REVIEW ARTICLE
`
`Drugs 44 (5): 709-719, 1992
`0012-6667/ 92/00 11-0709/$05.50/0
`© Adis International Limited. All rights reserved.
`
`DRU1208
`
`Histamine H2-Receptor Antagonists in
`Peptic Ulcer Disease
`Efficacy in Healing Peptic Ulcers
`
`Mark Deakin and John G. Williams
`Keele University Postgraduate Medical School, North Staffordshire Medical Centre, Stoke on Trent,
`West Midlands, England, and School of Postgraduate Studies, University College, Swansea, Wales
`
`Contents
`709
`710
`710
`711
`713
`713
`714
`714
`715
`715
`715
`716
`
`Summary
`
`Summary
`1. Duodenal Ulcer Healing
`1.1 Development of Dosing Regimens
`1.2 Comparisons Between Histamine H2-Receptor Antagonists
`1.3 Comparisons with Omeprazole
`1.4 Comparisons with Prostaglandin Analogues
`1.5 Comparisons with Bismuth-Containing Compounds
`2. Gastric Ulcer Healing
`3. Tolerability
`3.1 Adverse Effects and Drug Interactions
`3.2 Hypochlorhydria
`4. Conclusions
`
`Duodenal ulcer healing depends on the degree and length of inhibition of gastric secretion
`and upon the duration of therapy, while gastric ulcer healing is dependent mainly on the duration
`of therapy.
`Currently marketed doses of the histamine H2-receptor antagonists heal between 77 and 92%
`of duodenal ulcers at 4 weeks, and adjuvant treatment to eradicate Helicobacter pylori increases
`this rate. Once-daily administration is as effective as more frequent dosing regimens and may
`even result in higher healing rates. Gastric ulcers heal more slowly, but 75 to 88% of ulcers heal
`after 8 weeks of treatment.
`While newer more potent acid suppressors such as omeprazole heal ulcers slightly more quickly,
`the H2-receptor antagonists have an unparalleled safety record of over IS years. It is unlikely
`that the prostaglandin analogues can improve on the efficacy of the H2-receptor antagonists with
`as Iowan incidence of side effects.
`
`AVENTIS EXHIBIT 2228
`Mylan v. Aventis IPR2016-00712
`
`

`
`710
`
`Drugs 44 (5) 1992
`
`The development of H2-receptor antagonists,
`introduction of cimetidine to clinical practice in
`1976, and subsequent development of ranitidine,
`famotidine and nizatidine has revolutionised the
`treatment peptic ulceration. There is no doubting
`their overall effectiveness. The market is huge and
`at least 3 other H2-receptor antagonists, roxatidine,
`mifentidine and sufotidine are currently undergo(cid:173)
`ing clinical trials.
`The most clearly defined indications for the use
`of H2-antagonists is in the treatment of duodenal
`.and gastric ulceration and in reflux oesophagi tis.
`This review concentrates on the healing data for
`duodenal and gastric ulcers when treated with the
`4 compounds currently marketed in the UK. The
`introduction of more powerful gastric acid sup(cid:173)
`pressors such as the substituted benzimidazoles (e.g.
`omeprazole), prostaglandin analogues (e.g. miso(cid:173)
`prostol), and the realisation of the importance of
`Helicobacter pylori has caused us to review the ef(cid:173)
`ficacy of the H2-receptor antagonists in the context
`of these recent developments.
`Cimetidine was the third histamine H2-receptor
`antagonist developed by James Black and col(cid:173)
`leagues. The first 2 compounds, burimamide (Black
`et al. 1972) and metiamide (Black et al. 1973), were
`unsuccessful. Intravenous administration of buri(cid:173)
`mamide produced marked inhibition of pentagas(cid:173)
`trin and histamine-stimulated gastric acid secre(cid:173)
`tion in humans (Wyllie et al. 1972), but when taken
`orally the compound had limited activity. Modi(cid:173)
`fication of the side chain of burimamide led to the
`synthesis of metiamide which was effective when
`taken orally. Metiamide was actually used to treat
`active duodenal ulcers in clinical trials, but while
`initial studies were promising (Pounder et al. 1975),
`cases of reversible neutropenia were reported in
`humans and the drug was withdrawn (Forrest et al.
`1975). This adverse reaction was thought to have
`been caused by the thiourea moiety of metiamide
`which was replaced by a cyanoguanidine group, re(cid:173)
`sulting in cimetidine (fig. 1). Ranitidine was de(cid:173)
`veloped subsequently by Glaxo and is similar to
`cimetidine but has a furan ring as a nucleus instead
`of an imidazole ring. Famotidine is structurally re(cid:173)
`lated to cimetidine but has a thiazole ring instead
`
`Famotidine
`
`Fig. 1. Structural formulae of cimetidine, ranitidine, famot(cid:173)
`idine and nizatidine.
