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OESO©2015
 
Volume: The Esophageal Mucosa
Chapter: Antacids
 

Antacids and alginate-containing preparations: what is their mechanism of action and their place in the management of GERD?

C. Scarpignato, G. Gimbo (Parma)

S. Bruley des Varannes, J.-P. Galmiche (Nantes)

Although the pathogenesis of gastroesophageal reflux disease (GERD) is multifactorial [1], the damaging power of the refluxed material depends primarily on gastric acid secretion and the nature of refluxate is acid in most of patients with GERD [2]. As a consequence, until the 80s, the medical treatment of GERD consisted mainly of antacids and lifestyle modifications [3]. During the last decade new drugs have been developed, including very potent inhibitors of gastric acid secretion and more effective prokinetic agents [4]. However, in many countries, antacids and alginate containing preparations still remain the mainstay of treatment for patients with heartburn and the so-called "reflux-like dyspepsia".

Antacids are among the most widely used medicines. Often, to be sure, they are taken as a result of self-diagnosis and self-treatment (being available as over-the-counter drugs), and the trigger for buying and taking an antacid is not based on structural abnormalities, but on symptoms. Patients take antacids, as well as alginates, to feel better rather than to heal esophageal lesions.

This paper will summarize the pharmacology of both kinds of preparations and discuss their role in the medical treatment of GERD.

Antacids

Antacids are preparations that are primarily designed to neutralize gastric acid. The proliferation of antacid formulations includes combinations and varying proportions of a number of basic materials, in an attempt to produce improved neutralization characteristics with lowered untoward effects. Currently, the American Hospital Formulary lists over 120 antacid preparations, composed of single ingredients or mixtures, in every conceivable combination. Similarly, the British National Formulary and the French Pharmacopeia contain 58 and 64 formulations, respectively, many of these being very similar.

The chemistry of each antacid is unique [5,6]. On the basis of their biological properties, they can be divided as systemic (i.e., sodium salts), nonsystemic (calcium, magnesium and aluminum salts), and complex antacids (Fig. 1). Most prescribed antacids contain a mixture of aluminum and magnesium salts. Precise methods of preparation and presentation are important because they influence the physico-chemical properties and the therapeutic effects of antacids.

Pharmacological properties of antacids

The pharmacological actions of antacids are summarized in Table 1 [1,7]. Besides the neutralization of hydrogen ions present in gastric secretion, the increase in lower esophageal sphincter pressure (LESP) [8], which is independent of gastrin release [9], could - on theoretical grounds - contribute to the observed reduction of esophageal exposure to acid [10]. An increase in LESP, however, becomes evident only when intragastric pH is kept over 6 [8], a pH level only seldom reached with the common used schedules of antacids. It is worth mentioning that their effect on gastric pH is of short duration; antacids ingested in the fasting state reduce acidity for only approximately 30 min because of their rapid gastric emptying [5]. When antacids (30

0090F1.JPG

Fig. 1. Classification of antacids.

Table 1. .Pharmacological actions of antacids

• Neutralization of hydrogen ions present in gastric secretion and reduction of their concentration in the refluxed material

• Mucosal protection

• Adsorption and inactivation of pepsin

• Binding of bile salts

• Increase of LESP independently from gastrin release

• Inhibition of gastric emptying rate, mainly dependent on aluminum content

ml) are given 1 and 3 h after the meal, gastric pH is kept above 2.0 for only 3 h [11]. The second dose of antacid, given when most of the meal has left the stomach, is slightly less effective than the first one. Moreover, it must be pointed out that acid secretion actually increases while antacids are in the stomach; however, as long as the antacid remains in the stomach, acid can be neutralized. The nocturnal gastric acidity (which normally reaches its peak after midnight) is not adequately controlled by antacids, even when given at bedtime.

Could antacids reduce the esophageal exposure to acids?

Ten years ago, Galmiche's team [12] performed an elegant study comparing an aluminum-magnesium-hydroxide-containing antacid (Dimalan®) with two widely employed histamine H2-antagonists (cimetidine and ranitidine) in patients with symptomatic gastroesophageal reflux (GER). These were randomly allocated to one of the following therapeutic schedules:

- antacid 15 ml 1 h after meals and at bedtime;

- cimetidine 200 mg after meals and 400 mg at bedtime; and

- ranitidine 150 mg bid.

A standard 3-h postprandial pH test without treatment was also performed in all patients before entering the trial and a postprandial acid reflux score was then calculated. When compared to pretreatment levels of esophageal acidity, the three drugs were found to be almost equally effective in reducing the postprandial pH score. However, comparison of the results from the 20 h pH study showed that during the night H2-blockers (especially ranitidine) were clearly more efficacious than the antacid, in decreasing the time of exposure of the esophageal mucosa to low pH levels.

