Planificación y ejecución de la convivencia en el aula: código

Proton pump inhibitors (PPIs) are substituted benzimidazoles that irreversibly bind the H⁺- K⁺ ATPase, the final step in gastric acid secretion. They blocks the gastric H⁺/ K⁺ - adenosine triphosphatase (ATPase) via covalent binding to cysteine residues of the proton pump to inhibit gastric acid secretion and is the most potent type of acid suppressants nowadays.³⁹ Inhibition of H⁺/K⁺ - ATPase is more effective than antagonism of histamine type - 2 receptors in suppressing gastric acid secretion because H⁺/K⁺ - ATPase is the final step of acid secretion.³⁹

The common PPIs include omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole.⁷² Th newer PPIs have a more prolonged release of drug to effect longer serum concentration times and thereby extend the time of desired acid control.^120,121 They include Deslansoprazole (dual-delayed release formulation), extended release formulation of rabeprazole, and immediate release – omeprazole (IR-Ome, Pirsec^®).^120,121 Deslansoprazole’s formulation allows for absorption of active drug first in the duodenum and several hours later in the small intestine with 2 peaks in acid control at around 90 minutes and 4 to 5 hours after

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dosing.¹²¹ IR-OME offers the potential for rapid symptom relief because of the bicarbonate which itself activates the proton pumps such that this formulation eliminates the need for food to activate the pumps.^120,121 It allows for greater efficacy at bedtime.¹²¹

Proton pump inhibitors (PPIs) have revolutionized the treatment of GORD and there is a wealth of data supporting the current position of PPIs as the antisecretory drugs of choice in GORD patients. Better control of reflux disease symptoms was achieved over a four-to eight-week period in patients treated with PPIs (83%) than in those given H2RAs (60%) or placebo (27%).¹⁸ More so, 78% of patients with erosive oesophagitis have response to PPI treatment.¹²² Although H2RAs are less expensive than PPIs,PPIs are shown to be markedly more effective in symptom relief, healing of oesophagitis and significantly less likelihood for a relapse of symptoms.^5,32,41,42 The other PPIs (lansoprazole, rabeprazole, pantoprazole and esomeprazole) have a similar efficiency to omeprazole for controlling heartburn, healing rates, and relapse.^7,97,119 The decision to choose one over another should be based first on cost and second on individual patient response.⁴¹

2.8.1.1.2 Dosage and administration: PPIs are inactivated by exposure to gastric juice and are delivered in delayed-release gelation capsules containing enteric-coated granules (omeprazole and lansoprazole) or in delayed-release enteric-coated tablets rabeprazole and pantoprazole).^34,85 PPIs in general are best taken before the first meal of the day as food is a stimulus to activate the proton pumps.³⁴ Omeprazole, lansoprazole, esomeprazole and rabeprazole should be taken 30- to 60- minutes before breakfast.³⁴ In the case of optimizing PPI therapy in refractory GORD, a survey of 491 physicians found that nearly 70% of primary care physicians and 20% of gastroenterologists in the US advised patients to take the PPI dose at bedtime or did not believe that the relationship to meals was important.¹²³ Contrary to this practice, proper knowledge when given patients improves awareness on best time to take PPIs, before breakfast.¹²⁴ Pantoprazole may be taken without regard to meal.³⁴

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Omeprazole, lansoprazole, esomeprazole capsules should not be opened, chewed or crushed but swallowed whole. For patients who are unable to swallow, capsules may be opened and the granules sprinkled over a tablespoon of apple sauce, pudding, yogurt, or cottage cheese and the food must be swallowed immediately without stirring, crushing or chewing.³⁴

Standard daily doses for omeprazole depends on severity and condition being treated: 20mg daily (short-term sympotomatic GORD and active duodenal ulcer treatment); 20mg twice daily (in Helicobacter pylori eradication triple therapy); 40mg daily (short-term treatment of gastric ulcer, erosive oesophagitis, severe GORD).³⁴ Standard daily doses for lansoprazole is 30mg, pantoprazole 40mg, rabeprazole 20mg and esomeprazole 40mg.³⁴ Chey et al in a community-based study in US reported once a day PPI use in71.0% of patients, 22.2% used twice daily, and 6.8% more than twice a day or on an as-needed basis.¹²⁵ The timing of the PPI was however not considered. Approximately 42.1% of all patients supplemented their prescription PPIs with other GORD medications (over-the-counter medications and H2RAs).

Over 72.8% of the patients were satisfied or very satisfied with their PPI treatment.¹²⁵

GORD is a chronic-relapsing condition (high recurrence rate) because no currently available pharmacologic agent is available to correct the underlying cause or causes of the disease.

