25 December, 2023

Dengue Surveillance System: A Proposal

Author: Ismail Hossain
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Peptic ulcer disease (PUD) involves break down of the lining of the mucosa and submucosal layer of the stomach (pain after eating) or proximal duodenum (pain relief after eating) and is commonly due to the bacteria Helicobacter pylori or long-term usage of non-steroidal anti-inflammatory drugs (NSAID) like aspirin, ibuprofen, and naproxen. Stress, diet, alcohol, infection, tumors, and corticosteroid use can induce peptic ulcer as well 1.  

Physiology and Etiology of Peptic Ulcer Disease:

The stomach is a reservoir of acidic environment specifically for protein breakdown and protection against ingested infectious agents. The organ’s wall is composed of the mucosal layer, submucosa, muscularis externa and serosa from inside out with the mucosal layer folding to form rugae to increase the surface area. This layer invaginates into the deeper lamina propria layer to form the gastric pits and glands. These gastric glands are lined with four specialized cells, the concentrations of which differ in different parts of the stomach. These are the mucous/foveolar cells, parietal cells, chief cells, and neuroendocrine cells like the G-cells or Entero-Chromaffin like cells (ECL).

Figure-1: The basic action of Parietal Cell and H+/K+ ATPase 3

The surface mucus cells secrete the protective primary layer of mucus that acts as a barrier to the corrosive gastric acid. Parietal cells have canaliculi to increase the cells surface area to secrete gastric hydrochloric acid (HCL) and the intrinsic factor which is necessary for absorption of vitamin B12 in the terminal ileum. Parietal cell secretion is controlled by acetylcholine, histamine, and gastrin by their respective muscarinic, histamine and gastrin receptors. All these receptors are located on the basal side of the cell, and they control the proton pump H+/K+ ATPase on the luminal side of the cell 2.

Chief cells- secrete pepsinogen, the inactive form of the proteolytic enzyme pepsin that digests the proteins into small units of polypeptides. Pepsinogen only becomes activated by HCL. 

The G-cells and the Enterochromaffin-like cells (ECL) are the neuroendocrine cells that produce the hormone gastrin and Histamine respectively. Gastrin can increase H+/K+ ATPase activity directly by stimulating the parietal cells, and indirectly by stimulating the ECL-like cells to release Histamine.

Figure- 2: Gastric Pit and lining cells 4

D-cells secrete Somatostatin, an inhibitory molecule that is activated when acidity level reaches a certain amount. It suppresses the release of gastrin, reducing the overall production of gastric acid 2.

Prostaglandins need a mention as they are the lipid metabolites produced from arachidonic acid by the cyclooxygenase enzyme via cyclooxygenase (COX)-1 and COX-2 pathways in the parietal cells and macrophages in the gastric mucosa 5. They inhibit acid secretion in stomach 6. NSAIDs block the cyclooxygenase enzyme COX-1 pathway, thus blocking the production of prostaglandin, resulting in failure to inhibit acid secretion and exacerbating PUD 7.

Management of PUD:

The treatment protocol of PUD targets to reduce secretion of HCL by suppressing the H+/K+ ATPase pump and healing the crater 2. Historical documents reveal the use of coral powder, kaolin, powder of pearls, and chalk water many centuries ago to abate dyspeptic symptoms. Different regimens evolved since 1950s which includes diet, neutralizing substances, antacids, anticholinergics, prostaglandins, the pathbreaking Histamine receptor antagonists (H2 RA) since the mid-70s to the present-day proton pump inhibitors (PPI) and the potassium-competitive acid blockers (P-CABs) 8.   

Evolution of Drugs:

Earlier this century PUD was treated with milk or a combination of milk diet and antacid. Sodium bicarbonate, calcium carbonate, aluminum hydroxide, magnesium trisilicate, and magnesium hydroxide are the types of antacid used either alone or in combination for heartburn 9. The neutralizing effect is dose dependent, relative to meals and can cause constipation and milk alkali syndrome. They are short acting, known to relief symptoms with some healing effects on the duodenal ulcers only 10.

