Variability – Differ in Drug Response

April 13, 2017 Adverse Drug Reactions, Pharmacodynamics, Pharmacogenetics, Pharmacokinetics, Therapeutics No comments , , , , , , , , , , , , , ,

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Substantial differences in response to drugs commonly exist among patients. Such between or interindividual variability is often reflected by various marketed dose strengths of a drug. Because variability in response within a subject from one occasion to another (intraindividual variability) is generally smaller than interindividual variability, there is usually little need to subsequently adjust an individual’s dosage regimen, once well-established, unless the condition or treatment of the patient changes. Clearly, if intraindividual variability were large and unpredictable, finding and maintaining dosage for an individual would be an extremely difficult task, particularly for a drug with a low therapeutic index (e.g., warfarin).

Many patients stabilized on one medicine receive another for the treatment of the same or concurrent condition or disease. Sometimes, the second drug affects the response to the first. The change in response may be clinically insignificant for most of the patient population, with the recommendation that no adjustment in dosage be made. However, a few individuals may exhibit an exaggerated response, which could prove fatal unless the dosage of the first drug given to them is reduced. The lesson is clear: Average data are useful as a guide; but ultimately, information pertaining to the individual patient is all-important.

PS: Evidence for interindividual differences in drug response

  • Variability in the dosage required to produce a given response – daily dose of warfarin
  • Variability in pharmacokinetics – phenytoin’s wide scatter in plateau plasma concentration
  • Variability in pharmacodynamics – levels of endogenous agonists or antagonists

Clearly, variability exists in both pharmacokinetics and pharmacodynamics, and measurement of drug in plasma is a prerequisite for separating the two. The characterization of pharmacokinetic and pharmacodynamic variabilities within the population is called population pharmacokinetics and population pharmacodynamics, respectively.

The dependence on dose and time in the assignment of variability is minimized by expressing variability not in terms of observations but rather in terms of the parameter values defining pharmacokinetics and pharmacodynamics, that is, in F, ka, Cl, and V for pharmacokinetics, and in Emax, C50, and the factor defining the steepness of the concentration-response relationship for pharmacodynamics.

Why People Differ

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The reasons why people differ in their responsiveness to a given dose of a drug are manifold and include genetics, disease, age, gender, body weight, drugs given concomitantly, and various behavioral and environmental factors. Age, body weight, disease, and concomitantly administered drugs are important because they are measurable sources of variability that can be taken into account. Gender-linked differences in hormonal balance, body composition, and activity of certain enzymes manifest themselves in differences in both pharmacokinetics and responsiveness, but overall, the effect of gender is small. Although inheritance accounts for a substantial part of the differences in response among individuals for many drugs, much of this variability is still largely unpredictable, particularly in regard to pharmacodynamics.
Pharmaceutical formulation and the process used to manufacture a product can be important because both can affect the rate and extent of release, and hence entry, into the body. A well-designed formulation diminishes the degree of variability in the release characteristics of a drug in vivo.
Heavy cigarette smoking tends to reduce clinical and toxic effects of some drugs, including theophylline, caffeine, and olanzapine. The drug affected are extensively metabolized by hepatic oxidation catalyzed by CYP1A2; induction of this enzyme is the likely cause.
Although on average the body maintains homeostasis, many biological functions and many endogenous substances undergo temporal rhythms. The period of the cycle is often circadian, approximately 24 hr, although there may be both shorter and longer cycles upon which the daily one is superimposed. The menstrual cycle and seasonal variations in the concentrations of some endogenous substances are examples of cycles with a long period. Drug responses and pharmacokinetics may therefore change with time of the day, day of the month, or season of the year.
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[Clinical Skills] Therapeutics Planning

April 12, 2016 Clinical Skills, Pharmacotherapy, Practice, Therapeutics No comments , , , , , , , , , , , , , , ,

Also see Pharmacy Profession Forum for the thread "[Diagnosis] Diagnostic Series" at

Identify the Problems

Step 1 Obtain Patient Data

Consider all available patient data. Review all previously charted data (history, physical examination findings, results of laboratory and diagnostic tests) and interview the patient for the patient's medication history. Reviewall relevant data resources, including data from the current patient chart, data from past charts, data obtained from patient interviews or interviews with relatives or significant others if the patient is not capable of providing information, and uncharted data available from team members. Seeking out and then identifying relevant data requires patience and methodical scrutiny. Note that the patient's story may vary depending on who interviewed the patient and when the patient was interviewed. Some data may be contradictory. But it is important to gather and then consider all available data.

Patient factors that by themselves appear unimportant may be important when considered in the context of other patient data. Pertinent positive data (abnormal findings) include abnormal laboratory results such as a serum potassium level that exceeds the upper limit of the reference range, abnormal signs and symptoms described by the patient, and abnormalities noted on physical examination, and are easy to identify. Pertinent negative data (findings that are normal but, given the patient's disease or condition, would have been expected to be abnormal) are more difficult to recognize, and identifying them requires a good understanding of human disease and pharmacotherapeutics.

Create a working list of the data. Subdivide the data into lists of subjective data and objective data. Subjective data, such as coughing, pain, and itching, are describable but cannot be precisely measured or quantified. Some clinicians view all data obtained directly from the patient to be subjective data, because the data are not verifiable by an independent observer and must be considered just a story. Objective data, such as blood pressure, heart rate, and temperature, are data that can be precisely measured or quantified. By convention, data that are obtained by the health care professional by direct observation of the patient or are obtained during the physical examination but that cannot be precisely quantified are considered objective data because the data were obtained by an objective, trained clinician. Data documented by other health care professionals are considered objective data.

Step 2 Group Related Data

Evaluate the list of objective and subjective data for possible relationships among the data. This step requires comprehensive knowledge of the signs and symptoms of disease and pharmacotherapy and becomes easier with experience. For example, subjective complaints of fever, one episode of chills, and productive cough combined with objective data of leukocytosis with an increased percentage of bands, a chest radiograph showing right middle lobe consolidation, and sputum positive for gram-positive encapsulated cocci in pairs are related. A less experienced clinician should be able to recognize that the patient has some kind of lower respiratory tract bacterial infection.

