Introduction
Aims
Methods
Results
Discussion
Conclusion
References

Introduction

Proton pump inhibitors (PPIs) are used for the treatment of a variety of conditions such as dyspepsia, gastro-oesophageal reflux disease and peptic ulcer disease. PPIs are pro-drugs that are activated in the presence of acid. They work by irreversibly blocking the gastric H, K-ATPase present on parietal cells, thereby inhibiting gastric acid secretion.1 

As PPIs are pro-drugs, drug plasma levels must remain high until gastric acid is secreted resulting in their activation.  Since PPIs are rapidly metabolised by the liver, plasma levels of the drugs are greatly determined by the nature of its metabolism. PPI metabolism is dependent on the cytochrome P450 system.1 2 

One can reason that the potential for drug-drug interactions is in part dependent on inhibition and induction of the cytochrome P450 enzyme. Indeed, PPIs such as omeprazole have shown adverse interactions when taken with clopidogrel, methotrexate and digoxin.3  All of which have their metabolism either directly or indirectly affected by this pathway. Consequently, polypharmacy in the elderly makes this an area of interest.

Omeprazole is internationally one of the most prescribed drugs. It was first introduced in 1989 and subsequently, lansoprazole and pantoprazole have entered clinical practice. Recently, there have been concerns raised over its interaction with other drugs and the adverse effects of chronic PPI usage such as increased fracture risk and susceptibility to infections; all of which the older population are at high risk of.4 5 

Aims

The aim of this study was to assess the extent of omeprazole prescriptions in elderly care wards and to evaluate its potential interactions with other commonly used drugs in elderly patients.  

Methods

The study was undertaken at Conquest Hospital (DGH) across three acute elderly care wards. The older population was defined as age above 76 years. 84 (n) charts were randomly selected across these three wards. The number of omeprazole prescriptions was collated. Of these prescriptions, interactions of omeprazole and other drugs were documented. 

Results

71% of patients were above 80 years old and 58% of the patients were female. 28% (24/84) of treatment charts had omeprazole prescribed. Of these prescriptions, 41% (10/24) treatment charts did not record the interaction of omeprazole with other drugs, hence were excluded from the analysis. Four drugs were commonly found to interact with omeprazole – citalopram, clarithromycin, clopidogrel and digoxin. 71% (10/14) prescriptions had omeprazole interacting with one drug (Figure 1). 28% (4/14) prescriptions had omeprazole interacting with ≥ 2 drugs.

Figure 1: Proportion of omeprazole prescriptions that had one interaction with another drug (n=10). 37% of the treatment charts recorded interaction with citalopram, 36% with clarithromycin,18% with clopidogrel and 9% with digoxin.

Discussion

This study found that a large proportion of omeprazole prescriptions 59% (14/24) have interactions with commonly used drugs. A large proportion of these drugs interact with digoxin. Omeprazole has been shown to reduce digoxin clearance by inducing its absorption in the stomach and reducing its clearance, thereby increasing serum digoxin levels above the therapeutic range. This can have harmful effects on patients and clinicians must be alerted to this.

Trials have demonstrated that concurrent use of omeprazole and clopidogrel result in statistically significant reduced antiplatelet effects (p<0.0001).6 

The clinical significance of their interaction does remain uncertain and warrants further investigation. Until fully understood one could propose the use of an alternative PPI. Indeed, studies have shown that no interaction was found between both pantoprazole, esomeprazole and clopidogrel. Furthermore, lower levels for platelet aggregation were seen when pantoprazole and esomeprazole were used.7 

Brand et al. found that pantoprazole has less interaction with the cytochrome P450 system compared to omeprazole,7 which may account for its better drug interaction profile. Pantoprazole is shown to have no interactions with these commonly prescribed drugs in older patients (Table 1).

 

Table 1: Drug interaction profile for PPIs.

