date of death later. Length time bias occurs because screening is more likely to identify slowly progressive disease than rapidly progressive disease. Thus, within a fixed period of time, a screened population will have a greater proportion of these slowly progressive cases and will appear to have better disease survival than an unscreened population.


InternalMed_Harrison

InternalMed_Harrison. A variety of endpoints are used to assess the potential gain from screening and preventive interventions. 1.


InternalMed_Harrison

InternalMed_Harrison. 1. The absolute and relative impact of screening on disease incidence or mortality. The absolute difference in disease incidence or mortality between a screened and nonscreened group allows the comparison of size of the benefit across preventive services. A meta-analysis of Swedish mammography trials (ages 40–70) found that ~1.2 fewer women per 1000 would die from breast cancer if they were screened over a 12-year period. By comparison, ~3 lives per 1000 would be saved from colon cancer in a population (ages 50–75) screened with annual fecal occult blood testing (FOBT) over a 13-year period. Based on this analysis, colon cancer screening may actually save more women’s lives than does mammography. However, the relative impact of FOBT (30% reduction in colon cancer death) is similar to the relative impact of mammography (14–32% reduction in breast cancer death), emphasizing the importance of both relative and absolute comparisons. 2.


InternalMed_Harrison

InternalMed_Harrison. 2. The number of subjects screened to prevent disease or death in one individual. The inverse of the absolute difference in mortality is the number of subjects who would need to be screened or receive a preventive intervention to prevent one death. For example, 731 women ages 65–69 would need to be screened by dual-energy x-ray absorptiometry (DEXA) (and treated appropriately) to prevent one hip fracture from osteoporosis. 3.


InternalMed_Harrison

InternalMed_Harrison. 3. Increase in average life expectancy for a population. Predicted increases in life expectancy for various screening and preventive interventions are listed in Table 4-3. It should be noted, however, that the increase in life expectancy is an average that applies to a population, not to an individual. In reality, the vast majority of the population does not derive any benefit from a screening test or preventive intervention. A small subset of patients, however, will benefit greatly. For example, Pap smears do not benefit the 98% of women who never develop cancer of the cervix. However, for the 2% who would have developed cervical cancer, Pap smears may add as much as 25 years to their lives. Some studies suggest that a 1-month gain of life expectancy is a reasonable goal for a population-based screening or prevention strategy.


InternalMed_Harrison

InternalMed_Harrison. Just as with most aspects of medical care, screening and preventive interventions also incur the possibility of adverse outcomes. These adverse outcomes include side effects from preventive medications and vaccinations, false-positive screening tests, overdiagnosis of disease from screening tests, anxiety, radiation exposure from some screening tests, and discomfort from some interventions and screening tests. The risk of side effects from preventive medications is analogous to the use of medications in therapeutic settings and is considered in the Food and Drug Administration (FDA) approval process. Side effects from currently recommended vaccinations are primarily limited to discomfort and minor immune reactions. However, the concern about associations between vaccinations and serious adverse outcomes continues to limit the acceptance of many vaccinations despite the lack of data supporting the causal nature of these associations.


InternalMed_Harrison

InternalMed_Harrison. The possibility of a false-positive test occurs with nearly all screening tests, although the definition of what constitutes a false-positive Mammography: Women, 40–50 years 0–5 days Women, 50–70 years 1 month Pap smears, age 18–65 2–3 months Getting a 35-year-old smoker to quit 3–5 years


InternalMed_Harrison

InternalMed_Harrison. Beginning regular exercise for a 40-year-old 9 months–2 years man (30 min, 3 times a week) result often varies across settings. For some tests such as screening mammography and screening chest CT, a false-positive result occurs when an abnormality is identified that is not malignant, requiring either a biopsy diagnosis or short-term follow-up. For other tests such as Pap smears, a false-positive result occurs because the test identifies a wide range of potentially premalignant states, only a small percentage of which would ever progress to an invasive cancer. This risk is closely tied to the risk of overdiagnosis in which the screening test identifies disease that would not have presented clinically in the patient’s lifetime. Assessing the degree of overdiagnosis from a screening test is very difficult given the need for long-term follow-up of an unscreened population to determine the true incidence of disease over time. Recent estimates suggest that as much as 15–25% of breast


InternalMed_Harrison

InternalMed_Harrison. is very difficult given the need for long-term follow-up of an unscreened population to determine the true incidence of disease over time. Recent estimates suggest that as much as 15–25% of breast cancers identified by mammography screening and 15–37% of prostate cancers identified by prostate-specific antigen testing may never have presented clinically. Screening tests also have the potential to create unwarranted anxiety, particularly in conjunction with false-positive findings. Although multiple studies have documented increased anxiety through the screening process, there are few data suggesting this anxiety has long-term adverse consequences, including subsequent screening behavior. Screening tests that involve radiation (e.g., mammography, chest CT) add to the cumulative radiation exposure for the screened individual. The absolute amount of radiation is very small from any of these tests, but the overall impact of repeated exposure from multiple sources is still being


InternalMed_Harrison

InternalMed_Harrison. exposure for the screened individual. The absolute amount of radiation is very small from any of these tests, but the overall impact of repeated exposure from multiple sources is still being determined. Some preventive interventions (e.g., vaccinations) and screening tests (e.g., mammography) may lead to discomfort at the time of administration, but again, there is little evidence of long-term adverse consequences.


InternalMed_Harrison

InternalMed_Harrison. The decision to implement a population-based screening and prevention strategy requires weighing the benefits and harms, including the economic impact of the strategy. The costs include not only the expense of the intervention but also time away from work, downstream costs from false-positive results or adverse events, and other potential harms. Cost-effectiveness is typically assessed by calculating the cost per year of life saved, with adjustment for the quality of life impact of different interventions and disease states (i.e., quality-adjusted life-year). Typically, strategies that cost <$50,000 to $100,000 per quality-adjusted year of life saved are considered “cost-effective” (Chap. 3).


