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`What you need to know when you
`prescribe a proton pump inhibitor
`
`A Norman, C J Hawkey
`
`Nottingham Digestive Diseases
`Centre, University Hospitals Trust,
`Nottingham, UK
`
`Correspondence to
`C J Hawkey, Nottingham
`Digestive Diseases Centre,
`E Floor West Block, University
`Hospitals Nottingham,
`Nottingham NG7 2UH, UK;
`cj.hawkey@nottingham.ac.uk
`
`Accepted 16 April 2011
`Published Online First
`24 June 2011
`
`Abstract
`Ever since they were launched, proton
`pump inhibitors (PPIs) have been regarded
`as profl igate prescription interventions and
`have become a favourite target for pharmacy
`advisers. Now that they are cheap, with
`generic omeprazole 20 mg daily costing £1.88
`per month (£24.51 per annum) in the UK, it
`is time to ask whether this status should be
`reviewed, whether there are areas where the
`message should be reversed and whether there
`are any circumstances in which the extra cost
`of branded PPIs or combined preparations
`is justifi ed. Equally, with the recognition of
`an extended toxicity profi le, is prescribing
`profl igacy not an economic but a safety issue?
`
`Pharmacology and chemistry
`PPIs are easily protonated and therefore
`unstable at acid pH.1 2 In gastric juice, this
`would result in inactivation before absorp-
`tion. This is why PPIs are enteric coated.
`Following absorption, they partition by
`ionic trapping into the acidic environ-
`ment of the parietal cell cytoplasm, where
`the unstable
`sulphonamide/sulphenic
`acid species that result from protonation
`form irreversible disulphide bonds with
`cysteine residues in the proton pump.
`There are 28 of these, but two are thought
`to be important for proton pump inhibi-
`tion, CYS813 and CYS822. The need to
`achieve acid exposure in the parietal cell
`but not the stomach is why PPIs should be
`taken 20 min before breakfast.
`These properties give PPIs their selectiv-
`ity and potency and can explain potency
`differences between them. For example,
`rabeprazole as the most acid-labile PPI is
`the most potent, while the less reactive
`pantoprazole is the least potent1–4 The
`mechanism of action based on covalent
`binding is similar to the way that aspirin
`works. Just as aspirin achieves permanent
`irreversible inhibition of platelet throm-
`boxane synthesis to achieve an action that
`outlives its half-life, so too do PPIs. PPIs
`
`have quite a short pharmacological half-
`life (typically about 1 h), but this is largely
`irrelevant to their duration of activ-
`ity, with synthesis of new pumps being
`required for restoration of acid secretion
`after approximately 24 h. Because PPIs do
`not work through receptor mechanisms,
`there is no pharmacological loss of activ-
`ity by tachyphylaxis. However, long-term
`use can lead to a pseudo-tachyphylaxis in
`that parietal cell inhibition results in an
`increased parietal cell mass, which can be
`manifested as rebound hyperacidity on
`drug cessation.
`All PPIs are eliminated by metabolism
`via the CYP2C19 pathway.3 CYP3A4 also
`plays a role. Omeprazole and esomepra-
`zole are not only metabolised by this path-
`way but they inhibit it also. This, as well
`as PH-dependent changes in absorption,
`gives rise to a number of drug interactions,
`the most important of which are listed in
`table 1. Inhibition is generally less or non-
`existent with other PPIs. Enantiomerically,
`pure esomeprazole is said to have a low
`dependency on CYP2C19 than race-
`mate omeprazole and uses the CYP3A4
`pathway to a greater extent. Because of
`its intrinsic instability, cytochrome P450
`metabolism plays the least role in rab-
`eprazole metabolism resulting in the low-
`est risk of drug interactions. Patients with
`mutant in CYP2C19 (poor metaboliser)
`experience increased effectiveness from
`all PPIs except rabeprazole.
`
`Uses of PPIs
`The main indications for PPI use are listed
`in box 1. Reflux remains the main one.
`Gastroenterologists will be familiar with
`the use of high-dose PPI intravenously for
`the prevention of re-bleeding following
`endotherapy for bleeding peptic ulcer.