`
`of the imidazole ring, while nizatidine combines
`the thiazole ring of famotidine and the side chains
`of ranitidine (fig. 1).
`
`1. Duodenal Ulcer Healing
`1.1 Development of Dosing Regimens
`
`Cimetidine was introduced for clinical use at a
`time when other medical therapies for duodenal
`ulceration were relatively ineffective, although ant(cid:173)
`acids, anticholinergic drugs and bismuth were
`available. Surgical treatment for ulcer disease was
`commonplace and often the only effective treat(cid:173)
`ment option. Vagotomy reduced gastric secretion
`continuously and so the initial concept in H2-
`blockade was to achieve pharmacological suppres(cid:173)
`sion of gastric secretion throughout the whole 24-
`hour period. A 4-times-daily dosing regimen was
`proposed and tested, i.e. cimetidine 200mg 4 times
`a day. The effect of this dosing regimen on the con(cid:173)
`trol of intragastric acidity, measured by repeated
`
`

`
`Peptic Ulcer Healing with H2-Receptor Antagonists
`
`711
`
`aspiration of gastric contents using a nasogastric
`tube, was compared with the higher dose of ci(cid:173)
`metidine 400mg 4 times daily (Pounder et al. 1975,
`1976). The main conclusions from these studies
`were that cimetidine was better at suppressing basal
`rather than meal-stimulated gastric acid secretion,
`and while 400mg was more effective than 200mg
`at suppressing overnight gastric secretion, the extra
`effect on meal-stimulated secretion was small
`(mainly because both doses were relatively ineffec(cid:173)
`tive). These studies led to the recommendation of
`the somewhat complicated dosing regimen for ci(cid:173)
`metidine, i.e. 200mg 3 times daily with 400mg at
`night. In a review of the first 8 studies in the world
`literature in 1978, Winship (1978) reported an av(cid:173)
`erage 6-week healing rate of 71 % for cimetidine and
`37% for placebo.
`Ranitidine was introduced clinically in 1981 as
`a twice daily dosage regimen (i.e. 150mg twice
`daily). This acted as a stimulus to the study of Kerr
`(1981), which showed that cimetidine 400mg twice
`daily was as effective at healing ulcers as the more
`complicated regimen mentioned above. This sim(cid:173)
`plified regimen did not remain standard for long,
`however, and treatment with a large single night(cid:173)
`time dose (800mg) was proposed in 1983 (Gledhill
`at al. 1983), based on the fact that a larger night(cid:173)
`time dose can completely suppress acid secretion
`during the night while additional daytime doses add
`little 'extra' effect.
`As a final refinement to once-daily dosing, drug
`administration earlier rather than later in the even(cid:173)
`ing has certain theoretical advantages. Clinical
`pharmacolological studies such as those described
`by Gledhill et al. (1983) showed that although a
`large night-time dose results in near achlorhydria
`overnight, the effect is largely abolished by the
`stimulus of breakfast. Administration of the H2-
`receptor antagonist earlier in the evening has the
`advantage that the antisecretory effect is 'stretched
`out', to cover the longest single period of unbuf(cid:173)
`fered intragastric acidity - from the evening meal
`until breakfast. Studies where intragastric acidity
`has been measured over a 24-hour period have
`shown that early evening administration reduces
`mean 24-hour intragastric acidity to a greater ex-
`
`tent than late evening dosing (Deakin et al. 1985;
`Merki et al. 1987). One word of caution, however,
`is that if lower dose regimens are used in the early
`evening, the drug effect can tail off overnight.
`
`1.2 Compl;lrisons Between Histamine H2-
`Receptor Antagonists
`
`The literature on the different dosing regimens
`of cimetidine and on comparisons between the dif(cid:173)
`ferent H2-receptor antagonists is now vast. Table
`I summarises the earlier studies with different doses
`of cimetidine and placebo. Relief of symptoms can
`be difficult to reliably assess, but response is gen(cid:173)
`erally rapid with all the H2-receptor antagonists (see
`reviews by Grant et al. 1989; Langtry et al. 1989).
`Typical figures are 76% of patients free from night
`pain at 2 weeks and 88% at 4 weeks (Gitlin et al.
`1987).
`The rate of duodenal ulcer healing induced by
`antisecretory compounds depends mainly on 3
`variables: (a) the degree of acid inhibition; (b) the
`length of acid inhibition; and (c) the duration of
`therapy (Burget et al. 1990; Jones et al. 1987).
