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Viewpoint
Drug—Drug Interactions: Where Do We Go from Here?
David N. Juurlink, BPhm, MD, PhD, FRCPC
J Am Pharm Assoc (2003) 2004;44:128-134. doi:10.1331/154434504773062573
View Author Identification Section
Correspondence: David N. Juurlink, G Wing 106 (ICES), Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. E-mail: dnj@ices.on.ca
In this issue of the Journal, Malone, Abarca, and their colleagues make two contributions to our perpetually deficient fund of knowledge in the field of drug–drug interactions (DDIs).+1,+2 The first article describes the extent to which major DDI compendia agree—or perhaps, more accurately, disagree—on the clinical relevance of 406 selected DDIs, each with the potential to cause serious harm. While the discordant ratings provided by these compendia are perhaps not surprising, the revelation that more than two thirds of serious DDIs were listed as such in only one compendium is disquieting and must surely give us pause. After all, our patients rely on us and our unseen mechanisms, including these compendia, to prevent them from such harm. Fortunately, the second article provides us with some good news, describing the only meaningful way such discord can be resolved—by the deliberate and thoughtful consensus of a group of individuals with expertise in pharmacy, pharmacology, and clinical medicine.
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 warfarin+3 and increase the risk of hypoglycemia in patients receiving glyburide.+4,+5
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+1,+2), 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.+7 For years now, we have recognized that the actual mechanism of this interaction involves inhibition of P-glycoprotein.+8,+9 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.+10,+11
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 information+12 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 As Hansten+19 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,+20,+21 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.+22,+23 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.+22,+25 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.+26,+27 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.
+

Professional Development

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
+

Scientific Advances

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.+32,+33
+

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,+24,+26 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 detection+34 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 renal disease,+37 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.
Abarca J, Malone DC, Armstrong EP, et al. Concordance of severity ratings provided in four drug interaction compendia J Am Pharm Assoc. 2004;44:136–41.[CrossRef]
 
Malone DC, Abarca J, Hansten PD, et al. Identification of serious drug–drug interactions: Results of the partnership to prevent drug–drug interactions J Am Pharm Assoc. 2004;44:142–51.
 
Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment Blood. 2000; 96:1816–9.[PubMed]
 
Kirchheiner J, Brockmoller J, Meineke I, et al. Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers Clin Pharmacol Ther. 2002;71:286–96.[PubMed]
 
Niemi M, Cascorbi I, Timm R, et al. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes Clin Pharmacol Ther. 2002;72:326–32.[PubMed]
 
Juurlink DN, Mamdani M, Kopp A, et al. Drug–drug interactions among elderly patients hospitalized for drug toxicity JAMA. 2003;289: 1652–8.[PubMed]
 
Lindenbaum J, Rund DG, Butler VP Jr, et al. Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy N Engl J Med. 1981;305: 789–94.[PubMed]
 
de Lannoy IA, Silverman M. The MDR1 gene product, P-glycoprotein, mediates the transport of the cardiac glycoside, digoxin Biochem Biophys Res Commun. 1992; 189:551–7.[PubMed]
 
Wakasugi H, Yano I, Ito T, et al. Effect of clarithromycin on renal excretion of digoxin: Interaction with P-glycoprotein Clin Pharmacol Ther. 1998;64:123–8.[PubMed]
 
Gooderham MJ, Bolli P, Fernandez PG. Concomitant digoxin toxicity and warfarin interaction in a patient receiving clarithromycin Ann Pharmacother. 1999;33:796–9.[PubMed]
 
Zapater P, Reus S, Tello A, et al. A prospective study of the clarithromycin–digoxin interaction in elderly patients J Antimicrob Chemother. 2002; 50:601–6.[PubMed]
 
Monahan BP, Ferguson CL, Killeavy ES, et al. Torsades de pointes occurring in association with terfenadine use JAMA. 1990;264:2788–90.[PubMed]
 
Jinks MJ, Hansten PD, Hirschman JL. Drug interaction exposures in an ambulatory Medicaid population Am J Hosp Pharm. 1979;36:923–7.[PubMed]
 
Costa AJ. Potential drug interactions in an ambulatory geriatric population Fam Pract. 1991;8:234–6.[PubMed]
 
Heininger-Rothbucher D, Bischinger S, Ulmer H, et al. Incidence and risk of potential adverse drug interactions in the emergency room Resuscitation. 2001;49:283–8.[PubMed]
 
Gaeta TJ, Fiorini M, Ender K, et al. Potential drug–drug interactions in elderly patients presenting with syncope J Emerg Med. 2002;22:159–62.[PubMed]
 
Carter BL, Lund BC, Hayase N, Chrischilles E. The extent of potential antihypertensive drug interactions in a Medicaid population Am J Hypertens. 2002;15:953–7.[PubMed]
 
Gaddis GM, Holt TR, Woods M. Drug interactions in at-risk emergency department patients Acad Emerg Med. 2002;9:1162–7.[PubMed]
 
Hansten PD. Drug interaction management Pharm World Sci. 2003;25:94–7.[PubMed]
 
