Antacids are salts of weak bases (e.g., sodium bicarbonate, aluminum hydroxide) available as chewable tablets, liquids, and gum. Antacids have a rapid onset of action, making them ideal for treatment of ongoing reflux-like symptoms or PPI breakthrough symptoms [23–25], but the transient neutralizing effect (due to rapid esophageal and gastric emptying) limits effectiveness for prolonged or frequent symptom episodes [25]. Owing to their temporary effect, product labeling generally allows for numerous doses per day (up to 16 tablets per day for some products!) [26]. Antacids have relatively well-characterized safety profiles and are considered safe to use during pregnancy when lifestyle changes alone are not sufficient (although sodium-containing antacids should be avoided, see safety section) [27, 28].

Antacids act through direct neutralization of hydrochloric acid to form chloride salts and water, which reduces the hydrogen ion concentration, raising the pH [29]. Evidence suggests they act primarily to neutralize refluxed acid within the esophageal lumen (Fig. 2), having only a minimal effect on intragastric acidity [30–32]. The onset of neutralization occurs rapidly [32, 33], but the scale and duration of neutralizing effect depends on the specific formulation [30–33]. For example, the chewing and repeated swallowing associated with antacid chewable tablets and gum prolongs the neutralization effect by exposing the esophagus to multiple small doses over a somewhat longer period, as well as stimulating bicarbonate-rich salivary secretion to promote esophageal acid clearance [25].

In terms of symptom relief, patients report meaningful heartburn improvement within 10–20 min of taking antacid [34–36]. A meta-analysis to assess the efficacy of OTC treatments for reflux-like symptoms found the quantity and quality of studies for antacids inferior to those for the other products [37], most likely because the bulk of antacid research was conducted long ago. Using data from randomized controlled trials (RCTs), the therapeutic gain relative to placebo was 11% (0.11 [95% CI: 0.03–0.20]) [37]. The effectiveness and duration of response of each antacid is influenced by the formulation and its acid-neutralizing capacity. However, guidelines have concluded that there is a lack of evidence to favor one antacid over another [38]. Selection will most likely depend on local availability and an individual’s subjective response to the palatability of the product, which can vary considerably [39].

Antacids are quickly eliminated from the stomach and side effects are rare. Magnesium salts can cause diarrhea and aluminum salts constipation, so they are often combined to minimize these adverse effects [29, 40]. Magnesium has slow absorption and is rapidly excreted in the urine, putting individuals with chronic renal failure at risk of hypermagnesemia, especially elderly at-risk patients [40]. Sodium-containing antacids should be avoided in patients on a strict low-sodium diet (e.g., hypertension, cirrhosis, congestive heart failure) [41] and pregnancy, owing to risk of fluid overload and metabolic alkalosis in the mother and fetus [28]. Prolonged use of calcium-containing antacids may increase the risk of hypercalcemia or alkalosis [42]. Some antacids may affect the absorption of concurrently administered medicines including antibiotics (e.g., tetracyclines, quinolones) and antifungals (itraconazole, ketoconazole), so allowing a 2–4 h window between taking antacids and other medicines is advisable [43–45].

Alginate-based formulations are available as tablets or liquids for on-demand use after meals and at bedtime. Updated guidelines suggest empirical alginate treatment as an alternative to empirical PPI treatment for patients with typical symptoms, without risk factors for complications or family history of upper digestive tract malignancies and without alarm symptoms [46], as well as for add-on therapy for PPI breakthrough symptoms [46] and rescue therapy during PPI tapering [46, 47].

Most alginate-based formulations have an antacid component (e.g., sodium bicarbonate, calcium carbonate) to facilitate the primary mechanism of action, which is the formation of an alginate foam raft interface between gastric contents and the esophageal mucosa (Fig. 2) [48–50]. After entering the stomach, three simultaneous chemical reactions take place on contact with gastric acid: (i) alginate is converted to alginic acid; (ii) calcium carbonate releases free calcium ions which bind to alginic acid, cross-linking the polymers to provide raft strength; and (iii) sodium carbonate reacts to form carbon dioxide which becomes trapped with antacid within the matrix of the raft, causing the raft to float on top of the gastric contents [50, 51]. When taken postprandially, the alginate raft co-localizes with the acid pocket [52, 53] and refluxes in place of gastric contents (Fig. 2) [48, 49, 54]. The buoyant raft remains in place while the meal empties from the stomach [55] and in patients with hiatus hernia, it promotes subdiaphragmatic positioning of the acid pocket [52]. Studies have consistently shown that the acid pocket is longer in patients with hiatus hernia [22]. In small hiatus hernia, the acid pocket typically remains below the diaphragm, whereas in approximately 40% of patients with a large hiatus hernia, it extends above the diaphragm and is associated with increased esophageal acid exposure [22]. Promoting a subdiaphragmatic position of the acid pocket may therefore help reduce reflux. Accordingly, alginate-antacid therapy positioned the acid pocket below the diaphragm in 71% of patients compared with 21% receiving antacid alone (p = 0.08) and there was an inverse correlation between a subdiaphragm position of the acid pocket and acid reflux (r = −0.76, p < 0.001) [52]. Magnetic resonance imaging has been used to visualize the disposition of the alginate raft versus an antacid of equivalent acid-neutralizing capacity when taken after a meal [53]. An alginate raft developed at the air-meal interface within 15 min, whereas antacid sank to distal stomach [53]. Gastric acidity and pepsin measured at the esophagogastric junction after 30 min were lower with alginate use compared with patients taking an antacid [53]. Alginates have also demonstrated bioadhesive properties, adhering to the esophageal mucosa and providing protection by minimizing contact with gastric reflux (Fig. 2) [56–59].

