A New Solution for Weight LossUndernutrition is a pervasive problem in the long-term care environment, and the use of liquid dietary supplements is widespread. Fortunately, for some residents, the addition of these supplements provides adequate calories and nutrition to keep their weight stable. For many other residents, though, these supplements appear to have little if any beneficial effect. Nursing staff may fail to distribute the supplement, or they may provide it concurrently with meals, which may actually decrease the resident’s overall intake. For residents who often resist drinking even a few sips of water, it may be virtually impossible for nursing staff to convince them to consume 6–8 ounces of a nutritional supplement. Use of orexigenic medications such as cyproheptadine and megestrol acetate is often met with minimal success and may add significant side effects to the resident’s medical regimen. Over the past several weeks, I have monitored the weight changes of 57 patients with weight loss issues. These residents had failed on traditional supplements and were not showing positive response to their current therapies. The purpose of this informal study was observe whether a relatively new product, Epulor (marketed by VistaPharm, Birmingham, Alabama), resulted in weight gain in selected patients. Unlike other currently available treatments, Epulor is neither a medication nor a traditional dietary supplement. Epulor is a nutritional solution providing 320 calories, 40 vitamins, minerals, protein, and amino acids in one and one-half ounces (45 cc) of volume.
A Diverse, Challenging Patient Population Because Epulor delivers 320 calories in only 45 cc, we were able to schedule it to be given t.i.d. during the med pass. It appeared that many residents assumed that it was just another medication and, therefore, took it without question. It could be mixed with thickener for dysphagic patients, or added to coffee, applesauce, pudding, or ice cream per resident request. We easily achieved 100% compliance with Epulor. We quickly observed that providing residents with 960 extra calories each day, in addition to the vitamins, minerals, amino acids, and protein in Epulor, had almost immediate results. Of the 57 patients observed, 44 (77%) showed improvement in weight (Table 1). Among those for whom Epulor was effective, the average weight gain over an eight-week period was 6.1 pounds, with a range of 0.2–15 pounds. The overall average weight gain of all patients observed was four pounds in eight weeks. We saw improvement in the residents’ overall condition, with staff reporting that most residents began to eat more of their meals, appeared to engage in more activities, and generally required less nursing staff time. These improvements alone in the residents’ condition brought rave reviews from the nursing staff, but they also reported being pleased by the fact that Epulor, which comes in small individual packets, takes up much less room in the medication cart and medication room. Both the nursing staff and the facility liked that they could use this one product for everyone (including diabetics, using the sugar-free formulation of Epulor), avoiding both the hassle and expense of trying to stock large amounts of other specialty supplements.
Effective and Well Tolerated It didn’t take long for the facilities to become “sold” on this product, with some facilities even including Epulor as part of their resident activities. One facility began having regular Epulor parties, in which they developed numerous “recipes” for foods and drinks enhanced with Epulor! Facilities were easily convinced of the potential cost-effectiveness of this product, as well. At a cost to the facility that was virtually equivalent to that of liquid supplements, it quickly became apparent that the 100% compliance with Epulor, as opposed to the large amount of liquid supplements that had previously gone unconsumed and wasted each day, could result in a tremendous cost savings. In addition, the weight gains obtained with Epulor allowed for the discontinuation of medications that had previously been added to the residents’ regimens in an effort to promote appetite. For facilities concerned with the new HCFA quality indicator of “greater than 9 medications per resident,” Epulor provided the added potential benefit of being able to discontinue many multivitamins and expensive orexigenic drugs, as well as some of the antidepressants that had been prescribed purely to promote weight gain. We observed weight gain in 77% of patients receiving Epulor within 8-12 weeks of therapy. While this was not a scientific study, our findings remain positive. As residents began regaining weight, their appetites appeared to increase, and they were able to maintain their weight on their own, allowing for the discontinuation of Epulor. This leads us to believe that Epulor may be useful as a short-term therapy for undernutrition and offer advantages over many other agents used for weight gain, which are often prescribed indefinitely, creating a huge financial burden for the nursing facility. While not as easy to measure, the prevention of nutrition-related comorbidities such as pressure ulcers, infections, and skin tears also adds up to a tremendous cost savings for the facilities. In the current Medicare prospective payment system (PPS) environment, where the facility’s ability to contain costs predicts its ability to survive and flourish, these issues are of tremendous importance. In the continual quest for products designed to help promote weight gain in the elderly long-term care resident, it appears that Epulor is a bright spot on the horizon. For many of these residents who had failed on traditional supplements and therapies, Epulor helped reverse the pattern of weight loss. The apparent cost-effectiveness of Epulor, along with our ability to achieve 100% compliance with this product, will certainly make it one that I would recommend as first-line therapy for residents experiencing weight loss. Jan Allen
References
