Proton Pump Inhibitors

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Proton Pump Inhibitors or PPIs are commonly used to treat many Digestive System disorders. Research this class of drugs.

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  • Trade and generic names of these drugs, what disease(s) they treat and how they treat them (mechanism of action).
  • What are the possible side effects and are they safe in pregnancy?
  • Is it safe to take these drugs without a prescription?
  • For how long?

Include a title page and 2-3 references. Only one reference can be from the Internet (not Wikipedia). The other references must be from the Grantham University online library. Please adhere to the Publica-tion Manual of the American Psychological Association (APA), (6th edition, 2nd printing) when writing and submitting assignments and papers.

Proton Pump Inhibitors
Pharmacology Proton pump inhibitors: use, action and prescribing rationale Anila Anwar Abstract Proton pump inhibitors (PPIs) are a group of drugs that work by inhibiting the K+/iH+- adenosine tripinosphatase (ATPase) system, also known as the proton pump, in the gastric parietal ceii wali. They therefore efficiently reduce hydrochloric (HCI) acid secretion in the stomach. PPIs are used as the treatment of choice for gastro-oesophageai reflux disease, peptic uicer disease, non-steroidal anti-inflammatory drug- associated uicers, Helicobacter pylori eradication and excess acid secretion in Zollinger-Eiiison syndrome. They are also used as a short term therapy to treat intermittent gastric acid reflux when antacids and H2 receptor antagonists have proven to be ineffective. Their use, however, must be monitored to prevent secondary disease such as Clostridium difficile-assoaated diarrhoea and rebound excess gastric acid secretion (irritable bowel syndrome). T he human stomach secretes approximately 2.5 litres of gastric juice daily. The principal exocrine secretions being pepsinogens, hydrochloric acid (HCl), bicarbonate ions {HC03′), intrinsic factor, and mucus. Intrinsic factor, which is necessary for the absorption of vitamin-B12, and HCl are secreted from parietal cells and pepsinogens from peptic (chief) cells lining the stomach, which aid digestion. Mucus and bicarbonate form a gel-like layer to protect the mucosal cells from the gastric juice. The bicarbonate ions create a gradient pH from 1-2 in the lumen to a pH of 6-7 at the mucosal surface. Gastric juices and secretory functions Gastric juice is a hyperosmotic (325 mOsmoI/1) solution, containing 10 mM [K^], [H”^] 170 niM and [CV] 180 mM with an approximate pH of 1, forming a million-fold gradient of H+ across the gastric mucosa than in blood plasma. Pepsinogen is stored in granules of the peptic cell and exocytosis releases pepsinogen into the gastric juice, where it is cleaved into pepsin, if HCl is present. Pepsin is the major hydrolytic enzyme in the stomach, but it is only active in the acidic gastric juice. The HCl activates pepsinogen, maintains the optimal pH for pepsin activity and denatures proteins. Parietal cells regulate acid secretion (Figure I). The main stimuli that act on parietal cells to induce acid production are the neurotransmitter, acetylcholine, and the hormones gastrin and histamine. H2 receptors are located on the parietal cells and consequently histamine stimulates HCl secretion in the stomach lumen. In this way, H2 receptor antagonists such as cimetidine and ranitidine, act by preventing histamine from binding to the H2 receptors of the basolateral membrane of the parietal cells, thus reducing acid secretion. Locally Anila Anwar is a Semor Lecturer in pharmacy practice at De Montfort University, Leicester. Email: [email protected] 26 Nurse Prescribing 2008 Voi 6 No 1 Pharmacology Plasma Proton pump inhibitor HCI Figure 1. Carbonic acid (H2C0^, formed from carbon dioxide and water, dissociates into hydrogen ion (H+J and bicarbonate ion (HCO^’) in a reaction catalysed by carbonic anhydrase. The bicarbonate ion is exchanged across the basal membrane for a chloride ion (CI’) to within the parietal cell. This, alongside K*’ is then transported into the gut lumen whereby K^ is transported back within the parietal cell in exchange for H^ via the proton pump, K+ H*-ATPase, thus secreting HCI to aid digestion. Excessive HCI secretion or build up can lead to reflux into the oesophagus causing heartburn and/or ulceration. In this instance drugs that block the K’^/H^-ATPase system, known as proton pump