Alginate is a structural polysaccharide derived from various species of brown algae (seaweed) [60]. Formulations are complex, varying in the type and amount of alginate and antacid components, resulting in markedly different weights, volumes, raft strength, resilience, porosity, pepsin-binding capacity, and acid-neutralizing capacity (Table 1) [50, 60–62]. Thus, clinical evidence derived from one alginate formulation may not translate to others. While the general term “alginates” is used throughout this review, the reader should refer to individual studies to ascertain the formulation to which the evidence applies. Caution is also required because a brand name can represent different formulations in different countries. For example, “Gaviscon” sold in the USA (Haleon US Holdings LLC., NJ, USA) is a non-raft-forming antacid containing aluminum hydroxide and magnesium carbonate (sodium alginate listed as an inactive ingredient), whereas the range of chewable tablets and liquid formulations sold under the same brand name in other countries contain sodium alginate as the active ingredient (Table 1). Among the Rennie brand (Bayer, Leverkusen, Germany), some products (e.g., Rennie Liquid/Rennie Dual action) contain alginate/alginic acid, whereas other “Rennie” products do not; differences that may not be apparent to the consumer.

As monotherapy, meta-analyses have shown alginates to be more effective than placebo and antacids and statistically non-inferior to PPI and H₂RAs for improvement in reflux-like symptoms [37, 63]. Significant acid reflux reduction and/or symptom control has been demonstrated in patients with late night/night time symptoms [64, 65], with hiatus hernia [52, 66], during PPI tapering [67, 68] or PPI wash-out (in patients referred for investigation) [69], and in pregnancy [70]. Alginates have also demonstrated symptomatic benefit as add-on to PPI therapy in patients with breakthrough reflux symptoms [64, 71], although one RCT with an unusually large placebo response failed to demonstrate statistical significance [72]. A network meta-analysis of treatments for patients with heartburn and/or regurgitation found that the combination of alginate with omeprazole (20 mg) was more effective than either preparation alone after ≥4 weeks of treatment in patients without erosive esophagitis or evidence of severe gastroesophageal reflux disease [73]. By contrast, a study testing a pure non-bicarbonate-containing (i.e., non-raft forming) alginate formulation found no clinical benefit when added to PPI [74].

Owing to their nonsystemic mode of action, alginate-based formulations have a favorable safety profile [60], but caution is required regarding the sodium content (e.g., in some cases of congestive heart failure or renal impairment), calcium content (e.g., in patients with hypercalcemia, nephrocalcinosis, and recurrent calcium containing renal calculi), and potassium content (e.g., in some patients with kidney failure on a controlled potassium diet) [75]. As with antacids, a 2-h time interval is advisable before taking other medicines [75]. Clinical studies and post-marketing experience in pregnant women suggests no adverse effects during pregnancy or breastfeeding [75].

Nonprescription H₂RAs are available as tablets or liquids taken either at the onset of heartburn or 30 min prior to eating food or drink that is expected to trigger heartburn. Product labeling allows 14 days of continuous, twice-daily dosing. However, owing to tachyphylaxis, H₂RAs may be best used as a one-off or short-term treatment for reducing gastric acidity to treat or prevent infrequent episodes of heartburn (e.g., when expected owing to planned overindulgence of food or drink) [25].

H₂RAs block one of three pathways of acid secretion from gastric parietal cells by competitively and reversibly binding to the histamine H₂ receptor (Fig. 2) [25, 42]. By blocking this process, H₂RAs suppress gastric acid secretion under both stimulated and basal conditions, including nocturnal acid secretion [42, 77]. The antisecretory effect of H₂RAs is partly meal-dependent, reflecting differences in the physiological drivers of acid secretion. Basal (interdigestive) secretion is largely histamine-mediated, and H₂RAs are therefore most effective under these conditions, particularly at night (∼70% inhibition). In contrast, meal-stimulated secretion involves gastrin release, vagal cholinergic stimulation (acetylcholine), and histamine; consequently, selective histamine blockade yields only partial suppression of acid output (generally ≤50%) [78]. After famotidine administration, gastric pH begins to rise within 30 min [25], with pH >3 achieved within approximately 70 min [79], lasting for up to 12 h [80]. However, a comparative study found that the initial rise in gastric pH with nonprescription famotidine (10 mg or 20 mg twice daily) had diminished by day 3 owing to tachyphylaxis, and mean percentage time pH >4 was superior with nonprescription PPI (omeprazole 20 mg once daily) compared with famotidine after day 1 [81].