Drug Interactions: The Pharmacist’s Forte?Perception of ValueTo understand what the consultant pharmacist’s perception of value is to other health care professionals and our patients, I take a step back every so often and look at our own profession. When asked about the value pharmacists bring to patient care, the answer of other health care professionals, without hesitation, is drug therapy knowledge. It is to no surprise that consultant pharmacists are respected and admired by patients and peers for the vast understanding of drug therapy management. After all, consultant pharmacists have spent years in training for drug therapy management. However, within this classification, our clinical observation and judgement in the prevention of life-threatening drug-drug interactions, which directly affects patient care, is the aspect of our knowledge most sought after by health care professionals. No other health care professional spends as much time and effort preventing drug therapy misadventures than the consultant pharmacist who has complemented sound clinical judgement by embracing modern technology. Computers have revolutionized the practice of pharmacy. Each year, the Food and Drug Administration (FDA) approves multitudes of new pharmacological advancements and drug therapy regimens increase in complexity, which further challenges the clinical skills of the consultant pharmacist. Over time, we as clinicians have learned to develop an alliance with the laptop computer and software for drug regimen screening. We have reduced the incidence of human error through automation of the drug regimen screening process. But, are we using the latest technological advancements as a tool or a crutch? Although computers are very powerful tools for clinicians, they are no substitute for the critical thought process, clinical experience, or keen therapeutic perception and judgement. For the last several weeks, I have been approached by a number of individuals expressing concern over potentially life-threatening drug-drug interactions encountered in long-term care facilities. What bothered me most was not that the conditions were ripe for a drug therapy misadventure, but that the events went unrecognized and undocumented on the part of the facility and pharmacy. The discoveries were made not at the time the orders medications were ordered were written, but after days or weeks of administration, setting up the patient for negative outcome and potential hospitalization. In one case, the interaction at hand involved an elderly women receiving cisapride for symptoms of gastroesophageal reflux disease, who had been placed on clarithromycin for an upper respiratory tract infection. She had been receiving clarithromycin for seven days when a consultant pharmacist identified the drug-drug interaction. The dispensing pharmacist stated that he thought it was a relatively new drug interaction and that the error resulted from the fact that the pharmacy’s computerized screening system had not been updated to identify the interaction. When this incident was brought to my attention, my question was: What happened to the ability of the pharmacist to screen a patient’s profile based on his/her own knowledge? This is a significant drug interaction consultant pharmacists have been aware of for several years. Although it is a challenge to our profession to keep current with the changing pharmacological landscape, it is our professional obligation to ensure that we know the pharmacological mechanisms of action underlying the most common drug-drug interactions our patients will experience. To accomplish this goal, consultant pharmacists should fulfill personal educational needs by targeting resources that efficiently keep us up to date on the basic pharmacology of new therapeutic agents. It is a common-sense approach for recalling clinically significant drug interactions, based on our current basic knowledge of pharmacology. If consultant pharmacists have a thorough understanding of the concept of how the drug affects the human body, and how the human body affects the drug, identifying the drug interaction will be as clear as the place for the last puzzle piece. The process of recall revolves around comprehending the concept of the interaction.
Basic Mechanisms The second mechanism by which drug interactions occur involves pharmacokinetic mechanisms. Pharmacokinetic (time-course of free drug in the serum after administration, mediated through absorption, distribution, metabolism, and clearance) drug interactions may occur as a result of the following:
On the basis of our knowledge of physiological changes that occur with age, it is easy to see how each of the mechanisms described above has the potential to negatively affect the geriatric patient. Many of the potentially threatening drug interactions consultant pharmacists encounter have mechanisms originating in the hepatic cytochrome P450 system (CYP) with its various isoform enzymes. There are over 30 CYP isoenzymes, divided into four families in the hepatic metabolic system. Certain isoform families are responsible for the majority of metabolism of specific pharmacological agents. Listed in order of highest hepatic prevalence, these are as follows: CYP 3A, 2D6, 1A, 2A6, 2B6, 2C, and 2E1.2 Enzymes of significant importance to the geriatric practitioner are CYP 1A2, 2C, 2D6, and 3A3/4.3 Each isoform family has the capacity to be affected in one of two ways. Medications inducing metabolism have the potential to reduce the half-life of concomitantly administered agents, while those that inhibit metabolism have the potential to increase the half-life of coadministered agents. In either case, pharmacists have a tremendous opportunity to affect patient care, control unnecessary costs, and reduce nursing facility liability by identifying common drug interactions before they occur. Although a complete list of potential drug-drug interactions is beyond the scope of this article, some of the most common, clinically significant drug interactions in the elderly, based on hepatic metabolism, have been documented in Tables 1–4.