`The study by Jones et al. (1987) shows partic(cid:173)
`ularly elegantly the linear relationship which exists
`between the degree of suppression of total 24-hour
`intragastric acidity by different antisecretory regi(cid:173)
`mens and duodenal ulcer healing rate at 4 weeks.
`As alluded to earlier, suppression of nocturnal in(cid:173)
`tragastric acidity is the single most important fac(cid:173)
`tor in explaining healing with the H2-receptor ant(cid:173)
`agonists and daytime suppression has little 'extra'
`benefit.
`The currently recommended treatment regi(cid:173)
`mens are cimetidine 800mg, ranitidine 300mg, ni(cid:173)
`zatidine 300mg or famotidine 40mg taken once
`daily at bedtime. These are simpler than earlier
`regimens and may even lead to higher healing rates
`because of more effective suppression of night-time
`secretion or possibly through better patient com(cid:173)
`pliance.
`Ranitidine is between 5 and 8 times more po(cid:173)
`tent on a molar basis than cimetidine (Daly et al.
`1980; Walt et al. 1981), and a single dose of ran(cid:173)
`itidine 300mg is comparable to cimetidine 1600mg
`
`

`
`712
`
`Drugs 44 (5) 1992
`
`Table I. Median (range) percentage of duodenal ulcers healed in endoscopically controlled studies following 1 to 8 weeks' treatment
`with placebo or cimetidine (Cim)
`
`Treatment
`
`Week
`
`References
`
`Placebo
`Cim 200mg qid
`Cim 200mg tid
`and 400mg on
`Cim 400mg bid
`Cim 800mg on
`
`11.5 (8-15)
`15
`
`2
`
`21 (11-50)
`
`57 (42-83)
`
`3
`
`17a
`80a
`
`16a
`
`38a
`
`4
`
`6
`
`8
`
`48 (20-79)
`59a
`78 (61-85)
`
`38 (19-63)
`86a
`74 (66-82)
`
`73 (66-81)
`77a
`
`1,2,3,4,5,6,8,11,14
`1,5
`92.5 (90-95) 2,3,4,6,7,8,9,
`10,11,12,13,14
`12,13,16,17,18
`15,16,17,18
`
`94 (88-94)
`94 (92-96)
`
`a Data from 1 study only.
`Abbreviations: bid = twice daily; on = at night; qid = 4 times daily; tid = 3 times daily.
`Data taken from: 1 Bodemar & Walan (1976); 2 Gray et al. (1977); 3 Lambert et at (1977); 4 Dobrilla et at (1978); 5 Ippoliti et at
`(1978); 6 Villalobos et al. (1978); 7 Galmiche et al. (1979); 8 Bardhan et at (1979); 9 Fedeli et al. (1979); 10 Gilsanz et at (1979);
`11 Ubilluz (1979); 12 Eckardt (1981); 13 Kerr (1981); 14 Lam & Koo (1983); 15 Valenzuela et al. (1985); 16 Dickson (1986);
`17 Capurso et al. (1986); 18 Spencer-Mills (1986).
`
`in suppressing 24-hour intragastric acidity (Deakin
`et al. 1985; Merki et al. 1987). The recommended
`dose of cimetidine (800mg) is therefore less potent
`than the marketed dose of ranitidine (300mg). Ci(cid:173)
`metidine 800mg and ranitidine 300mg given at
`night have not been directly compared in large
`healing studies, but McIsaac et aI. (1987) reviewed
`the results of 14 endoscopically controlled double(cid:173)
`blind trials where ranitidine 150mg twice daily was
`compared with cimetidine 400mg twice daily over
`a 4-week period. The combined healing rate with
`ranitidine was 11.5% higher than that for cimeti(cid:173)
`dine, an advantage part of which may be due to
`the difference in the degree of acid inhibition by
`the 2 doses.
`The recommended doses of famotidine and ni(cid:173)
`zatidine have been shown in clinical pharmacology
`studies to be equipotent to those recommended for
`ranitidine (Dammann et al. 1989; Merki et al. 1988;
`Savarino et al. 1989; Thomson et al. 1989). In
`clinical trials, therefore, significant differences in
`healing rates between any of these 3 compounds
`would not be expected and this is essentially what
`has been found. A summary of the most recent
`studies of single daily dosing with H2-receptor ant(cid:173)
`agonists is shown in table II.
`As discussed earlier, there are theoretical ad-
`
`vantages to the administration of a single dose of
`H2-receptor antagonist in the early evening since
`the antisecretory effect can be prolonged by doing
`this, potentially leading to better symptom control
`as well as increased healing rates. Administration
`of 300mg of ranitidine after the evening meal in(cid:173)
`stead of before bed has indeed been shown to in(cid:173)
`crease healing at 2 weeks from 50% to 74% and
`from 94% to 100% (Merki et al. 1986).