Shaoul R, Shahory R, Tamir A, Jaffe M. Comparison between pediatricians and family practitioners in the use of the prokinetic cisapride for gastroesophageal reflux disease in children Pediatrics. 2002;109:1118–23.[PubMed]
 
Langdorf MI, Fox JC, Marwah RS, et al. Physician versus computer knowledge of potential drug interactions in the emergency department Acad Emerg Med. 2000;7:1321–9.[PubMed]
 
Cavuto NJ, Woosley RL, Sale M. Pharmacies and prevention of potentially fatal drug interactions JAMA. 1996;275: 1086–7.[PubMed]
 
Weideman RA, Bernstein IH, McKinney WP. Pharmacist recognition of potential drug interactions Am J Health Syst Pharm. 1999;56:1524–9.[PubMed]
 
Peterson JF, Bates DW. Preventable medication errors: Identifying and eliminating serious drug interactions J Am Pharm Assoc. 2001;41:159–60.
 
Hazlet TK, Lee TA, Hansten PD, Horn JR. Performance of community pharmacy drug interaction software J Am Pharm Assoc. 2001;41:200–4.
 
Hansten PD, Horn JR, Hazlet TK. ORCA: OpeRational ClassificAtion of drug interactions [editorial] J Am Pharm Assoc. 2001;41:161–5.
 
Glassman PA, Simon B, Belperio P, Lanto A. Improving recognition of drug interactions: Benefits and barriers to using automated drug alerts Med Care. 2002;40: 1161–71.[PubMed]
 
Dresser GK, Bailey DG. A basic conceptual and practical overview of interactions with highly prescribed drugs Can J Clin Pharmacol. 2002;9:191–8.[PubMed]
 
Shapiro LE, Shear NH. Drug interactions: Proteins, pumps, and P-450s J Am Acad Dermatol. 2002;47:467–84.[PubMed]
 
Michalets EL. Update: Clinically significant cytochrome P-450 drug interactions Pharmacotherapy. 1998;18: 84–112.[PubMed]
 
Juurlink DN, Mamdani M, Kopp A, et al. Drug-induced lithium toxicity in the elderly: A population-based study J Am Geriatr Soc.In press.
 
Lehmann DF. Observation and experiment on the cusp of collaboration: A parallel examination of clinical pharmacology and pharmacoepidemiology J Clin Pharmacol. 2000;40:939–45.[PubMed]
 
Penning-Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs Clin Pharmacol Ther. 2001; 69:451–7.[PubMed]
 
Halkin H, Katzir I, Kurman I, et al. Preventing drug interactions by online prescription screening in community pharmacies and medical practices Clin Pharmacol Ther. 2001; 69: 260–5.[PubMed]
 
Schepkens H, Van Holder R, Billiouw JM, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: An analysis of 25 cases Am J Med. 2001;110:438–41.[PubMed]
 
Wrenger E, Muller R, Moesenthin M, et al. Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: Analysis of 44 cases BMJ. 2003;327:147–9.[PubMed]
 
Svensson M, Gustafsson F, Galatius S, et al. Hyperkalaemia and impaired renal function in patients taking spironolactone for congestive heart failure: Retrospective study BMJ. 2003; 327:1141–2.[PubMed]
 
Jarman PR, Mather HM. Diabetes may be independent risk factor for hyperkalaemia BMJ. 2003;327:812.[PubMed]
 
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators N Engl J Med. 1999;341:709–17.[PubMed]
 

References

Abarca J, Malone DC, Armstrong EP, et al. Concordance of severity ratings provided in four drug interaction compendia J Am Pharm Assoc. 2004;44:136–41.[CrossRef]
 
Malone DC, Abarca J, Hansten PD, et al. Identification of serious drug–drug interactions: Results of the partnership to prevent drug–drug interactions J Am Pharm Assoc. 2004;44:142–51.
 
Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment Blood. 2000; 96:1816–9.[PubMed]
 
Kirchheiner J, Brockmoller J, Meineke I, et al. Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers Clin Pharmacol Ther. 2002;71:286–96.[PubMed]
 
Niemi M, Cascorbi I, Timm R, et al. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes Clin Pharmacol Ther. 2002;72:326–32.[PubMed]
 
Juurlink DN, Mamdani M, Kopp A, et al. Drug–drug interactions among elderly patients hospitalized for drug toxicity JAMA. 2003;289: 1652–8.[PubMed]
 
Lindenbaum J, Rund DG, Butler VP Jr, et al. Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy N Engl J Med. 1981;305: 789–94.[PubMed]
 
de Lannoy IA, Silverman M. The MDR1 gene product, P-glycoprotein, mediates the transport of the cardiac glycoside, digoxin Biochem Biophys Res Commun. 1992; 189:551–7.[PubMed]
 
Wakasugi H, Yano I, Ito T, et al. Effect of clarithromycin on renal excretion of digoxin: Interaction with P-glycoprotein Clin Pharmacol Ther. 1998;64:123–8.[PubMed]
 
Gooderham MJ, Bolli P, Fernandez PG. Concomitant digoxin toxicity and warfarin interaction in a patient receiving clarithromycin Ann Pharmacother. 1999;33:796–9.[PubMed]
 
