Introduction:
Proton pump inhibitors (PPIs) were distinguished in 1979 and endorsed for the administration of acid peptic illness; they were accordingly acquainted with the market in 1989 (1). PPIs irreversibly inhibit the gastric H+-K+ ATPase pump also known as proton pump and reduce both basal and stimulated gastric output. Currently the PPIs available in India are omeprazole, esomeprazole, pantoprazole, rabeprazole and lansoprazole (2). PPIs have succeeded histamine-2 receptor antagonists (H2-RAs) worldwide for the treatment of gastro esophageal reflux disorder (GERD) and peptic ulcer disease (PUD), support treatment for GERD or hypersecretory states and prevention of ulcers caused by Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)(3). Suppression of the gastric acid secretion is significantly stronger and longer with PPI than H2-RA, especially this suppression is markedly found in day time and also night time (4). This is due to the fact that other stimuli, in addition to histamine 2, stimulate acid production in the stomach and H2 blockers only block histamine 2. Proton pump inhibitors are demonstrated to be safe and well tolerated but may manifest short term adverse effects like headache, dizziness, diarrhoea, fatigue, rashes and abdominal pain in 5% of patients consuming PPIs (5). Several recent studies comparing omeprazole and ranitidine demonstrate the greater effectiveness of omeprazole in the treatment of PUD (6) and GERD leading to an increase in the use of PPIs (7). Intravenous administration of PPI is indicated in the treatment of high-risk peptic ulcers, complicated gastroesophageal reflux, stress-induced ulcer prophylaxis, Zollinger–Ellison syndrome and whenever it is impossible or impractical to give oral therapy (8). So as to acquire better treatment viability, physicians recommend parenteral PPIs instead of oral PPIs or oral H2-RAs (9). Besides, parenteral PPIs are moderately costly and improper utilize can expand the treatment cost fundamentally for patients, particularly in developing countries. Accomplishing appropriate prescribing practices with respect to parenteral PPIs will be important to deter these issues and challenges (10).
Globally few studies have reported improper utilization of PPIs in various health care facilities and are outside the current prescribing guidelines (11-14). The utilization of PPIs has started to stretch out to pathologies for which they were not outlined and for which there is deficient scientific evidence to justify their use (15). Enhanced utilization of PPIs is related with atrophic gastritis, interstitial nephritis, induction of ulcer symptoms, thrombocytopenia, osteoporosis and endocrine disorders, for example, gynecomastia and impotence (16-19). The probability of occurrence of adverse reactions to PPIs also increases with polypharmacy and is higher in patients with chronic diseases (20-21). This is expected to some degree to the metabolism of PPIs through cytochrome P450, which prompts different drug interactions by broadening their half-life and along these lines causes harmful systemic effects (21). An expansion in the prevalence of pneumonia, campylobacter enteritis, risk of hip fracture, infection with clostridium difficile, acute interstitial nephritis and osteoporosis have been accounted for as outcomes of long term treatment with PPIs (22-23).
The incidence of improper utilization of PPIs varies from 40-70% in various studies. Initiation and the consistent utilization of these medications without correct indications will result in huge expense to the patient (24-26). The increased consumption of PPIs provoked us to assess the prescribing pattern of PPIs in the Department of General Medicine.
Materials and Methods
A prospective observational study was conducted among the inpatients and outpatients of the Department of General Medicine of Ramaiah Hospital, Karnataka for a duration of 1 year from August 2017 to July 2018. The study protocol was approved by Human Ethics Committee of Ramaiah Medical College. All patients of both gender aged 18 years and above and met the study criteria were included. Patients admitted to intensive care units or other units were excluded. The medication charts of all patients were reviewed. Core information such as demographic characteristics, diagnosis and medications were recorded. In addition, patients with incomplete details were excluded. The inpatients were regularly monitored for Interactions or any other problems associated with the use of PPIs during the hospital stay and outpatients were monitored for PPI induced problems during their subsequent visits within the study period.