Work through the list of patient data making sure that every piece of patient data is considered. Note that it only takes one piece of data to identify a patient problem. For example, a patient may smoke tobacco but have normal physical examination findings and normal laboratory results. The patient's self-identification of the smoking history is enough to categorize the patient as a smoker (the problem). Some data may belong with more than one group of data. For example, a blood pressure of 160/110 mm Hg belongs with data related to the patient's diagnosis of hypertension, but if the patient had been prescribed antihypertensive drug therapy but missed many doses, the blood pressure of 160/110 mm Hg also belongs with data related to patient nonadherence.

Step 3 Determine Each Problem

Evaluate each group of related subjective and objective data items to determine the specific patient problem or issue. The problem is not always a specific diagnosis but may be a preliminary identification of the issue pending acquistition of additional data (e.g., acute diarrhea, not shigellosis). The problem list is refined as more data become available. Patient problems include current medical problems such as hypertension, pneumonia, asthma, diabetes, and gastrointestinal bleeding; past medical problems such as history of migraine headache, hip fracture, deep vein thrombosis, and myocardial infarction; past surgeries such as appendectomy, tonsillectomy, coronary artery bypass grafts, and transurethral resection of the prostate; and issue such as nonadherence, obesity, illicit drug abuse, alcohol use, tobacco use, and allergies.

Step 4 Assess Each Problem

  • Each problem is then assessed in terms of each of the following characteristics:
  • Acuity (acute or chronic)
  • Severity (mild, moderate, or severe)
  • Symptom level (symptomatic or asymptomatic)
  • Treatment status (treated or untreated)
  • Degree of control (controlled or uncontrolled)
  • Classification (staging of disease)

Knowing these characteristics is useful when prioritizing patient problems and when planning patient-specific drug and nondrug interventions. Management of a patient's acute, severe, uncontrolled, untreated asthma exacerbation will take precedence over treatment of any of the patient's other chronic and controlled problems. Because historical problems cannot be assessed for these characteristics, by convention these problems are simply documented as "S/P" (meaning "status post" or "a history of").

Prioritize The Problems

Prioritization means ranking the patient problems with the most urgent problems at the top of the list and the least urgent problems at the bottom of the list. Prioritization is a way of ordering the relative need for intervention and is not meant to imply a rank ordering of importance or significance to the patient's overall health care needs. Problems of equal urgency are still listed in a rank order although the plans document the need to address each problem simultaneously. Historical (inactive) problems are not ranked but are simply listed at the bottom of the problem list. Problem lists are dynamic lists that evolve and are modified as new data become available.

Step 1 Identify the Active Problems

Active problems are problems that require some kind of drug or nondrug intervention to resolve and/or manage the problem.

Step 2 Identify the Inactive Problems

Inactive problems are problems that do not require any kind of drug or nondrug intervention and are of historical interest only. Examples of inactive problems include a history of an appendectomy at age 12, a history of pneumonia 2 years ago, a history of smoking two packs of cigarettes per day until quitting 10 years ago, etc. Although inactive problems do not require planning for current drug or nondrug therapy interventions, inactive problems are still identified and listed on the patient problem list so that they can be considered when planning drug and nondrug interventions for active problems. For example, a patient with a history of splenectomy is at increased risk of infection with some pathogens. Knowledge of this risk will help in planning patient-specific antibiotic therapy in the event that the patient has signs and symptoms consistent with infection.

Step 3 Rank the Problems

Rank-order the active patient problems. One approach to ranking patient problems is to identify the problem that needs the most immediate attention and then rank the remaining active problems in order of need for intervention. The number one problem is the problem that if left untreated will cause the most harm to the patient in the shortest amount of time. Another approach is to work from the bottom of the list up by determining the problem requiring the lest attention. This problem is ranked as the least important problem. The pharmacist repeats the ranking process with the remaining problems until all are ranked. Regardless of the approach, the active problems are placed at the top of the list, inactive problems are at the botton of the list, and active but less acute problems are in the middle. As noted previously, the rank ordering is rather arbitrary if the the problems all have relatively equal need for intervention.

Clinicians given the same list of patient data may develop different prioritized lists. This is not unexpected; no one list is correct. Lists are developed based on the clinical judgment and experience of the practitioner. In addition, because the focus of the pharmacist is on therapeutic issues rather than on differential diagnosis, the pharmacist-generated patient problem list may be similar although not necessarily identical to the problem list generated by physicians, nurses, or other health care professionals.

Select Patient-Specific Drug and Nondrug Interventions

Once the prioritized patient problem list is developed, the next step is to select patient-specific drug and nondrug interventions for each and nondrug interventions.

Determine appropriate nondrug interventions, including patient eduation. For example, an important part of the management of allergic rhinitis is avoidance of allergens; patients may benefit from education regarding allergen avoidance.

Determine an appropriate medication regimen for each patient problem that can be treated and/or managed with medications. For each medication selected, include the dosage, the dosage formulation, the route of administration, dosing interval, duration of therapy, and rationale (the evidence-based reason for selecting the patient-specific therapeutic intervention). The general approach is to develop the therapeutic plan for each problem and then integrate the individual plans, with care taken to ensure that each component of the plan is appropriate given the other plans and that the overall integrated plan is achievable for the pateint. For example, when considered individually plans for therapeutic interventions for a patient with multiple chronic medical conditions may seem reasonable and appropriate, but when considered together they may not be doable if the multiple medication regimens require the patient to adhere to multiple sets of complicated instructions (e.g., take with food, take 2 hours before eating, take every 4 hours around the clock, take every 8 hours around the clock, do not take within 2 hours of taking another medication, etc.).

