Effects of proton pump inhibitors and electrolyte disturbances on arrhythmias

Article (PDF Available)inInternational Journal of General Medicine 6(default):515-518 · June 2013with134 Reads
DOI: 10.2147/IJGM.S46932 · Source: PubMed
Abstract
Several case reports have been written regarding the relationship between the use of proton pump inhibitors (PPI) and hypomagnesemia. Some of these reported cases have electrocardiogram abnormalities where electrolytes deficiencies were the contributing factor for these events. This study investigates the correlation between different arrhythmias and the use of PPI and hypomagnesaemia incidence. Four-hundred and twenty-one patients admitted to the critical care unit with unstable angina, non-ST elevation myocardial infarction, and ST-elevation myocardial infarction were included in this study. One-hundred and eighty-four patients (43.8%) received PPI and 237 patients (51.16%) did not, magnesium levels were low (<1.8 mg/dL) in 95 patients (22.5%), and 167 patients (39.6%) developed arrhythmias. The P-values for the regression coefficient association for the use of PPI and the level of magnesium were P = 1.31e(-29) and P = 8e(-102), respectively. The P-values indicate that there is a statistically significant association between the PPI use, magnesium levels, and the occurrence of cardiovascular events, with a strong correlation factor of 0.817. Patients receiving PPIs should be followed closely for magnesium deficiency, especially if they experience acute cardiovascular events, because this may contribute to worsening arrhythmias and further complications.
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International Journal of General Medicine 2013:6 515–518
International Journal of General Medicine
Effects of proton pump inhibitors and electrolyte
disturbances on arrhythmias
Elie El-Charabaty
Chadi Saifan
Mokhtar Abdallah
Ali Naboush
Daniel Glass
Georges Azzi
Yorg Azzi
Ahsan Khan
Hassan Baydoun
Chetana Rondla
Ninad Parekh
Suzanne El-Sayegh
Department of Medicine, Staten Island
University Hospital, Staten Island, NY,
USA
Correspondence: Chadi Saifan
Division of Nephrology, Staten Island
University Hospital, 475 Seaview Avenue,
Staten Island, NY 10305, USA
Email chadisaifan@hotmail.com
Abstract: Several case reports have been written regarding the relationship between the use
of proton pump inhibitors (PPI) and hypomagnesemia. Some of these reported cases have
electrocardiogram abnormalities where electrolytes deficiencies were the contributing factor
for these events. This study investigates the correlation between different arrhythmias and the
use of PPI and hypomagnesaemia incidence. Four-hundred and twenty-one patients admitted
to the critical care unit with unstable angina, non-ST elevation myocardial infarction, and
ST-elevation myocardial infarction were included in this study. One-hundred and eighty-four
patients (43.8%) received PPI and 237 patients (51.16%) did not, magnesium levels were low
(,1.8 mg/dL) in 95 patients (22.5%), and 167 patients (39.6%) developed arrhythmias. The
P-values for the regression coefficient association for the use of PPI and the level of magnesium
were P = 1.31e
-29
and P = 8e
-102
, respectively. The P-values indicate that there is a statistically
significant association between the PPI use, magnesium levels, and the occurrence of cardio-
vascular events, with a strong correlation factor of 0.817. Patients receiving PPIs should be
followed closely for magnesium deficiency, especially if they experience acute cardiovascular
events, because this may contribute to worsening arrhythmias and further complications.
Keywords: electrolyte disturbances, medications side effects, cardiac arrhythmias
Introduction
Proton pump inhibitors (PPIs) are widely used therapeutic agents with more than
119 million filled prescriptions in the USA in 2009.
1
They have been associated with a
wide variety of side effects including renal failure,
2,3
respiratory infections,
4
Clostridium
difficile colitis,
5
and hip fractures.
6
There have been several case reports and case series’
of proton pump related hypomagnesemia with a wide array of symptoms, including
cardiac arrhythmias and seizures.
7–18
Magnesium is the second most common intracellular cation and is involved in a
wide range of cellular functions, including protein synthesis, enzymatic reactions, and
the regulation of ion channels. Significantly low serum magnesium levels have been
associated with bradycardia, hypotension, seizures, tetany, and death.
19,21
Even mild
hypomagnesemia has been correlated with cardiovascular and total mortality.
