The patient was a female, age 89, with a BMI of 15.4 kg/m2 (underweight). Her presenting complaint was nausea and vomiting, bringing up coffee ground vomit, fatigue and loss of appetite since two days ago. Her past medical history included atrial fibrillation, paranoid psychosis and iron deficiency anaemia. She also had a cholestectomy done in year 2000. She was single and lived alone; she neither smoked nor drank. There was no relevant family history recorded for her case. On admission she was taking medication stated in Table 1 below. She was known to be allergic to ciprofloxacin.
Table 1 Repeat medication taken on admission
125 µg once daily
2.5 mg once in the morning
40 mg once daily
75 mg once daily
125 mg twice daily
100 mg twice daily
60 mg one to be taken as required
500 mg four times daily
5 mg once daily
322 mg twice daily (Last prescription dated three months ago)
Clinical data and diagnosis
On admission, her temperature was 36.4°C, pulse was 83 beats per minute, and her blood pressure was 124/46 mmHg. Her Abbreviated Mental Test (AMT) score was 7 out of 10, indicating mild confusion. A full blood count, renal function test, liver function test, and an electrocardiogram (ECG) were carried out. Her liver function test came back normal. The ECG showed some ST depression, but the patient denied any chest discomfort. Her haemoglobin levels were low at 9 g/dl (11.5-16.5 g/dl), while platelets were low at 108×109/l 150-400×109/l). her plasma urea was elevated at 38.2 mmol/l (2.5-7.5 mmol/l), and her creatinine was 273 µmol/l (50-80 µmol/l for female). Her creatinine clearance was calculated to be 8.1 ml/min, which indicated severe renal impairment. The diagnosis was acute renal failure, and gastritis or peptic ulcer disease.
On day 1, patient was dehydrated and had some upper abdominal discomfort (Dyspepsia). The plan was to stop tramadol, clopidogrel, lisinopril and furosemide, due to the coffee ground vomit and acute renal failure. Two units of RCC (Red cell concentrate) and IV fluids were given. A urinary catheter was used to monitor urine output. Patient was continued on ferrous fumarate and given gaviscon 10mls. Quetiapine fumarate was not given as it was not available.
On day 3, patient was paranoid; as quetiapine fumarate was still not available, haloperidol 1 mg was given as an intramuscular injection according to the hospital guidelines. Her haemoglobin levels were back to normal (12 g/dl) and her creatinine clearance improved to 33.3 ml/min; measurements were taken again because the values were so different. The catheter was taken out, but she was to receive subcutaneous fluids hourly. Patient was passing black stools. She was given Peptac 10mls for abdominal discomfort and was scheduled for an endoscopy the next day. Quetiapine fumarate was given on day 4 and patient was taken off haloperidol.
On day 6, the patient’s confusion was thought to be influenced by digoxin; levels were checked and found to be 1.1 µg/l (0.5-2.0 µg/l); however dose of digoxin was decreased to 62.5 µg. a rectum examination was conducted to make sure patient was not bleeding from the lower gastrointestinal tract. The gastroscopy report came back stating patient had grade D oesophagitis (Reflux oesophagitis), that is an extenxive mucosal breaks engaging at least 75% of oesophageal circumference. She was also found to have a large chronic duodenal ulcer, non-bleeding with visible vessels. The plan was to start the patient on IV proton-pump inhibitor (PPI, pantoprazole 8 mg/hr) for 72 hours, oral omeprazole 20 mg daily, and eradicate H. pylori if infection was present (CLO test).
On day 9, the CLO test came back negative. Patient was taken off IV PPI and put onto oral PPI (Omeprazole 40 mg daily). A repeat endoscopy was scheduled for the week after.