Selection of a specific regimen requires assessment of each patient problem in the context of everything that is known about the patient such as other patient problems and medications, social habits, cultural beliefs, and willingness to commit to a course of therapy, as well as external factors such as insurance coverage and access to refrigeration for storage of refrigerated medications. See below,

Patient-specific factors

  • What regimens have effectively managed the problem in the past?
  • What regimens have not effectively managed the problem in the past?
  • How might other patient problems influence the proposed regimen?
  • How might the proposed regimen influence other patient problem?
  • Does the patient have any culturally based needs?

External factors

  • State-of-the-art therapeutics (e.g., current guidelines)
  • Cost of the proposed therapy
  • Formulary limitations

For example, a patient who has responded well to a specific decongestant in the past will most likely respond well to the same decongestant in the future. A patient with renal insufficiency is at risk of developing seizures from the accumulation of normeperidine, a renally eliminated metabolite of meperidine. A drug with negative inotropic effects may worsen a patient's congestive heart failure.

Step 1 Determine Short-Term and Long-Term Goals of Therapy

All drug and nondrug interventions should be in the context of the specific short-term and long-term goals of therapy, which may or may not be the same depending on the specific patient problem. For example, the short-term goal for patient being treated for a hypertensive emergency is to reduce the diastolic blood pressure to 100 to 105 mm Hg within 2 to 6 hours of presentation with a maximum reduction of 25% or less of the initial diastolic blood pressure. The long-term goal is to reduce the diastolic blood pressure to 85 to 90 mm Hg over the next 2 to 3 months to reduce the long-term morbidity and mortality associated with the elevated diastolic blood pressure.

Determine specific goals and outcomes of therapy before doing any other planning. Set specific goals for each patient problem and for the overall therapeutic outcome in general. When setting therapeutic goals, consider long-term factors such as the impact of the therapeutic regimen on the patient's quality of life and survival. For example, a long-term weight reduction plan is not appropriate for a patient with a short life expectancy. Select target therapeutic ranges for all objective parameters (e.g., systolic blood pressure between 110 and 130 mm Hg; serum potassium level between 3.5 and 4.5 mEq/L, etc.)

Consider the severity of disease and the short-term or long-term nature of therapy when setting therapeutic goals. For example, consider the differences in the goals of insulin therapy for a young patient with newly diagnosed type 1 diabetes mellitus and significant cardiovascular and peripheral vascular disease. Evidence suggests that tight control of blood glucose levels may delay the onset and decrease the severity of the complications of diabetes. Therefore the target blood glucose level for the young patient with newly diagnosed daibetes is lower and has a narrower acceptable range than that for the elderly patient with diabetes and longstanding disease who has already developed complications from the disease and is at risk of hypoglycemia-related falls.

Step 2 Create A List of Options

Identify all classes of drugs and possible therapeutic approaches for each problem; do not eliminate any option at this stage of planning. The options list is usually a mental list, although students and inexperienced clinicians may find it helpful to create and then work from a written list. Depending on how familiar the pharmacist is with the management of the medical condition, this step may require review of current pharmacotherapeutics and human disease textbooks, literature searches of the current pharmacy and medical literature, review of current treatment guidelines, or consultation with colleagues. This step becomes easier and more time efficient with practice and experience. As the member of the heath care team with the most knowledge of pharmacotherapy, it is the pharmacist's responsibility to identify all possible drug therapy options.

Step 3 Eliminate Options Based on Patient-Specific and External Factors

Once all therapeutic options are identified, eliminate options based on the comparative effectiveness of the drugs; the suitability of the drug for the patient given the other patient medical conditions and drug therapies; the ability of the patient to adhere to the proposed regimen; and other factors such as the effectiveness of previous treatment regiments, cost, and formulary restrictions. Consider the impact of the therapeutic option on other patient problems and the influence of other patient problems on the therapeutic option.

Drug-specific factors

  • Effectiveness of the clinical outcome (e.g., evidence-based benefit)
  • Pharmacologic mechanisms
  • Effectiveness of the drugs (e.g., physiologic effect, potency, maximum effect, slope of effect-concentration curve)
  • Evidence-based toxicity of the drug
  • Toxicity of the drugs (e.g., therapeutic index/window)
  • Drug delivery systems (e.g., inhalant, sublingual, oral)
  • How drug get active in the body (e.g., prodrug)
  • In-body drug process/pharmacokinetics (e.g., absorption, distribution, metabolism, excretion)
  • Drug interactions

Patient-specific factors

  • What regimens have effectively managed the problem in the past?
  • What regimens have not effectively managed the problem in the past?
  • How might other patient problems influence the proposed regimen? (e.g., renal failure, hepatic failure, genetic variability/mutation, etc.)
  • How might the proposed regimen influence other patient problem?
  • Does the patient have any culturally based needs?
  • The severity of the problem
  • How the patient's life style affect the proposed regimen?
  • The past patient experiences
  • The patient's ability to adhere to the proposed regimen

External factors

  • State-of-the-art therapeutics (e.g., current guidelines)
  • Cost of the proposed therapy
  • Formulary limitations
  • Risk of medication errors

Step 4 Select Appropriate Drug and Nondrug Interventions

Decisions about appropriate drug and nondrug interventions are based on past patient experiences, assessment of the severity of the problem, drug-specific factors such as the therapeutic index of the drug, and specific patient factors such as the presence of chronic renal or hepatic disease that may influence the elimination or metabolism of the drug. Determine the best drug and nondrug regimen, including each specific drug to be used, dosage, route, duration of therapy, and rationle for the selection of each drug and nondrug component of the regimen. For example, if a patient failed to stop smoking because the patient developed varenicline-associated side effects and stopped taking the medication, then the patient should not be prescribed varenicline the next time the patient attempts to quite smoking. If a patient's prescription medication insurance no longer covers a specific branded product, then every effort should be made to find an equivalent medication, generic or otherwise, that is paid for by the prescription medication insurance plan.