inhibitors, prevent HCI secretion.. produced prostaglandins inhibit acid secretion and stimulate the secretion of both mucus and bicarbonate and hence are thought to be cytoprotective. Disturbances in secretory functions Disturbances in the secretory functions are thought to be involved in the pathogenesis of severai disorders such as gastritis, peptic ulcer disease and gastro- oesophageal reflux disease. Consequently, a potent group of drugs known as proton pump inhibitors (PPI) have been developed which inhibit the H^/K^^-ATPase system, thus suppressing acid secretion from the parietal cell. PPIs available include {with generic brand name): • l.ansoprazole (Zoton) • l-,someprazole (Nexium) • Omeprazole (Losec) • Pantoprazoie (Protium) • Rabeprazole (Pariet). Most are only available on prescription, except for omeprazole 10 mg which is now available over the counter in pharmacies as Zanprol. When there is retlux of gastric contents into the oesophagus owing to incomplete closure of the lower oesophageal sphincter (LOS) between the stomach and the oesophagus, symptoms of heartburn, inflammation (gastritis), erosion of the mucosa and bleeding may occur. This is also known as gastro-oesophageal reflux disease (GORD). The patient will often complain of heartburn which, if left chronically untreated, can lead to oesophageal stricture, which is usually treated by surgery Although chronic heartburn is the most common symptom of GORD, other symptoms may also be experienced: • Belching • Chronic sore throat • Difficulty or pain when swallowing • Excess of saliva (known as waterbrash) • Hoarseness • Sour taste in mouth • Bad breath • Inflammation of the gums • Erosion of tooth enamel • Persistent cough. Acute gastritis Acute gastritis is normally erosive and forms a local peptic ulcer. Drugs such as corticosteroids and NSAIDs, Nurse Prescribing 2008 Vol 6 No 1 27 Pharmacology effective anti-inflammatory pain killers which also inhibit the protective prostaglanciin synthesis in the gut lumen (Walt, 1992), and infections such as Helicobacter pylori {H. pylori) bacteria (Blaser, 1998) are contributory to duodenal and peptic ulcers. Chronic gastritis is most commonly caused by H. pylori and need to be treated with a course of antibacterials. Although not fully understood, H. pylori infection provokes excess acid production and destroys the protective mucus and bicarbonate layer. Peptic ulcer disease may present with or without H. pylori. Symptoms include epigastric pain following a meal and at night. Other risk factors for peptic ulcer disease are: • Zollinger-Ellisons syndrome (a gastrin producing tumour) • Increased parietal cells • Increased pepsinogen excretion from chief cells • Damage to the mucosal layer by bile or alcohol. In addition to treatment with a course of antibacterials for one week, drugs that act to reduce acid secretion are also used. Usually these are PPIs, and in some cases H2 receptor antagonists {Table 1). Although PPIs inhibit gastric acid secretion, there is no inhibition of gastrin, which subsequently increases blood gastrin levels. Long-term treatment with acid suppressing agents such as H2 antagonists and PPIs can lead to mucosal hypertrophy and a rebound rise in acid production. Hence, it is most beneficial to use Coloured X-ray of peptic ulcer (CNRI/SPL). Table 1- Helicobacter pylori treatment regimens Acid suppressing agent Lanzoprazole 30 mg twice daily Omeprazole 20 mg twice daily Esomeprazole 20 mg twice daily Pantoprazole 40 mg twice daily Rabeprazote 20 mg twice daily Anttbacterial aqent Amoxicillin 1 g twice daily 1 g twice daily 1 g twice daily 500 mg 3 times daily 1 g twice daily 1 g twice daily 1 g twice daily Clarithromycin 500 mg twice daily 250 mq twice daily 500 mg twice daily 400 mg 3 times daily 250 mq twice daily 500 mg twice daily 250 mq twice daily 500 mg twice daily 500 mq twice daily 500 mg twice daily 250 mq twice daily Metronidazole 400 mg twice daily 400 mq twice daily 400 mq twice daily 400 mq twice daily 400 mq twice daily 400 mq twice daily Ranitidine bismuth 1 g twice daily 500 mg twice daily citrate 1 g twice daily 400 mg twice daily 250 mg twice daily From: Joint Formulary Committee, 2007. 