Genetic Polymorphism
Elderly at Risk
All of these factors emphasize the need for consultant pharmacists to be knowledgeable in identifying potential drug-drug interactions before they occur. Potential solutions to reduce the exposure of geriatric patients to drug-drug interactions are dependent on those individuals responsible for providing their health care. Pharmacists are the rate-limiting step in the drug interaction screening process. When compared to physicians and nurses, pharmacists literally hold more of the necessary tools to screen for drug interactions in their hands.
Direct attention began to be drawn to the significance of drug interactions in the late 1960s with an editorial by G. P. Provost.5 Since that time, we have developed a vast array of educational programs, strategic initiatives, drug-drug interaction databases, and drug interaction screening programs to assist in preventing such misadventures. Yet, potentially fatal drug-drug interactions still occur on a regular basis. How can we improve efforts to reduce the risk to the elderly? One solution may lie in the implementation of a global approach. To address these issues, many institutions have developed multidisciplinary quality assurance and risk management teams to develop and institute specific strategies to ensure that every attempt is made to screen each patient’s profile for potential negative outcome. This will ultimately translate into dollar savings.6 All staff members should be well educated on the identified limitations of drug interaction screening software, as well as company policies regarding drug interaction prompt overrides. Some screening programs have the capacity to track drug interaction overrides for quality assurance purposes. Another strategy is for institutions to categorize specific drug-drug interactions according to levels of significance, once identified. Such an approach assists pharmacists in determining an appropriate course of action (e.g., notify the facility, discuss alternative therapeutic choices with the physician, recommend a monitoring plan). Staff education is of equal importance to the success of any drug interaction screening program. One way to ensure that all staff members are up to date on the most serious and potentially threatening drug-drug interactions in the elderly is to develop comprehensive, dynamic drug interaction educational initiatives that will provide ongoing updates at regular intervals. Policies and procedures of all institutions should reflect continuing education requirements of the staff and specify expectations pertaining to core knowledge of significant drug interactions. Many institutions have implemented competency testing to ensure staff proficiency.
Conclusion Not only do undetected drug interactions possess the potential to complicate treatment efforts, increase the odds of therapeutic failures, and escalate the cost of providing care, but they also increase the risk of malpractice liability for all providers of health care. Each individual in a position to make an appropriate intervention is at risk. That includes physicians, nurses, long-term care facilities, nursing staff, pharmacies, and individual pharmacists. We as consultant pharmacists have a foundation of core knowledge of drugs unmatched by that of any other health profession. We are just now on the forefront of realizing the rewards of years of hard work. In many cases, these rewards are taking the form of changes in state pharmacy practice acts that acknowledge the clinical skills pharmacists possess; however, our struggles have not yet ended. There are still a number of professional organizations that oppose our involvement in patient care outside of dispensing medication. In many cases, this is due to the fact that they themselves are lobbying for prescriptive privileges and realize that we pose a direct threat to their success. Regardless of the opposition we face, consultant pharmacists have reached a critical time in our profession, a time when we cannot afford to give other professions a reason to doubt our clinical skills nor our future role as health care providers. Remember, “We as pharmacists are paid for what we know, not what we can do.” Michael P. Slyk, PharmD, FASCP
References
Tetracyclines: More Than Just an Old Class of AntibioticsOld, low-use drugs eventually fall by the wayside as new drugs with similar indications are approved by the Food and Drug Administration (FDA). However, technology, trial, and happenstance sometimes reveal novel uses for old (and new) drugs. Oftentimes, the consultant pharmacist can determine possibilities for off-label use from a drug’s mechanism of action. Other times, a novel effect is revealed during routine use. This has been the case with tetracyclines, which are being studied in disorders with no infectious or microbial associations. This time, tetracyclines may again play a major role, but in disease states associated with connective tissue degradation.As a class of broad-spectrum antibiotics, tetracyclines are effective against aerobic and anaerobic gram-positive and gram-negative bacteria, as