The rationale, the reason why the specific intervention was selected, should be patient specific and based on current published evidence. The rationale should be documented in the SOAP note in the patient chart even if verbally discussed with the prescriber. For example, the recommendation to initiate antihypertensive drug therapy with hydrochlorothiazide 12.5 mg daily for a patient with newly diagnosed uncomplicated hypertension is based on the recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The recommendation to vaccinate or note vaccinate a person with the influenza vaccine is based on current Centers for Disease Control and Prevention recommendations.

Step 5 Identify Alternative Interventions

An important part of the planning process is anticipation of potential patient problems with the prescribed and/or recommended drug and nondrug interventions ("what if"). A well-though-out plan includes alternative medication regimens for common potential problems, such as the development of an allergy or adverse reaction to the initial therapeutic regimen, lack of desired therapeutic response to the initial therapeutic regimen, and identification of additional patient problems that may influence the effectiveness or pharmacokinetic profile of the initial therapeutic regimen. Anticipation of these potential issues allows the creation of well-thought-out alternative therapeutic plans instead of therapeutic plans hastily chosen when unanticipated patient problems suddenly appear. For example, therapeutic planning for a patient with newly diagnosed hypertension should include plans for what to do if the initial treatment fails to lower the blood pressure or has to be discontinued because of the development of intolerable side effects (both very common issues).

(The End)

Stage, Expression, and Causal Model of Diseases

December 29, 2015 Epidemiology, Therapeutics No comments , , , , , , , , ,

Natural History of Disease

Stage of Disease

Screen Shot 2015-12-26 at 8.46.43 PMThe natural history of disease refers to the progression of a disease in an individual over time. This includes all relevant phenomena from before initiation of the disease (the stage of susceptibility) until its resolution. In the period following exposure to the causal factor, the individual enters a stage of subclinical disease (also called the preclinical phase). For infectious agents, this corresponds to the incubation period during which the agent multiplies within the body but has not yet produced discernible signs or symptoms. For noninfectious diseases, this corresponds to the induction period between a causal action and disease initiation.

The stage of clinical disease begins with a patient's first symptoms and ends with resolution of the disease. Be aware that the onset of symptoms marks the beginning of this stage, not the time of diagnosis. The time-lag between the onset of symptoms and diagnosis of disease can be considerable. Resolution of the disease may come by means of recovery or death. When recovery is incomplete the individual may be left with disability.

Incubation periods of infectious diseases vary considerably. Some infectious diseases are characterized by short incubation periods. Others are characterized by intermediate incubation periods. Still others are characterized by extended incubation periods. Note that even for a given infectious disease, the incubation period may vary considerably. For example, the incubation period for human immunodeficiency virus (HIV) and AIDS ranges from 3 to more than 20 years.

Induction periods for noninfectious diseases also exhibit a range. For example, the induction period for leukemia following exposure to fallout from the atomic bomb blast in Hiroshima ranged from 2 to more than 12 years. Variability in incubation is due to differences in host resistance, pathogenicity of the agent, the exposure dose, and the prevalence and availability of cofactors responsible for disease.

Understanding the natural history of a disease is essential when studying its epidemiology. For example, the epidemiology of HIV/AIDS can only be understood after identify its multifarious stages. Exposure to HIV is followed by an acute response that may be accompanied by unrecognized flu-like symptoms. During this acute viremic phase, prospective cases do not exhibit detectable antibodies in their serum, yet may still transmit the agent. During a lengthy induction, CD4+ lymphocyte counts decline while the patient is still free from symptoms. The risk of developing AIDS is low during these initial years, but increase over time as the immune response is progressively destroyed, after which AIDS then may express itself in different forms (e.g., opportunistic infections, encephalitis, Kaposi's sarcoma, dementia, wasting syndrome).

Screen Shot 2015-12-26 at 9.29.53 PMA slightly more sophisticated view of the natural history of disease divides the subclinical stage of disease into an induction period and a latent period. Induction occurs in the interval between a causal action and the point at which the occurrence of the disease becomes inevitable. A latent period follows after the disease becomes inevitable but before clinical signs arise. During this latent phase, various causal factors may promote or retard the progression of the disease. The induction and promotion stages combined are referred to as the empirical induction period. This more sophisticated view better suits the consideration of multi-facored disease, where multiple factors must act together to result in a cause.

Stage of Prevention

Disease prevention efforts are classifed according to the stage of disease at which they occur. Primary prevention is directed toward the stage of susceptibility. The goal of primary prevention is to prevent the disease from occuring in the first place. Examples of primary preventiion include needle-exchange programs to prevent the spread of HIV, vaccination programs, and smoking prevention programs.

Secondary prevention is directed toward the subclinical stage of disease, after which the individual is exposed to the causal factor. The goal of secondary prevention is to prevent the disease from emerging or delay its emergence by extending the induction period. It also aims to reduce the severity of the disease once it emerges. Treating asymptomatic HIV-positive patients with antiretroviral agents to delay the onset of AIDS is a form of secondary prevention.

Tertiary prevention is directed toward the clinical stage of disease. The aim of tertiary prevention is to prevent or minimize the progression of the disease or its sequelae. For example, screening and treating diabetics for diabetic retinopathy to avert progression to blindness is a form of tertiary prevention.

Variability in The Expression of Disease

Spectrum of Disease

Diseases often display a broad range of manifestations and severities. This is referred to as the spectrum of disease. Both infectious and noninfectious diseases exhibit spectrums. When considering infectious diseases, there is a gradient of infection. As an example, HIV infection ranges from inapparent, to mild (e.g., AIDS-related complex), to severe (e.g., wasting syndrome). As an example of a noninfectious disease's spectrum, consider that coronary artery disease exists in as asymptomatic form (atherosclerosis), transient myocardial ischemia, and myocardial infarctions of various severities.

The epidemiologic iceberg

The bulk of a health problem in a population may be hidden from view. This phenomenon, referred to as the "epidemiologic iceberg", applies to infectious, noninfectious, acute, and chronic diseases alike.

