Chapter 47: Pharmacotherapy Principles for the Family Physician

Medication therapy is an integral element of healthcare interventions. In 2011, >4 billion prescriptions were dispensed in the United States. Medication use is often supported by “hard science” and evidence; clinical practice often shifts to the “soft science” of medicine, trying to understand patients, their histories, personalities, medication adherence, and a way to provide the best possible care.

Of the billions of prescriptions filled, it is estimated that half are taken improperly. Achieving a balance between “hard” and “soft” sciences—by providing evidence-based medication therapy that patients will adhere to—becomes paramount. This chapter explores patient adherence; provider’s considerations such as evidence, pharmacokinetics/pharmacodynamics, and safety; and healthcare system factors such as formulary systems/resources.

Discrepancies among documented medication therapy records and actual patient use of medications are common and occur with all classes of medications. Therefore, the first step for the provider in determining optimal medication therapy is to understand what medications patients are actually taking and how they are taking them. The physician must also inquire in a nonjudgmental manner whether patients are taking any over-the-counter (OTC) medications, herbal, or vitamin products. Over 17% of the population takes herbal supplements on a yearly basis, but only 45% of these patients report this to their physician. Table 47-1 lists five concise steps to a medication review. To obtain an accurate medication history, the physician should start by asking open-ended questions; for example, “What medications are you taking?” This approach avoids the common mistake of assuming the patient is taking all their medications as prescribed. Although conducting an open-ended medication history may take more time up front, it may ultimately prevent over- or underprescribing and may also improve patient relationships. Polypharmacy is defined as the concurrent use of multiple medications or the prescribing of more medications than are clinically indicated. Polypharmacy can be minimized by a thorough medication regimen review.

Evaluation & Change

A thorough medication history and safety assessment begins to clarify many aspects of a patient’s medication regimen and, paired with evidence, can help the clinician make a solid patient-specific decision about a regimen. Evidence-based medicine (EBM) is ‘a model for incorporating the tools of clinical epidemiology into clinical practice.’ This model entails obtaining the best external evidence to support clinical decisions and is, therefore, not restricted solely to randomized trials and meta-analysis.

It is critical to appreciate that EBM does not depend solely on the skills and aptitude of literature evaluation and application of data, but must also incorporate clinical experience. The most commonly reported barrier to practicing EBM is a lack of time. However, the goal of EBM is to provide appropriate allocation of effective and efficient care to all patients. It is estimated that >6 million references have been published in >4000 journals in the National Library of Medicines database, MEDLINE. Slawson and Shaughnessy (2001) propose that the practitioner should approach this “information jungle” with a basic equation:

Relevance is directly proportional to its applicability to the physician’s practice. Validity relates to the intrinsic methodology, study design, and conclusions. Thus, by maximizing the principles of the usefulness equation, one may locate the best source of information. The mnemonic patient-oriented evidence that matters (POEMs) is an easy way for practitioners to focus in on information that can directly affect practice. Table 47-2 lists EBM-related websites.

Clinical practice guidelines are defined by the Institute of Medicine as “statements that include recommendations intended to optimize patient care which is informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options.” Clinical practice guidelines are intended to support clinicians’ decision making by providing a comprehensive summary and critique of the available evidence. Several types of evidence-based guidelines exist and the strength of evidence of each is variable. Evidence-based clinical practice guidelines incorporate recent literature regarding the effectiveness of therapy and clinical experience. Expert consensus guidelines may be the simplest type of guideline; however, limitations to this approach are inherent author bias and limited evidence-based sources. Outcomes-based guidelines incorporate measures of effectiveness to validate a positive impact on patient care.

The Cochrane Collaboration produces systematic reviews, maintains a registry of trials, and is a leading provider of evidence-based guidelines. Cochrane reviews may be located in the Cochrane Library, Cochrane Collaboration, or Cochrane Reviews’ Handbook at the following site: http://www.cochrane.org. In addition to the Cochrane Collaboration, many medical/professional societies, health maintenance organizations, and the Agency for Health Care Policy and Research provide practice guidelines and Internet links to the guidelines.

Formulary systems are fundamental tools of hospitals, health systems, and managed care organizations to designate preferred products and provide rational, cost-effective prescribing decisions. A drug formulary may be defined as “a continuously revised list of medications that are readily available for use within an institution and reflect the current clinical judgment of the medical staff.”