Approximately one-third of patients with GORD fail to response symptomatically to a standard dose PPI, either partially/incompletely or completely.¹²⁶ Around 70% of GORD patients may suffer from chronic or relapsing symptoms once medication is discontinued.⁵⁴ Without maintenance therapy, most patients with erosive GORD, especially those with the greatest disease severity, will experience relapse within 3 months.⁵⁶ Among patients with nonerosive oesophagitis but frequent heartburn, a symptom relapse rate of 75% was seen at 6 months.⁵⁶ Therefore, many persons require long-term management by either on demand or continuous acid suppressant therapy (medical treatment) or surgery.⁴² Maintenance therapy (on-demand or continous therapy) is recommended at the lowest effective dose in GORD

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patients who continue to have symptoms after PPI is discontinued and patients with complications including erosive oesophagitis and Barrett’s oesophagus.⁸⁵ A number of factors have been identified that suggest early recurrence: a hypotensive LOS, longstanding symptoms, the need for long-term treatment to achieve initial symptom relief and healing, oesophagitis having a high initial endoscopic grade, hiatal hernia, and the presence of persistent symptoms despite endoscopically documented oesophagitis healing.⁵⁶

The advantages of long-term medical treatment are that they are non-invasive, simple and easy to use, very effective on symptoms and lesions of GORD, are relatively cheap, excellent tolerance and safety profile of PPIs, and have reproducible effect.⁹³ The disadvantages of long-term medical treatment are that it does not correct underlying pathophysiological mechanisms, persistence of symptoms in at least 10% of patients, continuous maintenance therapy is frequently required to control the disease, rare side effects and potential drug-drug interactions.⁹³

Treatment options, such as histamine type-2 receptor antagonist, TLOSR reducers, prokinetic agents, and alginates, could be considered as an add-on to PPI therapy for symptomatic patients after taking PPI.⁸⁵

2.8.1.1.3 Metabolism: The CYP2C19 isoform of cytochrome p450 is the principal enzyme responsible for the metabolism of PPIs; the genotypes of which are classified into three groups: extensive metabolizer, intermediate metabolizer, and poor metabolizer.¹²⁷ The relative impact of the CYP2C19 pathway on the metabolism of PPIs has been reported to be mostly in omeprazole and esomeprazole followed by pantoprazole, lansoprazole, and the least with rabeprazole.¹²⁷ This would therefore affect the metabolic and pharmacokinetic profiles of PPIs. Recent studies have brought to light the important role that this polymorphism may play in the therapeutic effectiveness of PPIs in the treatment of GORD and its complications. Genetic polymorphisms of CYP2C19 shows marked interracial

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differences, with the poor metabolizer phenotype representing 2-5% of whites and up to 11-24% of Asian populations (Chinese 11-24%, Japanese 18%).¹²⁸ Kawamura et al investigated the healing rates in 88 erosive oesophagitis patients treated with lansoprazole 30 mg for 8 weeks and determined if the CYP2C19 genotype plays a role in healing rates. The healing rates of erosive oesophagitis were found to be significantly lower in extensive metabolizers (77%) than intermediate (95%) and poor (100%) metabolizers (P < 0.05).¹²⁹ The effect of CYP2C19 genotype on gastric acid secretion, oesophageal acid exposure, and symptom occurrence was studied in 60 GORD patients while on PPI treatment. While the genotype predicted the degree of gastric acid suppression, there was no association between the CYP2C19 genotype and oesophageal acid exposure or reflux symptoms.¹³⁰ In routine clinical practice, determining CYP2C19 genotype will unlikely predict the clinical efficacy of a PPI. The possibility of extensive metabolizer phenotype should be entertained only in a small group of patients with severe erosive oesophagitis, who are refractory to treatment.¹³⁰

2.8.1.1.4 Response to PPIs: In NERD patients, only 50 - 60% respond to PPI therapy (40%

reported for H2RAs)and approximately 20% - 30% have a significantly lower response rate than erosive oesophagitis patient documentation.^11,33 Research is expanding to understand the complex aetiology of NERD. Clinical experience shows that 20 - 30% of patients with GORD continue to have persistent reflux symptoms even while taking PPI daily and one quarter of patients (22%) report the use of additional over-the-counter therapies to aid in symptom control.^131,132 El-Serag et al in systematic review reported 30% - 60% of continued symptom report in patients treated with once daily PPI therapy.¹³³ The different groups of GORD, erosive oesophagitis, NERD, and Barrett’s oesophagus, have different response rates to PPI.³⁹ Putative mechanisms for failure of PPI treatment are complicated and multifactorial.