Uncovering disease that might otherwise be "below sea level" by screening and better detection often allows for better control of health problems. Consider that for every successful suicide attempt there are dozens of unsuccessful attempts and a still larger number of people with depressive illness that might be severe enough to have them wish to end their lives. With appropriate treatment, individuals with suicidal tendencies would be less likely to have suicidal ideation and be less likely to attempt suicide. As another example: reported cases of AIDS represent only the tip of HIV infections. With proper antiretroviral therapy, clinical illness may be delayed and transmission averted.

Causal Models

Definition of Cause

A cause of a disease event is an event, condition or characteristic that preceded a disease without which the disease event either would not have occurred at all or would not have occurred until some later time. On a population basis, we expect that an increase in the level of a causal factor in inhabitants will be accompanied by an increase in the incidence of disease in that population, caeteris parabus (all other things being equal). We also expect that if the causal factor can be eliminated or diminished, the frequency of disease or its severity will decline.

Component cause model (causal pies)

Most diseases are caused by the cumulative effect of multiple causal components acting ("interacting") together. Thus, a causal interaction occurs when two or more causal factors act together to bring about an effect. Causal interactons apply to both infectious and noninfectious diseases and explains, for example, why two people exposed to the same cold virus will not necessarily experience the same outcome: one person may develop a cold while the other person may experience no ill effects.

Rothman's causal pies helps to clarify the contribution of causal components in disease etiology. Figure 2.6 displays two causal mechanisms for a disease. Wedges of each pie represent components of each causal mechanism, corresponding to risk factors we hope to identify. Each pie represents a sufficient causal mechanism, defined as a set of factors that in combination makes disease occurrence inevitable. Each casual componet (wedge) plays an essential role in a given causal mechanism (pie); a specific disease may result from a number of different causal combination mechanisms.Screen Shot 2015-12-28 at 6.19.20 PM

A causal factor is said to be necessary when it is a component cause member of every sufficient mechanism. In other words, the component cause is necessary if the disease cannot occur in its absence. In Figure 2.6, Component A is a necessary cause, since it is evident in all possible mechanisms – the disease cannot occur in its absence. Causal components that do not occur in every sufficient mechanism yet are still essential in some cases are said to be contributing component causes. In Figure 2.6, B, C, and D are nonnecessary contributing causal components. Component causes that complete a given causal mechanism (pie) are said to be causal complements. In Figure 2.6, for example, the causal complements of factor A in Mechanism 1 is (B + C). In mechanism 2, the causal complement of factor A is D. Factors that work together to form sufficient causal mechanism are said to interact causally.

Causal interactions have direct health relevance. For example, when a person develops an infectious disease, the causal agent must interact with the causal complement known as "susceptibility" to cause the disease. When considering hip fractures in elderly patients, the necessary element of trauma interacts with the causal complement of osteoporosis to cause the hip fracture. In similar veins, smoking interacts with genetic susceptibility and other environmental factors in causing lung cancer, and dietary excess interact with lack of exercise, genetic susceptibility, atherosclerosis and various clotting factors to cause heart attacks. Causal factors rarely act alone.

Causal pies demonstrate that individual risk is an all-or-none phenomenon. In a given individual, either a causal mechanism is or is not completed. This makes it impossible to directly estimate individual risk. In contrast, the notion of average risk is a different matter. Average risk can be estimated directly as the proportion of individuals regarded as a member of a recognizable group that develops a particular condition. For example, if one in ten smokers develop lung cancer over their lifetime, we can say that this population has a lifetime risk for this outcome of one in ten (10%). The effects of a given cause in a population depend on the prevalence of causal complements in that population. The effect of phenylketanines, for instance, depends not only on the prevalence of an inborn error of metabolism marked by the absence of phenylalanine hydroxylase, but depends also on the environmental prevalence of foods high in phenylalanine. Simiarly, the effects of falls in the elderly depend not only on the opportunity for falling, but also on the prevalence of osteoporosis. The population-wide effects of a pathological factor cannot be predicted without knowledge of the prevalence of its causal complements in the population.

Hogben's example of yellow shank disease in chickens provides a memorable example of how population effects of a given causal agent cannot be separated from the prevalence of its causal complements. The trait of yellow shank in poultry is a condition expressed only in certain genetic strains of fowl when fed yellow corn. A farmer with a susceptible flock who switches from white corn to yellow corn will perceive the disease to be caused by yellow corn. A farmer who feeds only yellow corn to a flock with mulltiple strains of chickens, some of which are susceptible to the yellow shank condition, will perceive the condition to be caused by genetics. In fact, the effects of yellow corn cannot be separated from the genetic makeup of the flock, and the effect of the genetic makeup of the flock cannot be separated from the presence of yellow corn in the environment. To ask whether yellow shank disease is environmental or genetic is like asking whether the sound of a faraway drum is caused by the drum or the drummer – one does not act without the other. This is what we mean by causal interaction.

Agent, Host, and Environment

Causal components can be classified as agent, host, or environmental factors. Agent are biological, physical, and chemical factors whose presence, absence, or relative amount (too much or too little) are necessary for disease to occur. Host factors include personal characteristics and behaviros, genetic predispositions, and immunologic and other susceptibility-related factors that influence the likelihoood or severity of disease. Host factors can be physiological, anatomical, genetic, behavioral, occupational, or constitutional. Environmental factors are external conditions other than the agent that contribute to the disease process. Environmental factors can be physical, biological, social, economic, or political in nature.

Polymorphisms in Pharmacotherapy

November 10, 2015 Pharmacodynamics, Pharmacogenetics, Pharmacokinetics, Pharmacotherapy, Therapeutics No comments

dna_istock_rustycloudPolymorphisms related to pharmacotherapy include polymorphisms in genes for drug-metabolizing enzymes, polymorphisms in drug transporter genes, and polymorphisms in drug target genes.

