Omeprazole-associated digoxin toxicity.

Abstract: Omeprazole is a commonly prescribed inhibitor of the gastric proton pump and has numerous indications in the treatment of gastrointestinal diseases. It is primarily metabolized through the CYP2C19 enzyme, a member of the P450 mixed-function oxidase group, although a minor pathway of metabolism is through CYP3A4, another P450 enzyme. Digoxin is primarily metabolized outside the P450 system, but a minor pathway of metabolism is by CYP3A4. To our knowledge, this is the first known case of digoxin toxicity associated with omeprazole. The possible pathways for such an interaction are reviewed, including increased stomach absorption, p-glycoprotein activity and interactions in the P450 system.

Key Words: omeprazole, digoxin, interaction, toxicity

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Digoxin and omeprazole have not been reported to have significant drug-drug interactions, although they are both minor substrates of the enzyme CYP3A4. Since this is a minor degradation pathway for both drugs, an interaction is unlikely, but possible, due to the variable activity of CYP3A4. (1-3) We present what we believe is the first documented case of digoxin toxicity secondary to the coadministration of omeprazole.

Case Report

A 65-year-old Caucasian woman was admitted to the intensive care unit at Madigan Army Medical Center for treatment of digoxin toxicity. The patient presented to the emergency department complaining of weakness, dysequilibrium, nausea and altered vision. She described her vision change as a "bright canary-yellow haze" that began two months before presentation. She had no prior history of neurologic disease. She denied fever, chills, headache, loss of visual acuity, diplopia or loss of consciousness. She reported one episode of emesis on the-morning of admission after taking her usual morning medications and denied a history of emesis during the preceding months.

Her past medical history included hyperlipidemia, osteoarthritis, type 2 diabetes mellitus and recurrent nephrolithiasis. In addition, she had paroxysmal atrial fibrillation which was diagnosed six years before presentation and treated with digoxin at a dose of 0.625 mg daily. She had never required dose adjustment and was not taking any other medications to control her atrial fibrillation. Other chronic medications included meloxicam 15 mg q.d., lisinopril 5 mg q.d., raloxifene 60 mg q.d., atorvastatin 20 mg nightly, gemfibrozil 600 mg q.d., warfarin 4 mg q.d., oxybutynin 5 mg q.d., hydrochlorothiazide 25 mg q.d. and potassium citrate 540 mg q.d. After further questioning, the patient recalled that three months before admission, she had been diagnosed with gastroesophageal reflux disease (GERD) by her primary care provider and started taking omeprazole 20 mg q.d. Her serum digoxin level just before starting the omeprazole was 1.1 ng/mL.

Examination of her medication history by review of computer-based pharmacy records confirmed the accuracy of the patient's reported medication list and also confirmed that she had been prescribed 0.625 mg digoxin daily for six years before presentation.

Her vital signs on presentation were blood pressure 123/74 mm Hg, heart rate 77 beats per minute, temperature 98.3[degrees] Fahrenheit, respiratory rate 19 breaths per minute and room air oxygen saturation of 95% by pulse oximetry. She was awake, alert and oriented to person, place and time. Her cardiovascular examination was significant for an irregularly irregular heart rate and a III/VI systolic ejection murmur. The rest of her physical examination, including a complete neurologic examination, was normal. Laboratory evaluation revealed a serum digoxin level of 3.9 ng/mL and a normal serum creatinine of 0.8 mg/dL. An electrocardiogram (EKG) demonstrated bigeminy.

The antidote Digoxin Immune Fab was administered and the patient was admitted to the intensive care unit for close monitoring. She remained stable throughout her stay. Her "canary yellow haze" cleared by the end of hospital day one and by hospital day two, her EKG had returned to baseline. She was discharged on all of her medications except digoxin and over the past seven months, has had an uneventful posthospital course.

Discussion

While there are numerous etiologies for medication toxicity, we believe that our patient's digoxin toxicity was directly associated with concurrent omeprazole therapy. Furthermore, based on a MEDLINE search from 1966 to April 2006, we believe that this is the first reported case of such an interaction.

Omeprazole is a member of the proton pump inhibitor class used to treat excessive gastric acid secretion in patients with chronic GERD. A typical starting dose for adult patients is 20 mg once daily. Most drug interactions with omeprazole occur as a result of interactions with the P450 cytochrome enzymes, specifically CYP2C19 and its genotypic variants. Both omeprazole and digoxin serve as minor substrates for CYP3A4. As these two compounds are only considered minor substrates of this particular enzyme, drug-drug interactions between digoxin and omeprazole have been deemed of limited clinical significance. (1-3) Of the proton pump inhibitors, omeprazole has been reported to be the most likely to alter pharmacokinetics of CYP3A4. (4) Variability of the activity of CYP3A4 could explain why our patient experienced what appeared to be a clinically significant interaction. Phenotypic variations in metabolism exist and manifest in some patients as slowed or delayed metabolism via enzymes or advanced age, both of which could lead to increased levels of omeprazole or digoxin. Independent of cytochrome P450 metabolism, omeprazole is known to increase the oral bioavailability of digoxin through gastric acid suppression. It is possible that this mechanism also contributed to toxicity. (5)