`There is no proven advantage in giving a larger
`daily divided dose. Gitlin et al. (1987) directly
`compared famotidine 40mg at night with 40mg
`twice daily. Healing rates were equivalent at both
`4 weeks (70% healing rate with the night-time dose,
`75% with the twice-daily dose), and 8 weeks (83%
`and 82%, respectively). The timing of dosing may
`not be as important as presupposed, however;
`equivalent healing rates at 4 and 8 weeks have been
`demonstrated with ranitidine 300mg at night or at
`0800h (Bianchi Porro et al. 1990).
`Roxatidine has been approved for clinical use
`in some countries and will shortly be widely avail(cid:173)
`able on the antiulcer market (for review see Mur(cid:173)
`doch & McTavish 1991). Again the dose has been
`matched to give a similar antisecretory effect to
`already marketed regimens. Healing rates with rox(cid:173)
`atidine 75mg twice daily have thus been shown to
`
`

`
`Peptic Ulcer Healing with H2-Receptor Antagonists
`
`713
`
`be comparable to ranitidine 150mg twice daily -
`93.5% vs 89.2% healing at 6 weeks (Huttemann
`1988). Also, as has been shown with the other H2-
`receptor antagonists, equivalent healing rates are
`obtained with a once-daily dose and a twice-daily
`dose (Hentschel & Schutze 1988), and following a
`night-time dose of roxatidine 150mg or ranitidine
`300mg (Walt et al. 1991).
`
`1.3 Comparisons with Omeprazole
`
`The H+,K+-ATPase (acid pump) inhibitor ome(cid:173)
`prazole causes achlorhydria in virtually all patients
`when given at a dose of 20 or 40mg (see review by
`McTavish et al. 1991). Duodenal ulcers, and par(cid:173)
`ticularly larger ulcers, heal slightly faster during
`omeprazole treatment and consequently early heal(cid:173)
`ing rates are higher than with the H2-receptor ant(cid:173)
`agonists.
`Following treatment with omeprazole 20mg once
`
`daily, healing rates of 42 to 79% at 2 weeks, 82 to
`97% at 4 weeks, and 88 to 100% at 8 weeks have
`been demonstrated (Archambult et al. 1988; Bar(cid:173)
`bara et al. 1987; Bigard et al. 1987; McFarland et
`at 1990; Valenzuela et al. 1991). A recent meta(cid:173)
`analysis of studies that directly compared omepra(cid:173)
`zole and ranitidine showed an overall increase of
`16.5% in the percentage of healed ulcers at 2 weeks
`(69.3% with omeprazole vs 52.8% with ranitidine);
`at 4 weeks, the healing rates were 92.8 vs 83.1 %
`(Mulder & Schipper 1990). Omeprazole 40 mg/day
`also heals the majority of duodenal ulcers that do
`not heal following treatment with the H2-receptor
`antagonists (Bardhan et al. 1991 a).
`1.4 Comparisons with Prostaglandin
`Analogues
`Prostaglandin analogues were introduced into
`ulcer treatment because of the proposition that they
`would combine the benefits of gastric acid secre(cid:173)
`tion inhibition with a 'cytoprotective' effect.
`
`Table II. Percentage of patients with acute duodenal ulcers healed after 2, 4 or 8 weeks of treatment with single night-time doses
`of cimetidine, ranitidine, famotidine or nizatidine in double-blind, endoscopically controlled studies
`
`Reference
`
`No. of pts
`
`Ranitidine
`300mg
`
`Cimetidine
`800mg
`
`Famotidine
`40mg
`
`Nizatidine
`300mg
`
`2 weeks
`Arnold et al. (1989)
`Cherner et al. (1989)
`Hartmann & Folsch (1988)
`Simon et al. (1987)
`
`4 weeks
`Arnold et al. (1989)
`Alcala-Santaella et al. (1989)
`Bovero et al. (1987)
`Cherner et al. (1989)
`Hartmann & Foisch (1988)
`Marks & Wright (1987)
`Rodrigo et al. (1989)
`Pace et al. (1988)
`Simon et al. (1987)
`
`8 weeks
`Arnold et al. (1989)
`Bovero et al. (1987)
`Cherner et al. (1989)
`Pace et al. (1988)
`Simon et al. (1987)
`
`367
`375
`78
`777
`
`367
`133
`165
`353
`78
`132
`105
`138
`777
`
`367
`165
`347
`138
`777
`
`63
`
`64
`
`90
`77
`78
`
`78
`
`77.5
`80
`
`96
`95
`
`94
`93
`
`31
`
`79
`
`95
`75
`91.6
`
`33
`23
`
`67
`85
`
`82.3
`
`75
`
`57
`41
`
`60
`
`87
`
`78
`73
`
`84.1
`81
`
`92
`91
`81
`92
`92
`
`

`
`714
`
`Drugs 44 (5) 1992
`
`Misoprostol, a synthetic prostaglandin El ana(cid:173)
`logue, is in current use but the effects on 24-hour
`intragastric pH are small in comparison with the
`H2-receptor antagonists (Savarino et al. 1988). In
`clinical trials, misoprostol 400mg twice daily re(cid:173)
`sulted in 4-week healing rates of 52 to 75% com(cid:173)
`pared with 69 to 91 % of patients treated with ran(cid:173)
`itidine 150mg twice daily (Goldin et al. 1988;
`Simjee et al. 1987). The corresponding healing rates
`at 8 weeks were 78 to 87% vs 85 to 100%.
