Molecular structure of cimetidine
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Cimetidine

Cimetidine is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet®, and was approved by the Food & Drug Administration for prescriptions starting January 1, 1979. more...

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Clinical Use

History and development

Cimetidine was the prototypical histamine H2-receptor antagonist from which the later members of the class were developed. Cimetidine was the culmination of a project at Smith, Kline & French (SK&F; now GlaxoSmithKline) to develop a histamine receptor antagonist to suppress stomach acid secretion.

At the time (1964) it was known that histamine was able to stimulate the secretion of stomach acid, but also that traditional antihistamines had no effect on acid production. In the process, the SK&F scientists also proved the existence of histamine H2-receptors.

The SK&F team used a rational drug-design structure starting from the structure of histamine - the only design lead, since nothing was known of the then hypothetical H2-receptor. Hundreds of modified compounds were synthesised in an effort to develop a model of the receptor. The first breakthrough was Nα-guanylhistamine, a partial H2-receptor antagonist. From this lead the receptor model was further refined and eventually led to the development of burimamide - the first H2-receptor antagonist. Burimamide, a specific competitive antagonist at the H2-receptor 100-times more potent than Nα-guanylhistamine, proved the existence of the H2-receptor.

Burimamide was still insufficiently potent for oral administration and further modification of the structure, based on modifying the pKa of the compound, lead to the development of metiamide. Metiamide was an effective agent, however it was associated with unacceptable nephrotoxicity and agranulocytosis. It was proposed that the toxicity arose from the thiourea group, and similar guanidine-analogues were investigated until the ultimate discovery of cimetidine.

Shortcomings

Cimetidine is a known inhibitor of many isozymes of the cytochrome P450 enzyme system (specifically CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). This inhibition forms the basis of the numerous drug interactions that occur between cimetidine and other drugs. For example, cimetidine may decrease metabolism of some drugs, such as oral contraceptives.

Adverse drug reactions were also found to be relatively common with cimetidine.

The development of longer-acting H2-receptor antagonists with reduced adverse effects such as ranitidine proved to be the downfall of cimetidine and, whilst it is still used, it is no longer amongst the more widely used H2-receptor antagonists.

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Association of age with the efficacy and safety of ranitidine and cimetidine in acute duodenal ulcer disease
From Age and Ageing, 11/1/93 by J.S. Dixon

Summary

This multinational double-blind trial compared the efficacy and safety of ranitidine 300 mg nocte, 300 mg post-evening meal (pem) and cimetidine 800 mg nocte in patients with endoscopically verified duodenal ulcer disease aged < 60 years (n = 1318) and [greater than or equal to] 60 years (n = 354). The relative efficacy of the treatments was not dependent upon age after either 2 or 4 weeks of therapy. However, ulcer healing after 2 weeks of therapy was significantly higher in patients receiving ranitidine 300 mg pem than in those receiving cimetidine (p = 0.003) in the < 60-year group, but the difference was not significant in the [greater than or equal to] 60-year group. Fewer patients aged [greater than or equal to] 60 years on cimetidine (62%) became pain free compared with those on ranitidine (72% in both groups). Relief of epigastric pain and heartburn was related to pre-trial severity in both age groups. The incidence and type of adverse events were similar in the two age groups. It is concluded that ranitidine and cimetidine are as effective at healing duodenal ulcer and relieving ulcer symptoms in elderly as in younger patients.

Introduction

The proportion of people considered |elderly' in the population of most countries is increasing, and is predicted to continue to increase into the next century [1]. The mortality and morbidity associated with peptic ulcer disease is also increasing in elderly people [2-7].

The efficacy and safety of [H.sub.2]-receptor antagonists is of considerable importance in the management of peptic ulcer disease in elderly people. A study comparing ranitidine (hydrochloride) 150 mg bd and placebo showed no difference in the healing of duodenal ulcer for patients < 60 years and those [greater than or equal to] 60 years (74% and 71%, respectively, for ranitidine) [8]. Ulcer symptom relief was also similar in the two age groups. Four-week ulcer healing frequencies in an open study of 695 patients aged [greater than or equal to] 65 years who received ranitidine 150 mg bd or ranitidine 300 mg nocte were 81% and 78%, respectively [9].

A large multinational clinical trial to compare ranitidine 300 mg post-evening meal (pem), 300 mg nocte and cimetidine 800 mg nocte in the treatment of acute duodenal ulcer [10], has provided an opportunity to compare the efficacy and safety of ranitidine and cimetidine in patients < 60 years and those [greater than or equal to] 60 years old.

