Is this medicine really involved in a drug interaction?

In today's advanced medical profession, there is an ever increasing amount of evidence developing in relation to a myriad of drug-drug interactions, (1,2) a trend which is set to continue with an aging population and further development of pharmaceutical technologies in the future. This begs to question as to whether it is safe to presume that a specific drug-drug interaction does not exist if it has not been identified and published. With an exponentially expanding number of drug combinations at our disposal for the treatment of various conditions upsetting our patients, all clinicians must remain vigilant to the possibility of an unknown situation affecting the patient under their care, in the interests of the patient's safety and well being. Our aim must always remain to provide the correct drug, at the correct dose, at the correct time, to the correct patient (and hopefully the correct number of medications to ensure compliance and avoid confusion by patients and clinicians alike!). Obviously, this is not always an easy task to accomplish considering the demands of the health profession and the continual need to remain informed and updated.

In this issue of the Southern Medical Journal, Kiley and colleagues (3) discovered that the health of one of their elderly female patients was adversely affected by the recent addition of a certain medication used for the management of gastroesophageal reflux disease (GERD). The agent in question was omeprazole, a proton-pump inhibitor, which was introduced in addition to her ongoing (and notably stable and unchanged) medication regimen, which included digoxin and warfarin in the setting of atrial fibrillation. The presenting complaint was related to an initial episode of emesis earlier that morning, in addition to visual changes described as a "bright canary-yellow haze," which had been ongoing for the previous two months. The reporting clinicians were alerted by these symptoms and immediately pursued the correct line of thought in relation to digoxin toxicity, which was confirmed by routine blood investigations.

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Piecing together unusual occurrences concerning a patient's health outcome can be analogous to detective work. What changes have occurred in the patient's treatment over the preceding few months? Are there any alterations occurring in the patient's physiologic function and handling of medications that can explain the situation at hand? Can the occurrence be explained by any other influencing factor? What is happening to the patient now compared with baseline or some other reference point in the past?

Kiley and colleagues performed extreme due diligence in relation to these matters and were able to deduce that there were no changes in the patient's drug regimen (apart from the addition of omeprazole), while also excluding any physiologic changes and any changes in the patient's compliance that might have explained the altered digoxin levels. In addition, the treating physicians were also very thorough in their investigation of the chronological time course of this patient's condition, identifying that the patient's digoxin levels were stable and within the normal range before initiation of omeprazole therapy three months earlier. In the setting of no other identifiable reason underlying the observed digoxin toxicity, it was not unreasonable to implicate omeprazole as the agent responsible for directly influencing digoxin therapy and precipitating the symptoms expressed by this patient. To satisfy the purists in relation to drug-drug interactions, a re-challenge of the offending medications would be an ideal method to definitively prove the association in this patient, (4) but is certainly not practical or ethical considering the underlying circumstances of digoxin toxicity.

This particular case has very important implications. It is well known that digoxin has quite a narrow therapeutic index, (5) an ever-delicate balance of dosage where too much leads to toxicity as demonstrated by this case, and too little would result in mismanagement of the underlying condition being treated. In the setting of atrial fibrillation and other indications for digoxin, which include maintenance therapy of patients with heart failure, (6) the consequences of such subtherapeutic dosing can be disastrous and catastrophic.

Interestingly, the symptoms expressed by this particular patient were triggered by a very commonly prescribed agent, which is thought to be a relatively benign therapy compared with numerous other medications available. Regardless of the mechanism in which this drug interaction had occurred (alterations of hepatic metabolism via cytochrome enzymes, gastric acid suppression or p-glycoprotein inhibition), this case reminds clinicians of the need to remain vigilant with respect to every conceivable factor in relation to their patient when presented with medication toxicity or changes in their patient's condition. This applies to all agents, not just medications with a narrow therapeutic index such as digoxin, warfarin, theophylline and phenytoin. After all, it was not that long ago when cisapride, a gastrointestinal agent used to increase peristalsis, was regarded as a very safe drug with a "clean" drug interaction profile (7,8)--how times have changed!

The potential for any medication to induce a drug-drug interaction is generally not discovered until the medication has been widely utilized in the real world, further highlighting the need for extensive postmarketing surveillance and reporting of even merely suspicious circumstances with as much detail as possible. (9,10) Only then can we truly realize the extent of a drug-drug interaction and increase the body of evidence available, while "flagging" potentially harmful combinations. This also enables further investigations using epidemiologic methods with proven ability to identify associations. At any rate, the work of clinicians, nurses, pharmacists and clinical pharmacologists will remain quite challenging and rewarding for many years to come.

References

1. Bjerrum L, Andersen M, Petersen G, et al. Exposure to potential drug interactions in primary health care. Scand J Prim Health Care 2003;21:153-158.

2. Maas R, Boger RH. Antihypertensive therapy: special focus on drug interactions. Expert Opin Drug Saf 2003;2:549-579.

3. Kiley CA, Cragin DJ, Roth BJ, et al. Omeprazole-associated digoxin toxicity South Med J 2007;100:400-402.

4. Kramer MS, Leventhal JM, Hutchinson TA, et al. An algorithm for the operational assessment of adverse drug reactions. I. Background, description, and instructions for use. JAMA 1979;242:623-632.

5. Bauman JL, Didomenico RJ, Galanter WL. Mechanisms, manifestations, and management of digoxin toxicity in the modern era. Am J Cardiovasc Drugs 2006;6:77-86.

6. Dec GW. Digoxin remains useful in the management of chronic heart failure. Med Clin North Am 2003;87:317-337.

7. Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use of cisapride: impact of food and drug administration regulatory action. JAMA 2000;284:3036-3039.

8. Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia. N Engl J Med 1996;335:290-291.

9. Aronson JK. Unity from diversity: the evidential use of anecdotal reports of adverse drug reactions and interactions. J Eva Clin Pract 2005;11:195-208.

10. Kelly WN. The quality of published adverse drug event reports. Ann Pharmacother 2003;37:1774-1778.

He who has a why to live for can bear with almost any how.
--Friedrich Nietzsche

Steven Joseph Haas, B Pharm, B Pharm Sci (Hons), MSHPA, MAEA 

From the Department of Epidemiology and Preventive Medicine and the Department of Medicine, NHMRC Centre of Clinical Research Excellence in Therapeutics, Monash University, Alfred Hospital, Melbourne, Australia. Email: [e-mail]

Reprint requests to Steven Joseph Haas, B Pharm, NHMRC Centre of Clinical Research Excellence in Therapeutics, Department of Epidemiology and Preventive Medicine and Department of Medicine, Monash University, Alfred Hospital, 89 Commercial Road, Melbourne, Victoria 3004, Australia.

Accepted December 14, 2006.