InternalMed_Harrison

InternalMed_Harrison. The U.S. Preventive Services Task Force (USPSTF) is an independent panel of experts in preventive care that provides evidence-based recommendations for screening and preventive strategies based on an assessment of the benefit-to-harm ratio (Tables 4-4 and 4-5). Because there are multiple advisory organizations providing recommendations for preventive services, the agreement among the organizations varies across the different services. For example, all advisory groups support screening for hyperlipidemia and colorectal cancer, whereas consensus is lower for breast cancer screening among women in their 40s and almost nonexistent for prostate cancer screening. Because the guidelines are only updated periodically, differences across advisory organizations may also reflect the data that were available when the guideline was issued. For example, multiple organizations have recently issued recommendations supporting lung cancer screening among heavy smokers based on the results of the


InternalMed_Harrison

InternalMed_Harrison. were available when the guideline was issued. For example, multiple organizations have recently issued recommendations supporting lung cancer screening among heavy smokers based on the results of the National Lung Screening Trial (NLST) published in 2011, whereas the USPSTF did not review lung cancer screening until 2014.


InternalMed_Harrison

InternalMed_Harrison. 29taBLe 4-4 sCreenInG tests reCoMMended By the u.s. preventIve servICes task forCe for averaGe-rIsk aduLts Abbreviations: DEXA, dual-energy x-ray absorptiometry; HCV, hepatitis C virus; HPV, human papillomavirus; PCR, polymerase chain reaction. Source: Adapted from the U.S. Preventive Services Task Force 2013. http://www.uspreventiveservicestaskforce.org/adultrec.htm.


InternalMed_Harrison

InternalMed_Harrison. For many screening tests and preventive interventions, the balance Although informed consent is important for all aspects of mediof benefits and harms may be uncertain for the average-risk population cal care, shared decision-making may be a particularly important but more favorable for individuals at higher risk for disease. Although approach to decisions about preventive services when the benefit-toage is the most commonly used risk factor for determining screening harm ratio is uncertain for a specific population. For example, many and prevention recommendations, the USPSTF also recommends expert groups, including the USPSTF, recommend an individualized some screening tests in populations with other risk factors for the dis-discussion about prostate cancer screening, because the decision-ease (e.g., syphilis). In addition, being at increased risk for the disease making process is complex and relies heavily on personal issues. often supports initiating screening at an earlier age


InternalMed_Harrison

InternalMed_Harrison. (e.g., syphilis). In addition, being at increased risk for the disease making process is complex and relies heavily on personal issues. often supports initiating screening at an earlier age than that recom-Some men may decline screening, whereas others may be more will-mended for the average-risk population. For example, when there is ing to accept the risks of an early detection strategy. Recent analysis a significant family history of breast or colon cancer, it is prudent to suggests that many men may be better off not screening for prostate initiate screening 10 years before the age at which the youngest family cancer because watchful waiting was the preferred strategy when member was diagnosed with cancer. quality-adjusted life-years were considered. Another example of


InternalMed_Harrison

InternalMed_Harrison. Chapter 4 Screening and Prevention of Disease shared decision-making involves the choice of techniques for colon cancer screening (Chap. 100). In controlled studies, the use of annual FOBT reduces colon cancer deaths by 15–30%. Flexible sigmoidoscopy reduces colon cancer deaths by ~60%. Colonoscopy offers the same benefit as or greater benefit than flexible sigmoidoscopy, but its use incurs additional costs and risks. These screening procedures have not been compared directly in the same population, but the estimated cost to society is similar: $10,000–25,000 per year of life saved. Thus, although one patient may prefer the ease of preparation, less time disruption, and the lower risk of flexible sigmoidoscopy, others may prefer the sedation and thoroughness of colonoscopy.


InternalMed_Harrison

InternalMed_Harrison. In considering the impact of preventive services, it is important to recognize that tobacco and alcohol use, diet, and exercise constitute the vast majority of factors that influence preventable deaths in developed countries. Perhaps the single greatest preventive health care measure is to help patients quit smoking (Chap. 470). However, efforts in these areas frequently involve behavior changes (e.g., weight loss, exercise, seat belts) or the management of addictive conditions (e.g., tobacco and alcohol use) that are often recalcitrant to intervention. Although these are challenging problems, evidence strongly supports the role of counseling by health care providers (Table 4-6) in effecting health behavior change. Educational campaigns, public policy changes, and community-based interventions have also proven to be important parts of a strategy for addressing these factors in some settings. Although the USPSTF found that the evidence was conclusive to recommend a relatively small set


InternalMed_Harrison

InternalMed_Harrison. have also proven to be important parts of a strategy for addressing these factors in some settings. Although the USPSTF found that the evidence was conclusive to recommend a relatively small set of counseling activities, counseling in areas such as physical activity and injury prevention (including seat belts and bicycle and motorcycle helmets) has become a routine part of primary care practice.


InternalMed_Harrison

InternalMed_Harrison. The implementation of disease prevention and screening strategies in practice is challenging. A number of techniques can assist physicians with the delivery of these services. An appropriately configured electronic health record can provide reminder systems that make it easier for physicians to track and meet guidelines. Some systems give patients secure access to their medical records, providing an additional means Alcohol and drug use 467, 468e


InternalMed_Harrison

InternalMed_Harrison. Alcohol and drug use 467, 468e Sexually transmitted infections 163, 226 to enhance adherence to routine screening. Systems that provide nurses and other staff with standing orders are effective for smoking prevention and immunizations. The Agency for Healthcare Research and Quality and the Centers for Disease Control and Prevention have developed flow sheets and electronic tools as part of their “Put Prevention into Practice” program (http://www.uspreventiveservicestaskforce.org/ tools.htm). Many of these tools use age categories to help guide implementation. Age-specific recommendations for screening and counseling are summarized in Table 4-7.