While PPIs are more potent gastric acid suppressants, H₂RAs have a faster onset of action, with most patients gaining meaningful heartburn relief within 1–2 h [34, 35]. On the other hand, while antacids have an immediate effect, H₂RAs exhibit greater and more durable symptomatic improvement [34, 37]. A 2007 meta-analysis comparing OTC therapies showed therapeutic gain of up to 41% with H₂RAs versus placebo, compared with 60% with alginate/antacid combinations, and 11% with antacids (nonprescription PPI not included in analysis) [37]. The addition of H₂RA to a PPI has been shown to reduce night symptoms, but this benefit diminished after day 1 [82, 83], emphasizing tachyphylaxis with H₂RA use for ≥2 consecutive days [84].

Nonprescription H₂RAs are generally well tolerated, with common adverse effects including headache, dizziness, diarrhea, and constipation [85]. Famotidine does not interact with the cytochrome P450-linked drug-metabolizing enzyme system, although the absorption of some medicines may be reduced, including ketoconazole, itraconazole, rilpivirine, cyanocobalamin, and most of tyrosines kinase inhibitors (excluding vandetanib, imatinib) [85]. Owing to a lack of sufficient safety data, they are generally not recommended in pregnant or breastfeeding women [85].

Nonprescription, low dose PPI formulations have been developed for esomeprazole, lansoprazole, pantoprazole, rabeprazole, and omeprazole (availability varies by country) [3]. Nonprescription PPIs are an “intermittent” therapy, usually sold as a 14-day course for once-daily oral dosing, with no more than 3 courses recommended within a 12-month period. They are appropriate for treating individuals experiencing frequent reflux-like symptoms (≥2 days per week) [86–88].

PPIs are prodrugs that require activation by acid to be converted into the active sulphenamide, which binds covalently to exposed cysteine residues on activated gastric H⁺K⁺ ATPase (“proton pump”) (Fig. 2) [89, 90]. Although PPIs have relatively short serum half-lives (<2 h), they continue to inhibit acid secretion after clearance from the serum [89]. After PPI dosing, the resumption of acid secretion is based on multiple physiological mechanisms including de novo pump synthesis, trafficking of inactive proton pumps to the canalicular membrane, reversal of the covalent disulfide bond leading to reactivation of the pump, and pharmacokinetic decline in systemic drug levels [78, 91]. Only a fraction of pumps are active at any given time so repeated doses are required for maximal effect (∼3–5 days to reach steady state) [89]. Further, PPIs are most effective when taken ∼30 min before a meal, thereby facilitating synchrony between optimal blood concentrations of the drug- and meal-induced activation of proton pumps [89]. An analysis of RCT data of PPIs at OTC doses showed that maintenance of intragastric pH >4 was variable among PPIs, with esomeprazole 20 mg performing best by maintaining pH >4 for more than half of the 14-h daytime period when dosed 30 min before breakfast [92]. If a patient experiences symptoms mostly at night, dosing before the evening meal may be preferable [87]. Alternatively, alginate could be taken at bedtime to suppress symptoms related to acid exposure that often occurs on lying down, especially in patients with obesity/hiatus hernia [64, 65].

Nonprescription PPIs are effective at reducing typical reflux-like symptoms versus placebo, with the greatest treatment benefit observed during days 5–14 of the treatment period [93]. They are the most effective self-management treatment option for the prevention of acid-related symptoms [87]. Nonprescription PPIs are proven more effective than H₂RAs at suppressing gastric acid and provide significantly greater symptom relief from day 2 [81, 94]. Patients with typical symptoms (and no evidence of erosive reflux disease) report high rates of satisfaction, with no rebound symptoms and therapeutic benefit that can last for weeks after completing the 14-day course [87, 95].

Nonprescription PPIs are at the lower end of dosing and are considered safe for intermittent use [88]. Specific safety data for nonprescription use of PPI are lacking, but a consensus panel concluded that there is a low risk of adverse effects potentially associated with long-term use, e.g., changes in micronutrient absorption (iron, calcium, magnesium, vitamin B₁₂), osteoporosis, community-acquired pneumonia, or Clostridioides difficile infection [88]. However, nonprescription PPIs are often not taken optimally (30–60 min before a meal) [10] and individuals should be reminded that PPIs are not effective when taken “on-demand” for existing symptoms [96]. Idiosyncratic PPI side effects include headache, rash, dizziness, nausea, abdominal pain, constipation, and diarrhea [24, 88]. PPIs may interact with co-administered medicines by changing their solubility or absorption (by reducing gastric acidity), by modifying metabolism (mostly through the cytochrome P450 enzyme system), or by inhibiting renal proton pumps (altering drug excretion) [88]. Some drug-drug interactions are well documented including atazanavir, ketoconazole, digoxin, and methotrexate [96]. In pregnancy, while most PPIs are considered safe, their use is generally reserved for women with complicated reflux disease or troublesome symptoms not responding to nonsystemic treatments [28].