They include poor adherence, improper dosing time, weakly acidic reflux, duodenogastro-oesophageal reflux (DGOR), delayed gastric emptying, large hiatal hernia duodenogastro-oesophageal

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hypersensitivity, eosinophilic oesophagitis, nocturnal acid breakthrough, residual acid reflux, reduced PPI bioavailability (CYP2C19 polymorphism rapid PPI metabolism), and psychological co-morbidity (depression, anxiety, life stress).¹³⁴

2.8.1.1.5 Adherence to PPI prescriptions

Studies have found that adherence to PPI prescriptions is poor though increases with disease severity. In one study, PPI prescriptions were filled by only about 60% - 66% of patients, with less than 40% actually being adherent with prescription PPIs beyond 6 months of therapy.¹³⁵ El-Serag also reported an adherence rate of 60% in a large population study in US.¹³⁶

Gunaratnam et al reported optimal PPI dosing (before meals) in only 46% of 100 patients who were referred for persistent GORD symptoms despite treatment.¹³⁷ Firty-four percent dosed sub-optimally with 21 of 54 (39%) dosing more than 60 minutes before meals, 16 (30%) after meals, 15 (28%) at bedtime and 2 (4%) as needed. Only 6% of the patients on once-daily dosing dosed in a manner that maximized acid suppression (30 minutes before a meal). Primary care providers need to appropriately and fully discuss medication – related issues with their patients.

2.8.1.1.6 Issues related to proton pump inhibitor therapy 2.8.1.1.6.1 On treatment with PPI and refluxate characteristics

Boeckxstaens and Smout reported that in patients with GORD taking PPI, 80% (76-84%) of reflux episodes were weakly acidic (pH 4 - 7) or alkaline (pH > 7) and both were associated with 83% (78-88%) of reflux symptom episodes.¹³⁸ In patients with GORD not taking a PPI, 63% (59-67%) of reflux episodes were acidic and 72% (57-87%) of reflux symptom episodes were associated with acidic reflux episodes. Weakly alkaline reflux accounted for < 5% of all reflux episodes both on and off PPI therapy.

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Nocturnal acid breakthrough (NAB) is defined as intragastric pH less than 4 for more than one hour during the night while patients are using twice daily proton pump inhibitor (PPI) therapy.⁹² Approximately 70% of patients with GORD have been shown to have NAB and associated nocturnal reflux, including asymptomatic patients on medical therapy.⁹² It was reported to have occurred in about two-thirds of patients with GORD and normal volunteers treated with omeprazole.⁸⁵ This decrease in intragastric pH occurs approximately between 1am and 2am when oesophageal acid exposure is common and potentially injurious for the oesophageal mucosa because of delayed oesophageal clearance during the night.⁸⁵ Patients with erosive oesophagitis and/or BE are more likely to exhibit NAB on twice daily PPI therapy.⁹² Helicobacter pylori eradication increases this nocturnal acid breakthrough. PPI therapy, when administered before dinner and H2RA therapy administered before bedtime have been shown to be effective in the reduction of NAB.^85,92

2.8.1.1.6.3 Inadequate GORD symptom control

Despite the clinical success of PPIs in treating GORD, for the majority of patients in both gastroenterology and primary care clinics, there is still a substantial subgroup (30 - 40%) who do not completely respond symptomatically to a once or twice daily dosing of PPI therapy after a standard 8-week course.^85,139 The severity of GORD is directly correlated with the degree and duration of oesophageal exposure to acid refluxate and healing of erosive oesophagitis has been directly correlated with the amount of time intragastric pH is > 4.¹⁴⁰ This emphasizes the need for better therapies for controlling regurgitation for patients with any significant volume of regurgitation and the consideration of the newer therapeutic strategies in development, the reflux inhibitors lesogaberan and arbaclofen.¹⁴¹ The possibilities for inadequate control of GORD symptoms despite taking a PPI include incomplete acid control, acid hypersecretion, Helicobacter pylori negative, alternate

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GORD diagnosis (like pill-induced oesophagitis, eosinophilic oesophagitis and irritable bowel syndrome). ¹³¹ Other reasons are as for those mentioned for PPI failure under response to PPI above.

2.8.1.1.7 Side effects with PPI therapy

Proton pump inhibitors are generally well tolerated but there are reports of minor side effects

such as headache, diarrhoea, and abdominal pain in about 1– 4% of patients. These resolve when the treatment is discontinued.¹⁴² Over the short term, PPIs are safe.¹⁴²

The long-term safety of PPIs is not completely understood, however, clinical effects always should be reviewed. Some safety issues like osteoporosis, fracture and Clostridium deficile infection have been raised in epidemiologic studies. Epidemiologic data are useful in looking for associations, which of course, should not be confused with causality.³⁹