Patients and Methods

A double-blind, randomized comparison of ranitidine 300 mg pem, ranitidine 300 mg nocte and cimetidine 800 mg nocte in the healing of acute duodenal ulceration during 4 weeks of therapy was carried out. The study was conducted in 130 study centres in 13 countries. The protocol was approved by the local Hospital Ethics Committee or equivalent in all participating centres. All patients gave their consent after details of the study had been discussed with them. The study was conducted in accordance with the Declaration of Helsinki, Venice amendment 1983.

Patients aged 18-75 years with an endoscopically confirmed duodenal ulcer measuring [greater than or equal to] 5 mm and [less than or equal to] 25 mm in the longest diameter were eligible for entry into the study. Patients were excluded if they had other concomitant upper gastro-intestinal disease, severe renal impairment, clinically relevant abnormal liver function, or mental impairment. Patients who were taking potentially ulcerogenic drugs were also excluded, as were pregnant women, nursing mothers, and night workers.

Routine laboratory screens were carried out and demographic details noted for eligible patients. Patients were allocated to treatment with ranitidine (Zantac[R]) 300 mg pem with matching placebo nocte, ranitidine 300 mg nocte with matching placebo pem, or cimetidine 800 mg nocte (tablets matching ranitidine and bio-equivalence with UK commercially available Tagamet[R] verified) with matching placebo pem in accordance with the predetermined randomization list. All patients therefore took two tablets each day - one immediately after the evening meal (18 h 30-19 h 00) and one at bedtime (22 h 45-23 h 15). Patients were also provided with a diary card to record the daily evening meal times, tablet consumption and ulcer-related pain.

After 2 weeks of treatment, patients returned for endoscopic and symptomatic assessment, which included the presence or absence of epigastric pain, heartburn (reflux), nausea and vomiting each graded as none, mild, moderate or severe. If the ulcer had healed at this time the patient was withdrawn from the study. If the ulcer was unhealed, treatment was continued for a further 2 weeks with repeat assessment.

Adverse events and intercurrent illnesses were monitored throughout the study. At each follow-up visit patients were questioned about any adverse events that had occurred.

Statistical analyses: The sample size was chosen to be able to detect a difference between ranitidine 300 mg nocte and cimetidine 800 mg nocte of 10% at 2 weeks with 80% power at the 5% level of significance. Three patient populations were considered:

(a) Total, i.e. all patients who received treatment.

(b) Total population re-endoscoped, i.e. all patients with evaluable pre-trial, 2-week and, where applicable, 4-week follow-up endoscopic results irrespective of any protocol violation.

(c) Per-protocol, i.e. all patients who complied with the protocol and who attended for endoscopy 14 [+ or -] 2 days and 28 [+ or -] 4 days after the start of treatment.

Ulcer healing was assessed after 2 weeks and cumulatively after 4 weeks of treatment. Healing was compared between the young (< 60 years) and elderly ([greater than or equal to], 60 years), and between treatments within these age bands using the Mantel-Haenszel [chi.sup.2] test without continuity correction. Confidence intervals (95%) for the differences in paired treatment comparisons were based on relative odds.

The treatments were also compared within the young and elderly groups for the number of patients with each symptom pre-trial who became symptom-free after 2 weeks and after 4 weeks of treatment using a Mantel-Haenszel [chi.sup.2] test adjusted for pre-treatment severity. The diary-card pain data were used to assess the numbers of patients with pain on each day during the first 2 weeks of therapy.

Patient compliance was assessed by returned tablet counts. Differences between treatments in routine biochemical and haematological results were assessed using shift tables.

Results

Baseline characteristics: The participating countries and the numbers of patients recruited by each are shown in Table I. Of the patients who entered the study, 1318 were < 60 years old while 354 were [greater than or equal to] 60 years old; for five patients the age was not recorded. The two groups were similar in most baseline characteristics but the proportions of smokers and alcohol drinkers were higher in the younger group (Table II). The pre-treatment characteristics were also similar between treatment groups within the < 60-years and [greater than or equal to] 60-years age groups. The only notable difference was that the proportion of men receiving ranitidine 300 mg pem in the [greater than or equal to] 60 years group was only 52% compared with 70% and 71% for ranitidine 300 mg nocte and cimetidine, respectively.

[TABULAR DATA OMITTED]

As expected, the elderly patients had a higher prevalence of other diseases, especially cardiovascular, compared with the younger patients (Table III). In conjunction with this, the elderly patients reported greater use of concurrent medication than the younger patients (56% compared with 34%). There was increased use of cardiovascular agents, NSAIDs, analgesics and sedatives in the elderly, while antacids were consumed more in the younger group. Five patients in the elderly cimetidine group were receiving co-medication which could have resulted in drug-drug interactions (2 theophylline, 2 propranolol, 1 diazepam) but no clinical sequelae were observed. No patient in the study was receiving warfarin.