Oesophagitis is the inflammation of the lining of the oesophagus, usually caused by irritation due to stomach acid reflux.1,2 It is included under the boarder term of gastro-oesophageal reflux disease (GORD), which also includes endoscopy-negative reflux disease.3 In the UK, there is a 28.7% prevalence of GORD, and the risk is found to increase with age, especially for those over 40 years of age. There is an estimated of over 50% of GORD patients between 45 and 60 years of age.4 About 25 to 40% of people with GORD are found to have oesophagitis on endoscopy.5
Pathophysiology, risk and diagnosis
Acid reflux can occur because of incompetence of the lower oesophageal sphincter, a transient complete relaxation resulting from a failed swallow, that is, a swallow without the usual peristalsis wave (Found in 65% of patients). It can also be caused by a transient increase in intra-abdominal pressure (17% of patients), or a spontaneous free reflux due to the lower oesophageal sphincter having a low resting pressure (18% of patients).6
Possible risk factors for GORD are pregnancy, excess alcohol consumption, smoking and hiatus hernia. Obesity is thought to be a risk factor, as well as certain foods like onions, citrus fruits and coffee. Drugs that are thought to relax the lower oesophageal sphincter like calcium channel blockers are thought to play a role in promoting GORD. There is however very limited evidence to support these claims.4,5 It is now thought that more than 50% of GORD risk is genetic, as it is found that a first degree relative of a person with GORD is four times more at risk of getting the disease.4
Diagnosis of GORD is based mainly on the patients’ symptoms, predominantly acid regurgitation or heartburn.7 An endoscopy is usually the main diagnostic procedure done to confirm GORD.
Pharmacological treatments and mechanisms of action
The main drug used for this disease is a proton-pump inhibitor (PPI). PPIs are one of the most prescribed drugs for the treatment of acid-peptic diseases, including GORD and peptic ulcer disease.8,9 They are substituted 2-pyridyl methysulfinyl benzimidazoles, with pKa around 4, and have a very short plasma half life of one to two hours. They are weak bases that are lipophilic, which allows them to cross the membranes of the parietal cells easily. Once inside the parietal cells, where the pH value is less than 4, they protonate into the activated tetracyclic sulphenamide form of the drug and accumulate inside the cells. Here they form covalent bonds with the cysteine residues in the hydrogen/potassium adenosine triphosphatase (H+/K+ ATPase) enzymes, forming disulphide bonds, inhibiting the acid secretion activity of the pump irreversibly. Due to the covalent bonds, their duration of action exceeds their plasma half life. To resume acid production, the parietal cells must then generate, or activate, new proton pumps.8,9 Examples of PPIs are omeprazole, lansoprazole, pantoprazole, and rabeprazole, the last of which has a pKa of 5, and is activated at a broader range of pH compared to the other three, leading to a higher acid-suppression activity.
The common side-effects of PPIs are nausea, diarrhoea, abdominal pain and headache. Diarrhea seems to occur because of a change in the gut flora brought about by the PPI, and appears to be age-related.8 PPIs, especially omeprazole, are known to alter the activity of cytochrome P in the liver, an important consideration for patients taking drugs with narrow therapeutic windows like warfarin and phenytoin. They also cause a prominent gastric pH increase, and are able to inhibit or decrease the absorption of weak bases that require acid for absorption, like iron salts, griseofulvin, and vitamin B12.8
Other drugs that may be used in this case are H2 receptor antagonists, which inhibit the secretion of acid by stopping histamine from binding to the H2 receptors on the parietal cells; and prokinetic drugs, usual examples like cisapride, metoclopramide and domperidone, which work by increasing the pressure of the lower oesophageal sphincter, and accelerating gastric emptying.10
Evidence for treatment of the condition
The National Institute for Health and Clinical Excellence (NICE) guidelines state that, for the management of oesophagitis on endoscopy, patients are to be given full dose PPI for one to two months. If there is a response to the treatment, low dose PPI is given, probably on an as required basis. If there is no response, the dose of PPI is doubled for another month, before switching to low dose PPI. If there is no response to the doubled dose of PPI, treatment is then switched to a histamine H2 receptor antagonist or a prokinetic.11
Klinkenberg-Knol EC et al1 compared the effects of omeprazole and ranitidine in a randomised, double-blind, endoscopically-controlled trial done on patients with reflux oesophagitis. Omeprazole was given at a dose of 60 mg daily while ranitidine was given at 150 mg twice daily. The symptoms were evaluated before starting the trial, and at the second, fourth and eighth week. Endoscopy was done at the start of the trial, and repeated during week 4, with another after 8 weeks if there was an absence of healing at week 4. For patients taking omeprazole, 19 out of 25 patients improved from Grade 2 or 3 (erosions or ulcerations) to Grade 0 or 1 (erythema and friability)12 after 4 weeks; while for patients taking ranitidine 7 out of 26 showed similar improvement (P = 0.002). At week 8, corresponding improvement was shown in 22 out of 25 for the omeprazole group, and 10 out of 26 for the ranitidine group (P = 0.001). Omeprazole showed a significantly higher healing rate, which was reflected in a better improvement of reflux symptoms as well. Patients receiving omeprazole experienced a more profound and faster relief of heartburn, which was the most common symptom complained by the patients (P = 0.0001). After 2 weeks, 92% (23 out of 25 patients) of patients receiving omeprazole reported that their reflux symptoms were either gone or had improved, while only 65 % (17 out of 26) of the ranitidine group reported the same (P = 0.01). This study however, only showed the superiority of omeprazole over ranitidine in the short term treatment of reflux oesophagitis. Further studies were needed to evaluate the effects of omeprazole in long term management and at a lower dose.