22
Despite
a recent retrospective study demonstrating an association between hypomagnesaemia
and PPI use in patients on diuretics, there is no large scale study on PPI use and the
incidence of cardiac arrhythmias. To address this question, we examined the associa-
tion between the use of PPI, serum magnesium levels, and the incidence of cardiac
arrhythmia in a large group of patients admitted to the intensive care unit (ICU) with
an acute coronary syndrome and subsequently started on a PPI.
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International Journal of General Medicine
27 June 2013
International Journal of General Medicine 2013:6
Methods
This study included patients admitted to a tertiary care
hospital to the ICU or critical care unit (CCU) with a
diagnosis of unstable angina, ST elevation myocardial
infarction (STEMI), non-STEMI (NSTEMI), between
2007 and 2012 started on PPI during their hospital stay.
This was a retrospective chart review study. Analysis
involved checking occurrence of arrhythmias such as
ventricular fibrillation, ventricular tachycardia, non-
sustained ventricular tachycardia, atrial f ibrillation,
and atrial tachycardia. Potassium and magnesium
blood levels were checked. Electrocardiograms with
associated arrhythmias were reviewed. Any ICU or
CCU patients older than 18 years of age diagnosed
on admission with unstable angina, NSTEMI, or STEMI,
were included in this study. Pregnant women, cognitively
impaired patients, patients less than 18 years of age, and
patients diagnosed with chronic atrial fibrillation on admis-
sion were excluded.
Results
Four-hundred and twenty-one patients admitted to the CCU
with unstable angina, NSTEMI, or STEMI were included in
this study. One-hundred and eighty-four patients (43.8%)
received PPI and 237 patients (51.16%) did not. The normal
level of magnesium is 1.8–2.4 mg/dL and a normal potassium
level is 3.5–5 mmol/L. Of our sample, 81.7% of patients were
older than 55, 95.2% had hypertension, 37.5% had diabetes
mellitus type II, 47% had chronic kidney disease (glomeru-
lar filtration rate , 60), 71.2% had NSTEMI, and 25% had
STEMI. PPI were prescribed during the hospital admission
as either part of the gastrointestinal prophylaxis protocol for
patients admitted to CCU (171 patients) or because they had
peptic ulcer disease (13 patients).
Low magnesium levels (,1.8 mg/dL) were present in
95 patients (22.5%) and 167 patients (39.6%) developed
arrhythmias. The P-values for the tests of significance
determined using regression coefficient association for the
use of PPI and the level of magnesium were P = 1.31e
-29
and P = 8e
-102
, respectively, indicating that there is a statis-
tically significant association between PPI use, the level of
magnesium, and the occurrence of cardiovascular events,
with a strong correlation factor of 0.817.
Discussion
In this large, hospital-based cross-sectional study, PPI expo-
sure during hospitalization was correlated with lower serum
magnesium concentrations and cardiac arrhythmias.
Although the risk of hypomagnesemia and the inci-
dence of cardiac arrhythmias has been suggested by smaller
observational studies and case reports, this study is the first
to our knowledge to provide an analysis between PPI use
and magnesium concentrations and correlation with cardiac
arrhythmias in a large sample, and supports the notion that
PPI use may lead to hypomagnesemia and arrhythmias in
susceptible individuals.
The pathophysiology of PPI-induced hypomagnesemia
is still not certain. Magnesium homeostasis depends on the
balance between renal excretion and intestinal absorption.
Intestinal absorption occurs through two major pathways:
active and passive. Active transcellular transport across the
apical lumen occurs via the channel transient receptor poten-
tial melastatin 6.
24
Tight junction proteins claudin-16 and
claudin-19 modulate passive movement down a concentration
gradient which occurs paracellularly and is thought to be the
major route of magnesium absorption.
25
Tubular reclamation
in the proximal tubule and thick ascending limb via paracel-
lular absorption accounts for most renal excretion,
26
with
some active absorption in the distal convoluted tubule.
27
New scientific data suggest that PPIs can cause hypo-
magnesaemia by inhibiting intestinal absorption and not
by increasing renal wasting.
23
In a case series of hypomag-
nesemic patients on PPI therapy,
10
urine magnesium levels
were appropriately low. Intravenous magnesium rapidly
corrected serum concentrations, but oral magnesium did
not,
7,9
except in one case.