Drug formulary policies are based on comparative efficacy, safety, drug interactions, dosing, pharmacology, pharmacokinetics, and cost. Decisions are made by consensus of a pharmacy and therapeutics (P&T) committee made up of healthcare professionals of all major disciplines of practice who serve to represent the medical staff. A P&T committee has been described as “an advisory committee that is responsible for developing, managing, updating, and administering a formulary system.” The goal of this body is to guide the appropriate, safe, and cost-effective use of medications.

Medication Adherence

“Drugs don’t work in patients who don’t take them” – C. Everett Coop, MD, former US Surgeon General.

Medication adherence, or the degree to which a patient’s medication-taking behaviors comply with a prescribed regimen, represents a serious and insidious barrier to optimal patient care. Many factors may affect adherence to a regimen, including perceived acuity of the disease being treated, regimen complexity, sequelae of the patient’s underlying illness, and provider-patient relationships. Regardless of the reasons for nonadherence, it is clear that patients may not receive the full benefit of a medication regimen as a consequence of not taking the medication. In the United States, an estimated 33–69% of medication-related hospitalizations result from poor medication adherence.

While many studies report percentages of “adherence” and “nonadherence” as dichotomous and mutually exclusive variables, the true nature of medication adherence more likely resembles a continuum. Recognizing medication non-adherence and acting to improve patient self-efficacy present opportunities to improve both patient care and provider-patient relationships.

Because it is difficult to predict patient adherence behavior, it is critical to identify barriers to adherence that may be controlled or modified. Many techniques may be used to assess compliance, including directly observed therapy, pill counts, review of prescription refill records, and patient interviews. Directly questioning the patient, while efficient and easy to do in an office visit, may create a bias towards perceived compliance that is not actually true. Morisky and colleagues developed a validated four-question assessment to gauge patient adherence behaviors. Patients are asked these questions:

1. Do you ever forget to take your medications?

2. Are you careless at times about taking your medications?

3. When you are feeling better, do you sometimes stop taking your medications?

4. Sometimes if you feel worse, do you stop taking your medications?

Techniques from motivational interviewing may be useful in eliciting useful responses. In particular, empathizing with the patient about their medication regimen may be helpful. For example, a physician might ask about medication adherence while providing support, as in the following example: “I know it is difficult to take all of your medications—how often do you miss taking them?” This approach makes a patient comfortable and allows the physician to gain useful and truthful information.

If nonadherence to a medication regimen is identified, consider assisting the patient by helping them to create a medication list or calendar, provide refill reminders, use a pill organizer, develop a medication reminder chart, or consider electronic devices and compliance services. Additionally, consider referring the patient to their pharmacist for support.

Clear communication with patients when prescribing new medications is imperative. Improved medication adherence has been associated with patients who receive better general communication, more medication information, and better explanations about how to take medications. Despite the importance of conveying this information, prescribers often fall short. Tarn and colleagues (2006a, b) studied physician communication for new medications and found that physicians failed to describe the medication’s name 26% of the time, potential side effects 65% of the time, and cost 88% of the time.

The measurement tool used by Tarn and colleagues, known as the medication communication index (MCI), was developed from national guidelines for communication about new medications. This simple five-category index can be used as a guide for the five points to discuss with patients each time a new medication is started: (1) name of the medication, (2) purpose or justification for use, (3) duration of intake, (4) directions for use, and (5) potential adverse effects.

Managing Medication Cost

In 2011, spending on prescription drugs in the United States amounted to $263 billion, or 9.7% of national health expenditures. These costs continue to rise from year to year; between 2001 and 2011, prescription drug spending increased by almost 90%. For patients who have trouble affording their prescriptions, there are several ways to combat the high costs of drug therapy.

If the patient has prescription insurance coverage, prescribing within the payer’s formulary will aid in reducing out of pocket costs. Many third-party payers now post their formularies online where patients and providers may easily reference them. Prescribing of generic or lowest-tier drugs is encouraged whenever possible. Some retail pharmacy chains provide generic drug pricing plans that can decrease patients’ medication costs even further. Overall medication burden may also cause financial strain for patients. In this case, a thorough medication regimen review may identify drugs that can be discontinued, if medically appropriate.