Havelund T et al12 performed a double blind study on patients with Grade 1, 2 and 3 reflux oesophagitis. Patients were allocated randomly in this study to a treatment with omeprazole (40 mg once daily), and ranitidine (150 twice daily), for a period of 12 weeks. It was found that patients treated with omeprazole had a faster response to the treatment than those taking ranitidine (P < 0.0001). For the omeprazole group, healing rates were reported at 4, 8 and 12 weeks to be 90%, 100% and 100% respectively for those with Grade 1 reflux oesophagitis. For Grade 2 and 3, corresponding healing rates were 70%, 85% amd 91%. While for the ranitidine group, healing rates were 55%, 79% and 88% for Grade 1, and 26%, 44% and 54% for Grade 2 and 3. This pointed to a superiority of omeprazole at a lower dose (40 mg) over ranitidine. Sandmark S et al13 did a similar study, but with an omeprazole dose of 20 mg daily. Healing of oesophagitis was targeted in this study to be a complete healing of all ulcerative and erosive lesions in the oesophagus. At 4 weeks, healing rates were shown to be 67% in the patients taking omeprazole and 31% in those taking ranitidine (P < 0.0001). Corresponding healing rates were 85% (Omeprazole group) and 50% (Ranitidine group) after 8 weeks (P < 0.0001). This was also reflected in a more profound – and faster- improvement in reflux symptoms in the patients taking omeprazole (51% by the end of the first week compared to 27% for patients taking ranitidine).
Robinson M et al14 conducted a study to compare, in patients with erosive oesophagitis the efficacy and tolerability of omeprazole at a dose of 20 mg daily to ranitidine at a dose of 150 mg twice daily together with a prokinetic drug metoclopramide at a dose of 10 mg four times daily. It was found that healing rates for omeprazole were significantly greater than that for ranitidine in combination with metoclopramide. Omeprazole also provided a more profound relief for patients with reflux symptoms. More side effects and treatment-related withdrawals were found among the patients allocated the ranitidine-metoclopramide combination. Omeprazole was thus found to be more effective and better tolerated. Iskedjian M and Einarson TR conducted a meta-analysis15 of the three drugs cisapride, omeprazole and ranitidine for GORD treatment. At 12 weeks, 95% of patients were cured in the omeprazole group (40 mg daily), 81% in the ranitidine group (600 mg daily), and approximately 60% in the cisapride group (40 mg daily). In mild GORD, healing rate was 56% for cisapride versus 38% for ranitidine, while healing rates for cisapride and omeprazole showed no significant difference. In severe GORD, the healing rate for cisapride was only a half of that of omeprazole (43% versus 87%), while showing no significant difference when compared to that of ranitidine (50%). Thus it was concluded that omeprazole is favoured for treating severe GORD, while cisapride may be that of mild GORD.