Polymorphisms in Genes for Drug-Metabolizing Enzymes

Polymorphisms in the drug-metabolizing enzymes represent the first recognized and, so far, the most documented examples of genetic variants with consequences in drug response and toxicity. eTable 6-1 lists examples of polymorphic metabolizing enzymes and corresponding drug substrates whose plasma concentrations and pharmacologic effects may be altered as a consequence of genetic variation.

Screen Shot 2015-11-10 at 2.38.46 PMPolymorphisms in the CYP2D6 gene are the best characterized among all polymorphisms in genes for drug-metabolizing enzymes. For example, the presence of two defective alleles coding for CYP2D6 in PM (poor metabolizer) results in significant impaired ability to metabolize CYP2D6-dependent substrates. Depending on the importance of the affected CYP2D6 pathway to overall drug metabolism and the drug's therapeutic index, clinically significant side effects may occur in PMs as a result of elevated drug concentrations.Screen Shot 2015-11-10 at 2.39.27 PM
Conversely, if the polymorphisms in CYP2D6 genes significantly enhance the activity of the drug-metabolizing enzyme, large amount of drugs will be metabolized and as a result the serum concentraton and pharmacologic effect of the drug would probablely be significantly lower.Screen Shot 2015-11-10 at 2.39.54 PM

The therapeutic implication of CYP2D6 polymorphism is different if the substrate in question is a prodrug. In this case, PMs would not be able to convert the drug into the therapeutically active metabolite (if low CPY2D6 activity).

Polymorphisms in Drug Transporter Genes

Certain membrane-sparnning proteins facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine, drug distribution across the blood-brain barrier, and drug uptake into target cells.


Polymorphisms in drug transporters on gastrointestinal tract would affect the absorption of drugs. The role of drug transproters on gastrointestinal tract is to put the drug molecule back into GI lumen. So the activity of these drug transporters would significantly alter the bioavailability/absorption of the drug.


Genetic variations for drug transport proteins may affect the distribution of drugs that are substrates for these proteins and alter drug concentrations at their therapeutic sites of action. P-glycoprotein is one of the most recognized of the drug transport proteins that exhibit genetic polymorphism.


Some drug are transported into bile or urine by drug transporters. So the polymorphisms in these transporters which result in significant change of the activity of the drug transporters would enhance or weaken the ability of these drug transporters's ability to excret the drug.

Drug Uptake by Target Cells

Even the drug could reach the therapeutic sites of action, efflux pumps (drug transporters) available on the surface of target cells could put the drug molecules back into extracellular environment, which prevent the pharmacologic effect of the drug if the drug's target receptors are inside the target cells.

Polymorphisms in Drug Target Genes

Genetic polymorphisms occur commonly for durg target proteins, including receptors, enzymes, ion channels, and intracellular signaling proteins. Drugs could bind to enzymes, ion channels, and intracellular signaling proteins directly to produce pharmacologic effects, or they just only bind to the receptor and the after-binding (drug-receptor) process is altered by polymorphisms in enzymes, ion channels, and intracellular signaling proteins.

Receptor Genotypes and Drug Response

The beta1-adrenergic receptor gene (ADRB1) has been the primary focus of research into genetic determinants of responses to beta-adrenergic receptor antagonists in hypertension and cardiovascular disease. The polymorphisms in beta1-adregergic receptors causes pharmacologic (or even clinical) responses in different extent to its agonists and antagonists.

Enzyme Genes and Drug Response

Some drugs exert their clinical efficacy by affect enzymes which play some roles in the life of a cell. Polymorphisms in these enzymes therefore determine what degree of responsiveness they respond to these drugs. One example is the warfarin resistance, where there is a SNP in the VKORC1. Warfarin exerts its anticoagulant effects by inhibiting VKOR and thus preventing carboxylation of the vitamin K-dependent clotting factors II, VII, IX, and X. VKORC1 encodes for the warfarin-sensitive component of VKOR. Mutations in VKORC1 coding region cause rare case of warfarin resistance, with carriers of these mutations requiring either exceptionally high doses (>100 mg/wk) to achieve effective anticoagulation or failing to respond to warfarin at any dose (the mutated VKOR lose sensitivity to warfarin).

Genes For Intracellular Signaling Proteins, Ion Channels, and Drug Response

Cellular responses to many drugs are mediated through receptor-coupled guanosine diphosphate (GDP)-bound proteins also called G-proteins. Following receptor activation, the receptor couples to the G-protein, resulting in dissociation of GDP from the alpha subunit in exchange for guanosine triphosphate (GTP) and activation of the alpha, beta, and gamma subunits. The alpha subunit and beta-gamma subunit complex are released intracellularly and interact with various effectors to produce a cellular responses. Changes in the activity of G-proteins might influence response to agonists/antagonists which bind the receptors coupled with G-proteins.

The Management of Hypertension (Clinical Evaluation)

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Frequently, the only sign of essential hypertension is elevated BP. The rest of the physical examination may be completely normal. However, a complete medical evaluation including a comprehensive medical history, physical examination, and laboratory and/or diagnostic test is recommended after diagnosis to identify secondary causes, identify other CV risk factors or comorbid conditions that may define prognosis and/or guide therapy, and assess for the presence of absence of hypertension-associated target-organ damage.

For the patients who have been diagnosed with hypertension, we should ask a few questions that are necessary to make a clinical evaluation for these patients. Here is an example of a patient with hypertension.

D.C. is a 44-year-old black man who presents to his primary care provider concerned about high BP. At an employee health screening last month he was told he has stage 1 hypertension. His medical history is significant for allergic rhinitis. His BP was 144/84 and 146/86 mm Hg last year during an employee health screening at work. D.C.’s father had hypertension and died of an MI at age 54. His mother had diabetes and hypertension and died of a stroke at age 68. D.C. smokes on pack per day of cigarettes and thinks his BP is high because of job-related stress. He does not engage in any regular exercise and does not restrict his diet in any way, although he knows he should lose weight.