InternalMed_Harrison

InternalMed_Harrison. Many patients see a physician for ongoing care of chronic illnesses, and this visit provides an opportunity to include a “measure of prevention” for other health problems. For example, a patient seen for management of hypertension or diabetes can have breast cancer screening incorporated into one visit and a discussion about colon cancer screening at the next visit. Other patients may respond more favorably to a clearly defined visit that addresses all relevant screening and prevention interventions. Because of age or comorbidities, it may be appropriate with some patients to abandon certain screening and prevention activities, although there are fewer data about when to “sunset” these services. For many screening tests, the benefit of screening does not accrue until 5 to 10 years of follow-up, and there are generally few data to support continuing screening for most diseases past age 75. In addition, for patients with advanced diseases and limited life expectancy, there is


InternalMed_Harrison

InternalMed_Harrison. of follow-up, and there are generally few data to support continuing screening for most diseases past age 75. In addition, for patients with advanced diseases and limited life expectancy, there is considerable benefit from shifting the focus from screening procedures to the conditions and interventions more likely to affect quality and length of life.


InternalMed_Harrison

InternalMed_Harrison. mitted disease; UV, ultraviolet. principles of Clinical pharmacology Dan M. Roden Drugs are the cornerstone of modern therapeutics. Nevertheless, it is well recognized among physicians and in the lay community that the 5 Leading Causes of Age Group Age-Specific Mortality Screening Prevention Interventions to Consider for Each Specific Population Note: The numbers in parentheses refer to areas of risk in the mortality column affected by the specified intervention. Abbreviations: AAA, abdominal aortic aneurysm; ATV, all-terrain vehicle; HPV, human papillomavirus; MMR, measles-mumps-rubella; PSA, prostate-specific antigen; STD, sexually trans-


InternalMed_Harrison

InternalMed_Harrison. Chapter 5 Principles of Clinical Pharmacology 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.


InternalMed_Harrison

InternalMed_Harrison. 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 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 resulting 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 on drug actions and 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 often the


InternalMed_Harrison

InternalMed_Harrison. drug action can now be reinterpreted as variability in expression or function of specific genes whose products determine pharmacokinetics and pharmacodynamics. Nevertheless, it is often 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.


InternalMed_Harrison

InternalMed_Harrison. 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 and rare polymorphisms across the human genome, comes the opportunity to reinterpret descriptive mechanisms of variability in drug action as a consequence of specific DNA variants, or sets of variants, among individuals. This approach defines the 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.


InternalMed_Harrison

InternalMed_Harrison. Drug therapy is an ancient feature of human culture. The first treatments were plant extracts discovered empirically to be effective for indications like fever, pain, or breathlessness. This symptom-based empiric approach to drug development was supplanted in the twentieth century by identification of compounds targeting more fundamental biologic processes such as bacterial growth or elevated blood pressure; the term “magic bullet,” coined by Paul Ehrlich to describe the search for effective compounds for syphilis, captures the essence of the hope that understanding basic biologic processes will lead to highly effective new therapies. An integral step in modern drug development follows identification of a chemical lead with biologic activity with increasingly sophisticated medicinal chemistry-based structural modifications to develop compounds with specificity for the chosen target, lack of “off-target” effects, and pharmacokinetic properties suitable for human use (e.g., consistent


InternalMed_Harrison

InternalMed_Harrison. structural modifications to develop compounds with specificity for the chosen target, lack of “off-target” effects, and pharmacokinetic properties suitable for human use (e.g., consistent bioavailability, long elimination half-life, no high-risk pharmacokinetic features described further below).


InternalMed_Harrison

InternalMed_Harrison. A common starting point for contemporary drug development is basic biologic discovery that implicates potential target molecules: examples of such target molecules include HMG-CoA reductase or the BRAF V600E mutation in many malignant melanomas. The development of compounds targeting these molecules has not only revolutionized treatment for diseases such as hypercholesterolemia or malignant melanoma, but has also revealed new biologic features of disease. Thus, for example, initial spectacular successes with vemurafenib (which targets BRAF V600E) were followed by near-universal tumor relapse, strongly suggesting that inhibition of this pathway alone would be insufficient for tumor control. This reasoning, in turn, supports a view that many complex diseases will not lend themselves to cure by target ing a single magic bullet, but rather single drugs or combinations will a symptom and those designed to prolong useful life. An increasing emphasis on the principles of evidence-based


InternalMed_Harrison

InternalMed_Harrison. cure by target ing a single magic bullet, but rather single drugs or combinations will 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 broad patient populations. Establishing the balance between risk and benefit is not always simple. An increasing body of evidence supports the idea, with which practitioners are very familiar, that individual patients may display responses that are not expected from large population studies and often have comorbidities that typically exclude them from large clinical trials. In addition, 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 considerations illustrate the continuing, highly personal nature of the relationship between the prescriber and the


InternalMed_Harrison

InternalMed_Harrison. with serious and highly symptomatic diseases such as heart failure or cancer. These considerations illustrate the continuing, highly personal nature of the relationship between the prescriber and the patient.


InternalMed_Harrison

InternalMed_Harrison. Adverse Effects 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. By contrast, 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.


InternalMed_Harrison

InternalMed_Harrison. Therapeutic Index Beneficial and adverse reactions to drug therapy can be described by a series of dose-response relations (Fig. 5-1). 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 widely used to guide therapy with specific agents, such as certain antiarrhythmics, anticonvulsants, and antibiotics. Many of the principles in clinical pharmacology and examples need to attack multiple pathways whose perturbation results in disease.