Results
During the study period, 1019 prescriptions were reviewed, out of which 908 (89%) prescriptions were found to have PPIs. Out of 908 patients, 468 (51.54%) were males while 440 (48.46%) were females. Gender distribution of patients on PPIs is shown in [Table 1].
| Table 1: Gender distribution of patients on PPIs |
| Gender |
Number of Patients (%) |
Male |
440 (48.46) |
Female |
468 (51.54) |
Total |
908 (100) |
Age distribution of total population revealed that patients aged >60 years, 366 (40.3%) were prescribed with more PPIs when compared to other age groups. Age wise distribution of patients on PPIs is depicted in [Table-2].
| Table 2: Age wise distribution of patients on PPIs |
| Age (Years) |
Number of Patients (% ) |
<20 |
40 (4.41) |
20-40 |
190 (20.93) |
41-60 |
312 (34.36) |
>60 |
366 (40.3) |
Total |
908 (100) |
Majority of PPIs were prescribed to patients with 1- 2 comorbidities 475 (52.31%) followed by patients without any comorbid conditions 272 (29.95%) which is shown in [Table-3].
| Table 3: Number of Comorbidities |
| Number of Comorbidities |
Number of Patients (%) |
0 |
272 (29.95) |
1-2 |
475 (52.31) |
>2 |
161 (17.73) |
Total |
908 (100) |
It was observed that patients who received 6-10 drugs 648 (71.37%) were prescribed with more number of PPIs than patients who received 2-5 drugs 198 (21.8%) and more than 10 drugs 62 (6.83%).
| Table 4: Number of Drugs Prescribed |
| Number of Drugs |
Number of Patients (%) |
2-5 |
198 (21.8) |
6-10 |
648 (71.37) |
>10 |
62 (6.83) |
Total |
908 (100) |
Number of drugs prescribed in patients is mentioned in [Table – 4].
| Table 5: Commonly prescribed PPIs |
| Commonly prescribed PPIs |
Number of prescriptions (%) |
Cost per day |
PANTOPRAZOLE |
749 (82.49) |
|
Inj. Pan |
615 (67.73) |
45.25 |
Inj. Pantop |
12 (1.32) |
45.25 |
Inj. Pantodac |
7 (0.77) |
7.3 |
T. Pan |
98 (10.8) |
9.2 |
T. Pan D |
6 (0.66) |
11.33 |
T. Pantocid |
3 (0.33) |
8.67 |
T. Pantop |
4 (0.44) |
9.2 |
T. Pantodac |
2 (0.22) |
9.9 |
T. Panwar |
2 (0.22) |
5.86 |
ESOMEPRAZOLE |
124 (13.66) |
|
Inj. Esoser |
106 (11.67) |
101.5 |
Inj. Esomac |
2 (0.22) |
101.5 |
Cap. Sompraz D |
9 (0.99) |
7.2 |
T. Esomac |
1 (0.11) |
7.97 |
T. Nexpro |
2 (0.22) |
12.3 |
T. Sompraz D |
3 (0.33) |
10.7 |
T. Sompraz |
1 (0.11) |
9.2 |
RABEPRAZOLE |
30 (3.30) |
|
Inj. R jet |
10 (1.10) |
125 |
Inj Rabicip |
9 (0.99) |
80.5 |
Inj Ravier |
4 (0.44) |
81 |
Cap. Rabium DSR |
3 (0.33) |
8.27 |
T. Rabicip |
3 (0.33) |
3.7 |
T. Rabium |
1 (0.11) |
6 |
OMEPRAZOLE |
5 (0.55) |
|
Inj. Ocid |
3 (0.33) |
33.7 |
Cap. Omez |
1 (0.11) |
2.53 |
T. Omez D |
1 (0.11) |
9 |
Total |
908(100) |
|
Screening of prescriptions revealed that four PPIs were predominantly prescribed. Pantoprazole 749 (82.49%) was the most commonly prescribed PPI [Table - 5]. From our study, it was observed that 103 (11.34%) patients with acute gastroenteritis, 7 (0.77%) patients with ulcers, 5 (0.55%) patients with Gastro Esophageal Reflux Disease (GERD), 3 (0.33%) with gastrointestinal bleed and 2 (0.11%) patients with ulcerative colitis were prescribed with PPIs. 785 (86.45%) patients received PPIs improperly for various indications and also prophylactically with NSAIDs and antibiotics.