`
`Dyspepsia
`Dyspepsia is a broad term that has prob-
`ably changed its meaning over the course
`of history. PPIs are recommended for
`
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`Table 1
`
`Interactions between proton pump inhibitors (PPIs) and other drugs*
`
`Drug class
`
`Drug
`
`PPI
`
`Effect on drug
`
`Effect on PPI
`
`Anticoagulants
`Antiepileptic
`Antibacterial
`Antifungal
`
`Antiviral
`
`Antidepressant
`Vasodilator
`Antiplatelet
`
`Coumarins
`Phenytoin
`Clarithromycin
`Ketoconazole
`Itraconazole
`Atazanavir
`Nelfi navir
`Raltegravir
`Saquinavir
`Tipranavir
`Escitalopram
`Cilostazole
`Clopidogrel
`
`Omeprazole, esomeprazole, pantoprazole
`Omeprazole, esomeprazole
`Omeprazole
`
`PPIs
`Omeprazole
`Omeprazole
`Omeprazole
`Omeprazole and esomeprazole
`Omeprazole
`Omeprazole
`Omeprazole
`
`Probably enhanced effect
`Enhanced effect
`Increased plasma level
`Reduced absorption
`Reduced absorption
`Reduced plasma level
`Reduced plasma level
`Increased plasma level
`Increased plasma level
`
`Increased plasma level
`Increased plasma level
`Reduced activation
`
`Increased plasma level
`
`Reduced plasma level
`
`*See text for description of interaction with clopidogrel.
`
`Box 1 Uses of proton pump inhibitors
`
`Pragmatic treatment of dyspepsia
`Gastro-oesophageal refl ux disease, including
` Management of upper airways complications*
` Diagnostic test*
` Prevention of strictures*
` Barrett’s oesophagus and prevention of cancer*
`Helicobacter pylori eradication
`Peptic ulcer healing
`Ulcer prophylaxis, principally in aspirin and non-steroidal anti-
`infl ammatory drug users
`Treatment of bleeding peptic ulcer
` Prevention of stress ulceration
`Zollinger–Ellison syndrome
`Reducing iron absorption in haemochromatosis*
`
`*Unlicensed and/or unproven use
`
`the pragmatic treatment of dyspepsia. While this is
`probably true for acid-like and reflux-like dyspepsia,
`their value in dysmotility-like dyspepsia has not been
`established.
`
`Medical or surgical therapy of refl ux?
`This question has been subject to a Cochrane review.5
`PPIs are very effective treatment for reflux, but long-
`term use is necessary. The surgical alternative of lapar-
`oscopic fundoplication results in a quality of life that is
`similar to that of patients on PPIs, albeit with a number
`of adverse consequences such as dysphagia and an ina-
`bility to belch and a need for supplemental PPI therapy
`in 36% of patients over 12 years.6 The procedure has
`been analysed as cost-effective, but this merits a revisit
`in the light of the reduced cost of generic omepra-
`zole and lansoprazole. In reality, the great majority of
`patients are managed medically, with laparoscopic fun-
`doplication being reserved for a minority of patients
`who are drug averse or whose reflux is resistant to PPI
`therapy.
`
`Upper gastrointestinal bleeding
`High-dose PPI therapy (80 mg followed by 8 mg/h of
`omeprazole) is well established in the management of
`
`patients with ulcer bleeding and endoscopic stigmata,7
`and this role in the management of high-risk lesions
`has been confirmed in a large multinational ran-
`domised placebo controlled trial.8 Furthermore, in cer-
`tain populations, this strategy improves outcomes and
`increases cost-effectiveness of the overall treatment.9
`Their value prior to endoscopy in all comers has been
`much more difficult to establish. As long as 20 years
`ago, omeprazole was shown to be associated with an
`improvement in endoscopic signs, but did not show
`any effect on re-bleeding, surgery or death.10 A more
`recent similarly designed trial, while being given a
`more positive interpretation by its authors, essentially
`showed the same results as the one previously conduct-
`ed.11 However, a Cochrane review of six relevant trials
`involving 2223 patients favours the former interpreta-
`tion, that is, an improvement in the appearance of the
`bleeding lesion and a reduction in endoscopic inter-
`vention, but no impact on clinically meaningful end
`points.12 Thus, while the notion of giving PPIs early
`in the presentation of unselected bleeders is appeal-