Are antacids capable of relieving heartburn?

Although the degree by which acidity must be reduced to relieve heartburn is not yet clearly established [13], a study by Smith and co-workers [14] showed that a solution of pH over 2.5, infused into the esophagus, may not cause pain even if it is of low pH (e.g., pH 3).

The analgesic effect of a liquid antacid (30 ml aluminum and magnesium hydroxides in vitro, buffering capacity 144 µmol) on episodes of heartburn, has been

studied by Meyer et al. [15] in 20 chronically symptomatic GER patients (Fig. 2). Their first study compared the effect of single doses of antacid and placebo on two spontaneous heartburn episodes. The second trial compared single doses of the same antacid and placebo on acid induced heartburn. Lastly, antacid and placebo were given on demand for multiple heartburn episodes. In all these studies, antacid and placebo resulted in nonstatistically different degrees of pain relief. Moreover, esophageal pH monitoring during the Bernstein test was not correlated with the degree of pain relief after either antacid or placebo.

Is there any healing effect of antacids on esophageal lesions?

Clinical investigations with antacids on GERD patients concern their effects on both symptoms (heartburn, regurgitation, dysphagia) of GERD and esophageal lesions. As shown in Table 2, there are few published trials [16-19] in which antacids and true placebo were compared. It is evident that a significant symptomatic relief was seldom reported and that an improvement of esophageal lesions was never revealed by endoscopy.

Based on the present knowledge, it should therefore be concluded that antacids are of little, if any, therapeutic value in GERD.

Alginate-containing drugs

These pharmaceutical preparations, of which the most widely known is Gaviscon®, contain alginic acid combined with small doses of antacids. Commercial antireflux

0090F2.JPG

Figure 2. .Effect of antacids on spontaneous and acid-induced heartburn in patients with GERD. Each column represents the percentage of patients symptom-free 30 min after administration of either placebo or antacid (drawn from data in [15]).

Table 2. .Placebo-controlled trials with antacid preparations in GERD

Authors

Year

Control therapy

Symptomatic improvement

Endoscopic improvemnt

Furman et al. [16]

1982

Placebo

No

No

Graham and Patterson [17]

1983

Placebo

No

No

Grove et al. [18]

1985

Placebo

Yes

No

Weberg and Berstad [19]

1989

Placebo

Yes

NE

NE = not evaluated.

preparations use a wide range of alginate materials. It is difficult to correlate their properties with those of alginate, since the alginate used is rarely specified by the manufacturer and a wide range of particulates are added to many formulations (e.g., particulate antacids). Even in the same formulation, the composition varies greatly from country to country (Table 3). This is the case with liquid Gaviscon®, which is manufactured under license by different pharmaceutical companies. An interesting study [20] compared four international preparations of liquid Gaviscon® and found that each formulation possesses markedly different raft strength (Fig. 3) and neutralization profiles.

Alginate-containing preparations: how do they work?

Scintigraphic studies have clearly established that Gaviscon® floats on the surface of the gastric pool, providing a mechanical barrier to reflux at the cardia. Using a dual-isotope scintigraphic technique, Malmud and Fisher [21] as well as McKay et al. [22], showed that most of the ingested alginic acid is located in the upper half of the stomach, in both normal subjects and patients with GER (Fig. 4). In those subjects in whom reflux did occur after treatment with alginic acid, the labeled compound refluxed preferentially compared with the liquid contents of the stomach. Therefore, when reflux occurs, this viscous foam first contacts the esophageal mucosa. Compared with antacids, alginate containing preparations float and show a selective retention in the fundus [6].

Optimal dosing in relation to meal intake is needed for alginate to be completely effective (Table 4). To ensure gastric floatation, antireflux agents must indeed be given 30 min after the meal.

Table 3. .Composition of the liquid Gaviscon® formulations in various countries [20]

Formulation

U.K.

Canada

U.S.A.

Sweden

Sodium alginate

500 mg

500 mg

267 mg

500 mg

Sodium bicarbonate

267 mg

a

-

170 mg

Aluminum hydroxide

-

200 mg

63.3 mg

1 g

Magnesium carbonate

-

275 mg

-

Calcium carbonate

150 mg

aQuoted as 60 mg of sodium/10 ml which is equivalent to 219 mg of sodium bicarbonate/10 ml.

0090F3.JPG

Figure 3. .Raft strengths of the minimum recommended doses of liquid Gaviscon® available in four different countries (from [20]).