InternalMed_Harrison

InternalMed_Harrison. The use of combination therapy in settings such as hypertension, tuber culosis, HIV infection, and many cancers highlights potential for such a “systems biology” view of drug therapy. It is true across all cultures and diseases that factors such as compliance, genetic variants affecting pharmacokinetics or pharmacodynamics, and drug interactions contribute to drug responses. In addition, cultureor ancestry-specific factors play a role. For example, the frequency of specific genetic variants modulating drug responses often varies by ancestry, as discussed later. Cost issues or cultural factors may determine the likelihood that specific drugs, drug combinations, or over-the-counter (OTC) remedies are prescribed. The broad principles of clinical pharmacology enunciated here can be used to analyze the mechanisms underlying successful or unsuccessful therapy with any drug. INdICATIoNS FoR dRUg THERAPY: RISK VERSUS BENEFIT


InternalMed_Harrison

InternalMed_Harrison. INdICATIoNS FoR dRUg THERAPY: RISK VERSUS BENEFIT It is self-evident that the benefits of drug therapy should outweigh the risks. Benefits fall into two broad categories: those designed to alleviate


InternalMed_Harrison

InternalMed_Harrison. FIgURE 5-1 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.


InternalMed_Harrison

InternalMed_Harrison. outlined below, which can be applied broadly to therapeutics, have been developed in these arenas. The processes of absorption, distribution, metabolism, and excretion—collectively termed drug disposition—determine the concentration of drug delivered to target effector molecules.


InternalMed_Harrison

InternalMed_Harrison. The processes of absorption, distribution, metabolism, and excretion—collectively termed drug disposition—determine the concentration of drug delivered to target effector molecules. When a drug is administered orally, subcutaneously, intramuscularly, rectally, sublingually, or directly into desired sites of action, the amount of drug actually entering the systemic circulation may be less than with the intravenous route (Fig. 5-2A). The fraction of drug available to the systemic circulation by other routes is termed bioavailability. Bioavailability may be <100% for two main reasons: (1) absorption is reduced, or (2) the drug undergoes metabolism or elimination prior to entering the systemic circulation. Occasionally, the administered drug formulation is inconsistent or has degraded with time; for example, the anticoagulant dabigatran degrades rapidly (over weeks) once exposed to air, so the amount administered may be less than prescribed.


InternalMed_Harrison

InternalMed_Harrison. When a drug is administered by a nonintravenous route, the peak concentration occurs later and is lower than after the same dose given by rapid intravenous injection, reflecting absorption from the site of administration (Fig. 5-2). 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. Slow absorption rates are deliberately designed into “slow-release” or “sustained-release” drug formulations in order to minimize variation in plasma concentrations during the interval between doses. “First-Pass” Effect When a drug is administered orally, it must traverse the intestinal epithelium, the portal venous system, and the liver prior


InternalMed_Harrison

InternalMed_Harrison. FIgURE 5-2 Idealized time-plasma concentration curves after a single dose of drug. A. The time course of drug concentration after an instantaneous 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 drugs have the same elimination (parallel) time course. B. The decline of central compartment concentration when drug is distributed both to and from a peripheral compartment and eliminated from the central compartment. The rapid initial decline of concentration reflects not drug elimination but distribution.


InternalMed_Harrison

InternalMed_Harrison. FIgURE 5-3 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.) to entering the systemic circulation (Fig. 5-3). Once a drug enters the enterocyte, it may undergo metabolism, be transported into the portal vein, or be excreted 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 be taken up into the hepatocyte, where bioavailability can be further limited by metabolism or excretion into the bile. This


InternalMed_Harrison

InternalMed_Harrison. bioavailability. Once a drug passes this enterocyte barrier, it may also be taken up into the hepatocyte, where bioavailability can be further limited by metabolism or excretion into the bile. This elimination in intestine and liver, which reduces the amount of drug delivered to the systemic circulation, is termed presystemic elimination, presystemic extraction, or first-pass elimination.


InternalMed_Harrison

InternalMed_Harrison. Drug movement across the membrane of any cell, including enterocytes and hepatocytes, is a combination of passive diffusion and active transport, mediated by specific drug uptake and efflux molecules. One widely studied drug transport molecule is P-glycoprotein, the product of the MDR1 gene. P-glycoprotein is expressed on the apical aspect of the enterocyte and on the canalicular aspect of the hepatocyte (Fig. 5-3). In both locations, it serves as an efflux pump, limiting availability of drug to the systemic circulation. P-glycoprotein–mediated drug efflux from cerebral capillaries limits drug brain penetration and is an important component of the blood-brain barrier.


InternalMed_Harrison

InternalMed_Harrison. Drug metabolism generates compounds that are usually more polar and, hence, more readily excreted than parent drug. Metabolism takes place predominantly in the liver but can occur at other sites such as kidney, intestinal epithelium, lung, and plasma. “Phase I” metabolism involves chemical modification, most often oxidation accomplished by members of the cytochrome P450 (CYP) monooxygenase superfamily. CYPs that are especially important for drug metabolism are presented in Table 5-1, and each drug may be a substrate for one or more of these enzymes. “Phase II” metabolism involves conjugation of specific endogenous compounds to drugs or their metabolites. The enzymes aInhibitors affect the molecular pathway, and thus may affect substrate. bClinically important genetic variants described; see Table 5-2. Note: A listing of CYP substrates, inhibitors, and inducers is maintained at http://medicine .iupui.edu/flockhart/table.htm.


InternalMed_Harrison

InternalMed_Harrison. Note: A listing of CYP substrates, inhibitors, and inducers is maintained at http://medicine .iupui.edu/flockhart/table.htm. that accomplish phase II reactions include glucuronyl-, acetyl-, sulfo-, and methyltransferases. Drug metabolites may exert important pharmacologic activity, as discussed further below. Clinical Implications of Altered Bioavailability Some drugs undergo near-complete presystemic metabolism and, thus, cannot be administered orally. 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.


InternalMed_Harrison

InternalMed_Harrison. Some drugs with very extensive presystemic metabolism can still be administered by the oral route, using much higher doses than those required intravenously. Thus, a typical intravenous dose of verapamil is 1–5 mg, compared to the usual single oral dose of 40–120 mg. 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 aspirin deacylation in the liver. This is an example of presystemic metabolism being exploited to therapeutic advantage.