`Unlike the H2-receptor antagonists, significant
`numbers of patients treated with prostaglandin
`analogues develop diarrhoea, although this is usu(cid:173)
`ally mild and self-limiting. While prostaglandin
`analogues might be helpful in patients with duo(cid:173)
`denal ulcers that have not healed following H2-re(cid:173)
`ceptor antagonist therapy (Newman et al. 1987), or
`in compromised patients such as smokers (Wat(cid:173)
`kinson et al. 1988), and patients with multiple ulcers
`(Hui & Lam 1987), it is difficult to conclude that
`the currently available prostaglandin analogues of(cid:173)
`fer significant treatment advantages over the H2-
`receptor antagonists.
`
`1.5 Comparisons with Bismuth-Containing
`Compounds
`
`There is no doubt that bismuth-containing com(cid:173)
`pounds are also effective in duodenal ulcer healing.
`Healing rates as high as 70% at 4 weeks and 88%
`at 8 weeks have been reported with a twice daily
`dose of tripotassium dicitrato bismuthate (colloi(cid:173)
`dal bismuth subcitrate) [Lazzaroni et al. 1989].
`There have been few trials where bismuth-contain(cid:173)
`ing compounds have been compared directly to H2-
`receptor antagonists, and no direct comparisons
`with large single night-time doses. Although these
`studies need to be performed, it is likely that the
`comparative efficacy of bismuth-containing com(cid:173)
`pounds would be lower since the H2-receptor ant(cid:173)
`agonists commonly heal above 90% of ulcers at 4
`weeks.
`The main advantage in treating ulcers with bis(cid:173)
`muth rather than with H2-receptor antagonists lies
`in the evidence that relapse rates are lower, pos(cid:173)
`sibly due to the control of Helicobacter pylori.
`
`Eradication of H. pylori by treatment regimens
`which include bismuth leads to lower relapse rates,
`particularly in those patients who remain Helico(cid:173)
`bacter-free (George et al. 1990; Rauws & Tytgat
`1990). However, bismuth compounds need to be
`combined with antibiotics such as tetracycline, am(cid:173)
`picillin or metronidazole to fully eradicate Helico(cid:173)
`bacter in the majority of patients (O'Riordan et al.
`1990).
`Currently the best policy is to recommend treat(cid:173)
`ment with an H2-receptor antagonist, but to com(cid:173)
`bine this initially with a bismuth-containing regi(cid:173)
`men that can eradicate H. pylori. Use of this
`combination for the first 1 to 2 weeks of treatment
`has been shown to increase the healing rate from
`53 to 74% after 4 weeks' treatment with ranitidine
`300mg/day (Graham et al. 1991) while also de(cid:173)
`creasing the rate of relapse from 27 to 8% at 6
`months (Coelho et al. 1991) when compared with
`treatment by H2-receptor antagonists alone.
`
`2. Gastric Ulcer Healing
`
`Cimetidine, ranitidine, famotidine and nizati(cid:173)
`dine are all effective in the treatment of gastric
`ulcers (Graham et al. 1985; Naccaratto et al. 1987;
`Schultz et al. 1984; Simon et al. 1987; Wright et
`al. 1982) even though gastric ulcers heal at a slower
`rate than duodenal ulcers. The majority do heal,
`but within 8 to 12 weeks.
`There is very little difference in healing rates
`achieved with any of the H2-receptor antagonists;
`rates of 58, 71, 84 and 91% have been achieved at
`4, 6, 8 and 12 weeks, respectively (fig. 2). Howden
`et al. (1988) compared gastric ulcer healing rates
`reported in published studies with the antisecre(cid:173)
`tory effects of the compounds used and found that
`an increasing antisecretory effect was not associ(cid:173)
`ated with a rise in the reported healing rate. This
`suggests that the rate of gastric ulcer healing de(cid:173)
`pends more on the duration of theraPY than upon
`the degree of acid inhibition, and if a:. benign gastric
`ulcer does not heal after 4 to 6 weeks of treatment
`then it is more important to extend the duration
`of therapy than to increase the dose of the drug.