Effect of alginate-containing preparations on esophageal exposure to acid

Stanciu and Bennett [23] first showed a significant decrease in the number of reflux episodes and in the percentage time during which the esophageal pH was in the acidic range after the administration of eight tablets per day of an alginate containing preparation (Gaviscon®). Antacid alone (Gaviscon® without alginate) had no effect

0090F4.JPG

Figure 4. .Dual isotope scintigraphic evaluation of an alginate containing preparation (Algicon®). Patients with symptomatic GERD were given 300 ml 99mTc labelled milk (blue) followed by 10 ml suspension of 113mIn-labeled alginate (red) (from [22]).

Table 4. .Alginate-containing preparations: optimal dosing in relation to meals

• Antireflux preparations must be given 30 min after a meal to ensure gastric floatation.

• When the antireflux agent is taken on an empty stomach, the formation sinks to the base of the greater curvature and 50% is emptied within 20 min after administration.

• When the formulation is taken 30 min before, the antireflux agent does not float on a meal ingested subsequently. It will be diluted with the fluid from the meal and thus emptied ahead of the meal without forming a raft.

on esophageal pH. By using postprandial and 24-h intraesophageal pH-metry, respectively, Dudicourt et al. [24], Branicki et al. [25] and Castell et al. [26] confirmed this finding and clearly showed that Gaviscon® is more effective in controlling GER in upright than in supine position (Fig. 5). This finding is not unexpected if one takes into account that gastric emptying of Gaviscon® is strongly influenced by posture. Bennett et al. [27], indeed, demonstrated in healthy volunteers that this raft-forming alginate formulation emptied faster than food in subjects lying on their left sides and slower in subjects lying on their right sides. The recently developed Algicon® behaves quite similarly [28]. More recently, Washington [29] used an esophageal pH probe, coupled with a small GAMMA-detector strapped to the chest wall and, by using a radiolabeled meal, was able to show that 20 ml of liquid Gaviscon®, administered 30 min after the meal, significantly reduced the amount of both acid and food reflux into the esophagus.

Alginate-containing preparations: clinical efficacy in GERD

The clinical efficacy of Gaviscon® has not been definitively established by large placebo-controlled trials [30-32]. The studies in which Gaviscon® appeared superior

0090F5.JPG

Figure 5. .Upright reflux time (min) and numbers of reflux episodes after a high-fat meal in 10 subjects following administration of an alginic acid-antacid formulation vs. equal strength antacid (redrawn from [26]).

Table 5. .Controlled trials with alginate containing preparations

Authors

Year

Control therapy

Symptomatic improvement

Endoscopic improvement

Barnardo et al. [30]

1975

Placebo

Yes

NE

Beeley and Warner [31]

1972

Placebo

Yes

NE

Grossman et al. [32]

1973

Placebo

No

No

Stanciu and Bennett [23]

1974

Placebo

No

NE

McHardy [33]

1978

Antacid

No

No

Scobie [34]

1976

Antacid

No

No

Chevrel [35]

1980

Antacid

Yes

NE

Graham et al. [36]

1984

Antacid

No

No

NE = not evaluated.

to placebo concerned symptoms without information regarding endoscopic or histological findings (Table 5).

In some studies, Gaviscon® was compared with antacids [33-36]. These trials did not show any statistically significant difference between these two drugs, in terms of symptom relief and improvement of lesions [37] but, as pointed out previously, efficacy of antacids themselves remains controversial.

On the whole, clinical experience in general practice suggests that alginates (Gaviscon®) or alginate-antacid preparations (Algicon®) are very effective for the relief of heartburn [38-40], but their efficacy in the healing of esophagitis is at least doubtful.

Antacids and alginates for GERD: are they useful?

In clinical practice, there is generally a consensus to apply a stepwise strategy for the treatment of GERD [4]. In patients with mild symptoms and no lesions at endoscopy (or only an erythema of mucosa), lifestyle modifications and antacids are still recommended as the classical "phase 1" therapy. However, for symptom relief, alginate-containing preparations should certainly be preferred to pure antacids. In France, for instance, a large multicenter trial [38], performed in primary care patients with typical heartburn, showed that about 92% of patients were asymptomatic after a 2-week treatment with an alginate-antacid preparation; moreover, even in those incompletely relieved by treatment, endoscopy showed no or mild esophageal lesions in 60% of them. Antacids or antacid/alginates, however, should not be used alone in severe GERD, when there are persistent or nocturnal symptoms, grade 2 or more esophagitis and/or marked sphincter incompetence with consequent complications.

Acknowledgement

The authors are indebted to Miss Sabina Cavagni for her invaluable help in checking the references and her diligence in the preparation of the manuscript.

References

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Publication date: May 1994 OESO©2015