Currently a combination of aluminum and magnesium hydroxides is used to relieve acute symptoms.

Propantheline, glycopyrronium, poldine, oxyphencyclimine and 1-hyoscyamine were some of the very old anticholinergics used in the treatment of duodenal ulcer (DU) 11.

Pirenzepine, another anticholinergic acts on the muscarinic receptors of the parietal cells to inhibit acid secretion along with reducing the gastric emptying time. It has shown to prevent DU recurrence 12.

Carbenoxolone a derivative of glycyrrhetinic acid (licorice) 13, Sucralfate- a protectant 14 and Tri-potassium di-citrato bismuthate- a complex bismuth salt stable 15  – are all used for healing the ulcer by coating the crater. The bismuth salt also has the property of liberating prostaglandin 16, 17.

The histamine released by ECL cells binds to the Histamine 2 (H2) Receptor on the basolateral surface of the parietal cells which triggers release of HCL by activating the H+/K+ ATPase pump. The H2 receptor antagonists (H2RA) binding to H2 receptor to block histamine’s action has been a game changer in the treatment of PUD. From the late 70s to the early 90s, four types of H2RA namely- cimetidine, ranitidine, famotidine, and nizatidine were developed. They suppress HCL secretion for 24 hours by about 70% and are effective in nocturnal acid secretion 18.

It takes one hour to provide gastric relief and has a duration of action ranging from 4 to 10 hours. H2RAs are eliminated by both liver and kidneys. Drug interaction may occur, particularly with cimetidine. Cimetidine inhibits the liver cytochrome P450 (CYP450) which is a group of isoenzymes that metabolizes steroids, carcinogens, and other drugs like theophylline, selective serotonin reuptake inhibitors, and warfarin 19. Cimetidine use is avoided as its half-life is prolonged in patients with hepatic impairment and it has adverse effects like gynecomastia, reduced sperm count, and impotence in men and galactorrhea in women 20. Patients unfortunately develop tolerance to H2RAs as a result of other pathway upregulation 21.

The Current Dominant Drugs

Proton Pump Inhibitors:

Proton pump inhibitors (PPI) are the major drugs in use for PUD and other acid related disorders at present. Omeprazole, developed in 1989 paved the way for the next generation PPIs- the Esomeprazole, Lansoprazole, Dexlansoprazole, Pantoprazole, Rabeprazole, and Tenatoprazole. Compared to previous anti- ulcer drugs, PPIs demonstrated consistent patient tolerance, excellent safety, and superior acid suppressing capability 22. This group of drugs is the main choice for esophagitis, non-erosive reflux disease (NERD), PUD, prevention of NSAID associated ulcers, Zollinger-Ellison syndrome (ZES), and functional dyspepsia 22. PPIs along with antibiotics effectively increases the gastric pH to eradicate Helicobacter pylori 22.

PPIs are prodrugs that first concentrate in the canaliculi of active parietal cells, then they are cleaved into sulfonamide after being exposed in the acidic environment, which then bind covalently to cysteine residues on the H+/K+ ATPase to actively inhibit acid secretion until replacement pumps can be synthesized (up to 36 hours) 22.

PPIs take three days to achieve maximum acid suppression as they require actively secreting H+/K+ATPase pump on the parietal cells’ surface facing the secretory canaliculus. All pumps are not activated at the same time and the ones inhibited by PPIs will remain inhibited unless reversed by reducing agents like glutathione. However, the newly synthesized pumps or pumps that were activated after the PPIs threshold has fallen will not be inhibited. So, during a single meal neither all parietal cells, nor all pumps are activated. The following meals will recruit more enzymes to the canaliculi which will again pump out HCLs. This rationale along with short half-lives (one hour) of PPIs is an indicator of pre-prandial dosing and explains why it takes few days to achieve full efficacy 23.

