How can these studies help us avoid DDIs, perhaps the most preventable form of drug-related injury? In what direction should our future efforts be directed? These are deceptively simple questions that first compel a précis of the major hurdles we face each time a patient takes two or more medications simultaneously. In this Viewpoint article, I discuss some of these obstacles, and suggest strategies by which they might be overcome.
The obstacles we face in our efforts to understand and avoid DDIs span three overlapping themes—problems inherent to the entity of DDIs, the science behind them, and application of knowledge we already possess.
Problems Inherent to DDIs
Perhaps the most daunting aspect of DDIs is their sheer number. Tens of thousands of different DDIs have been described, and even the most diligent clinician cannot reasonably be expected to remember the established ones, let alone keep abreast of the new ones reported each year. Fortunately, the burden has been lessened by the past decade's advances in pharmacology. Because we now appreciate that many DDIs are mechanistically similar, remembering countless 2 × 2 combinations is not necessary. For example, if a drug inhibits cytochrome P450 (CYP) 2C9, we may infer that it will heighten the response to warfarin3
and increase the risk of hypoglycemia in patients receiving glyburide., 45
Another difficulty concerns judgments about the potential consequences of individual DDIs. Some interactions are necessarily more important than others, either by virtue of their severity (which, as the articles in this issue point out, is sometimes a matter of dispute even among experts, 12
), or because they involve common drugs and therefore affect many patients. Conversely, “minor” interactions preponderate in our list of thousands, yet what exactly constitutes a minor interaction is rarely defined, perhaps because many of these can have severe consequences under the right conditions.
What exactly defines a major interaction? Among those listed in Table 2 of the article by Abarca et al.1
(on page 140, anticoagulants, immunosuppressants, and monoamine oxidase inhibitors dominate because of their pharmacologic promiscuity. However, closer inspection of this table makes us shake our heads at the disconnect from clinical reality. Where are the DDIs that experience tells us bring so many patients (those lucky enough not to die suddenly) to medical attention? Sulfonylureas and CYP 2C9 inhibitors, digoxin and P-glycoprotein inhibitors, angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diuretics—the severity of these DDIs is undisputable, and countless patients are exposed to them each year.6
Their absence from the list is conspicuous and should lead us to question the extent to which our compendia reflect clinical practice.
Problems with the Science of DDIs
The last decade has yielded tremendous advances in our understanding of the mechanisms by which DDIs occur. Yet adoption of this knowledge is too often sluggish. One example is the interaction between digoxin and some macrolide antibiotics. First explained by the ability of erythromycin to inhibit Eubacterium lentum
, this interaction was inexplicably observed in only 10% of patients, and for some reason did not occur with other antibiotics active against E. lentum
For years now, we have recognized that the actual mechanism of this interaction involves inhibition of P-glycoprotein., 89
The ongoing maldescription of this interaction in the medical literature is understandable, given that some of the expert compendia studied by Abarca et al.1
have yet to update their science, and continue instead to proffer the same outmoded explanation., 1011
The other major problem concerning the science of DDIs is a paucity of useful literature. By this I do not mean the case reports or volunteer studies that dominate the landscape. We should embrace these sources of new and occasionally sentinel information12
while recognizing their sometimes limited generalizability. The greater deficiency regards information about the consequences of DDIs in clinical practice. We know virtually nothing about the epidemiology of DDIs, save for several studies showing that “potential” drug interactions are common, but whither the clinical consequences?13–18
has said, we need more “weavers” to spin the tale of what happens (or does not happen) following exposure to potential DDIs—not just in healthy young volunteers, but in actual patients.
Problems with Application of Knowledge
When bench science eventually does make its way into the clinical setting, it is often not applied as quickly and as pervasively as it might be. One reason for this, as noted, is that health professionals cannot possibly keep up with the deluge. Physicians are often oblivious to serious DDIs,, 2021
and many expect pharmacists to detect and prevent them. Yet despite more extensive training in pharmacology, pharmacists also miss important and sometimes life-threatening interactions., 2223
How often this translates into actual harm is unknown.
The most important weapon in our arsenal of defenses against DDIs is the computer.24
The various software programs undoubtedly help prevent some DDIs, but serious ones still sometimes escape detection., 2225
In contrast, the surfeit of alerts perceived to be clinically irrelevant generates contempt for the computer's “ability” and may beget a dangerous complacency for more meaningful warnings., 2627
Despite strides in the right direction, the untapped potential of computers to help prevent injury and death from DDIs is enormous.
Like the obstacles before us, the solutions encompass several overlapping themes—professional development, advances in the science of DDIs, and progress in the development and application of technology.