11
Cell culture data suggests that
PPIs disrupt passive magnesium absorption across intestinal
epithelial cells.
28
Table 1 The total number of patients (421) separated by those who received PPIs (184) and those who did not (237)
PPI (184) No PPI (237)
Low magnesium (47) No low magnesium (137) Low magnesium (48) No low magnesium (189)
CV
(+15) (-32) (+32)
(–105)
(+25) (-23) (+59) (-130)
Notes: The second row shows the number of patients who developed low magnesium levels for both groups. The third row shows the number of patients who developed
(or not) cardiac arrhythmias. The numbers in brackets indicate the number of patients in that category.
Abbreviations: CV, cardiac arrhythmias; PPI, proton pump inhibitor.
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International Journal of General Medicine 2013:6
By irreversibly blocking the hydrogen/potassium adenosine
triphosphatase enzyme, PPIs inhibit the secretion of the acidic
hydrogen
+
ions into the gastric lumen. Studies on both animals
and human showed expression of the hydrogen
+
/potassium
+
ATPase enzyme in their myocardium, and ribonucleic acid
(RNA) was isolated from heart muscle strips of patients with
end stage heart disease undergoing heart transplantation.
29,30
Subsequent studies on the electrophysiological effects of PPI
on the myocardial cells were conducted, and showed a dose
dependent reduction in isometric and isotonic shortening of
myocytes cells as a consequence of the impairment of calcium
uptake by the sarcoplasmic reticulum, leading to intracellular
increased calcium concentration.
30
Since calcium concentra-
tion is an important factor in myocytes automaticity
31
and
since focal arrhythmias are usually secondary to increased
automaticity, a case control study was conducted on
80 patients undergoing an electrophysiological study and
found that there was a 4-fold increase in focal arrhythmias in
the group of the 40 patients on PPI when compared to the con-
trol group not on PPI.
32
There are several important limitations of our analysis.
Given the observational nature of the study, causality cannot
be established between PPI exposure and serum magnesium
concentration and cardiac arrhythmias. In addition, as our
sample is comprised of critically ill patients, generalization to
the outpatient population is uncertain. Diuretic use has been
proven to be associated with PPI-induced hypomagnesemia.
Our research did not collect data on diuretic use and
stratification by diuretic use may have demonstrated a greater
effect. Therefore, well-controlled prospective studies are
needed to clarify all the clinical issues related to the use of
this widely prescribed class of medication.
Disclosure
The authors report no conflicts of interest in this work.
References
1. IMS Health INSP, Top Therapy Classes by United States Dispensed
Presciptions, Data from 2007. Available at: http://www.imshealth.
com/cds/ims/Global/Content/Corporate/Press%20Room/Top-line%20
Market%20Data/2009%20Top-line%20Market%20Data/Top%20Ther-
apy%20Classes%20by%20U.S.Sales.pdf. Accessed March 3, 2011.
2. Ray S, Delaney M, Muller AF. Proton pump inhibitors and acute inter-
stitial nephritis. BMJ. 2010;341:c4412.
3. Sierra F, Suarez M, Rey M, Vela MF. Systematic review: Proton pump
inhibitor-associated acute interstitial nephritis. Aliment Pharmacol Ther.
2007;26(4):545–553.
4. Herzig SJ, Howell MD, Ngo LH, Marcantonio ER. Acid-suppressive
medication use and the risk for hospital-acquired pneumonia. JAMA.
2009;301(20):2120–2128.
5. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid sup-
pression and the risk of nosocomial Clostridium difficile infection. Arch
Intern Med. 2010;170(9):784–790.
6. Faulhaber GA, Furlanetto TW. Could magnesium depletion play a role
on fracture risk in PPI users? Arch Intern Med. 2010;170(19):1776.
7. Epstein M, McGrath S, Law F. Proton-pump inhibitors and hypo-
magnesemic hypoparathyroidism. N Engl J Med. 2006;355(17):
1834–1836.
8. Metz DC, Sostek MB, Ruszniewski P, Forsmark CE, Monyak J,
Pisegna JR. Effects of esomeprazole on acid output in patients with
Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion.
Am J Gastroenterol. 2007;102(12):2648–2654.
9. Shabajee N, Lamb EJ, Sturgess I, Sumathipala RW. Omeprazole and
refractory hypomagnesaemia. BMJ. 2008;337:a425.
10. Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term
users of proton-pump inhibitors. Clin Endocrinol (Oxf). 2008;69(2):
338–341.
11. Broeren MA, Geerdink EA, Vader HL, van den Wall Bake AW.
Hypomagnesemia induced by several proton-pump inhibitors. Ann
Intern Med. 2009;151(10):755–756.
12. Kuipers MT, Thang HD, Arntzenius AB. Hypomagnesaemia due to use of
proton pump inhibitors – a review. Neth J Med. 2009;67(5):169–172.
13. Hoorn EJ, van der Hoek J, de Man RA, Kuipers EJ, Bolwerk C, Zietse R.
A case series of proton pump inhibitor-induced hypomagnesemia.
Am J Kidney Dis. 2010;56(1):112–116.
14. Regolisti G, Cabassi A, Parenti E, Maggiore U, Fiaccadori E. Severe
hypomagnesemia during long-term treatment with a proton pump
inhibitor. Am J Kidney Dis. 2010;56(1):168–174.
15. Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibi-
tor therapy: a clinical case series. QJM. 2010;103(6):387–395.
16. Cundy T, Mackay J. Proton pump inhibitors and severe hypomagnesaemia.
Curr Opin Gastroenterol. 2011;27(2):180–185.
17. Quasdorff M, Mertens J, Dinter J, Steffen HM. Recurrent hypomag-
nesemia with proton-pump inhibitor rechallenge. Ann Intern Med.
2011;155(6):405–407.
18. Furlanetto TW, Faulhaber GA. Hypomagnesemia and proton pump
inhibitors: below the tip of the iceberg. Arch Intern Med. 2011;171(15):
1391–1392.
19. Flink EB. Magnesium deficiency. Etiology and clinical spectrum. Acta
Med Scand Suppl. 1981;647:125–137.
20. Vallee BL, Wacker WE, Ulmer DD. The magnesium-deficiency tetany
syndrome in man. N Engl J Med. 1960;262:155–161.
21. Moore MJ, Flink EB. Magnesium deficiency as a cause of serious
arrhythmias. Arch Intern Med. 1978;138(5):825–826.
22. Reffelmann T, Ittermann T, Dörr M, et al. Low serum magnesium
concentrations predict cardiovascular and all-cause mortality.
Atherosclerosis. 2011;219(1):280–284.
23. Danziger J, William JH, Scott DJ, et al. Proton-pump inhibitor use is
associated with low serum magnesium concentrations. Kidney Int.
2013;83(4):692–699.
24. Schlingmann KP, Weber S, Peters M, et al. Hypomagnesemia
with secondary hypocalcemia is caused by mutations in TRPM6,
a new member of the TRPM gene family. Nat Genet. 2002;31(2):
166–170.
25. Hou J, Renigunta A, Konrad M, et al. Claudin-16 and claudin-19 inter-
act and form a cation-selective tight junction complex. J Clin Invest.
2008;118(2):619–628.
26. Quamme GA. Control of magnesium transport in the thick ascending
limb. Am J Physiol. 1989;256(2 Pt 2):F197–F210.
27. Dai LJ, Ritchie G, Kerstan D, Kang HS, Cole DE, Quamme GA.
Magnesium transport in the renal distal convoluted tubule. Physiol
Rev. 2001;81(1):51–84.
28. Thongon N, Krishnamra N. Omeprazole decreases magnesium trans-
port across Caco-2 monolayers. World J Gastroenterol. 2011;17(12):
1574–1583.
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29. Nagashima R, Tsuda Y, Maruyama T, Kanaya S, Fujino T, Niho Y. Pos-
sible evidence for transmembrane K(+)-H+ exchange system in guinea
pig myocardium. Jpn Heart J. 1999;40(3):351–364.
30. Schillinger W, Teucher N, Sossalla S, et al. Negative inotropy of
the gastric proton pump inhibitor pantoprazole in myocardium
from humans and rabbits: evaluation of mechanisms. Circulation.
2007;116(1):57–66.
31. Mangoni ME, Nargeot J. Genesis and regulation of the heart
automaticity. Physiol Rev. 2008;88(3):919–982.