Zapater P, Reus S, Tello A, et al. A prospective study of the clarithromycin–digoxin interaction in elderly patients J Antimicrob Chemother. 2002; 50:601–6.[PubMed]
 
Monahan BP, Ferguson CL, Killeavy ES, et al. Torsades de pointes occurring in association with terfenadine use JAMA. 1990;264:2788–90.[PubMed]
 
Jinks MJ, Hansten PD, Hirschman JL. Drug interaction exposures in an ambulatory Medicaid population Am J Hosp Pharm. 1979;36:923–7.[PubMed]
 
Costa AJ. Potential drug interactions in an ambulatory geriatric population Fam Pract. 1991;8:234–6.[PubMed]
 
Heininger-Rothbucher D, Bischinger S, Ulmer H, et al. Incidence and risk of potential adverse drug interactions in the emergency room Resuscitation. 2001;49:283–8.[PubMed]
 
Gaeta TJ, Fiorini M, Ender K, et al. Potential drug–drug interactions in elderly patients presenting with syncope J Emerg Med. 2002;22:159–62.[PubMed]
 
Carter BL, Lund BC, Hayase N, Chrischilles E. The extent of potential antihypertensive drug interactions in a Medicaid population Am J Hypertens. 2002;15:953–7.[PubMed]
 
Gaddis GM, Holt TR, Woods M. Drug interactions in at-risk emergency department patients Acad Emerg Med. 2002;9:1162–7.[PubMed]
 
Hansten PD. Drug interaction management Pharm World Sci. 2003;25:94–7.[PubMed]
 
Shaoul R, Shahory R, Tamir A, Jaffe M. Comparison between pediatricians and family practitioners in the use of the prokinetic cisapride for gastroesophageal reflux disease in children Pediatrics. 2002;109:1118–23.[PubMed]
 
Langdorf MI, Fox JC, Marwah RS, et al. Physician versus computer knowledge of potential drug interactions in the emergency department Acad Emerg Med. 2000;7:1321–9.[PubMed]
 
Cavuto NJ, Woosley RL, Sale M. Pharmacies and prevention of potentially fatal drug interactions JAMA. 1996;275: 1086–7.[PubMed]
 
Weideman RA, Bernstein IH, McKinney WP. Pharmacist recognition of potential drug interactions Am J Health Syst Pharm. 1999;56:1524–9.[PubMed]
 
Peterson JF, Bates DW. Preventable medication errors: Identifying and eliminating serious drug interactions J Am Pharm Assoc. 2001;41:159–60.
 
Hazlet TK, Lee TA, Hansten PD, Horn JR. Performance of community pharmacy drug interaction software J Am Pharm Assoc. 2001;41:200–4.
 
Hansten PD, Horn JR, Hazlet TK. ORCA: OpeRational ClassificAtion of drug interactions [editorial] J Am Pharm Assoc. 2001;41:161–5.
 
Glassman PA, Simon B, Belperio P, Lanto A. Improving recognition of drug interactions: Benefits and barriers to using automated drug alerts Med Care. 2002;40: 1161–71.[PubMed]
 
Dresser GK, Bailey DG. A basic conceptual and practical overview of interactions with highly prescribed drugs Can J Clin Pharmacol. 2002;9:191–8.[PubMed]
 
Shapiro LE, Shear NH. Drug interactions: Proteins, pumps, and P-450s J Am Acad Dermatol. 2002;47:467–84.[PubMed]
 
Michalets EL. Update: Clinically significant cytochrome P-450 drug interactions Pharmacotherapy. 1998;18: 84–112.[PubMed]
 
Juurlink DN, Mamdani M, Kopp A, et al. Drug-induced lithium toxicity in the elderly: A population-based study J Am Geriatr Soc.In press.
 
Lehmann DF. Observation and experiment on the cusp of collaboration: A parallel examination of clinical pharmacology and pharmacoepidemiology J Clin Pharmacol. 2000;40:939–45.[PubMed]
 
Penning-Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs Clin Pharmacol Ther. 2001; 69:451–7.[PubMed]
 
Halkin H, Katzir I, Kurman I, et al. Preventing drug interactions by online prescription screening in community pharmacies and medical practices Clin Pharmacol Ther. 2001; 69: 260–5.[PubMed]
 
Schepkens H, Van Holder R, Billiouw JM, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: An analysis of 25 cases Am J Med. 2001;110:438–41.[PubMed]
 
Wrenger E, Muller R, Moesenthin M, et al. Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: Analysis of 44 cases BMJ. 2003;327:147–9.[PubMed]
 
Svensson M, Gustafsson F, Galatius S, et al. Hyperkalaemia and impaired renal function in patients taking spironolactone for congestive heart failure: Retrospective study BMJ. 2003; 327:1141–2.[PubMed]
 
Jarman PR, Mather HM. Diabetes may be independent risk factor for hyperkalaemia BMJ. 2003;327:812.[PubMed]
 
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators N Engl J Med. 1999;341:709–17.[PubMed]
 
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