[TABULAR DATA OMITTED]

Endoscopic results: Ulcer healing at week 2 in the < 60-year group was significantly higher in patients receiving ranitidine 300 mg pem than in those receiving cimetidine (p = 0.003), but the difference was not significant in the [greater than or equal to] 60-year group (Table IV).

[TABULAR DATA OMITTED]

The relative efficacy of the treatments was not dependent upon age after either 2 or 4 weeks of therapy. Breakdown of ulcer healing results by age (decades) also supported this observation (Table V). These results were based on the total population re-endoscoped but similar results were obtained from analysis of the per-protocol population. The effect of country on these results could not be investigated in detail owing to small numbers from some countries, but overall the relative efficacy of the treatments was not dependent on the countries involved.

[TABULAR DATA OMITTED]

Symptomatic relief. The incidence and degree of severity of epigastric pain and heartburn were similar for both age groups at the pre-treatment, 2- and 4-week visits. Both ranitidine dosage regimens provided symptom relief for more patients than did cimetidine after 2 and 4 weeks of therapy in both age groups. These differences between treatments achieved statistical significance at 2 weeks only within the younger group (Figure 1). Relief of epigastric pain and heartburn was related to pre-trial severity in both age groups (Figure 2).

The diary-card data did not show any marked differences between the younger and older patients in the numbers becoming pain-free after 2 weeks of therapy. However, fewer patients aged [greater than or equal to] 60 years on cimetidine (62%) became pain-free compared with those on ranitidine (72% in both groups). The average time to become pain-free (i.e. the time after which no pain occurred for the remainder of the study) was one or two days longer in younger patients (about 9 days) than in the older group (7-8 days).

Adverse events: The proportion of patients reporting adverse events in the elderly group for ranitidine 300 mg pem, 300 mg nocte and cimetidine was 3.7%, 3.3% and 7.1%, respectively (4.8% overall), which was slightly less than for the younger group of 8.7%, 5.9% and 7.4%, respectively (7.4% overall). The types of events reported are shown in Table VI. There were three deaths in patients aged 53, 62 and 63 and none was considered to be related to the study medication.

Discussion

The present study has shown that age does not affect the absolute or relative efficacy of the treatments given. Ranitidine and cimetidine were well tolerated and the incidence of adverse events was slightly lower in the older patients.

This is in contrast to what might have been predicted. Retrospective review of clinical trials in the USA also shows no difference in the adverse event profile between elderly and younger patients treated with ranitidine[8,11].

The increasing mortality and morbidity associated with peptic ulcer disease in elderly people[2-7] may be due partly to differences in presentation of peptic ulcer disease in elderly compared with younger patients, with the first manifestation often relating to a complication of the disease[12-14]. In addition, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is widespread in the elderly population leading to an increased incidence of ulceration, haemorrhage[15-18] and perforation[17-20]. Elderly NSAID users may be four times more likely to develop peptic ulcer disease than non-users[21], but the analgesic effects of NSAIDs may modify pain symptoms hence delaying treatment and increasing the risk of complication[22].

Polypharmacy among elderly people increases the chances of clinically relevant drug interactions occurring. In addition, the pharmacokinetics of some drugs may be altered in elderly people, particularly the rate of elimination[23]. These factors, in combination with multiple illnesses require that greater care is taken in the selection of medication for the treatment of peptic ulcer disease in elderly people. Ranitidine therapy results in considerably fewer drug interactions than cimetidine[24-27], is less likely to result in neuropsychiatric effects than cimetidine[23], and, unlike sucralfate or bismuth, has a convenient once-daily dosage regimen.

Helicobacter pylori may be less important as a factor in the pathogenesis of peptic ulcer in elderly than in younger patients[28]. Patient compliance is a particular problem with existing anti-H. pylori therapy[29] and is likely to be even more of a problem in elderly patients who may be also more at risk of side-effects from such therapy. The eradication of H. pylori may prove an unsatisfactory approach to the management of peptic ulcer disease in an elderly patient.

The data presented in this paper support the view that ranitidine and cimetidine are as effective at healing duodenal ulcer and relieving ulcer symptoms in elderly as in younger patients. When viewed in the context of the above discussion, it can be seen that ranitidine in particular provides a safe and effective therapy for use in the management of elderly patients with duodenal ulcer disease.