`ing, there is no evidence to justify its adoption. Indeed
`a recent international consensus has supported endo-
`scopic methods rather than pre-endoscopy PPIs as cen-
`tral to the achievement of haemostasis.13
`
`Use of PPIs for patients on non-steroidal
`anti-infl ammatory drugs
`A wide range of studies have shown that PPIs are
`effective in preventing non-steroidal anti-inflamma-
`tory drug (NSAID)-associated endoscopic ulcers and
`ulcer bleeding.14 15 16 In contrast to cyclo-oxygenase-2
`(COX-2) inhibitors, no outcome studies have been
`performed to evaluate directly their ability to pre-
`vent NSAID-related ulcer complications in unselected
`populations, but indirect analyses suggest benefits.14
`Consequently, several meta-analyses have concluded
`that they are likely to be beneficial in this respect. As
`generic PPIs such as omeprazole have become cheaper,
`their use has become highly cost-effective for users of
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`both NSAIDs and COX-2 inhibitors. This has led the
`National Collaborating Centre for Chronic Conditions
`on behalf of the National Institute for Health and
`Clinical Excellence and the Royal College of Physicians
`to advise that all patients taking an NSAID or a COX-2
`inhibitor should be given a PPI.14 Indeed, in the high-
`est risk patients, those who have already experienced
`a life-threatening gastric ulcer bleed, subsequent use
`of both a COX-2 inhibitor and a PPI was remarkably
`associated with no recurrent events at all.17 In fact,
`fewer than a quarter of NSAID patients are on PPIs,
`and this is a prime example of an area where older
`messages are wrong, where pharmacy advisers should
`mount educational initiatives and where prescribers
`could make a major improvement in the safety of pre-
`scribing to their patients.18
`
`Combination pills
`VIMOVO is a novel combination of esomeprazole and
`naproxen and is likely to be launched in the UK during
`2011.19 The preparation uses non-enteric coated esome-
`prazole around enteric-coated naproxen. Impressively—
`and surprisingly, in view of the instability of PPIs in
`gastric acid1—a clinical trial has shown a reduction
`from 23% to 9% in the proportion of patients develop-
`ing NSAID-associated gastric ulcers on VIMOVO com-
`pared with similar doses of naproxen alone.10 Axorid
`is a preparation of ketoprofen and omeprazole, which
`is already available in the UK. Initially, it was rejected
`by the Scottish Medicine Consortium on economic
`grounds (although this decision was reversed follow-
`ing a resubmission by the manufacturers20). Similarly,
`when VIMOVO is launched, the issue will be whether
`the increased PPI adherence achieved by incorporation
`into a single pill justifies its price premium.
`
`Use of PPIs in patients using aspirin
`Some studies suggest that Helicobacter pylori eradica-
`tion is sufficient to protect patients on aspirin from ulcer
`complications,16 but the evidence is not good enough to
`be sure of this strategy. In patients taking aspirin, PPIs
`inhibit the development of ulcers and the recurrence of
`ulcer complications.21 22 As with NSAIDs, PPI prophy-
`laxis has been analysed as cost-effective in unselected
`patients on aspirin.23 Such a precautionary approach is
`also wise given that some studies suggest cardiovascular
`disease may be a risk factor for ulcer complications.24
`As with NSAIDs, educational initiatives are needed
`to achieve an easy cost-effective improvement in the
`safety of aspirin prescribing. However, there may be
`problems in patients who also take clopidogrel.25
`
`Do PPIs inhibit the effects of clopidogrel?
`Clopidogrel is a pro-drug, requiring biotransforma-
`tion via the CYP2C19 pathway to become active.
`PPIs, particularly omeprazole, are degraded through
`this pathway and can compete to reduce the activation
`of clopidogrel.25 Whether these interactions are func-
`tionally or clinically significant remains controversial,
`
`REVIEW
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`but there are enough data for some conclusions to be
`drawn.