`When once-daily has been compared directly to
`
`

`
`Peptic Ulcer Healing with H2-Receptor Antagonists
`
`715
`
`100
`
`'0 80
`C
`.~ 60
`1ii
`~
`'l5 40
`~ a: 20
`
`0
`
`4
`
`8
`6
`Time (weeks)
`
`10
`
`12
`
`Fig. 2. Rate of healing of gastric ulcer (median number of
`ulcers healed, with range) during treatment with H2-receptor
`antagonists. The data for healing after 4, 6, 8 or 12 weeks
`were calculated by combining data from the following stud(cid:173)
`ies: Arnold et al. (1989); Bate et al. (1989); Blum et al. (1990);
`Brazer et al. (1989); Danish Omeprazole Study Group (1989);
`Di Mario et al. (1990); Frank et al. (1989); Gonvers et al.
`(1987); Hjortrup et al. (1989); McCullough et al. (1989); Walan
`et al. (1989).
`
`twice-daily nizatidine administration, healing rates
`are almost identical (Arnold et a1. 1989; Naccaratto
`et a1. 1987). Nevertheless, giving the drug earlier
`in the evening may be an advantage, since healing
`rates have been shown to increase from 63 to 76%
`at 4 weeks and from 81 to 98% at 6 weeks by giving
`nizatidine after the evening meal rather than be(cid:173)
`fore bed (Brinkhoff et al. 1990).
`Comparing the H2-receptor antagonists with
`omeprazole, early healing rates have been found to
`be higher with omeprazole, an advantage that is
`maintained at 8 weeks by omeprazole 40mg but
`not by 20mg (Walan et al. 1989). Omeprazole is
`also effective in healing gastric ulcers that remain
`unhealed after treatment with H2-receptor antag(cid:173)
`onists (Bardhan et a1. 1991 a; Brunner & Creutz(cid:173)
`feldt 1989).
`Sucralfate 2g twice daily is as effective as ci(cid:173)
`metidine, with healing rates at 4, 8 and 12 weeks,
`respectively, of 52, 79 and 91 % with sucralfate, and
`55, 81 and 94% with cimetidine (Hjortrup et a1.
`1989). Rates are also equivalent after 12 weeks of
`sucralfate 4g or ranitidine 300mg daily (Blum et a1.
`1990). The prostaglandin analogues misoprostol,
`enprostil and rioprostil have also all shown equiv(cid:173)
`alent healing rates at 4 and 8 weeks when com-
`
`pared with ranitidine (Bardhan et a1. 1991 b; Gon(cid:173)
`vers et a1. 1987; Rutgeerts et a1. 1989).
`
`3. Tolerability
`3.1 Adverse Effects and Drug Interactions
`
`The H2-receptor antagonists are perhaps one of
`the safest classes of compound that has ever been
`introduced. Side effects occur in less than 1 % of
`patients and are mostly reversible on stopping
`therapy. Adverse effects include central nervous
`system effects (confusion, delirium, hallucinations,
`depression and rarely Parkinsonism, reported most
`commonly with cimetidine and less often with ran(cid:173)
`itidine and famotidine); gynaecomastia (cimetidine
`not ranitidine); impotence; lack of libido (cimeti(cid:173)
`dine and famotidine); renal dysfunction (cimeti(cid:173)
`dine impairs creatinine clearance although this is
`reversible); hepatotoxicity (cimetidine, ranitidine
`and famotidine all can cause reversible increases
`in transaminase levels but drug-induced hepatitis
`is rare); neutropenia; thrombocytopenia; agranu(cid:173)
`locytosis (rare: 0.01 to 0.7% with cimetidine); and
`fever (see reviews by Feldman & Burton 1990;
`Lipsy et a1. 1990).
`Problems with drug interactions are more com(cid:173)
`mon. Cimetidine inhibits the cytochrome P450 en(cid:173)
`zyme system and thus increases serum concentra(cid:173)
`tions of drugs such as warfarin, phenytoin and
`theophylline which are the 3 drugs most likely to
`result in clinically significant toxic combinations
`with cimetidine. The effect is less likely with ran(cid:173)
`itidine which binds 5 to 10 times less avidly than
`cimetidine; famotidine and nizatidine do not in(cid:173)
`terfere with this enzyme system. Interactions are
`also seen with the benzodiazepines, fj-adrenergic
`blockers, imipramine, ketoconazole, metronida(cid:173)
`zole, lidocaine (lignocaine), procainamide, carba(cid:173)
`mazepine, nifedipine and quinidine (see review by
`Lipsy et a1. 1990).