Physical examination show he is 175 cm tall, weighs 108 kg (BMI, 35.2 kg/m2), BP is 148/88 mm Hg (left arm) and 146/86 mm Hg (right arm) while sitting, heart rate is 80 beats/minute. Six months ago, his BP values were 152/88 mm Hg and 150/84 mm Hg when he was seen by his primary-care provider for allergic rhinitis. Funduscopic examination reveals mild arterial narrowing and arteriovenous nicking, with no exudates or hemorrhages. The other physical examination findings are essentially normal.

D.C.’s fasting laboratory serum values are as follows:

Blood urea nitrogen, 24 mg/dL

Creatinine, 1.0 mg/dL

Glucose, 105 mg/dL (Fasting?)

Potassium, 4.4 mEq/L

Uric acid, 6.5 mg/dL

Total cholesterol, 196 mg/dL

Low-density lipoprotein cholesterol, 141 mg/dL

High-density lipoprotein cholesterol, 32 mg/dL

Triglycerides, 170 mg/dL

An electrocardiogram is normal except for left ventricular hypertrophy.

PS: Normal values are marked in green and abnormal values are marked in orange.

Clinical Presentation

Question 1 What is the clinical presentation D.C.?

All the information above could be the part of D.C.’s clinical presentation. Besides, we could classify the stage of D.C.’s hypertension as shown below.

D.C. has uncontrolled stage 1 hypertension. He has had elevated BP values, measured in clinical environments, and meets the diagnostic criteria for hypertension because two or more of his BP measurements are elevated on separate days. SBP values are consistently stage 1, whereas DBP values are all in the prehypertension range. The higher of the two classifications is used to classify hypertension.

Question 2 Why does D.C. have hypertension?

D.C. has essential hypertension; therefore, the exact cause is not known. He has several characteristics (e.g., family history of hypertension, obesity) that may have increased his chance of developing hypertension. Race and sex also influence the prevalence of hypertension Across all age groups, black have a higher prevalence of hypertension than do whites and Hispanics. Similar to other form of CV disease, hypertension is more server, more like to include hypertension-associated complications, and occurs at an earlier age in black patients.

Patient Evaluation and Risk Assessment

The presence of absence of hypertension-associated complications as well as other major CV risk factors (Table 14-5) must be assessed in D.C. Also, secondary cause of hypertension (Table 14-3), if suggested by history and clinical examination findings, should be identified and managed accordingly. The presence of concomitant medical conditions (e.g., diabetes) should be assessed, and lifestyle habits should be evaluated so that they can be used to guide therapy.

  • Hypertension-associated complications
  • Secondary causes of hypertension
  • Concomitant medical conditions

Question 3 Dose D.C. has secondary cause of hypertension?

The most common secondary causes of hypertension are list in Table 3-1. Patients with secondary hypertension might have signs or symptoms suggestive of the underlying disorders.

Table 3-1 Secondary Causes of Hypertension.

  • Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, and palpitations. Over half of these patients suffer from episodes of orthostatic hypotension.
  • In primary hyperaldosteronism symptoms related to hypokalemia usually include muscle cramps and muscle weakness.
  • Patients with Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscle weakness and have several classic physical features (e.g., moon face, buffalo hump, hirsutism).
  • Patient with coarctation of the aorta may have higher BP in the arms than in legs and diminished or even absent femoral pulses.
  • Patient with renal artery stenosis may have an abdominal systolic-diastolic bruit.

Also, routine laboratory tests may also help identify secondary hypertension. For example, Baseline hypokalemia may suggest mineralocorticoid-induced hypertension. Protein, red blood cells, and casts in the urine may indicate renovascular disease. Some laboratory tests are used specifically to diagnose secondary hypertension. These include plasma norepinephrine and urinary metanephrine for pheochromocytoma, plasma and urinary aldosterone concentrations for primary hyperaldosteronism, and plasma rennin activity, captopril stimulation test, renal vein renin, and renal artery angiography for renoascular disease.

Certain drugs and other products can result in drug-induced hypertension. For some patients, the addition of these agents can be the cause of elevated BP or can exacerbate underlying hypertension. Identify a temporal relationship between starting the suspected agent and developing elevated BP is most suggestive of drug-induced BP elevation.

Question 4 Which hypertension-associated complications are present in D.C.?

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A complete physical examination to evaluate hypertension-associated complications includes examination of the optic funds; auscultation for carotid, abdominal, and femoral bruits; palpation of the thyroid gland; heart and lung examination; abdominal examination for enlarged kidney, masses, and abnormal aortic pulsation; lower extremity palpation for edema and pulses; and neurologic assessment. Routine laboratory assessment after diagnosis should include the following: EKG; urinalysis; fasting glucose; hematocrit; serum potassium, creatinine, and calcium; and fasting lipid panel. Optional testing may include measurement of urinary albumin excretion or albumin-to-creatinine ratio, or additional tests specific for secondary causes if suspected.

Question 5 What other forms of hypertension-associated complications is D.C. at risk for?

Hypertension adversely affects many organ systems, including the heart, brain, kidneys, peripheral circulation, and eyes (Table 14-5). Damage to these systems resulting from hypertension is termed hypertension-associated complications, target-organ damage, or CV disease. There are often misconceptions about the term CV disease and CAD. CV disease encompasses the broad scope of all forms of hypertension-associated complications. CAD is simply a subset of CV disease and refers specifically to disease related to the coronary vasculature, including ischemic heart disease and MI.

Hypertension can affect the heart either indirectly, by promoting atherosclerotic changes, or directly, via pressure-related effects. Hypertension can promote CV disease and increase the risk for ischemic events, such as angina and MI. Antihypertensive therapy has been shown to reduce the risk of these coronary events. Hypertension also promotes the development of LVH, which is a myocardial (cellular) change, not an arterial change. These two conditions often coexist, however. It is commonly believed that LVH is a compensatory mechanism of the heart in response to the increased resistance caused by elevated BP (more accurately, the afterload). Recall the definition of afterload, that is, wall tension=(pressure * radius)/(wall thickness). LVH is a strong and independent risk factor for CAD, left ventricular dysfunction, and arrhythmia. LVH does not indicate the presence of left ventricular dysfunction, but is a risk for progression to left ventricular dysfunction, which is considered a hypertension-associated complication. This may be caused by ischemia, excessive LVH, or pressure overload. Ultimately, left ventricular dysfunction results in a decrease ability to contract (systolic dysfunction).