InternalMed_Harrison

InternalMed_Harrison. Most pharmacokinetic processes, such as elimination, are first-order; that is, the rate of the process depends on the amount of drug present. Elimination can occasionally be zero-order (fixed amount eliminated per unit time), and this can be clinically important (see “Principles of Dose Selection”). In the simplest pharmacokinetic model (Fig. 5-2A), a drug bolus (D) is administered instantaneously to a central compartment, from which drug elimination occurs as a first-order process. Occasionally, central and other compartments correspond to physiologic spaces (e.g., plasma volume), whereas in others they are simply mathematical functions used to describe drug disposition. The first-order nature of drug elimination leads directly to the relationship describing drug concentration (C) at any time (t) following the bolus:


InternalMed_Harrison

InternalMed_Harrison. C = D • e(0.69/− tt1/2) where V c 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 versus time is a straight line (Fig. 5-2A, inset). Half-life is the time required for 50% of a first-order process to be complete. Thus, 50% of drug elimination is achieved 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–five half-lives.


InternalMed_Harrison

InternalMed_Harrison. 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 plasma concentration versus time after a bolus may demonstrate two (or more) exponential components (Fig. 5-2B). In general, the initial rapid drop in drug concentration represents not elimination but drug distribution into and out of peripheral tissues (also first-order processes), while the slower component represents drug elimination; the initial precipitous decline is usually evident with administration by intravenous but not by other routes. Drug concentrations at peripheral sites are determined by a balance between drug distribution to and redistribution from those sites, as well as by elimination. Once distribution is near-complete (four–five distribution half-lives), plasma and tissue concentrations decline in parallel.


InternalMed_Harrison

InternalMed_Harrison. Clinical Implications of Half-Life Measurements The elimination half-life not only determines the time required for drug concentrations to fall to near-immeasurable levels after a single bolus, it is also the sole determinant of the time required for steady-state plasma concentrations to be achieved after any change in drug dosing (Fig. 5-4). This applies to the initiation of chronic drug therapy (whether by multiple oral doses or by continuous intravenous infusion), a change in chronic drug dose or dosing interval, or discontinuation of drug. Steady state describes the situation during chronic drug administration when the amount of drug administered per unit time equals drug eliminated per unit time. With a continuous intravenous infusion, plasma concentrations at steady state are stable, while with chronic oral drug administration, plasma concentrations vary during the dosing interval but the time-concentration profile between dosing intervals is stable (Fig. 5-4).


InternalMed_Harrison

InternalMed_Harrison. In a typical 70-kg human, plasma volume is ∼3 L, blood volume is ∼5.5 L, and extracellular water outside the vasculature is ∼20 L. The volume of distribution of drugs extensively bound to plasma proteins but not to tissue components approaches plasma volume; warfarin is one such example. By contrast, for drugs highly bound to tissues, the volume of distribution can be far greater than any physiologic space. For example, the volume of distribution of digoxin and tricyclic antidepressants is hundreds of liters, obviously exceeding total-body volume. Such drugs are not readily removed by dialysis, an important consideration in overdose. Initiation of therapy Change of chronic therapy ChangedosingDose = D * 10th dose Dose = 2•D Dose = 2•D Dose = 0.5•D Discontinue drug Loading dose + dose = D Concentration


InternalMed_Harrison

InternalMed_Harrison. Initiation of therapy Change of chronic therapy ChangedosingDose = D * 10th dose Dose = 2•D Dose = 2•D Dose = 0.5•D Discontinue drug Loading dose + dose = D Concentration FIgURE 5-4 Drug accumulation to steady state. In this simulation, drug was administered (arrows) at intervals = 50% of the elimination half-life. Steady state is achieved during initiation of therapy after ∼5 elimination half-lives, or 10 doses. A loading dose did not alter the eventual steady state achieved. A doubling of the dose resulted in a doubling of the steady state but the same time course of accumulation. Once steady state is achieved, a change in dose (increase, decrease, or drug discontinuation) results in a new steady state in ∼5 elimination half-lives. (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.)


InternalMed_Harrison

InternalMed_Harrison. Clinical Implications of drug distribution In some cases, pharmacologic effects require drug distribution to peripheral sites. In this instance, the time course of drug delivery to and removal from these sites determines the time course of drug effects; anesthetic uptake into the central nervous system (CNS) is an example. loadIng doses For some drugs, the indication may be so urgent that administration of “loading” dosages is required to achieve rapid elevations of drug concentration and therapeutic effects earlier than with chronic maintenance therapy (Fig. 5-4). Nevertheless, the time required for true steady state to be achieved is still determined only by the elimination half-life.


InternalMed_Harrison

InternalMed_Harrison. rate of Intravenous admInIstratIon Although the simulations in Fig. 5-2 use a single intravenous bolus, this is usually inappropriate in practice because side effects related to transiently very high concentrations can result. Rather, drugs are more usually administered orally or as a slower intravenous infusion. Some drugs are so predictably lethal when infused too rapidly that special precautions should be taken to prevent accidental boluses. For example, solutions of potassium for intravenous administration >20 mEq/L should be avoided in all but the most exceptional and carefully monitored circumstances. This minimizes the possibility of cardiac arrest due to accidental increases in infusion rates of more concentrated solutions.


InternalMed_Harrison

InternalMed_Harrison. Transiently high drug concentrations after rapid intravenous administration can occasionally be used to advantage. The use of midazolam for intravenous sedation, for example, depends upon its rapid uptake by the brain during the distribution phase to produce sedation quickly, with subsequent egress from the brain during the redistribution of the drug as equilibrium is achieved. Similarly, adenosine must be administered as a rapid bolus in the treatment of reentrant supraventricular tachycardias (Chap. 276) to prevent elimination by very rapid (t1/2 of seconds) uptake into erythrocytes and endothelial cells before the drug can reach its clinical site of action, the atrioventricular node.