Concomitant drug

Omeprazole

 Lansoprazole

 Rabeprazole

 Pantoprazole

 Esomeprazole

Warfarin

PT decreased by 10%

 

 

 

 

Diazepam

T ½ increased by 130%

 

 

 

Decreased vy clearance

Phenytoin

T ½ increased by 27%

 

 

 

-

Theophylline

 

AUC increased by 10%

 

 

Unknown

Digoxin

AUC increased by 10%

 

AUC. Cmax. T1/2 increased.

-

Unknown

Carbamazepine

AUC increased by 75%

 

 

 

Unknown


There is an insignificant cost difference between omeprazole, lansoprazole and pantoprazole (Table 2).

 

Table 2. The cost-comparison of PPIs8 

 

Active Ingredient

 Size                  Prices

Omeprazole 20mg gastro resistant capsules

  28                     0.40p

Lansoprazole 15mg gastro resistant capsules

  28                     0.42p

Pantoprazole 20mg gastro resistant tablets

  28                     0.46p

Esomeprazole 20mg gastro resistant tablets

  28                     1.62p

Rabeprazole 20mg gastro resistant tablets

  28                     0.96p

 

 

It is unclear that prolonged PPI use is associated with an increase in the risk of death. In an observational cohort study, the incident death rate among new PPI users was higher than among new histamine-2 receptor antagonist (H2RA) users.9  After adjusting for confounders, PPI use was associated with increased risk of death in all-cause mortality. Additionally, among new PPI users, increased duration of PPI use was associated with increased risk of death compared to no use.9 

Although this study was limited by its generalisability, one could suggest that PPIs should only be prescribed for the shortest duration at the lowest possible dose for treatment.

Conclusion

This study should help inform our clinical risk management. PPIs should be prescribed at the lowest dose for the shortest duration appropriate for the condition being treated. Patients who are prescribed PPIs should undergo periodic assessment as to whether continued use is beneficial given the adverse effects and increased risk with polypharmacy in the complex elderly patients.

This includes periodic evaluation of treatment charts by the ward pharmacists to alert clinicians of any harmful interactions. Alternative safer PPIs with better drug-drug interaction profiles such as pantoprazole should be considered either as a first-line treatment or an alternative treatment in the complex elderly patients.

Authors

Owasil R, Foundation year 1 trainee, Department of Health and Ageing, Conquest Hospital, East Sussex Healthcare Trust

MJH Rahmani, Consultant Physician. Department of Health and Ageing, Conquest Hospital, East Sussex Healthcare Trust

Conflict of interest: none

 

References

1.Moo shin J, Sachs G. Pharmacology of proton pump inhibitors. Curr Gasteroeneterol Rep.2008; 10 (6): 528-534 

2.Moo shin J, Kim N. Pharmacokinetics and Pharmacodynamics of the proton pump inhibitors. Journal of Neurogasteroenterology and Motility. 2013: 19 (1): 25-35

3.Li W, Yu Lu-Shan, Zhou Q. Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management. Therapeutic and clinical risk management. 2013: 9; 259-271

4.Maes ML, Fixen DR, Linnebur SA. Adverse effects of proton-pump inhibitor use in older adults: a review of the evidence. Therapeutic advances in drug safety. 2017, Vol. 8(9) 273–297

5.Evan SD, Shaheen NJ, Scholl S. Treatment of GERD and Proton Pump Inhibitor Use in the elderly: Practical Approaches and Frequently Asked Questions. Journal of Gastroenterology. 2011; 106:386-392

6.Jeong JW, Kim NH, Oh SK, Park HY, Rhee SJ, Yun KH. Effects of omeprazole on the antiplatelet activity of clopidogrel. Int heart journal. 2010; 51(1):13-6

7.Christ G, Jilma B, Kreiner G, Lang IM, Siller-Matula JM, Spiel AO. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Amercian Heart Journal. 2009;157(1)148.

8.East Sussex Formulary 2019.

9.Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorder. https://www.uptodate.com/contents/proton-pump-inhibitors-overview-of-use-and-adverse-effects-in-the-treatment-of-acid-related-disorders#H3309582559. (accessed01/02/19)