Individual physicians and pharmacists must strive to play an even greater role in the prevention of DDIs. Simply developing a greater appreciation of the potential harm DDIs can cause and being more vigilant for them is a good start. Other measures include committing to memory a “short list” of commonly involved medications and ensuring one's Internet browser has a few bookmarked Web sites for quick clinical queries. Continuing education in such a rapidly changing field is also of paramount importance, and for those who feel in need of a refresher, several concise reviews crystallize a decade's worth of advances in xenobiotic metabolism and drug transporters for even the most intimidated reader.28–30
The sometimes painfully slow translation of new knowledge regarding DDIs into practice is difficult to justify. However, the scientists who study the issue are unlikely to alter how they disseminate their findings, and we must rely on other means by which their insights can routinely achieve prompt clinical application. As noted earlier, purveyors of DDI compendia should strive for timely updates, and since pharmacists and pharmacy computer systems rely on these information sources, they are the best mechanism for diffusion.
The other pressing scientific need surrounds the dearth of information regarding the consequences of DDIs. More studies of potential DDIs are not needed; rather, clinically meaningful outcomes research linking medication use and outcomes in large patient groups is the best way to examine the real-world consequences of DDIs.31
Historically, this has been a difficult endeavor, especially in ambulatory patients. The proliferation of administrative databases, especially those integrated with laboratory data, offers much promise in this area., 3233
Progress in Development and Application of Technology
Optimizing the use of technology is the area in which our greatest potential to minimize the occurrence of DDIs rests. Eight strategies to this end, some of which have been highlighted by others,, 19, 2426
are outlined below.
Electronic Information Sharing
Patients are not obliged to visit only one pharmacy. While our data-sharing capabilities have grown (as evidenced by real-time claims adjudication), computerized DDI detection software has often lagged behind, remaining oblivious to prescriptions on the other side of town. Electronic information sharing between pharmacies and physicians' offices will help improve DDI detection34
and will also lessen the problems of therapeutic duplication and illegitimate acquisition of controlled substances from multiple unsuspecting sources.
Individualizing DDI Warnings
Integration of individual patient characteristics in the assessment of risk is essential if computerized DDI detection is to improve in a meaningful way.26
For example, hyperkalemia secondary to combined use of ACE inhibitors with potassium-sparing diuretics should probably always be flagged,35–37
but the severity of the interaction is clearly greatest in patients with diabetes,38
or baseline hyperkalemia.39
Future software should modulate the intensity of warnings to reflect this.
Defining and Eliminating Trivial DDIs
Respect for computerized DDI warnings will grow as trivial alerts are minimized. What defines trivial is not always clear, yet some low-hanging fruit is immediately apparent. Many of the interactions graded by compendia at the lowest range of severity could be eliminated, perhaps after cautious consideration by consensus panels such as the one described in the article by Malone et al.2
(although selected alerts might be retained for patients at higher risk). Interactions involving refills of two long-term medications should not prompt warnings, even if the usual alert is a major one (e.g., verapamil–digoxin). Similarly, alerting pharmacists that two antihypertensive agents can cause hypotension, or that two oral hypoglycemic agents can cause hypoglycemia, makes little sense. Finally, flags involving chronologically remote prescriptions are pointless, such as warnings of digoxin toxicity elicited by last month's—or last year's—prescription for erythromycin.
Prompt Application of New Findings
DDI detection software must remain up-to-date with advances in pharmacology, not just with new medications but also extrapolating, when appropriate, to existing ones. For example, a new antibiotic that inhibits P-glycoprotein should be assumed to have a serious interaction with digoxin, even if no such interaction has ever been reported. Waiting for the first case report to wind its way into the literature is imprudent.
Eliminating Inappropriate Class-Specific Warnings
The past decade's advances in pharmacology have made many class-specific warnings inappropriate.
Pharmacokinetic DDI alerts involving macrolide antibiotics, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), or selective serotonin reuptake inhibitors, for example, have little justification today. These unnecessarily clutter our practice or, worse yet, trigger confusion and inappropriate therapeutic changes.
Providing Optional Links to Additional Information
At the time of prescribing or dispensing, warnings about potential DDIs are likely to carry more weight when the operator can easily obtain more than just a brief description of the interaction. This may take the form of additional evidence-based information installed directly on the computer or Internet-based hyperlinks to seminal articles.
Proposing Therapeutic Alternatives
Computerized warnings are more likely to be heeded when an alternate plan of action is presented. For example, when a prescription for clarithromycin triggers a warning of digoxin toxicity, practitioners need to know that cefuroxime and azithromycin are noninteracting potential alternatives that could be substituted if the clinical scenario warrants.
Making Serious DDIs More Difficult to Override
Interactions with a potentially serious outcome should not be skirted with the push of a button. At a minimum, the final authority for such overrides should rest with the pharmacist rather than pharmacy technicians, dispensary assistants, or trainees. Point-of-care electronic documentation of the rationale for each override of a serious DDI would heighten the likelihood that the clinical consequences are adequately assessed and appropriate action taken. In most pharmacies, such occurrences are sufficiently rare that the additional labor costs are likely to be minimal.
Harm resulting from DDIs will never be fully extinguished. The solutions proposed above are not exhaustive, and some are easier to deploy than others. However, each holds some promise to aid us in our efforts to minimize injuries and deaths from DDIs. The stakes are high, but there is ample room for improvement. Surely we can do better than we have thus far.
See related articles on pages 136 and 142.
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