`
`3.2 Hypochlorhydria
`
`The consequences of hypo- and achlorhydria
`have been discussed continuously since the intro(cid:173)
`duction of the H2-receptor antagonists (Elder et a1.
`
`

`
`716
`
`Drugs 44 (5) 1992
`
`1979). Besides the potential for increasing cancer
`risk, hypochlorhydria leads to impaired intestinal
`calcium and iron absorption (Hunt 1988) and in(cid:173)
`creases the risk of orally transmitted infection
`(Howden & Hunt 1987).
`Postmarketing surveillance studies of cimeti(cid:173)
`dine have not shown an excessive increase in cases
`of carcinoma of the stomach (Colin-Jones et al.
`1985) and it is unlikely that the currently available
`H2-receptor antagonists, which are relatively short
`acting and allow for periods of normal intragastric
`acidity, will cause significant problems. Hypoch(cid:173)
`lorhydria is said to favour the production of car(cid:173)
`cinogenic n-nitroso compounds in the stomach, but
`there are doubts about the validity of this hypoth(cid:173)
`esis since the formation of nitroso compounds is
`favoured by acid and not neutral pH (Hall et al.
`1986, 1987). The problem of potential carcinogen(cid:173)
`icity has been recently discussed again following
`the demonstration of pathology in the stomachs of
`rats chronically treated with omeprazole, and the
`H2-receptor antagonists tiotidine, loxtidine and lu(cid:173)
`pitidine (Betton & Salmon 1984; Poynter et al.
`1985; Streett et al. 1984; Tielemans et al. 1989).
`Until the problem is resolved, long term therapeu(cid:173)
`tic achlorhydria or hypergastrinaemia should prob(cid:173)
`ably be avoided (Creutzfeldt & Lamberts 1991;
`W ormsley 1991).
`
`4. Conclusion
`
`In the 17 years since cimetidine was first intro(cid:173)
`duced into clinical practice, the H2-antagonists have
`revolutionised the management of acid peptic dis(cid:173)
`orders while their safety has survived the test of
`time. Earlier healing and slower relapse may be
`achieved by more potent acid-suppressing drugs and
`exploitation of newer concepts (e.g. eradication of
`H. pylon), but it is unlikely that the combination
`of safety, efficacy and complete evaluation will be
`repeated.
`
`References
`
`Alcala-Santaella R, Guardia J, Pajares J, Pique J, Pita L, et al. A
`multicenter, randomized, double-blind study comparing a daily
`bedtime administration of famotidine and ranitidine in short-
`
`term treatment of active duodenal ulcer. Digestion 42: 79-85,
`1989
`Archambult AP, Pare P, Bailey RJ, Navert H, Williams CN, et
`al. Omeprazole (20mg daily) versus cimetidine (1200mg daily)
`in duodenal ulcer healing and pain relief. Gastroenterology 94:
`1130-1134, 1988
`Arnold R, Beckenbach P, Bock H, Bormann R, Daake H, et al.
`Nizatidine versus ranitidine in the treatment of acute duo(cid:173)
`denal ulcer. Comparison of 300mg nizatidine and 300mg ran(cid:173)
`itidine in a single evening dose. Fortschritte der Medizin 107:
`467-470, 1989
`Arnold R, Beckenbach P, Bock H, Bormann R, Brunner G. Treat(cid:173)
`ment of acute stomach ulcer with H2-receptor antagonists. A
`direct therapy comparison with 300mg nizatidine nightly and
`2 times 150mg nizatidine with twice daily 150mg ranitidine.
`Fortschritte der Medizin 107: 390-394, 1989
`Barbara L, Blasi A, Cheli R, Corinaldesi R, Dobrilla G, et al.
`Omeprazole vs. ranitidine in the short-term treatment of duo(cid:173)
`denal ulcer: an Italian multicenter study. Hepato-Gastroenter(cid:173)
`ology 34: 229-232, 1987
`Bardhan KD, Saul DM, Edwards JL, et al. Comparison of two
`doses of cimetidine and placebo in the treatment of duodenal
`ulcer: a multicentre trial. Gut 20: 68-74, 1979
`Bardhan KD, Naesdal J, Bianchi Porro G, Petrillo M, Lazzaroni
`M, et al. Treatment of refractory peptic ulcer with omeprazole
`or continued H2-receptor antagonists: a controlled clinical trial.
`Gut 32: 435-438, 1991a
`Bardhan KD, Walker R, Hinchliffe RF, Bose K, Morris P, et al.