For patients who do not have insurance, a few options can be pursued to help them obtain medications at a reduced cost:

1. A patient aged ≥65 years can apply for drug coverage through Medicare Part D. To determine which plans the patient is eligible for, and associated costs, visit www.medicare.gov.

2. Determine whether your patient qualifies for any federal, state, or military-operated program. Income restrictions apply.

3. Have contact information available for state Medicaid programs.

4. Consider applying for medication assistance programs sponsored by pharmaceutical manufacturers. Pharmaceutical manufacturers supplied free or low-cost medications to >5 million people in the United States. Several Internet sites are available to aid in obtaining information on how to use these programs, including www.needymeds.com, www.rxhope.com, and www.themedicineprogram.com.

Patient harm as a consequence of a medical error or drug effect is a common, costly, and largely preventable problem. Fatalities related to adverse drug reactions (ADRs) have been estimated to rank between the fourth and sixth leading cause of death in the United States.

During premarketing trials, if ≥1500 patients are exposed to a drug, the most common ADRs will be detected. However, >30,000 patients must be exposed to the drug in the postmarketing period to detect an ADR in one patient with a power of 0.95 to discover an incidence of 1 in 10,000. For both new and older medications alike, primary care providers play an important role in detecting and reporting unexpected or previously unreported reactions to medications. Physicians can anonymously report ADRs simply by (1) logging onto www.fda.gov/MEDWATCH or calling 800-FDA-1088, or (2) if in a hospital or nursing home setting, contacting the pharmacy or local drug information center. Adverse reactions to vaccines should be reported to the, Vaccine Adverse Event Reporting (VAERS) program, which is cosponsored by the CDC and FDA.

Although a subset of ADRs is unpredictable, those that are preventable include drug-drug interactions. A grasp of basic pharmacokinetic/pharmacodynamic principles is needed to prevent interactions. Pharmacokinetics characterizes the rate and extent of absorption, distribution, metabolism, and elimination of a drug. Pharmacodynamics is the study of the relationship between the drug concentration at the site of action and the patient response. In reviewing the patient history, consider the following characteristics in relation to drug pharmacokinetics:

• Age: Most drugs are studied in adult patients and recommended dosages may vary in different age groups.

• Gender: Although data are limited, male and female patients can metabolize and eliminate drugs differently, so the optimal drug dosages may differ.

• Weight: For patients who are obese or cachectic, changes in drug absorption, clearance, or volume of distribution may necessitate dosage adjustments or selection of a different drug or dosage form.

• Disease conditions: Three conditions that must be approached with special caution when prescribing any drug are heart failure (HF), renal disease, and hepatic failure. As HF progresses, bodily organ blood flow declines; the ensuing drug clearance decline necessitates lower dosages for many agents. As kidney or liver function declines, the renal and hepatic elimination of drugs decreases, leading to lower dosage requirements for renally and hepatically cleared agents, respectively. Additionally, fluid retention that is commonly seen with these diseases may affect drug dosing.

• Genetics: Pharmacogenomics is the study of the relationship of genetics in drug metabolism and response. In a systematic review by Phillips and colleagues, of 27 drugs known to frequently cause ADRs, 59% were known to be influenced by individual patient genetic characteristics.

Once the patient-specific characteristics noted in the preceding section have been established, the physician can begin to examine the drug-specific characteristics. The main enzymatic system responsible for drug metabolism is the cytochrome P450 (CYP) system. Metabolism through the CYP system occurs mainly in the liver, but CYP isozymes are also found in the intestines and other organs. Identifying different CYP isozymes is an area of ongoing research. There are six isozymes for which there is a reasonable amount of knowledge: CYP 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. Understanding this system allows prediction of drug-drug interactions among many patients. To do this, it is necessary to identify which drugs are metabolized by the CYP 450 system, and how they interact with the enzyme system. There are three ways in which a drug can interact with the isozymes:

• Substrate: Drug is metabolized by an isozyme that is specific for an individual CYP receptor.

• Inducer: Drug activates the isozyme system, allowing a greater metabolism capacity.

• Inhibitor: Drug competes with another drug(s) for a specific isozyme-binding site, rendering the isozyme inactive.

A review of the patient’s medication list may reveal drugs that compete or use the same enzyme system. A change in drug selection may prevent a drug interaction. Physicians may check on whether a drug is a CYP substrate, inducer, or inhibitor in the “interactions” section of drug information resources.