400 mg twice daily 400 mg twice daily 28 Nurse Prescribing 2008 Vol 6 No 1 Pharmacology i’lMs intermittently and to eliminate the cause of acid secretion in the first place. In addition, PPI’s could mask the symptoms of gastric cancer and consequently patients presenting with unexplained weight loss, bleeding, dysphagia and recurrent vomiting should be investigated further before commencing or continuing PPI therapy. NICE guidance Ihe National Institute for Health and Clinical Excellence (NICE) has guidance for health professionals on the management of dyspepsia in adults in primary care (NICE, 2004). In general, patients with ongoing, intermittent dyspepsia should be maintained on the lowest effective dose of PPI and reviewed at least annually to justify its ongoing use and where possible, maintained on over-the-counter antacids, containing aluminiuim or magnesium compounds and/or with alginate preparations such as Gaviscon. Lifestyle advice such as weight reduction, avoiding excess alcohol and fatty foods, raising the upper body while sleeping and smoking cessation must also be given to maintain remission. H2 receptor antagonists relieve acid reflux symptoms by preventing histamine binding to its H2 receptors on the parietal cell, consequently reducing acid secretion. However, most H2 receptor antagonists have a half-life of approximately 3 hours, and therefore do not provide effective nocturnal acid suppression. PPIs on the other hand provide more effective relief of excess gastric acid since these drugs accumulate within the parietal cell giving an ostensible half-life of 48 hours. Gastro-oesophageai reflux disease Patients suflering from CORD should be offered a full dose PPI for 1-2 months. For those patients with peptic ulcer disease, the patient should be tested for H. pylori using either a carbon-I3 urea breath test or a stool antigen test. If a patient has commenced on PPI tberapy or taken an over-the-counter preparation, then a 2-week wash-out period must be observed before H. pylori testing to avoid a false result. If a positive result is found, eradication should be offered with a full dose PPI and a combination of antibacterials; metronidazole 400 mg and clarithromycin 250 mg or amoxicillin I g and ciarithromycin 500 mg, twice daily for a one week course {Table I). In those patients with an NSAID-induced peptic ulcer, the NSAID should be withdrawn and a full dose PPI recommended for 2 months. If NSAID use is imperative then a prostaglandin analogue, such as misoprostol, or a concomitant acid suppressive agent such as a H2 receptor antagonist or PPI should also be prescribed. The dose of a PPI should not normally be reduced in those patients continued on NSAID therapy who have suffered from a peptic ulcer in the past. This is to prevent asymptomatic deterioration of the Coloured TEM o/Clostridium difficile (Dr Kari Lounatmaa/SPL). ulcer occurring. Clostridium difficile and the use of PPIs With the rise in Clostridium difficile {C difficile) cases in UK hospitals and the community, there is increasing speculation that increased use of PPIs and H2 receptor antagonists play a contributory role (Dial et al, 2005; Jayatilaka et al, 2007). Inhibition of gastric acid secretion in the stomach may predispose the patient to C. difficile-associated diarrhoea because of increased bacterial colonization. In a retrospective study, drug histories were examined in 126 elderly patients admitted to an acute medical hospital ward with C. (//^”ti/£?-positive diarrhoea and 126 C. difficile-negative diarrhoeal patients were used as control during 1995-1996. The study found that there was no significant difference in the use of PPIs and H2 receptor antagonists between both groups, suggesting this was not a contributing factor to C difficile diarrhoea (Shah et al, 2000). However, more recent studies have shown that there is a direct casual link of C. rfi^ci/e-associated diarrhoea and tbe use of PPI. A 5-year study between 2001 and 2005 in hospitahzed patients investigated the use of Nurse Prescribing 2008 Vol 6 No 1 29 Pharmacology PPI and H2 receptor antagonists and the incidence of C di^cile diarrhoea. They found a direct correlation with PPI use and C. difficile diarrhoea, but not with H2 receptor antagonists (Jayatilaka et al, 2007). The same was found for use of PPI in the community (Dial et al, 2005). It is for this reason that PPIs would have continued to be prescribed in the past, but it is now advisable to review PPI use and gauge a real need for its present use. Where possible, in cases of suspected C. difficile, all antibiotics must be stopped and the use of PPIs reviewed. Usually, PPIs must also be stopped or the dose changed to the lowest possible effective dose. The use of PPIs in pregnancy Heartburn is a common complication in pregnancy, thought to be because of increased