InternalMed_Harrison

InternalMed_Harrison. Clinical Implications of Altered Protein Binding Many drugs circulate in the plasma partly bound to plasma proteins. Since only unbound (free) drug can distribute to sites of pharmacologic action, drug response is related to the free rather than the total circulating plasma drug concentration. In chronic kidney or liver disease, protein binding may be decreased and thus drug actions increased. In some situations (myocardial infarction, infection, surgery), acute phase reactants transiently increase drug binding and thus decrease efficacy. These changes assume the greatest clinical importance for drugs that are highly protein-bound since even a small change in protein binding can result in large changes in free drug; for example, a decrease in binding from 99% to 98% doubles the free drug concentration from 1% to 2%. For some drugs (e.g., phenytoin), monitoring free rather than total drug concentrations can be useful.


InternalMed_Harrison

InternalMed_Harrison. Drug elimination reduces the amount of drug in the body over time. An important approach to quantifying this reduction is to consider that drug concentrations at the beginning and end of a time period are unchanged and that a specific volume of the body has been “cleared” of the drug during that time period. This defines clearance as volume/ time. Clearance includes both drug metabolism and excretion. Clinical Implications of Altered Clearance While elimination half-life determines the time required to achieve steady-state plasma concentration (C ss), the magnitude of that steady state is determined by clearance (Cl) and dose alone. For a drug administered as an intravenous infusion, this relationship is: C = dosing rate/Cl or dosing rate = Cl . C When drug is administered orally, the average plasma concentration within a dosing interval (C ) replaces C , and the dosage (dose avg,ss ss per unit time) must be increased if bioavailability (F) is less than 1:


InternalMed_Harrison

InternalMed_Harrison. Dose/time = Cl . C /F avg,ss Genetic variants, drug interactions, or diseases that reduce the activity of drug-metabolizing enzymes or excretory mechanisms lead to decreased clearance and, hence, a requirement for downward dose adjustment to avoid toxicity. Conversely, some drug interactions and genetic variants increase the function of drug elimination pathways, and hence, increased drug dosage is necessary to maintain a therapeutic effect. Metabolites may produce effects similar to, overlapping with, or distinct from those of the parent drug. Accumulation of the major metabolite of procainamide, N-acetylprocainamide (NAPA), likely accounts for marked QT prolongation and torsades des pointes ventricular tachycardia (Chap. 276) during therapy with procainamide. Neurotoxicity during therapy with the opioid analgesic meperidine is likely due to accumulation of normeperidine, especially in renal disease.


InternalMed_Harrison

InternalMed_Harrison. Prodrugs are inactive compounds that require metabolism to generate active metabolites that mediate the drug effects. Examples include many angiotensin-converting enzyme (ACE) inhibitors, the angiotensin receptor blocker losartan, the antineoplastic irinotecan, the anti-estrogen tamoxifen, the analgesic codeine (whose active metabolite morphine probably underlies the opioid effect during codeine administration), and the antiplatelet drug clopidogrel. Drug metabolism has also been implicated in bioactivation of procarcinogens and in generation of reactive metabolites that mediate certain adverse drug effects (e.g., acetaminophen hepatotoxicity, discussed below).


InternalMed_Harrison

InternalMed_Harrison. When plasma concentrations of active drug depend exclusively on a single metabolic pathway, any condition that inhibits that pathway (be it disease-related, genetic, or due to a drug interaction) can lead to dramatic changes in drug concentrations and marked variability in drug action. This problem of high-risk pharmacokinetics is especially pronounced in two settings. First, variability in bioactivation of a prodrug can lead to striking variability in drug action; examples include decreased CYP2D6 activity, which prevents analgesia by codeine, and decreased CYP2C19 activity, which reduces the antiplatelet effects of clopidogrel. The second setting is drug elimination that relies on


InternalMed_Harrison

InternalMed_Harrison. Chapter 5 Principles of Clinical Pharmacology a single pathway. In this case, inhibition of the elimination pathway by genetic variants or by administration of inhibiting drugs leads to marked elevation of drug concentration and, for drugs with a narrow therapeutic window, an increased likelihood of dose-related toxicity. Individuals with loss-of-function alleles in CYP2C9, responsible for metabolism of the active S-enantiomer of warfarin, appear to be at increased risk for bleeding. When drugs undergo elimination by multi-ple-drug metabolizing or excretory pathways, absence of one pathway (due to a genetic variant or drug interaction) is much less likely to have a large impact on drug concentrations or drug actions.


InternalMed_Harrison

InternalMed_Harrison. PRINCIPLES oF PHARMACodYNAMICS The onset of drug Action For drugs used in the urgent treatment of acute symptoms, little or no delay is anticipated (or desired) between the drug-target interaction and the development of a clinical effect. Examples of such acute situations include vascular thrombosis, shock, or status epilepticus.


InternalMed_Harrison

InternalMed_Harrison. For many conditions, however, the indication for therapy is less urgent, and a delay between the interaction of a drug with its pharmacologic target(s) and a clinical effect is clinically acceptable. Common pharmacokinetic mechanisms that can contribute to such a delay include slow elimination (resulting in slow accumulation to steady state), uptake into peripheral compartments, or accumulation of active metabolites. Another common explanation for such a delay is that the clinical effect develops as a downstream consequence of the initial molecular effect the drug produces. Thus, administration of a proton pump inhibitor or an H2-receptor blocker produces an immediate increase in gastric pH but ulcer healing that is delayed. Cancer chemotherapy similarly produces delayed therapeutic effects.