Hypertension is one of the most frequent causes of cerebrovascular disease. Cerebrovascular signs can manifest as transient ischemic attacks, ischemic strokes, multiple cerebral infarcts, and hemorrhages. Residual functional deficits caused by stroke are among the most devastating forms of hypertension-associated complications. Clinical trials have demonstrated that antihypertensive therapy can significantly reduce the risk of both initial and recurrent stroke. A sudden, prolonged increase in BP also can cause hypertensive encephalopathy, which is classified as a hypertensive emergency.

The GFR is used to estimate kidney function, which declines with aging. This rate of decline is greatly accelerated by hypertension. Hypertension is associated with nephrosclerosis, which is caused by increased intraglomerular pressure. It is unknown whether a primary kidney lesion with ischemia causes systemic hypertension or whether systemic hypertension directly causes glomerular capillary damage by increasing intraglomerular pressure. Regardless, CKD, whether mild or severe, can progress to kidney failure (stage 5 CKD) and the need for dialysis. Studies have demonstrated that controlling hypertension is the most important strategy to slow the rate of kidney function decline, but it may not be entirely effective in slowing the progression of renal impairment in all patients.

In hypertension, stage 3 CKD or worse is considered a hypertension-associated complication (GFR values of <60 mL/min/1.73 m2). An estimated GFR of less than 60 mL/min/1.73 m2 corresponds approximately to a serum concentration of greater than 1.5 mg/dL in an average man and greater than 1.3 mg/dL in an average woman. This level of kidney compromise lowers an individual’s BP goal to less than 130/80 mm Hg according to multiple guidelines. The presence of persistent albuminuria (>300 mg albumin in a 24-hour urine collection or 200 mg albumin/g creatinine on a spot urine measurement) also indicates significant CKD, for which achieving the more aggressive BP goal is a strategy to minimize the rate of progression to kidney failure.

Peripheral arterial disease, a non coronary form of atherosclerotic vascular disease, is considered a hypertension-associated complication. It is equivalent in CV risk to CHD. Risk factor reduction, BP control, and anti platelet agent(s) are needed to decrease progression. Complications of peripheral arterial disease can include infection and necrosis, which in some cases require revascularization procedures or extremity amputation.

Hypertension causes retinopathies that can progress to blindness. Retinopathy is evaluated according to the Keith, Wagener, and Barker funduscopic classification system. Grade 1 is characterized by narrowing of the arterial diameter, indicating vasoconstriction. Arteriovenous nicking is the hallmark of grade 2, indicating atherosclerosis. Longstanding, untreated hypertension can cause cotton wool exudates and flame hemorrhages (grade 3). In severe cases, papilledema occurs, and this is classified as grade 4.

Question 6 Which major CV risk factors are present in D.C.?

As shown in Table 14-5, major CV risk factors include advanced age (>55 years for men, >65 years for women), cigarette smoking, diabetes mellitus, dyslipidemia, family history of premature atherosclerotic vascular disease (men <55 years or women <65 years) in primary relatives, hypertension, kidney disease (microablubuminuria or estimated GFR <60 mL/min/1.73 m2), obesity (BMI >=30 kg/m2), and physical inactivity.

PS: Estimated GFR calculated from online calculator for D.C. is 105 mL/min/1.73 m(online calculator:

So according to D.C.’s clinical presentation, he has major CV risk factors that are marked in orange, that is, 5 factors in total, including the essential hypertension.

Question 7 What is D.C.’s BP goal and how can Framingham risk scoring influence BP goal determination?

D.C. is a primary prevention patient because he does not yet have any hypertension-associated compilations (or compelling indications). He has multiple CV risk factors, so controlling his BP is of paramount importance to reduce the risk of developing hypertension-associated complications. The JNC-8 guidelines recommend the initial BP goal for hypertension patients with age of <60 years should be 140/90 mm Hg, which has grade A evidence (strong recommendation) for patients from 30 through 59 years of age, and grade E (expert opinion) for those from 18 through 29 years of age. So D.C.’s initial BP goal should be below 140/90 mm Hg.

The framingham risk scoring system is available as an online calculator at NIH site of According to D.C.’s clinical presentation, he will has a CV risk of  14% in a next 10-year period of expectation before we intervention, which means in a population cohort such as D.C., 14 in 100 individuals will develop CV diseases after a period of 10-year, if we don’t treat these CV risk factors (if these risk factors worsen, the incidence of developing CV diseases would be higher). If we treat D.C.’s current hypertension target the BP goal, with other interventions that target D.C.’s rest risk factors like habit of smoking, etc., the incidence of developing CV diseases would be attenuated (In D.C.’s example, the incidence would decrease to 5%, that is 5 in 100 of individuals will develop CV diseases in a period of 10-year). Compare the results without/with interventions to D.C.

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The intervention above does not include the management of dyslipidemia. According to the latest AHA guideline, four types of patients need the intervention for dyslipidemia, including: 1.secondary prevention in individuals with clinical ASCVD; 2. primary prevention in individuals with primary elevations of LDL-C >=190 mg/dL; 3.primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL; and 4.primary prevention in individual without diabetes and with estimated 10-year ASCVD risk>=7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. (References: So we need to calculate D.C.’s ASCVD risk from another tool developed by ACC/AHA (American College of Cardiology/American Heart Association), which is available as iOs apps. So the result of ASCVD risk of D.C. is 9.7% (>=7.5%) without any intervention, whereas ASCVD risk is 8.6% (still >=7.5%) with interventions of antihypertensive therapy and smoke cessation. Therefore, the dyslipidemia should be treated for D.C.

PS: ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin.