Effect of Esomeprazole on serum creatinine and urea in patients with Peptic Ulcer

 

Marwan M. Merkhan1,2*, Eman Abdullah1, Zeina Althanoon1

1College of Pharmacy, University of Mosul, Iraq.

2College of Pharmacy, Ninevah University, Iraq.

*Corresponding Author E-mail: marwan.mohammed@uoninevah.edu.iq

 

ABSTRACT:

Peptic ulcers are best treated by proton pump inhibitors (PPIs), however, other simple gastrointestinal (GIT) disorders should be better treated by other acid neutralizing or anti-secretory agents. Unfortunately, most GIT diseases were reported to be treated by PPIs even though non-indicated cases. The reasons might include ease availability with/without prescription, reduce patient awareness, and overprescription of PPIs by the health care professionals. This study aims to highlight the effect of these drugs on the renal function test. Patients were recruited and enrolled in the study from outpatients private clinics and plasma samples were withdrawn from control healthy, esomeprazole and omeprazole users individuals. Plasma samples were frozen for further analysis, creatinine and urea test were conducted on overall samples and the results were displayed confirming significant dysfunctioning of the renal system from PPIs use. The study concluded that creatinine and urea are higher in a patient on esomeprazole than omeprazole and the control group. The study recommends general awareness of the society about regular use of these medications unless otherwise carefully required.

 

KEYWORDS: Esomeprazole, PPIs, Renal, Urea, Creatinine.

 

 


INTRODUCTION:

Proton pump inhibitors (PPIs) are one of the most widely dispensed medicines for gastroduodenal ulcer1. The most commonly dispensed PPI members are omeprazole and lansoprazole. PPIs are dispensed for both prescription-based and off-label cases2. FDA affirmed PPIs are shown in gastroduodenal ulcer, gastric inflammation, NSAIDs actuated gastroduodenal ulcer, hemorrhagic ulcer, Gastroesophageal Reflux disorder (GERD), and Zollinger Ellison disorder3. The reason behind the over-usage of PPIs is their easy accessibility even over the counter (OTC) and up to 70% is surprisingly out of appropriately scheduled indications4 and studies have confirmed that PPIs are among overused drugs due to their efficacy in diminishing the symptoms5.

 

A survey study conducted by Heidelbaugh et al.6 2012; reported that 7.8% of the USA population has used one of PPI members due to their OTC availability. Moreover, the medication most often used by patients irregularly based on self-prescription which might result in some serious adverse events on chronic use7.

 

The reported adverse effects associated with PPIs vary widely ranging from mild to serious reactions8. The commonly reported adverse effects include, headache, floating, constipation9, increase chance of infectious diseases, such as pneumonia10 and Cl. Difficile11 infection. Moreover, the range of adverse effects might extend to include some serious but rare effects, such as osteoporosis, hypomagnesemia, anemia, and renal disorder12,13,14, although renal disorders being rare; they are serious and includes; interstitial nephritis, kidney injury. The kidney-related adverse events are considered as the most deleterious impacts of PPIs. These renal disorders could be misconfused with other disorders which might coexist with PPIs-use and could be the primary cause of the renal disorder and PPIs could only play an additive drastic mode of induction of renal disorders. Collectively, these disorders share the immunological point as an underlying cause of these renal disorders. However, Antoniou et al.15, reported that PPIs-users show a three-fold higher chance of developing renal problems compared to non-PPIs users of the same demographic parameters.

 

The outcome of most published data is elusive due to the unavailability of concrete objectively measured parameters confirming the relationship. The explanation of the association between PPI use and the development of renal problems is based on the precipitation of these drugs together with their metabolites in renal interstitium. These later effects stimulate local immune response resulting in T cell stimulation and propagation of immune response which might end up with tissue necrosis and this will ensure discontinuing the offending drugs and start corticosteroids to avoid initiation of renal failure6,16.

 

MATERIALS AND METHODS:

Sample collection:

The study were conducted in outpatient clinics and consent agreement were included into patients record each. Thirty control subjects and Forty-eight patients with diagnosed peptic ulcer were enrolled in the study and the patients were either treated with omeprazole or esomeprazole for a 2-month duration at an optimal dose (40mg of omeprazole or esomeprazole on daily basis). Demographic parameters regarding age, sex, and weight were mentioned below in table 1. The exclusion criteria involve any chronic disease, pregnant or lactating mothers were also excluded. Blood samples were withdrawn from enrolled patients and serum collected and frozen for future analysis.

 

Laboratory analysis:

Serum urea were quantified based on the enzymatic method (Reflotron strips, Mannheim, Germany). The principle of the assay was based on dropping a serum sample into a specified zone where urea will be lysed into ammonium carbonate resulting in ammonia release resulting in an alkaline reaction producing color transition of yellowish-green indicator into blue and the intensity is reciprocal to urea concentration in the serum sample. The result was read after drop application 190 seconds at 37C and in 642nm wavelength (Price and Koller, 1988). Serum creatinine was measured by an enzymatic method based on the Chemwell T system (figure 1). The principle of an assay based on the elimination of interference with creatine and ascorbic acid by two consecutive steps utilizing amidohydrolase and amidohydrolase enzyme followed by subsequent oxidation with sarcosine oxidase enzyme-producing peroxide molecule. Peroxidation reaction results in quinone imine dye formation and the intensity of which is reciprocal to creatinine present in the sample. Hydrogen peroxide was detected by reduction at the surface of an electrode.

 

Figure 1. A schematic diagram describing Creatinine measurement.

 

In vitro solubility determination:

The solubility of different commercially available PPIs was determined by dissolving PPIs in solvents (water, ethanol, dimethylsulphoxide) at room temperature using a magnetic stirrer.

 

Statistical analysis:

Data presented as mean ± standard deviation. T-test used to compare studied group and p<0.05 indicates that the difference was statisti­cally significant. Statistics performed using GraphPad Prism 5.0 (GraphPad Software Inc., La Jolla, CA, USA).

 

Table 1. Biochemical and Demographic Characteristics of the Studied Groups.

 

PPIs Therapy

Control

(n=25)

Parameters

Omeprazole

(n=31

Esomeprazole

(n=29)

Age (years)

39.41±3.8

35.1±6

38.2±2.6

BMI (kg/m2)

28.2±3

27.1±2.8

26.1±3.6

Duration of treatment

6 months

 

------

 *p<0.05, BMI=body mass index, kg=kilogram, m2=square meter

 

RESULTS:

The study results are demonstrating that esomeprazole has precipitated damage indicated by creatinine increase compared to control and omeprazole (prototype of PPI group). These results were further confirmed by their solubility in vitro were low compared to other PPIs indicated by their insolubility in water. This Finding could be a mirror reflecting their insolubility in renal tubules and their accumulation could be the triggering factors for immune stimulation which might attack these abnormal molecules resulting in a local immune reaction which could be with time a causative agent for renal damage and subsequent renal failure.

 

The PPIs include different members in the class, including omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. These members vary in their structural and physicochemical properties (Figure 2, Table 2). Variation in their structure and solubility might be responsible for the variation in the range of adverse drug reactions associated with PPI members. The solubility of PPIs in DMSO and ethanol were quite similar apart from lansoprazole showed slight solubility in ethanol (Table 1). This variation in solubility might be responsible for the accumulation of esomeprazole rather than omeprazole in renal interstitial tubules resulting in kidney damage.


 

Figure 2. Chemical structure of proton pump inhibitors.

 

The plasma concentration (mg/dl) of urea and creatinine in esomeprazole users showed a significantly higher (p<0.05) level than control and omeprazole users, however, there were a non-significant (p>0.05) difference between omeprazole and control group (figure 3)

 


Figure 3. Esomeprazole increased serum urea/creatinine levels.

 


The renal deposit of PPIs and their metabolite were reported to be due to their insolubility in the renal fluid. Therefore, table 1 below showed their solubility in different solvents compared to water to simulate the deposition in renal tubules. The solubility was better for all PPIs compared to esomeprazole/lansoprazole which has shown insolubility in water.