well as against Rickettsia, Mycoplasma, and Chlamydia species. Tetracyclines are primarily bacteriostatic, but in high concentrations they are bactericidal, inhibiting bacterial protein synthesis.1,2 In the past, tetracyclines were used as first-line agents to treat infectious diseases and as additives to animal feed to promote physical growth.1 Increased bacterial resistance, as well as the development of less toxic, infection-specific antimicrobial agents, has decreased the use of tetracyclines.1 Often second- or third-line therapy for common gram-negative or gram-positive bacteria, tetracyclines are used, unless other appropriate anti-infectives are contraindicated or ineffective. The first tetracycline, chlortetracycline, was discovered in 1948 during systematic screening of soil specimens for antibiotic-producing microorganisms.1 Chlortetracycline and oxytetracycline come from Streptomyces aureofaciens and Streptomyces rimosus, respectively. Tetracycline is produced semisynthetically from chlortetracycline. Demeclo- cycline is the product of a mutant strain of Streptomyces aureofaciens, and doxycycline and minocycline are both semisynthetic derivatives of tetracycline.1 Connective tissue (bone, skin, ligaments, tendon, cartilage, blood vessels, basement membranes) is found throughout the body and acts to support and bind other tissues, to store nutritional substances and/or to produce protective and regulatory materials. Connective tissue varies by content of specific components and in three-dimensional organization of macromolecular components, and it contains more extracellular, insoluble matrices than cells.3 The most common cell within the connective tissue is the fibroblast, which has the ability to differentiate into chondroblasts (immature cartilage-producing cells), collagenoblasts (immature collagen- and/or cartilage-producing cells), or osteoblasts (immature bone-producing cells). Fibroblasts produce fibers that are made of macromolecules: collagen, proteoglycans, and elastin. Collagen provides tensile strength and resistance to shear, elastin provides elasticity, and proteoglycans are responsible for tissue stiffness and the ability to withstand load. These macromolecules are not confined to connective tissue. They are also major constituents of lungs, kidneys, blood vessel walls, vitreous gel of the eye, and synovial fluid.3 Collagen fibers in most tissue of normal adults undergo very little metabolic turnover. One exception is collagen fibril, which undergoes repeated degradation for remodeling of bone. During growth and development, collagen fibril in all tissues is repeatedly synthesized, degraded, and resynthesized. Although collagen in many types of adult tissue is metabolically stable, metabolic turnover can change in certain circumstances (Table 1).3 Many normal biological processes require proteinases (enzymes) that are capable of degrading extracellular matrix for routine remodeling and repair.5 Matrix metalloproteinases (MMPs) such as collagenase, stromelysin, gelatinase, matrilysin, and metallo-elastase are believed to be important for many normal processes requiring matrix turnover, as well as for pathological processes such as tumor metastasis, arthritis, aneurysm formation, atherosclerosis, pulmonary emphysema, and those mentioned in Table 1.5
Scientists serendipitously discovered that tetracyclines are potent inhibitors of MMPs. In the early 1970s, Golub, Lee, and Ryan7 were interested in explaining how diabetes increased the severity of periodontal disease. They wanted to understand why people with diabetes are often refractory to periodontal therapy. In the diabetic rat, they found increased collagenase activity in gingiva and skin, compared with that found in nondiabetic control rats. Golub, Lee, and Ryan7 hypothesized that the rapid loss of soluble collagen in diabetic rat gingiva and subsequent severe periodontal destruction observed months after collagenolytic activity was due to a rapid shift to a more gram-negative microflora in subgingival plaque after onset of induced diabetes.4,7 It was believed that this shift increased the endotoxin level in gingival sulcus and subepithelial tissues, subsequently stimulating host cells (e.g., fibroblasts, macrophages) to elevate levels of collagenase and accelerate collagen breakdown.4,7 Additional experiments revealed unexpected therapeutic benefits of tetracyclines. In the lab, Golub, Lee, and Ryan7 tested their hypothesis and introduced two variables: germ-free rats and tetracycline therapy. This eliminated oral microbial factors, leaving only two other possibilities for increased collagenase activity (i.e., hormonal or metabolic alterations). They initially used conventional rats treated with minocycline, which is absorbed more rapidly and exhibits longer serum half-life than tetracycline HCl, and found that collagenolytic activity was reduced. To test the effect of tetracyclines in a situation where bacteriostatic properties would be irrelevant, in a parallel experiment using germ-free rats they found that collagenolytic activity was also reduced.4,7,8 This experiment