`Using vasodilator-stimulated phosphoprotein as an
`index of platelet reactivity, several placebo control-
`led studies have shown that omeprazole reduces the
`response to clopidogrel, making a potential clinical
`interaction biologically plausible.25 There are fewer
`data for other PPIs, but they appear to show less effect
`for pantoprazole.26 A number of non-randomised
`descriptive clinical studies have shown that patients
`taking PPIs (principally the most widely used ome-
`prazole) who are taking clopidogrel have an increased
`incidence of cardiovascular events.27 28 In most of
`these studies, those on PPIs can be shown to or are
`likely to have higher cardiovascular risk factors, lead-
`ing many authorities to conclude that the association
`arises through confounding.29 Where groups are better
`balanced, the evidence for a clinical interaction dimin-
`ishes sharply.30–36 Moreover, in COGENT (Clopidogrel
`and the Optimization of Gastrointestinal Events) trial,
`a large randomised controlled clinical trial compar-
`ing a clopidogrel/omeprazole combination pill with
`clopidogrel alone, there was no difference in the inci-
`dence of cardiovascular death and myocardial infarc-
`tion between the two groups (HR for omeprazole
`0.99, 95% CI 0.68 to 1.44).37 By contrast, omepra-
`zole significantly reduced gastrointestinal events (HR
`0.34, 95% CI 0.18 to 0.63), suggesting substantial net
`benefit. This study was halted early due to sponsor
`bankruptcy, but this is unlikely to have influenced the
`results, beyond a relatively wide CI.
`
`What should the prescriber do?
`The COGENT study has not supported the hypoth-
`esis that omeprazole has a clinically significant effect
`on the activity of clopidogrel, while there was a clear-
`cut reduction in gastrointestinal events (figure 1). It
`seems that concerns over the effect of PPIs on clopi-
`dogrel may have been a storm in a teacup that should
`not detract from the recognition of their net bene-
`fit. Nevertheless, the COGENT study was not large
`enough to exclude anything less than a 44% increase
`in vascular end points with omeprazole. Where there
`are persisting concerns, pantoprazole 40 mg (the near-
`est bioequivalent to omeprazole 20 mg) could, on a
`theoretical and precautionary basis, be used instead.
`
`Adverse effects of PPIs
`In some ways, it was surprising how readily PPIs dis-
`placed H2 antagonists. Although their key feature was
`their greater efficacy, they are less effective in the short
`term for sporadic relief of dyspepsia because degrada-
`tion by acid during the first few days of treatment makes
`them relatively ineffective during this time. In addition,
`they have a higher incidence of adverse effects, includ-
`ing headache, rash and diarrhoea (whether because of
`microscopic colitis, frank infection or by other mecha-
`nisms). However, recent data suggest that PPIs may
`have a more extended toxicity profile.
`
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`Figure 1 Clopidogrel and omeprazole. Reproduced with permission from Bhatt et al.37
`
`Figure 2
`Infl uence of proton pump inhibitors (PPIs) on iron absorption. (A) Need for venesection in haemochromatosis patients
`before (closed bar) and during PPI therapy (open bar). (B) Reduced serum iron levels after an iron-containing meal off (closed points)
`and on a PPI (open points). Reproduced with permission from Hutchinson et al.43
`
`Osteoporosis
`Two epidemiological studies have identified an asso-
`ciation between PPI prescription and the development
`of hip fracture and fractures overall. The adjusted
`OR for hip fracture ranges between 1.22 and 1.5938
`and between 1.1 and 1.4 for overall fracture risk.39
`What is not clear is whether this observed association
`is causal or consequential. In favour of a causal rela-
`tionship, acid suppression has been shown to reduce
`the absorption of mineral calcium in the diet.40 41 PPIs
`can also inhibit magnesium absorption, resulting in
`hypomagnesaemia menia, which may then impede
`magnesium-dependent secretion of parathormone and
`result in hypocalcaemia.42 However, PPIs also inhibit
`osteoplastic activity thereby impeding bone absorp-
`tion and therefore have a theoretical potential even
`to protect against osteoporosis. A non-causal relation-
`ship is also possible: patients in poorer general health
`and therefore more prone to osteoporosis may well
`
`have PPIs prescribed. This is at present an unresolved
`issue.
`
`Iron defi ciency
`There are published case studies of iron malabsorption
`secondary to PPI use in iron-deficient people, probably
`due to the inability to oxidise iron from the ferrous to
`the absorbable ferric state (figure 2A). This is prob-
`ably analogous to the situation in atrophic gastritis and
`loss of stomach acidity through infection with H pylori
`leading to iron deficiency. There is also evidence to
`suggest that PPIs can reduce the need for venesection
`in those with haemochromatosis43 (figure 2B). There
`is, however, no evidence to suggest that even long-
`term use of PPIs can lead to an iron deficiency in an
`otherwise normal individual.