`Gastric ulcer healing: a comparison of enprostil versus rani(cid:173)
`tidine. Journal ofOinicai Gastroenterology 13: 157-162, 1991b
`Bate CM, Wilkinson SP, Bradby GV, Bateson MC, Hislop WS,
`et al. Randomised, double blind comparison of omeprazole
`and cimetidine in the treatment of symptomatic gastric ulcer.
`Gut 30: 1323-1328, 1989
`Betton G R, Salmon GK. Pathology of the forestomach in rats
`treated for 1 year with a new histamine H2-receptor antagonist,
`SK&F 93379 trichloride. Scandinavian Journal ofGastroenter(cid:173)
`ology 19 (Suppl. 10 I): 103-108, 1984
`Bianchi-Porro G, Parente F, Sangaletti O. Inhibition of nocturnal
`acidity is important but not essential for duodenal ulcer heal(cid:173)
`ing. Gut 31: 397-400, 1990
`Bigard MA, Isal JP, Galmiche JP, Ebrard F, Bader JP. Compar(cid:173)
`ative efficacy of omeprazole and cimetidine in the treatment
`of duodenal ulcer in the acute stage. Gastroenterologie Cli(cid:173)
`nique·et Biologique II: 753-757, 1987
`Black JW, Duncan W AM, Durant CJ, Ganellin CR, Parsons EM.
`Definitions and antagonism of histamine H2-receptors. Nature
`236: 385-390, 1972
`Black JW, Duncan WAM, Emmett JC, Ganellin CR, Hesselbo T,
`et al. Metiamide - an orally active histamine H2-receptor ant(cid:173)
`agonist. Agents and Actions 3: 133-137, 1973
`Blum AL, Bethge H, Bode JC, Domschke W; Feurle G, et al.
`Sucralfate in the treatment and prevention of gastric ulcer:
`multicentre double blind placebo controlled study. Gut 31: 825-
`830, 1990
`Bodemar G, Walan A. Cimetidine in the treatment of acute duo(cid:173)
`denal and pre-pyloric ulcers. Lancet 2: 161-164, 1976
`Bovero E, Poletti M, Boero A, Mura BC, Camarri E, et al. Ni(cid:173)
`zatidine in the short-term treatment of duodenal ulcer - an
`Italian multicenter study. Hepato-Gastroenterology 34: 269-271,
`1987
`BrinkhoffH, Kohler CO, Koch EM. Ranitidine in stomach ulcer.
`Controlled clinical trial of a comparison of administration after
`the evening meal or before bedtime. Fortschritte der Medizin
`108: 343-346, 1990
`Brazer SR, Tyor MP, Pancotto FS, Brice RS, Garbutt Jr JT, et
`al. Randomized, double-blind comparison of famotidine with
`raniti\iine in treatment of acute, benign gastric ulcer disease.
`
`

`
`Peptic Ulcer Healing with H2-Receptor Antagonists
`
`717
`
`Community-based study coupled with a patient registry.
`Digestive Diseases and Sciences 34: 1047-1052, 1989
`Brunner G, Creutzfeldt W. Omeprazole in the long-term man(cid:173)
`agement of patients with acid-related diseases resistant to ran(cid:173)
`itidine. Scandinavian Journal of Gastroenterology 166: 101-
`105, 1989
`Burget DW, Civerton SG, Hunt RH. Is there an optimal degree
`of acid suppression for healing of duodenal ulcers? Gastro(cid:173)
`enterology. 99: 345-351, 1990
`Capurso L, Dalonte PR, Mazzeo F, Menardo G, Morettini A, et
`al. Cimetidine 800mg at night versus 400mg twice daily in the
`treatment of duodenal ulcer. Scandanavian Journal of Gastro(cid:173)
`enterology 21 (Suppl. 121): 6-10, 1986
`Cherner JA, Cloud ML, Offen WW, Latz JE. Comparison of ni(cid:173)
`zatidine and cimetidine as once-nightly treatment of acute
`duodenal ulcer. Nizatidine Multicenter Duodenal Ulcer Study
`Group. American Journal of Gastroenterology 84: 769-774,1989
`Coelho LG, Passos MC, Chausson Y, Castro L de P. Five-day
`bismuth-free triple therapy for the eradication of Helicobacter
`pylori and reduction of duodenal ulcer relapse. American Jour(cid:173)
`nal of Gastroenterology 86: 971-975, 1991
`Colin-Jones DF, Langman MJS, Lawson DH, Vessey MP. Post(cid:173)
`marketing surveillance of the safety of cimetidine: mortality
`during second, third and fourth years of follow up. British
`Medical Journal 291: 1084-1088, 1985
`Creutzfeldt W, Lambe