InternalMed_Harrison

InternalMed_Harrison. drug Effects May Be disease Specific A drug may produce no action or a different spectrum of actions in unaffected individuals compared to patients with underlying disease. Further, concomitant disease can complicate interpretation of response to drug therapy, especially adverse effects. For example, high doses of anticonvulsants such as phenytoin may cause neurologic symptoms, which may be confused with the underlying neurologic disease. Similarly, increasing dyspnea in a patient with chronic lung disease receiving amiodarone therapy could be due to drug, underlying disease, or an intercurrent cardiopulmonary problem. Thus, the presence of chronic lung disease may argue against the use of amiodarone.


InternalMed_Harrison

InternalMed_Harrison. While drugs interact with specific molecular receptors, drug effects may vary over time, even if stable drug and metabolite concentrations are maintained. The drug-receptor interaction occurs in a complex biologic milieu that can vary to modulate the drug effect. For example, ion channel blockade by drugs, an important anticonvulsant and anti-arrhythmic effect, is often modulated by membrane potential, itself a function of factors such as extracellular potassium or local ischemia. Receptors may be upor downregulated by disease or by the drug itself. For example, β-adrenergic blockers upregulate β-receptor density during chronic therapy. While this effect does not usually result in resistance to the therapeutic effect of the drugs, it may produce severe agonist-mediated effects (such as hypertension or tachycardia) if the blocking drug is abruptly withdrawn.


InternalMed_Harrison

InternalMed_Harrison. The desired goal of therapy with any drug is to maximize the likelihood of a beneficial effect while minimizing the risk of adverse effects. Previous experience with the drug, in controlled clinical trials or in postmarketing use, defines the relationships between dose or plasma concentration and these dual effects (Fig. 5-1) and has important implications for initiation of drug therapy: 1. The target drug effect should be defined when drug treatment is started. With some drugs, the desired effect may be difficult to measure objectively, or the onset of efficacy can be delayed for weeks or months; drugs used in the treatment of cancer and psychiatric disease are examples. Sometimes a drug is used to treat a symptom, such as pain or palpitations, and here it is the patient who will report whether the selected dose is effective. In yet other settings, such as anticoagulation or hypertension, the desired response can be repeatedly and objectively assessed by simple clinical or laboratory


InternalMed_Harrison

InternalMed_Harrison. the selected dose is effective. In yet other settings, such as anticoagulation or hypertension, the desired response can be repeatedly and objectively assessed by simple clinical or laboratory tests.


InternalMed_Harrison

InternalMed_Harrison. 2. The nature of anticipated toxicity often dictates the starting dose. If side effects are minor, it may be acceptable to start chronic therapy at a dose highly likely to achieve efficacy and down-titrate if side effects occur. However, this approach is rarely, if ever, justified if the anticipated toxicity is serious or life-threatening; in this circumstance, it is more appropriate to initiate therapy with the lowest dose that may produce a desired effect. In cancer chemotherapy, it is common practice to use maximum-tolerated doses. 3. The above considerations do not apply if these relationships between dose and effects cannot be defined. This is especially relevant to some adverse drug effects (discussed in further detail below) whose development are not readily related to drug dose. 4. If a drug dose does not achieve its desired effect, a dosage increase is justified only if toxicity is absent and the likelihood of serious toxicity is small.


InternalMed_Harrison

InternalMed_Harrison. 4. If a drug dose does not achieve its desired effect, a dosage increase is justified only if toxicity is absent and the likelihood of serious toxicity is small. Failure of Efficacy Assuming the diagnosis is correct and the correct drug is prescribed, explanations for failure of efficacy include drug interactions, noncompliance, or unexpectedly low drug dosage due to administration of expired or degraded drug. These are situations in which measurement of plasma drug concentrations, if available, can be especially useful. Noncompliance is an especially frequent problem in the long-term treatment of diseases such as hypertension and epilepsy, occurring in ≥25% of patients in therapeutic environments in which no special effort is made to involve patients in the responsibility for their own health. Multidrug regimens with multiple doses per day are especially prone to noncompliance.


InternalMed_Harrison

InternalMed_Harrison. Monitoring response to therapy, by physiologic measures or by plasma concentration measurements, requires an understanding of the relationships between plasma concentration and anticipated effects. For example, measurement of QT interval is used during treatment with sotalol or dofetilide to avoid marked QT prolongation that can herald serious arrhythmias. In this setting, evaluating the electrocardiogram at the time of anticipated peak plasma concentration and effect (e.g., 1–2 h postdose at steady state) is most appropriate. Maintained high vancomycin levels carry a risk of nephrotoxicity, so dosages should be adjusted on the basis of plasma concentrations measured at trough (predose). Similarly, for dose adjustment of other drugs (e.g., anticonvulsants), concentration should be measured at its lowest during the dosing interval, just prior to a dose at steady state (Fig. 5-4), to ensure a maintained therapeutic effect.


InternalMed_Harrison

InternalMed_Harrison. Concentration of drugs in Plasma as a guide to Therapy Factors such as interactions with other drugs, disease-induced alterations in elimination and distribution, and genetic variation in drug disposition combine to yield a wide range of plasma levels in patients given the same dose. Hence, if a predictable relationship can be established between plasma drug concentration and beneficial or adverse drug effect, measurement of plasma levels can provide a valuable tool to guide selection of an optimal dose, especially when there is a narrow range between the plasma levels yielding therapeutic and adverse effects. Monitoring is commonly used with certain types of drugs including many anticonvulsants, antirejection agents, antiarrhythmics, and antibiotics. By contrast, if no such relationship can be established (e.g., if drug access to important sites of action outside plasma is highly variable), monitoring plasma concentration may not provide an accurate guide to therapy (Fig. 5-5A).