| Table 6: Indications for prescribing PPIs |
| Indication |
Number of Patients (%) |
Acute gastroenteritis |
103 (11.34) |
GERD |
5 (0.55) |
Gastrointestinal Bleed |
3 (0.33) |
Ulcers |
|
Peptic Ulcer Disease |
3 (0.33) |
Multiple gastric ulcer |
1 (0.11) |
Duodenal ulcer |
1 (0.11) |
Gastric ulcer |
1 (0.11) |
Oral ulcer |
1 (0.11) |
Ulcerative colitis |
2 (0.22) |
IBD |
1 (0.11) |
Esophageal and gastric injury |
1 (0.11) |
Gastric erosion |
1 (0.11) |
Miscellaneous |
785 (86.45%) |
Total |
908(100) |
Indications for prescribing PPIs are described in [Table 6].
| Table 7: Route of Administration of PPIs |
| Route |
Number of patients (%) |
Oral |
140 (15.4) |
IV |
768 (84.6) |
Total |
908 (100) |
Intravenous therapy with PPIs was prescribed in 768 (84.6 %) patients and Oral PPIs in 140 (15.4%) patients [Table - 7].
| Table 8: Frequency of Administration of PPIs |
| Frequency |
Number of patients (%) |
Once daily |
891 (98.13) |
Twice daily |
16 (1.76) |
Stat |
1 (0.11) |
Total |
908 (100) |
Majority 891 (98.13%) of the patients were prescribed with PPIs once daily and only in 16 (1.76%) patients twice daily therapy was administered as shown in [Table – 8]. The number of NSAIDS, Antibiotics and Antiplatelets prescribed along with PPIs in each prescription was counted. It was observed that 179 (19.7%) prescriptions contained NSAIDs, 681 (75%) prescriptions contained antibiotics and 215 (23.67%) prescriptions contained antiplatelets along with the PPI.
| Table 9: Prescriptions with NSAIDs, Antibiotics and Antiplatelets |
| Prescriptions |
Number of prescriptions (%) |
PPI with NSAIDs |
179 (19.7) |
PPI with Antibiotics |
681 (75) |
PPI with Antiplatelets |
215 (23.67) |
Prescriptions with NSAIDs, antibiotics and antiplatelets is mentioned in [Table – 9]. Totally seven types of NSAIDS were used by the physicians during the study. More than 44% of NSAIDs contains aspirin while 36.87% prescriptions were of acetaminophen. Aceclofenac was another more commonly prescribed NSAID with 8.93%. Etodolac (0.56%) as NSAID is a least commonly prescribed NSAID.
| Table 10: PPI used along with NSAIDs |
| Commonly prescribed NSAIDs |
Number of prescriptions (%) |
Aspirin |
79 (44.13) |
Acetaminophen |
66 (36.87) |
Aceclofenac |
16 (8.93) |
Naproxen |
9 (5.03) |
Diclofenac |
6 (3.35) |
Etorocoxib |
2 (1.12) |
Etodolac |
1 (0.56) |
Total |
179 (100) |
Different types of NSAIDs used along with PPIs are described in [Table – 10]. Our study showed that 14 different classes of antibiotics were used by the physicians. Out of the total 681 (75%) prescriptions containing antibiotics, cephalosporins were more commonly used antibiotics 515 (52.1%).
| Table 11: PPI used along with the antibiotics |
| Commonly prescribed antibiotics |
Number of prescriptions (%) |
Cephalosporins |
515 (52.1) |
Ceftriaxone |
371 (37.51) |
Cefotaxime |
97 (9.81) |
Cefixime |
14 (1.41) |
Cefoperazone + Sulbactum |
11 (1.11) |
Cefoperazone |
4 (0.4) |
Cefoperazone + Clavulunic Acid |
4 (0.4) |
Cefuroxime |
3 (0.3) |
Cefpirome |
3 (0.3) |
Cefpodoxime |
3 (0.3) |
Cefotaxime + ofloxacin |
2 (0.2) |
Cefipime |
2 (0.2) |
Ceftazidine |
1 (0.1) |
Penicillins |
116 (11.73) |
Piperacillin + Tazobactam |
82 (8.3) |
Amoxicillin + Clavulunic Acid |
34 (3.43) |
Macrolides |
120 (12.13) |
Azithromycin |
118 (12) |
Clarithromycin |
2 (0.2) |
Fluoroquinolones |
83 (8.39) |
Ciprofloxacin |
36 (3.64) |
Ofloxacin + Ornidazole |
21 (2.12) |
Levofloxacin |
13 (1.31) |
Ofloxacin |
10 (1.01) |
Ciprofloxacin + Tinidazole |
2 (0.2) |
Norfloxacin |
1 (0.1) |
Tetracycline |
|
Doxycycline |
25 (2.53) |
Nitrofurans |
|
Nitrofurantoin |
22 (2.22) |
Metronidazole |
57 (5.76) |
Carbapenem |
|
Meropenem |
16 (1.62) |
Lincomycin |
|
Clindamycin |
12 (1.21) |
Rifaximin |
11 (1.11) |
Aminoglycoside |
|
Amikacin |
4 (0.4) |
Glycopeptide |
|
Vancomycin |
3 (0.3) |
Glycycline |
|
Tigecycline |
3 (0.3) |
Oxazolidine |
|
Linezolid |
2 (0.2) |
Total |
989 (100) |
Classes of antibiotics used along with PPIs are shown in [Table – 11].