`
`Vitamin B12 defi ciency
`Gastric acidity is necessary to activate pepsinogen to
`pepsin in order to release vitamin B12 from binding
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`Figure 3 Rising Clostridium diffi cile infection rates despite falling antibiotic prescription but increasing proton pump inhibitor
`usage. Reproduced with permission from Dial et al.51
`
`proteins. Acid suppression with therapeutic doses of
`PPI has been shown to reduce the absorption of vitamin
`44 and to lead to the food-cobalamin malabsorption
`B12
`syndrome.45 With long-term use, there is a significant
`downward trend in vitamin B12 levels on those taking
`PPIs for 3 years or more.46 47 In Zollinger–Ellison syn-
`drome patients who require longer term high-dose PPI
`treatment, more profound reduction in B12 levels has
`been identified.48 Monitoring would be wise in these
`individuals.
`
`Cancer
`Use of PPIs is associated with an increased incidence
`of gastric cancer.49 The most prevalent view is that this
`arises by confounding rather than because PPIs cause
`cancer. Most cancers found in patients taking PPIs
`occur within 1 year of their commencement.
`With longer term use, the possibility of a causal rela-
`tionship cannot be entirely excluded, particularly since
`hypergastrinaemia and accelerated gastric atrophy
`could provide a mechanistic link. The possibility that
`long-term use of PPIs could increase the risk of gastric
`cancer cannot be dismissed, but a major effect seems
`unlikely on current evidence.
`
`Enteric infections
`Since the major physiological role of acid in the stom-
`ach is to sterilise food prior to delivery to the small
`intestine, it is to be expected that acid suppression will
`increase the risk of enteric infection. Early studies have
`shown an association between PPI use and Salmonella
`and Campylobacter infection.50 Recently, a similar
`relationship has been found for Clostridium difficile
`infection and pseudomembranous colitis,51 52 with C
`difficile infection rates rising in the face of declin-
`ing antibiotic prescription but increasing use of PPIs
`(see figure 3). While there is debate about whether
`the relationship is causal or arises by confounding, it
`seems highly likely that it is a truly causal relationship.
`
`It has not been shown that acidic conditions found
`in the stomach reduce C difficile spore survival, but
`it has been postulated that the effect is on the bacilli
`in their vegetative state following germination in the
`stomach.
`
`PPIs and eosinophilic oesophagitis
`The increased recognition of eosinophilic oesophagi-
`tis in children and, to a growing extent, in adults
`has led to the recognition of a continuum between
`reflux oesophagitis through eosinophil-predominant
`oesophagitis to full-blown eosinophilic oesophagitis.
`Idiopathic eosinophilic oesophagitis is thought to arise
`by an allergic mechanism. It has been proposed that
`use of PPIs also leads to at least a forme fruste of the
`syndrome as a result of impaired initial digestion of
`food proteins secondary to acid inhibition and reduced
`pepsin activation,53 but more research is needed.
`
`Microscopic colitis
`Although the formal evidence is relatively limited,
`most gastroenterologists clinically detect an associa-
`tion between PPIs, perhaps particularly lansoprazole,
`and microscopic colitis. A recent retrospective case-
`controlled study has suggested that PPI use was signifi-
`cantly higher in patients with collagenous colitis than
`in controls (38% vs 13%).54
`
`Conclusion
`Now that price has ceased to be an issue, the advan-
`tages and limitations of PPIs are easier to assess.
`Within the current landscape, they are grossly under-
`used in patients taking aspirin or NSAIDs. Conversely,
`the recognition of new or potential adverse effects
`emphasises the fact that no drug comes medically
`cost free. But generic PPIs now come at an economic
`cost that is close to free, establishing a context that
`shows them to be widely underused. In particular, all
`patients taking NSAIDs or aspirin should be given a
`
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`PPI co-prescription. For those also taking clopidogrel,
`it would be sensible to use pantoprazole as prophy-
`laxis. Prescribers are not used to being urged to use
`more of drugs like PPIs, but they need to adjust to the
`new circumstances and use much more liberally drugs
`that will achieve net financial saving for the NHS and
`save many lives.
`
`Acknowledgements Pauline Stapleton of the
`Nottingham Digestive Diseases Centre
`for invaluable clerical assistance.
`Competing interests None.
`Provenance and peer review Commissioned;
`internally peer reviewed.
`
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