Acid-inhibition criteria and choice of acid-inhibiting agents for acid-related diseases

Source: Chinese Journal of Digestion, 2023,43(9) : 579-582.

The author of this article is Yuan Yaozong

Acid-related diseases (ARD) are a class of diseases related to gastric acid secretion, and acid suppression therapy can significantly improve the treatment outcomes of ARD, but the criteria for acid suppression vary among ARD. Since the launch of proton pump inhibitors (PPIs), their good acid suppression has greatly improved the prognosis of clinical patients with ARD, and has now become the "gold standard" therapy for ARD. Potassium-competitive acid blockers (P-CAB) have stronger acid suppression effects, and the advent of this new class of drugs can further improve the efficacy of patients with ARD. This article will explain the importance of acid suppression in the treatment of ARD, the common criteria for acid suppression in ARD, as well as the acid suppression effects of PPI and P-CAB and their clinical application in the treatment of ARD, aiming to provide strong evidence for the selection of acid suppression drugs in the clinical treatment of ARD.

1. The importance of acid inhibition in the treatment of ARD

ARD is a common digestive disorder that involves multiple digestive organs such as the esophagus, stomach and duodenum. It mainly includes gastroesophageal reflux disease (GERD), peptic ulcer, Helicobacter pylori (H. pylori) infection, upper gastrointestinal bleeding, and Zollinger-Ellison syndrome.

GERD refers to uncomfortable symptoms or complications caused by the reflux of gastric and duodenal contents into the esophagus, mainly nonerosive relfux disease (NERD), reflux esophagitis (RE), and Barrett's esophagage. GERD is one of the common diseases of the upper gastrointestinal tract, and many factors are associated with this disease, such as excess weight (characterized by obesity), lifestyle, diet, etc. The pathophysiological mechanism of GERD is complex, including functional and structural disorders of the gastroesophageal junction, dysfunction of esophageal clearance and weakened epithelial defense, life-related factors such as obesity and diet weaken the anti-reflux function of the esophagus, and increased esophageal sensitivity. In addition, immune-mediated esophageal mucosal injury and changes in esophageal function may also be associated with the pathogenesis of GERD. Acid-suppressive therapy is the main treatment for GERD, which can reduce the pH value in the stomach, reduce the irritation of the esophagus by reflux gastric acid, effectively alleviate clinical symptoms such as GERD reflux and heartburn, and prevent complications.

Peptic ulcer refers to the inflammatory reaction and necrosis, shedding and ulceration of the mucosa of the digestive tract under the action of various pathogenic factors, and the lesions can reach deep into the muscular layer of the mucosa, and gastric and duodenal ulcers are common. The pathogenesis of peptic ulcer is mainly related to the imbalance between the damage factors of the gastric and duodenal mucosa and the mucosal self-defense-repair factors, among which gastric acid and/or pepsin induce mucosal autodigestion is the damage factor leading to ulcer formation. Acid-suppressive therapy reduces gastric acidity and is directly related to the healing of ulcers, especially duodenal ulcers.

H.pylori infection has been shown to be one of the main causes of peptic ulcer disease and chronic gastritis. Regarding the mechanism of H.pylori-induced peptic ulcer, the results of different studies have differed. The mechanism of gastritis caused by H.pylori infection is related to the inflammatory response induced by direct or indirect damage to the gastric mucosa by bacterial virulence factors, and chronic active gastritis can almost always occur in patients infected with H.pylori. Eradication of H.pylori is of great significance for promoting the healing of peptic ulcer, reducing its recurrence and improving gastritis. For clinical eradication of H. pylori, a quadruple regimen of bismuth is often used, i.e., antacid + bismuth + 2 antibiotics. In addition, some antibiotics in the H.pylori eradication protocol (such as clarithromycin and amoxicillin) are acid-sensitive, and antacids help to improve its stability, prevent its degradation in an acidic environment, and improve the antibacterial and bactericidal effects of H.pylori eradication.

Since the occurrence of ARD is mostly related to gastric acid secretion, acid suppression therapy can quickly relieve related symptoms and provide a good environment for mucosal healing, so acid suppression is the key to the treatment of ARD.

2. Acid suppression standards for common ARD

The efficacy of acid suppression depends on the degree of acid suppression (pH), the holding time ratio (HTR), and the duration of acid suppression. Median or mean pH >3 or >4 alone does not improve cure rates for ARD, pH control time is key, and HTR is associated with drug half-life. Acid inhibition criteria vary for different ARDs (Table 1).

1．GERD：

Reflux of gastric contents can cause damage to the esophageal mucosa when the gastric pH is < 4. Multiple studies have shown that symptom relief and mucosal healing in GERD are associated with an HTR with a gastric pH of > 4.0. A single-center, prospective study showed a lower incidence of persistent acid reflux in patients with GERD at a gastric pH > 5.05. At present, the clinical recommendation for acid suppression therapy for GERD is to achieve 4 weeks of mucosal healing with a pH value of > 4 and HTR > 90%, or to achieve 8 weeks of mucosal healing with a pH value of > 4 and HTR > 75%.

2. Digestive:

In the treatment of peptic ulcer, the pH value in the stomach should be raised to more than 3 for more than 18 hours per day. The results of a meta-analysis showed that when the gastric pH value was increased to more than 3 and the HTR was 75%~85%, the duodenal ulcer could heal within 3~4 weeks, which has been reaffirmed in the "Standard for the Diagnosis and Treatment of Peptic Ulcer (2016, Xi'an)". Therefore, a pH value of > 3 and an HTR of > 75% for 4 weeks can effectively promote peptic ulcer healing.