| Table 12: Use of PPI in Fixed Drug Combination |
| Drug in combination with PPI |
Number of patients (%) |
Domperidone |
21 (2.3) |
No Combination |
887 (97.7) |
Total |
908 (100) |
When we evaluated the different in fixed drug combinations of PPI used in study we observed that 21 (2.3%) patients PPI were used FDC with domperidone which is shown in [Table - 12]. Out of 908 patients who were prescribed with PPIs, a total of 443 interactions were observed from 367 (40.42%) patients.
| Table 13: Interactions with PPI |
| Commonly found interactions |
Number of Interactions (%) |
Mechanism of interactions |
PPI + Budesonide |
153 (34.54) |
PD Antagonism |
PPI + Optineuron |
135 (30.47) |
PK Absorption |
PPI + Levothyroxine |
64 (14.45) |
PK Absorption |
PPI + Iron |
55 (12.42) |
PK Absorption |
PPI + Fluconozole |
12 (2.71) |
PK Metabolism |
PPI + Propranolol |
10 (2.26) |
PK Metabolism |
PPI + Rifaximin |
8 (1.81) |
PK Distribution |
PPI + PPI |
2 (0.45) |
PK Absorption |
PPI + Escitalopram |
1 (0.22) |
PK Metabolism |
PPI + Cefuroxime |
1 (0.22) |
PK Absorption |
PPI + Methotrexate |
1 (0.22) |
PK Excretion |
PPI + Clopidogrel |
1 (0.22) |
PK Metabolism |
Total |
443 (100) |
|
Commonly drugs found to produce drug interactions with PPI and its possible mechanism of interactions are described in [Table – 13].
Discussion
Since PPIs are more effective and relatively have low toxicity than other anti-ulcer medications, they are more commonly prescribed globally (15). The present study shows that a total of 89% of patients were on PPIs during the study period. This is in accordance with the previous study by Ramirez et al (27), who reported that the use of PPIs ranges from 28.65 % to 82.65% and Sandozi et al., (24) who reported use in 45% of hospitalized patients.
Interestingly, female patients 468 (51.54%) were found to be at higher risk of receiving an unjustified PPI than male patients 440 (48.46%). This study is similar to the study conducted by Machado-Alba et al., in Colombia on prescribing patterns and economic costs of proton pump inhibitors (15). The elderly population were prescribed with more PPIs 366 (40.3%) when compared to other age groups. This may be due to the reason that elderly population has higher prevalence of chronic multiple diseases, leading to polypharmacy, which makes physicians to prescribe them with more number of PPIs.
When assessing the comorbidities leading to the prescription of co-medications, it was found that majority of PPIs were prescribed in patients with 1- 2 comorbidities 475 (52.31%) followed by patients without any comorbid conditions 272 (29.95%). Such patients must therefore use drugs that are not associated with gastric or duodenal mucosal injury.
Our results also revealed that patients who received 6-10 drugs 648 (71.37%) were prescribed with more number of PPIs than patients who received 2-5 drugs 198 (21.8%). This shows that polypharmacy can make physicians to prescribe the patients with more number of PPIs.
Pantoprazole 749 (82.49%) was the most commonly prescribed PPI while esomeprazole, rabeprazole and omeprazole were other commonly used PPI in our study. This study is in line with the study conducted by Tadvi et al., on use of proton pump inhibitors in general practice where 82% of prescriptions contained pantoprazole (2).