progesterone levels (Richter, 2003). Progesterone usually relaxes the smooth muscles of the uterus; however, it also relaxes the lower oesophageal sphincter (LOS) between the stomach and the oesophagus, causing heartburn (Fisher et al, 1978). These symptoms are usually controlled with antacids and alginates initially, nonetheless these symptoms can be quite severe in some women during pregnancy, requiring stronger acid suppression therapy. Several studies investigating the use of the oldest PPI, omeprazole, have shown no significant fetal malformations, pre-term deliveries or other neo-natal health concerns compared with control groups (Nava-Ocampo et al, 2006). In fact, omeprazole is used in children and is the only PPI licensed for use in pregnancy if ranitidine is not effective. There is no published data on the use of rabeprazole or esomeprazole in pregnancy and the little data with the use of lansoprazole and pantoprazoie also showed no pattern of fetal anomalies in the babies born with malformations compared with the control group (Wilton et al, 1998; Diav-Citrin et al, 2005). Conclusions PPIs work to reduce excess acid secretion in the stomach. They should be used when drugs such as alginates and antacids have not provided effective relief and following advice on lifestyle changes. Treatment for H. pylori with a combination of antibacterials is for 1 week and for GORD or peptic ulcer disease it is 1-2 months. After this time, PPI use should be withdrawn or the patient maintained on the lowest effective dose of PPI, except for those patients maintained on NSAIDs. This is to reduce the incidence of C. difficile-associated diarrhoea from the over-use of PPIs, which contributes to increased morbidity and even mortality. It will also reduce the occurrence of rebound acid secretion on withdrawal of the PPI. Key Points ” Proton pump inhibitors (PPIs) inhibit the K+/H+-ATPase system thus reducing HCI secretion. “‘ They are used at fuli dose for 1-2 months to treat gastric and duodenal uicers and gastro-oesophageal reflux disease. • They are also used as a twice daily dose in the eradication of H. pylori when used in combination with antibacterials for 1 week. • They are used as short term treatment to treat dyspepsia and intermittent gastric acid reflux when other compounds such as alginates, antacids and H2 receptor antagonists have not been sufficient. • Overuse can cause C. d/ff/c/7e-associated diarrhoea. • Omeprazole is the only PPI licensed for use in children and in pregnancy. References Btaser M) (1998) Helicobacter pylori and gastric diseases. BMJ 316(7143): 1507-10 Dial S, Delaney JA, Barkun AN, Suissa S (2005) Use of gastric acid- suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 294(23): 2989-95 Diav-Citrin O, Arnon |, Shechtman S et al (2003) “Ihe safety ol prolcm pump inhibitors in pregnancy: A muKicentre prospective conlmlled study. Aliment Pharmacol Ther 21(3): 269-75 Fisher RS, Roberls GS. drabowski CI. Cohen S (1978) Altered lower esophageal sphincter function during early pregnancy Gastrocnterology 74(6): 1233-7. layatilaka S, Shakov R. Hddi R, Bakaj G, Baddoura W|, DeBari VA (2007) Ciostridium difficile infeclion in an urban medical center: Five-year analysis of infection rales among adull admissions and association with the use of prolon pump inhibitors. Ann Cliii iah Sn37(3):24i-7 Joint Formulary Committee (2007) British National Formulary 54. September, BMJ Publishing Group Ltd and RPS Publishing. London National Institute for Health and Clinical Excellence (2004) Dyspepsia: Management of dyspepsia in adults in primary care, ukynicemedia/pdf/CG017NlCKguideline.pdf (accessed 3 January 2007) Nava-Ocampo AA. Velazquez-Armenta FY. Han |Y, Koren (i (200(i) Use of proton pump inhibitors during pregnancy and breast ieeding. Can Fam Physician 52:853-4 Richter JE (2003) Gastroesophageal retlux disease during pregnancy Gaslroeiilerol Clin North Am 32( 1): 235-61 Shah S. Lewis A, Leopold D. Dunstan F, Woodhouse K (2000) Gastric acid suppression does not promote clostridial diarrhoea in the elderly. Q/M 93(3): 175-81 Walt RP (1992) Misoprostol for the treatment of peplic uicer and antiintlammatory-drug-iniiucedgastroduodenal ulceration. N EngI I Med 327(22): 1575-80 Wilton LV. Pearce GL, Martin RM. Mackay F], Mann RD (1998) The outcomes of pregnancy in women exposed to newly marketed drug.s in general practice in England. BrjObstet Gynaecol 105(8): 882-9 30 Nurse Prescribing 2008 Vol 6 No 1

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