Supratherapeutic dosing is one common cause of digoxin toxicity. Our patient had been on the same dose for 6 years before admission and had regular checks of her digoxin level. We reviewed laboratory records for our patient dating back to initiation of therapy and there were no digoxin levels recorded above our laboratory's normal range of 0.8 to 2.0 ng/mL. Her most recent level was 1.1 ng/mL just before initiation of omeprazole therapy, three months before admission. Furthermore, review of pharmacy records confirmed that the patient was taking 0.625 mg daily based on the prescribed doses, the number of tablets dispensed and the frequency of refills and renewals.

A second common cause of digoxin toxicity is renal or hepatic insufficiency with decreased clearance of the medication. Again, laboratory review dating back several years revealed that the patient had no episodes of acute renal insufficiency and her calculated creatinine clearance at the time of admission was within normal range at 103 mL/min/1.73 [m.sup.2]. Although liver-associated enzymes were not measured at admission, there were no signs, symptoms, clinical or physical examination evidence of an acute hepatitis that might have altered hepatic clearance of digoxin. Review of the medical record revealed no history of altered liver enzymes and no history of acute or chronic liver disease and liver function tests were completely normal two months after presentation.

Another common cause for digoxin toxicity is an interaction with other medications. Except for the omeprazole, the patient had been on stable doses of all of her medications for greater than one year before admission, as confirmed by computer pharmacy records and the patient's report of medication compliance. Therefore, it is quite unlikely that a drug-drug interaction (apart from digoxin and omeprazole) is responsible for this patient's situation; however, a pharmacokinetic drug interaction is not readily explained since digoxin is primarily removed from the body via renal excretion and is not dependent on hepatic cytochrome P450 as a form of metabolism. Clearance of digoxin is also affected by p-glycoprotein, a transporter protein located in renal tubules and intestinal epithelial cells. Inhibition of p-glycoprotein decreases intestinal and renal clearance of digoxin, the most common example of which is the interaction between digoxin and quinidine. Omeprazole is also known to inhibit p-glycoprotein, although the extent of this inhibition has not been reported to be of clinical significance.

Conclusion

We have reported a case of a 65-year-old woman on long-term digoxin therapy at a stable dose and stable blood levels who presented with digoxin toxicity three months after initiation of omeprazole therapy. Careful review of records confirmed that the patient had no history of toxic levels, no history of hepatic or renal failure, and no recent change in any of her other chronic medications for at least five years before presentation. While there have been no other clinically significant reports of a drug-drug interaction between omeprazole and digoxin, we believe that this possibility should be considered in patients on digoxin therapy who require treatment with a proton pump inhibitor. Proposed mechanisms include increased bioavailability of digoxin with gastric acid suppression, phenotypic or age-related alterations in metabolism resulting in slow or delayed metabolism of omeprazole or digoxin, inhibition of the p-glycoprotein system or a previously unexplained interaction. Further investigation of the potential mechanism behind this possible interaction is certainly warranted.

References

1. Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors: focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 1996;31:9-28.

2. Oosterhuis B, Jonkman JH, Andersson T, et al. Minor effect of multiple dose omeprazole on the pharmacokinetics of digoxin after a single oral dose. Br J Clin Pharmacol 1991;32:569-572.

3. Andersson T. Omeprazole drug interaction studies. Clin Pharmacokinet 1991;21:195-212.

4. Humphries TJ, Merritt GJ. Review article: drug interactions with agents used to treat acid-related diseases. Aliment Pharmacol Ther 1999;13 (Suppl 3):18-26.

5. Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practicing physician needs to know. Drugs 2003;63:2739-2754.

Cristin A. Kiley, MD, Douglas J. Cragin, MD, and Bernard J. Roth, MD

From the Department of Medicine, Madigan Army Medical Center, Tacoma, WA.

The opinions expressed herein are the private views of the authors and are not to be construed as official or as reflecting the policy of the Department of the Army or the Department of Defense.

Reprint requests to Dr. Bernard J. Roth, Madigan Army Medical Center, Attn: MCHJ-EDME, Tacoma, WA 98431-1100. Email: [e-mail]

Accepted September 22, 2006.

RELATED ARTICLE: Key Points

* Proton pump inhibitors are widely prescribed medications without many major known side effects or drug interactions.

* Drug-drug interactions are common with medications metabolized through the P450 enzyme system.

* Patients who are taking digoxin and require proton pump inhibition to treat concurrent gastrointestinal disorders should be monitored for the potential of a drug interaction.