Tenatoprazole is an exceptional PPI that has a prolonged half-life of eight hours 22

Figure- 3: Parietal Cell Canaliculi 24

PPIs noncompetitively inhibit the H+/K+-ATPase, the final pathway of acid formation unlike the previous drugs that blocked the muscarinic or H2 receptor that indirectly inhibited HCL secretion. They are the most potent anti-ulcer drugs that reliably maintain intragastric pH >4 for between 15 and 21 hours daily, as compared to only 8 hours for H2RAs. It has clinical importance for some patients due to its long last action and it being more effective post-prandial and controlling nocturnal intragastric pH. Unlike H2RAs,  PPIs maintain its effectiveness for a long time without the need for dose escalation 25.

Potassium-Competitive Acid Blockers & Vonoprazan:

Despite their proven efficacy, PPIs have several limitations that are being reported. First and foremost is the delayed onset of action and their vulnerability to gastric acid degradation 26.

A reported 50% of patients suffering from nonerosive gastro-esophageal reflux disease (GERD) who are on PPIs had unresolved symptoms; 40% patients taking PPIs twice a day had persistent nocturnal symptoms. Long-term use hampered absorption of calcium, magnesium, and vitamin B12. PPIs are contraindicated with clopidogrel because PPIs are metabolized by cytochrome P450 isoenzyme 2C19 and inhibits this enzyme, whereas clopidogrel requires this enzyme to convert to its active molecule. The timing of drug dosing is critical, PPIs must be taken within 1 hour of meals to deactivate the continuously newly expressed proton pumps and to ensure the drug’s bioavailability 22.

These limitations of PPIs spurred the development of the novel drug Potassium-competitive acid blockers (P-CABs) that competitively block the potassium binding site of gastric H+ /K+ ATPase. Once P-CABs are absorbed into the systemic circulation, they accumulate in the canalicular membrane of the parietal cells, where they are exposed to the acidic environment and promptly protonated. In contrast to PPIs, P-CABs are acid-stable and do not require enteric-coated formulations. P-CABs bind ionically to proton pumps and will bind to both active and inactive pumps, thus they do not have to be dosed around meals. This drug has a faster onset of action than PPIs to block acid secretion and elevate intragastric pH due to their ability to quickly achieve peak plasma levels and have shown highest efficacy in inhibiting acid 27, 28.

Vonoprazan is a recently developed novel P-CAB that is characterized by its potent, rapid, and long-lasting effect and reversible inhibition of gastric proton pump by competitively blocking the potassium binding site on the luminal surface of H+ /K+ ATPase 29. Compared to previous P-CABs and PPIs, Vonoprazan has a higher alkaline value when exposed to acid, it undergoes instant protonation and accumulate at high concentrations in the canaliculi of parietal cells, thus determining higher stability in an acidic environment than PPIs 30.

 Vonoprazan is highly selective for binding to H+ /K+ ATPase, can block the proton pump in both acidic and neutral conditions. Furthermore, vonoprazan has stronger potency to inhibit gastric proton pump than other P-CABs resulting in a longer duration of antisecretory effect with a half-life of 12.5 hours. It is absorbed rapidly and reaches high plasma concentration within 2 hours after oral intake. Vonoprazan dissociation rate from proton pump is slow and is not degraded by acid. The molecule has ionic binding to the pump and its effects are reversible and dose dependent. Vonoprazan metabolism has limited influence by CYP polymorphisms and is metabolized to its inactive form mainly by CYP3A4. Due to its rapid, strong, and continuous gastric acid suppression, vonoprazan was approved in Japan for the treatment of acid related diseases 29.

Figure-4: Difference between PPIs and P-CABs 27

The history of anti-ulcer drugs is an ongoing saga. Just when we think, the best is already here, a superior drug comes along. We need to also remember that each person responds differently. It will not be surprising if novel group of drugs arrive in the near future that caters to individual needs. 

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