3. Peptic acne:

Bleeding is the most common complication of peptic ulcers. Studies have shown that an increase in pH can shorten the bleeding time of the gastric mucosa, and when the pH value is > 6.0, the bleeding time of the gastric mucosa is significantly shortened. Jia Lin et al. confirmed through in vivo trials and clinical studies that ≥ 6.0 is the optimal pH for ulcer healing and hemostasis. Another clinical study also showed that pH is closely related to hemostasis, and that gastric pH can only be effective when it is raised to 6.0. Therefore, for peptic ulcer bleeding, a pH of >6 and an HTR of >83% can effectively stop bleeding and promote ulcer healing.

4.H.pylore:

The eradication rate of H. pylori is closely related to the degree of acid inhibition. In the past, it was clinically believed that a gastric pH of >5 and HTR of >75% were effective in eradicating H. pylori. The results of an in vitro study showed that the minimum inhibitory concentration of H. pylori was reduced and the antimicrobial activity of most antibiotics increased when the pH value was increased from 5 to 6. In addition, a number of clinical studies have shown that the 24-hour and nighttime gastric pH values of patients with successful H. pylori eradication were significantly higher than those of patients with failed eradication. Ke et al. found that the pH ≥4, ≥5, and ≥6 of patients with successful H. pylori eradication were higher than those of patients with failed eradication, and most of H. pylori could be successfully eradicated when the median 24-hour pH in the stomach was > 5.7. Sugimoto et al. also found that H. pylori was effective in eradicating H. pylori in clarithromycin-resistant patients > 6, or < 4 with an HT<R of 10%. Based on these results, an intragastric pH of >6 and HTR > 75% are recommended for H. pylori eradication therapy.

3. The acid-inhibiting effect of PPI and P-CAB and their clinical application in the treatment of ARD

At present, the drugs that exert acid-inhibiting effect by inhibiting the activity of H+/K+-ATPase mainly include PPI and P-CAB.

PPI is currently the most commonly used acid suppression drug in clinical practice, and since the first PPI (omeprazole) was launched in 1988, pantoprazole, lansoprazole, rabeprazole, esomeprazole and ilaprazole have been marketed successively. The acid suppression data in healthy people showed that the HTR with a pH value of >3 in the stomach > 70% after 7 days of administration of the standard dose of PPI, the HTR with a pH value of >4 could be maintained at 40%~70%, and the HTR with a pH value of >5 was reduced to about 50%, and the pH value was >The HTR of 6 is further reduced to 29%~44%. The maximum acid suppression effect cannot be achieved after the first dose of PPI administration, and multiple doses are required. At the same time, there are still many deficiencies in PPI in exerting acid suppression effects. As a prodrug, PPI needs to be activated under acidic conditions before inhibiting proton pump activity, so it can exert its maximum acid suppression effect when taken 30~60 min before meals; pharmacokinetic data show that PPI has a slow onset of effect, usually 3~5 days of administration to achieve the maximum acid suppression effect; most of the PPI have a short half-life (1~2 h), resulting in a non-lasting acid suppression ability, and a considerable number of GERD patients will still have nocturnal acid breakthrough after PPI treatment. In addition, PPI is mainly metabolized by cytochrome P450 (CYP) 2C19 metabolic enzymes, and the acid suppression effect is susceptible to the influence of CYP2C19 gene polymorphisms.

P-CAB is a new class of acid-suppressing drugs, which are currently approved for marketing in China, such as vonorasen, tegolasen, and caprassen. P-CAB can competitively and reversibly inhibit gastric acid secretion by blocking the potassium ion exchange channel of H+/K+-ATPase. After 1 day of administration of standard dose (20 mg/time, 1 time/day), the HTR of gastric pH >4 and >5 was >80%, and the HTR of 7 days was >90%, which was significantly better than traditional PPI drugs such as esomeprazole and rabeprazole and other P-CABs, and the HTR of nighttime pH >4 and >5 remained high (>80%). After increasing the number of administrations (20 mg/time, 2 times/d), the acid inhibition effect of vonorasan was significantly improved, and the HTR of pH >5 reached 99% and pH >6 reached 85% on the 7th day of administration. In addition, P-CAB overcomes the limitations of PPIs. Compared with PPI, P-CAB can inhibit H+/K+-ATPase in both activated and resting states without acid activation, and can take effect quickly after administration, reaching the peak plasma concentration in 1.5~2.0 h, and has a longer half-life, of which vonorasen can be as long as 9 h, so P-CAB is better than traditional PPI drugs such as esomeprazole and rabeprazole in inhibiting gastric acid secretion at night. In addition, P-CAB is mainly metabolized by CYP3A4 and is not affected by CYP2C19 genotype, so P-CAB can effectively inhibit acid in patients with different CYP2C19 genotypes.

In conclusion, acid suppression is an important means of treating ARD. Among them, peptic ulcer had the lowest acid suppression standard, which required a pH value of >3 and an HTR of >75% for 4 consecutive weeks, followed by GERD, which had a pH value of >4 and HTR >75% for 8 consecutive weeks, and H. pylori infection and peptic ulcer bleeding had the highest acid suppression standard, with a pH value of >6 and HTR >75% and a pH value of >6 and HTR >83%。 PPI has a good acid suppression effect, but the onset of action is slow, the acid suppression is not complete, it is easily affected by CYP2C19 gene polymorphisms, and it needs to be taken 30~60 min before meals, which affects its efficacy in the clinical application of ARD. Compared with traditional PPIs, new acid-suppressing drugs P-CAB (such as vonorasene) have better acid-inhibition effects, and are more likely to meet the above acid-inhibition criteria for the treatment of ARD than traditional PPIs. At present, a number of P-CAB drugs have been approved for marketing in China, and it is believed that these new antacids will bring good news to more patients with ARD.

Editor: Xu Haiyan