Subscribing to survey services is one way to stay current with the pertinent literature, while decreasing the amount of work and time required. Survey services provide an efficient means of reviewing a host of medical journals and articles. However, one should do this cautiously because of the potential for bias toward positive conclusions or embellishment of study results. The conclusions and recommendations presented by such services should be critically evaluated before applying the information in practice.

Three basic categories of survey services exist: (1) abstracting services, (2) review services, and (3) traditional newsletters. Abstracting services for family medicine practitioners include, but are not limited to, the ACP Journal Club, the Journal of Family Practice, and Journal Watch Online. All have a goal of providing relevant information in a timely manner. ACP Journal Club (http://acpjc.acponline.org/) is published by the American College of Physicians–American Society of Internal Medicine. This service provides brief, high-level summaries of current original articles and systematic reviews in a structured abstract format. The ACP Journal Club reviews over 100 journals and uses prestated criteria to select and evaluate data. Pertinent information summaries are provided to subscribers on a bimonthly basis. The Journal of Family Practice (http://www.jfponline.com) provides family practice physicians with timely, reliable information supplemented with expert commentary on clinically applicable topics. Journal Watch Online (http://www.jwatch.org) is supported by the publishers of the New England Journal of Medicine. This service, similar to the others, provides current summaries of the most important primary literature. An editorial board, composed of physicians from many specialty areas reviews, analyzes, and summarizes 55–60 critically important articles. The summaries are published on a bimonthly basis. In addition, this service features Clinical Practice Guidelines Watch and editorials of the year’s top medical stories.

Review Services provide a succint summary of a specific topic, rather than a survey of the literature. One example of a review service is The Medical Letter (http://www.medletter.com). The Medical Letter is published by an independent nonprofit organization and provides critical appraisals of new medications or uses for medications in a clinical context, comparing and contrasting the new medications to similar established agents. This concise publication is printed bimonthly. Another example of a review service is Primary Care Reports. This service is printed bimonthly and is intended to provide review articles on critical issues in primary care; treatment recommendations are provided with each review.

Traditional newsletters provide brief reviews of current literature with topics from news media and other sources. Examples of this type of newsletter include The Drug and Therapeutics Bulletin and Therapeutics Letter. The Drug and Therapeutics Bulletin (http://www.dtb.bmj.com) is a concise monthly bulletin that provides evaluations of medications and summarizes randomized, controlled, clinical trials, and consensus statements. This service provides informed and unbiased assessments of medications and their overall place in therapy. The Therapeutics Letter (http://www.ti.ubc.ca/TherapeuticsLetter) is a bimonthly newsletter that targets problematic therapeutic issues and provides evidence-based reviews written and edited by a team of specialists and working groups of the International Society of Drug Bulletins.

It is recommended that physicians use these services as a filtering tool to determine which primary literature articles are critical to read in-depth. Survey services provide condensed forms of information, but it is the clinician’s responsibility to analyze, interpret, and apply this information effectively in patient care decisions.

Traditionally, textbooks have been the cornerstone reference for physicians for drug information such as the Physician’s Desk Reference (PDR), American Hospital Formulary Services (AHFS), Drug Facts and Comparisons (Facts & Comparisons), and the Drug Information Handbook. However, as we move into this digital era where instantaneous, accurate information is expected, physicians and residents alike are turning toward their computers and handheld devices for drug information resources.

There are numerous drug information resources available to address general or specific pharmaceutical categories (eg, ADRs, drug interactions, therapeutic use, dosing) that are well referenced with the prescribing information from drug manufacturers, counseling tips and FDA warnings. MICROMEDEX is a computerized drug information resource that contains facts from the DRUGDEX Information System. This is a well-referenced, easily searchable, expansive drug information reference, housing information on prescription, nonprescription, and herbal products. Facts & Comparisons contains information on prescription and nonprescription medications. This reference provides tables and comparative drug class data along with patient counseling information. Clinical Pharmacology is another digital resource available to address drug questions including interaction information and a wide array of printouts available for patient-friendly information. Finally, Lexicomp is a thorough drug information resource to search for drug information questions. With a user friendly mobile application, Lexicomp is a widely utilized resource.

With increases of natural products, The Natural Medicines Comprehensive Database and the National Library of Medicine are two electronic references that consistently provide valid natural production information. ePocrates Rx has been advocated by insurance companies and government agencies to enhance clinical management and decrease medication errors.