The indications for PPI use considered in this analysis included a group of well-accepted indications such as acute gastroenteritis 103 (11.34%), ulcers 7 (0.77%), GERD 5 (0.55%), gastrointestinal bleed 3 (0.33%) , ulcerative colitis 2 (0.22%), IBD 1 (0.11%), esophageal and gastric injury 1 (0.11%) and gastric erosion 1 (0.11%). 785 (86.45%) of patients received PPIs improperly for unjustified indication or as a prophylaxis therapy with NSAIDs and antibiotics.
Majority of patients received PPIs as IV therapy 768(84.6%) than oral therapy 140(15.4%). These findings are in contrary with the findings observed by Tadvi et al., on use of PPIs in general practice where most of the patients received oral PPIs (70%) than intravenous therapy (30%) (2). The frequency of administration of PPIs was once daily in 891 (98.13%) patients and twice daily only in 16 (1.76%) patients. These results are in parallel with the results documented by Tadvi et al (2). The doses of PPIs are recommended as once daily but can be given twice daily also for rapid action as steady state is achieved rapidly.
Kumar et al in his study observed that 37.1% of NSAIDs were prescribed with PPIs (28). This is more as compared with our studies. Our study showed that only 179(19.7%) patients were prescribed with NSAIDs along with PPIs. Aspirin 79(44.13%) and acetaminophen 66 (36.87%) were the most commonly prescribed NSAIDs in our study. The use of NSAIDs is an important predisposing factor for peptic ulcer disease in the patients, thus one of the important indications of PPIs is co-administration with NSAIDS to reduce the risk of gastrointestinal bleeding and peptic ulcers.
The most common concomitant medications used with PPIs were antibiotics, this is a serious issue as 75% of the prescriptions of PPI contained antibiotics and it is well known fact that patients on PPIs are also susceptible to colonization of pathogens which can lead to bacterial gastroenteritis and also there is higher risk of development of infection by Clostridium difficile (antibiotic associated diarrhoea). Cephalosporin 515 (52.1%) were the most commonly prescribed class of antibiotics along with PPI in our study. These results are contradictory with the results documented by Pendhari et al., where fluoroquinolones 204 (13.92%) were the most commonly prescribed class of antibiotics (29).
A total of 443 interactions were observed from 367(40.42%) patients. The major interactions were found between Budesonide and PPI 153 (34.54%) and between Optineuron and PPI 135 (30.47%). This shows that special attention and care should be provided to the patients who are prescribed with the drugs that are capable of interacting with PPIs.
The results of our study are found to be comparable with the studies conducted by Patil et al., on Drug Utilisation Study of PPIs in inpatients of a Tertiary Care Hospital (30), and Tadvi et al., on use of PPIs in general practice (2) which indicated that PPI are preferred and prescribed as gastro protective agents alone or along with antibiotics and NSAIDs. Thus they will reduce the gastrointestinal adverse effects of NSAIDs and some antibiotics, but in due course of time may give rise to some other adverse effects.
No serious or life threatening adverse effect was observed in patients receiving proton pump inhibitors. Cost analysis revealed that rabeprazole was more costly than pantoprazole, esomeprazole and omeprazole formulations available in the hospital pharmacy. These results are in contrary with the results documented by Tadvi et al where cost analysis revealed that pantoprazole was twice more costly than omeprazole and esomeprazole formulations available in the hospital pharmacy (2).
Conclusion
This study showed great inappropriateness in prescribing patterns of PPIs in a tertiary care hospital in India, main to increased therapeutic burden and treatment cost. These information are treasured due to the fact they can be used to set up standard guidelines for the rational use of PPIs and promote rational drug use in India and other developing countries.
The study also found out that PPI are still depended upon by way of the various physicians for their capability to produce gastro protecting impact. Especially when NSAIDs or some antibiotics are concurrently administered. However their contribution toward adverse effects is to be evaluated with continued pharmacovigilance studies.
Increased awareness have to be created among the clinicians inside the health care facilities so that appropriate prescription of PPIs will improve the affected patient care at low cost. More drug utilization and pharmaco-economic studies ought to be conducted in future to examine the rationality of use of proton pump inhibitors and different anti secretory medications like H2 blockers to recognise the exact scenario and plan the remedial measures.
Acknowledgements
We respect and thank our Guide, Dr. E Maheswari, Professor and Head, Department of Pharmacy Practice, Faculty of Pharmacy, M.S Ramaiah University of Applied Sciences, Bangalore, Karnataka, for giving us an opportunity to carry out this research work and also who through her hard work, patience and tolerance has contributed to the success of this work.
Conflict of Interest: Nil
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