and a series of subsequent in vitro and in vivo experiments in a variety of tissues and cellular sources and in a number of different laboratories confirmed the anticollagenase activity of tetracyclines. There are at least 18 different collagenases from different tissues and cells, and they vary in susceptibility to tetracycline inhibition. Likewise, members of the tetracycline family differ in their anticollagenase effectiveness.4,7 It was also discovered that tetracyclines inhibit MMPs other than collagenase (gelatinase A, gelatinase B, and macrophage metalloelastase). Furthermore, MMPs are inhibited by tetracyclines, but other proteinases (serine proteinases, acid proteinases) are not.7 Initial clinical trials focused on the response of collagenase to tetracycline in the gingival crevicular fluid (GCF) of patients with periodontitis. Minocycline and doxycycline are more effective in reducing GCF collagenase activity than tetracycline.4,7 Also, tetracyclines have a positive effect on cell attachment to dental root surfaces. Subsequently, in September 1998, doxycycline (Periostat) was approved by the FDA for use as an adjunct to scaling and root planning in patients with adult periodontitis for up to nine months as a 20-mg capsule twice daily. This low dose does not induce development of tetracyline-resistant microorganisms and induces few gastrointestinal side effects. Doxycycline hyclate 10% liquid formulation (Atridox), which solidifies after gum application, was also introduced in 1998. Golub, Lee, and Ryan7 chemically modified the tetracycline molecule and discovered the molecular site responsible for this new property during their investigations. Before long, they produced the first chemically modified tetracycline (CMT) that had no antimicrobial properties, but had enhanced anticollagenase activity. Thereafter, at least 10 CMTs were developed, CMT-1 through CMT-10, nine of which lack antibacterial properties and one of which has no anti-MMP activity.7 CMTs differ in their anticollagenase effectiveness and abilities to inhibit specific MMPs or other proteinases. For example, unlike any other tetracycline or CMT, CMT-3 inhibits polymorphonuclear (PMN) elastase, a serine proteinase. CMT-5 has no anti-MMP activity. Also, CMT-1, CMT-3, CMT-6, CMT-7, and CMT-8 are effective inhibitors of bone resorption in culture. In various studies, CMT-1 administered orally in vivo reduced pathologically excessive collagenase and gelatinase activity and/or inhibited matrix breakdown in gingival tissue and GCF of humans, in synovial tissue and fluid of humans with rheumatoid arthritis, in skin and gingiva of rats with diabetes, in cartilage of dogs with osteoarthritis, in rats with rickets, and in humans and rabbits with sterile corneal ulcers.7 Studies have also shown the therapeutic potential of anti-MMP activity of CMTs using in vivo and cell culture models of cancer invasion, metastasis, and angiogenesis.7,9 In addition to the ability to inhibit proteinases and prevent breakdown of connective tissue, tetracyclines and CMTs have demonstrated anti-inflammatory and immunosuppressive properties. Tetracyclines and CMTs can suppress neutrophil function, suppress leukocyte chemotaxis, and scavenge reactive oxygen species.8,10 These properties have been described in dermatologic literature.8,11 Tetracycline HCl has been used for acne for over 30 years by inhibiting neutrophil chemotaxis and directly inhibiting extracellular lipases.11 Studies have shown that minocycline and doxycycline inhibit phospholipase A2 (PLA2).12 PLA2 is an enzyme that plays an important role in inflammation by releasing arachidonic acid. It has been implicated in the pathology of several diseases. Also, high concentrations are found in assays of serum in diseases such as acute pancreatitis, sepsis and septic shock, infections, rheumatoid arthritis, osteoarthritis, other arthropathies, and multiple injuries.13 Studies have shown that tetracyclines may be useful adjuncts to anti-inflammatory drugs in the treatment of inflammatory arthritides.5,8,12 Tetracycline HCl (no longer available in the United States in the parenteral formulation), doxycycline, and minocycline have been used by intracavitary injection as a sclerosing agent to control pleural and pericardial effusions caused by metastatic tumors.2 By happenstance, tetracyclines have demonstrated abilities that no other antibiotics have to date. Tetracyclines and CMTs may some day be approved for use in the treatment of various arthritides, sterile corneal ulcers, tumor-induced angiogenesis, cancer metastasis, and dermatological conditions other than inflammatory acne vulgaris, and for treatment of other diseases on the long list of connective tissue disorders. Doxycycline and minocycline offer more promise than tetracycline HCl because lipophillic characteristics enable them to penetrate fluids and tissues more readily, and they have longer half-lives. CMTs have not yet been approved by the FDA.
B. V. Borders-Hemphill, PharmD
References
American Society of Consultant Pharmacists. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Forum