InternalMed_Harrison

InternalMed_Harrison. The common situation of first-order elimination implies that average, maximum, and minimum steady-state concentrations are related linearly to the dosing rate. Accordingly, the maintenance dose may be adjusted on the basis of the ratio between the desired and measured concentrations at steady state; for example, if a doubling of the steady-state plasma concentration is desired, the dose should be doubled. This does not apply to drugs eliminated by zero-order kinetics (fixed amount per unit time), where small dosage increases will produce disproportionate increases in plasma concentration; examples include phenytoin and theophylline. Normal P-glycoprotein function and increased drug levels are associated 37 with adverse effects, drug dosages must 5 be reduced in patients with renal dysfunc tion to avoid toxicity. The antiarrhythmics renal excretion and carry a risk of QT pro-


InternalMed_Harrison

InternalMed_Harrison. Chapter 5 Principles of Clinical Pharmacology longation and arrhythmias if doses are not reduced in renal disease. In end-stage renal disease, sotalol has been given as 40 mg after dialysis (every second day), compared to the usual daily dose, 80–120 mg every 12 h. The extensive hepatic metabolism, so that renal Time failure has little effect on its plasma concentration. However, its metabolite, norme-Decreased P-glycoprotein function peridine, does undergo renal excretion, accumulates in renal failure, and probably accounts for the signs of CNS excitation, such as irritability, twitching, and seizures, that appear when multiple doses of meperi dine are administered to patients with renal disease. Protein binding of some drugs (e.g., phenytoin) may be altered in uremia, so measuring free drug concentration may be desirable.


InternalMed_Harrison

InternalMed_Harrison. In non-end-stage renal disease, changes in renal drug clearance are generally proportional to those in creatinine clear- ance, which may be measured directly or estimated from the serum creatinine (Chap. 333e). This estimate, coupled with the knowledge of how much drug is normally excreted renally versus nonrenally, allows an estimate of the dose adjustment required. In practice, most decisions involving dosing adjustment in patients with renal failure use published recommended adjustments in dosage or dosing interval based on the severity of renal dysfunction indicated by creatinine clearance. Any such modification of dose is a first approximation and should be followed by and clinical observation to further opti mize therapy for the individual patient. FIgURE 5-5 A. The efflux pump P-glycoprotein excludes drugs from the endothelium of capillaries in the brain and so constitutes a key element of the blood-brain barrier. Thus, reduced


InternalMed_Harrison

InternalMed_Harrison. FIgURE 5-5 A. The efflux pump P-glycoprotein excludes drugs from the endothelium of capillaries in the brain and so constitutes a key element of the blood-brain barrier. Thus, reduced P-glycoprotein function (e.g., due to drug interactions or genetically determined variability in gene transcription) increases penetration of substrate drugs into the brain, even when plasma LIVER dISEASE concentrations are unchanged. B. The graph shows an effect of a β1-receptor polymorphism on Standard tests of liver function are not use-receptor function in vitro. Patients with the hypofunctional variant (red) may display lesser heart-ful in adjusting doses in diseases like heparate slowing or blood pressure lowering on exposure to a receptor blocking agent. titis or cirrhosis. First-pass metabolism may


InternalMed_Harrison

InternalMed_Harrison. An increase in dosage is usually best achieved by changing the drug dose but not the dosing interval (e.g., by giving 200 mg every 8 h instead of 100 mg every 8 h). However, this approach is acceptable only if the resulting maximum concentration is not toxic and the trough value does not fall below the minimum effective concentration for an undesirable period of time. Alternatively, the steady state may be changed by altering the frequency of intermittent dosing but not the size of each dose. In this case, the magnitude of the fluctuations around the average steady-state level will change—the shorter the dosing interval, the smaller the difference between peak and trough levels.


InternalMed_Harrison

InternalMed_Harrison. Renal excretion of parent drug and metabolites is generally accomplished by glomerular filtration and by specific drug transporters. If a drug or its metabolites are primarily excreted through the kidneys decrease, leading to increased oral bioavail ability as a consequence of disrupted hepatocyte function, altered liver architecture, and portacaval shunts. The oral bioavailability for high first-pass drugs such as morphine, meperidine, midazolam, and nifedipine is almost doubled in patients with cirrhosis, compared to those with normal liver function. Therefore, the size of the oral dose of such drugs should be reduced in this setting.


InternalMed_Harrison

InternalMed_Harrison. Under conditions of decreased tissue perfusion, the cardiac output is redistributed to preserve blood flow to the heart and brain at the expense of other tissues (Chap. 279). As a result, drugs may be distributed into a smaller volume of distribution, higher drug concentrations will be present in the plasma, and the tissues that are best perfused (the brain and heart) will be exposed to these higher concentrations, resulting in increased CNS or cardiac effects. As well, decreased perfusion of the kidney and liver may impair drug clearance. Another consequence of severe heart failure is decreased gut perfusion, which may reduce drug absorption and, thus, lead to reduced or absent effects of orally administered therapies.


InternalMed_Harrison

InternalMed_Harrison. In the elderly, multiple pathologies and medications used to treat them result in more drug interactions and adverse effects. Aging also results in changes in organ function, especially of the organs involved in drug disposition. Initial doses should be less than the usual adult dosage and should be increased slowly. The number of medications, and doses per day, should be kept as low as possible. Even in the absence of kidney disease, renal clearance may be reduced by 35–50% in elderly patients. Dosages should be adjusted on the basis of creatinine clearance. Aging also results in a decrease in the size of, and blood flow to, the liver and possibly in the activity of hepatic drug-metabolizing enzymes; accordingly, the hepatic clearance of some drugs is impaired in the elderly. As with liver disease, these changes are not readily predicted.


InternalMed_Harrison

InternalMed_Harrison. Elderly patients may display altered drug sensitivity. Examples include increased analgesic effects of opioids, increased sedation from benzodiazepines and other CNS depressants, and increased risk of bleeding while receiving anticoagulant therapy, even when clotting parameters are well controlled. Exaggerated responses to cardiovascular drugs are also common because of the impaired responsiveness of normal homeostatic mechanisms. Conversely, the elderly display decreased sensitivity to β-adrenergic receptor blockers.