Vigneri S et al16 compared 5 maintenance therapies after an initial treatment of omeprazole 40 mg daily for 1 to 2 months, and healing was confirmed by endoscopy. Patients were then randomly assigned 12 months of treatment in the 5 following groups: cisapride (10 mg three times daily), ranitidine (150 mg three times daily), omeprazole (20 mg daily), ranitidine and cisapride, or omeprazole and cisapride. At 12 months 54% of the cisapride group, 49% of the ranitidine group, 80% of the omeprazole group, 66% of the ranitidine-cisapride group, and 89% of the omeprazole-cisapride group were found to be in remission at 12 months of maintenance therapy. Omeprazole showed a significantly better efficacy than cisapride (P = 0.02), and ranitidine (P = 0.003). Ranitidine-cisapride combination therapy was found to show a more profound improvement than ranitidine alone (P = 0.05). Omeprazole-cisapride combination therapy showed better efficacy than cisapride (P = 0.003), ranitidine (P < 0.001), and also ranitidine and cisapride combination therapy (P = 0.03). Omeprazole as monotherapy or in combination with cisapride is found to be more effective for maintenance therapy of reflux oesophagitis, compared to ranitidine or cisapride alone. Omeprazole in combination with cisapride shows more efficacy than ranitidine and cisapride.
The effects of newer PPIs lansoprazole (30 mg daily), rabeprazole (20 mg daily) and pantoprazole (40 mg daily) were compared with that of omeprazole (20 mg daily), ranitidine (300mg daily) and placebo in randomised clinical trials brought together by Caro JJ et al.17 The healing rate ratios noted for the newer PPIs as well as omeprazole were as follow: lansoprazole 1.62; rabeprazole 1.36; pantoprazole 1.60; and omeprazole 1.58. There was a greater decrease in the heartburn symptoms in patients taking PPIs than those taking ranitidine (P < 0.002), as well as in the healing of ulcers (P < 0.05), and relapse (P < 0,01). Compared to placebo, the PPIs obtained a much more profound relief of reflux symptoms (P < 0.01), healing of ulcers (P < 0.001) and relapse (P < 0.006). From this study, it was found that there is not much difference between the newer PPIs and omeprazole when it comes to relief of reflux symptoms, ulcer healing and rate of relapse, while all PPIs are better than ranitidine and of course, placebo in terms of treatment for erosive oesophagitis.
Kahrilas PJ et al18 compared esomeprazole and omeprazole efficacies in reflux oesophagitis patients. It was found that more patients (P < 0.05) on esomeprazole 40 mg and esmoprazole 20 mg were healed after 8 weeks of treatment compared to omeprazole (94.1% and 89.9% compared to 86.9%). Adverse effects were common in both treatments. Esomeprazole was found to have a greater efficacy compared to omeprazole in reflux oesophagitis and both have a similar tolerability profile. Rohss K et al19 showed that esomeprazole at 40 mg daily had better acid control than omeprazole 40 mg daily. Since maintenance of intragastric pH > 4 is important for the effective management of GORD, the mean percentage of a 24 hour period with intragastric pH > 4 was taken as an indication of the efficacy of the treatments. Measurements were taken on day 1 and day 5, and on both days esomeprazole showed a greater mean percentage (P < 0.001) at 48.6% and 68.4% versus 40.6% and 62.0% for omeprazole.
Wahlqvist P et al20 compared,from the perspective of the National Health Service (NHS),the cost effectiveness of the actue treatment of esomeprazole (40 mg daily) with omeprazole (20 mg daily) in reflux oesophagitis patients.It was estimated that, taking into consideration of the healing probabilities over 8 weeks, treatment with esomeprazole saves up toa total of 1290 pounds compared to treatment with omeprazole. Esomeprazole was found to provide a greater effectiveness at a lower cost. This is reflected in another study conducted by Plumb JM and Edwards SJ,21 which found that esomeprazole is cost effective in comparison to all other PPIs for the treatment of reflux oesophagitis.
The treatment given to this patient was appropriate in terms of the algorithms stated in the NICE guidelines; she was started on a full dose PPI after eosophagitis was confirmed on the endoscopy. As stated above, PPIs are proven to have superior effects in comparison with histamine H2 receptor antagonists and prokinetic drugs, both providing relief of reflux symptoms but not healing the oesophagitis itself.10 Among all the PPIs currently available, esomeprazole, the S-isomer of omeprazole, has been found to show more improvement than all other PPIs. Current studies have shown that the treatment of reflux oesophagitis with esomeprazole is more cost effective than treatments using any other PPI, providing a greater healing rate at a lower cost. Thus it might be in the interest of the NHS to treat this patient with esomeprazole than omeprazole.