References

[1.] Perspectives-implications of aging worldwide: a health care communications special report. New York: Burson Marsteller, Winter 1989/1990. [2.] Sonnenberg A. Factors which influence the incidence and course of peptic ulcer. Scand J Gastroenterol 1988; 23(suppL 155): 119. [3.] Sonnenberg A, Fritsch A. Changing mortality of peptic ulcer disease in Germany. Gastroenterology 1983;84:1553. [4.] Tilvis RS, Vuoristo M, Varis K. Changed profile of peptic ulcer disease in hospital patients during 1969-1984 in Finland. Scand J Gastroenterol 1987;22:1238. [5.] Walt R, Katschinski B, Logan R, et al. Rising frequency of perforation in elderly people in the United Kingdom. Lancet 1986;i:489. [6.] Permutt RP, Cello JP. Duodenal ulcer disease in the hospitalized elderly patient. Dig Dis Sci 1982;27:1. [7.] Negre J. Perforated ulcer in elderly people. Lancet 1985;ii: 1118. [8.] Mills JR, Begun JM, Holland CE, Rogenes PR. Ranitidine for duodenal ulcer disease in the elderly: a retrospective review of four multicentre trials. J Geriatr Drug Ther 1988;3:43-56. [9.] Di Mario F, Vio A, Grassi SA, et al. Peptic ulcer in the elderly: a prospective multicentric study with ranitidine 300 mg vs ranitidine 150 mg bid/daily. World Congress of Gastroenterology, Sydney 1990; Abstract PD342. [10.] Dixon JS, Ehsanullah RSB, Mills JG, Wood JR. Effect of early evening dosing of ranitidine: a comparison with night-time dosing of ranitidine or cimetidine in duodenal ulceration. Dig Dis Sci 1993 (in press). [11.] Sirgo M, Walker S. A comparison of the adverse event profile of ranitidine in elderly and non-elderly patients. Y Clin Pharmacol 1990; 30:849. [12.] Gilinsky NH. Peptic ulcer disease in the elderly. Gastroenterol Clin North Am 1990;19:255-71. [13.] Freston MS, Freston JW. Peptic ulcers in the elderly: unique features and management. Geriatrics 1990;45:39-45. [14.] McHardy G. Peptic ulcer therapy and drug interactions in the elderly. Pract Gastroenterol 1989;13:8-18. [15.] Llewellyn JG, Pritchard MH. Influence of age and disease state in non-steroidal anti-inflammatory drug associated gastric bleeding. J Rheumatol 1988;15:691-4. [16.] Holvoet J, Terriere L, Van Hee W, et al. Relation of upper gastrointestinal bleeding to non-steroidal and anti-inflammatory drugs and aspirin: a case-control study. Gut 1991;32:730-4. [17.] Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut 1987;28:527-32. [18.] Beardon PHG, Brown SV, McDevitt DG. Gastrointestinal events in patients prescribed non-steroidal anti-inflammatory drugs: a controlled study using record linkage in Tayside. Q J Med 1989;77:497-505. [19.] Collier D St J, Pain JA. Non-steroidal anti-inflammatory drugs and peptic ulcer perforation. Gut 1985;26:359-63. [20.] Jick SS, Perera DR, Walker AM, Jick H. Non-steroidal anti-inflammatory drugs and hospital administration for perforated peptic ulcer. Lancet 1987;ii:380-2. [21.] Griffin MR, Piper JM, Daugherty JR, et al. Non-steroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in the elderly. Ann Intern Med 1991;114:257-63. [22.] Skander MP, Ryan FP. Non-steroidal anti-inflammatory drugs and pain free peptic ulceration in the elderly. Br Med J 1988;297:833-4. [23.] Chiverton SG, Hunt RH. Pharmacokinetics and pharmacodynamics of treatments for peptic ulcer disease in the elderly. Am J Gastroenterol 1988;83:211-15. [24.] Mitchard M, Harris A, Mullinger BM. Ranitidine drug interactions - a literature review. Pharmacol Ther 1987;32:293-325. [25.] Klotz U, Kroemer HK. The drug interaction potential of ranitidine: an update. Pharmacol Ther 1991;50:233-44. [26.] Somogyi A, Muirhead M. Pharmacokinetic interactions of cimetidine 1987. Clin Pharmacokinet 1987;12:321-66. [27.] Dixon JS, Page MC. Interactions between non-steroidal anti-inflammatory drugs and [H.sub.2]-receptor antagonists or prostaglandin analogues. Rheumatol Int 1991;11:13-8. [28.] Wyatt JI, Shallcross T, Heatley RV. Peptic ulcers in the elderly: not a Helicobacter related disease? Italy J Gastroenterol 1991;23(suppl 2):8-9. [29.] Graham DY, Lew GM, Malaty M, et al. Factors influencing the eradication of Helicobacter pylori with triple therapy. Gastroenterology 1992; 102:493-6.

COPYRIGHT 1993 Oxford University Press
COPYRIGHT 2004 Gale Group

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