 

Table 2. In vitro solubility (mM) of PPIs in different solvents at 25°C

PPIs member*

Water

Ethanol

DMSO

Esomeprazole

Insoluble

200S

200S

Omeprazole

198S

198S

198S

Pantoprazole

199S

199S

199S

Lansoprazole

Insoluble

24SS

200S

Rabeprazole

199S

199S

199S

*Sodium salt is used in all PPIs, DMSO=dimethylsulphoxide. SSoluble, SSSlightly Soluble

 

DISCUSSION:

Chronic kidney disease (CKD) is recognized as any functional or structural abnormalities of the renal system lasting for more than 3 months, usually represented functionally as a glomerular filtration rate lower than normal less than 60ml/min/1.73m2 and the presence of albuminuria alongside structural presentation as tubular damage diagnosed by radioimmaging)17. PPIs produced CKD by more than one mechanism (Moledina DG) including interstitial nephritis18 and acute tubular necrosis19. Yang et al. reported a significant association between the developing of AKI and using PPIs with an increased risk for up to 1.61 folds20.

 

However, a study conducted reported that idiosyncratic immune reaction involved in the pathogenesis of the symptomatic disease based on assumption that the nephritis symptom is PPIs-class mediated21 25. Moreover, renal biopsy in PPI users documented that T cell and eosinophilic infiltration is the whole mark of the samples collected from PPIs-users21,22 

 

Meta-analysis study conducted by confirmed that young PPIs-users (less than 60 years) showed a greater association with the development of AKI than elderly users, the researcher has related that to the fact that elderly immune reaction is lower than young. However, a case-series study conducted on the elderly showed a higher prevalence of AKI in the elderly compared to the young. Moreover, Arora et al, confirmed that young patients exposed to PPIs developed a more serious condition with CKD, and these results consistent with our results confirming that PPIs use impairs kidney function20,23

 

Data analysis from cohort studies demonstrated that there is an association between PPI use and the development of CKD with a hazard ratio (HR) of 1.1724. Similarly, Xie et al.25, confirmed that PPIs increase the risk for developing CKD to 1.28 compared to H2-receptor blockers. Moreover, a case-controlled study demonstrated an odd ratio of 1.1 for the development of CKD among PPI users26. Four case study reported by Sampathkumar et al.27, confirmed that omeprazole, pantoprazole, and esomeprazole has induced AIN in these patients after using these PPIs for certain relevant GIT problems, the kidney impairment has been restored partially after discontinuing the therapy with PPIs and starting steroid therapy.

 

A retrospective survey study that included up to 50000 subjects confirmed that PPIs use increases the risk of developing CKD and this risk reciprocally related to dose and duration, however, no clear mechanism was reported to explain the association between CKD and PPIs use15.

 

Although that the fate of PPIs-induced renal injury is not fully understood, however, interstitial fibrosis developed early followed by AIN. AIN is non-reversible damage that might develop into CKD when left untreated. Moreover, a 5-year cohort study confirmed that long term exposure to PPIs results in hypomagnesemia with subsequent stimulation of inflammatory reaction resulting in renal damage alongside deposition of insoluble drugs (esomeprazole in particular) in renal interstitial cells which further complicate the conditions resulting in further renal damage (figure 4)20.

 

Figure 4. Potential mechanism of PPIs-induced renal disease.

 

CONCLUSION:

The study provides an important highlight about public risk from developing renal damage due to regular PPIs use even without prescription. The risk further signifies the presence of underlying kidney disease or using high dose PPIs. The study recommends awareness of healthcare professional and the public from this issue to take steps which prohibit regular PPIs use unless otherwise indicated.

 

ACKNOWLEDGMENTS:

The authors are very grateful to the University of Mosul/College of Pharmacy and the University of Ninevah/ College of Pharmacy for their provided facilities, which helped to improve the quality of this work. Thanks are also in order for the scientific committee in the department of pharmacology and toxicology of the college of pharmacy/university of Mosul.

 

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Received on 11.03.2021            Modified on 29.04.2021

Accepted on 25.05.2021           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(1):160-164.

DOI: 10.52711/0974-360X.2022.00026