32. Marcus GM. Proton Pump Inhibitors Associated With Focal
Arrhythmias. 2010. Division of Cardiology, Electrophysiology Sec-
tion, University of California, San Francisco, CA, USA. Available at
http://www.innovationsincrm.com/cardiac-rhythm-management/2010/
december/29-proton-pump-inhibitors-focal-arrhythmias.
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    • "Hypomagnesemia is usually accompanied by hypocalcemia and hypokalemia, which contribute to further alter cardiac rhythm. In a cross-sectional study based on patients with hypomagnesemia admitted to a critical care unit, a strong correlation with arrhythmias and PPI use was observed [42]. In conclusion, our case report emphasizes the occurrence of arrhythmias in patients with hypomagnesemia following the long-term use of a PPI. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Magnesium is an important electrolyte for very many cell functions and its deficiency may lead to a wide spectrum of diseases. We report a clinical case of hypomagnesemia resulting from the chronic use of a proton pump inhibitor (PPI). PPIs are drugs widely used in medical practice, and a growing number of cases of PPIs causing hypomagnesemia have been described. Our aim was to monitor the clinical and electrolyte findings during recovery from hypomagnesemia caused by long-term PPI use. Results: A 65-year old female who had been using omeprazole for 10 years, presented with arrhythmia and paresthesia of the lower and upper limbs that had been attributed to severe hypomagnesemia, hypocalcemia, and hypoparathyroidism. Her laboratory tests revealed the following results: magnesium 0.6 mg/dL (NR: 1.5 to 2.5 mg/dL), calcium 7.3 mg/dL (NR: 8.5 to 10.2 mg/dL), parathyroid hormone (PTH) 13.3 pg/mL (NR: 15 to 65 pg/mL), and low urinary calcium and magnesium excretion. Her electrocardiogram disclosed typical, prolonged QT interval, ST depression, and U waves. We discuss the differential diagnoses, pathophysiology, and reversibility of symptoms after effective treatment of the hypomagnesemia. Conclusion: this report emphasizes that even if long-term PPI users appear largely asymptomatic, life-threatening arrhythmias can present very suddenly. Long-term PPI users should be monitored for otherwise unexplained hypomagnesemia, hypocalcemia, functional hypoparathyroidism and associated symptoms.
    Full-text · Article · Feb 2016
  • Full-text · Article · Aug 2013
  • [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND:Proton pump inhibitors (PPIs) are a class of medications indicated for the treatment of gastric acid-related diseases. Hypomagnesemia is a rare but serious adverse effect of PPIs.OBJECTIVE:TTo address the association between the use of different PPIs and hypomagnesemia by examining the frequency of occurrence of hypomagnesemia among the reported adverse drug reactions from the Food and Drug Administration (FDA) Adverse Event Reporting System database.METHODS:We conducted a cross-sectional study of PPI-associated adverse effect cases reported to the FDA between November 1, 1997, and April 1, 2012. Logistic regression was used to examine the association of sex, age, and different PPIs with hypomagnesemia. χ(2) Analysis was conducted to investigate the association of PPI-associated hypomagnesemia with hypocalcemia and hypokalemia.RESULTS:Among 66,102 subjects identified as experiencing 1 or more adverse effects while taking a PPI, 1.0% (n = 693) were reported to have hypomagnesemia. The mean (SD) age of PPI users presenting with hypomagnesemia was 64.4 (12.9) years. Results from logistic regression indicated that, compared with esomeprazole, all other PPIs had a higher rate of hypomagnesemia, with pantoprazole having the highest rate (OR 4.3; 95% CI 3.3-5.7; p < 0.001). The risk of female subjects having hypo magnesemia (OR 0.83; 95% CI 0.71-0.97; p = 0.016) was significantly lower than that of males. Elderly subjects (age >65 years) were at increased risk of PPI-associated hypomagnesemia (OR 1.5; 95% CI 1.2-1.7; p < 0.001). χ(2) Analysis showed strong association between hypomagnesemia and both hypocalcemia (p < 0.001) and hypokalemia (p < 0.001).CONCLUSIONS:All PPIs were associated with hypomagnesemia, with esomeprazole having the lowest risk and pantoprazole having the highest risk. The risk of PPI-associated hypomagnesemia was higher in males and the elderly population. Hypocalcemia and hypokalemia commonly coexisted with PPI-associated hypomagnesemia.
    Full-text · Article · Apr 2013
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