Acid Control

• Peptic ulcer formation from an imbalance between the mucosal damaging

  (acid, pepsin) and the mucosal protecting agents (mucus,

  bicarbonate, prostaglandins E 2 and I 2 , and NO. Also can be caused by infection of gastric mucosa with h. pylori
• the secretion of the parietal cells is an isotonic solution of HCl (150mmol/L) with a pH < 1
• H+ is exported by the proton pump, and this is one of the target of gastric acid secretion inhibition
• The protective prostaglandins E2 and I 2 (local hormones) inhibit acid secretion.
• simple chemical drugs (antacids) are a therapeutic agent that reduce gastric activity. drugs interfering with biological processes: muscarinic receptor antagonists, H2 receptor antagonists (different to allergy pathway), proton pump inhibitors (PPIs)
• antacids neutralise the acid once it's in the stomach. DO NOT prevent the over-production of acid
• Antacids can be magnesium salts (carbonate, hydroxide, oxide, trisilicate). dangerous when used with renal failure, as failing kidneys can't excrete magnesium causing accumulation. eg Maalox.
• Antacid = calcium salts. carbonate predominant form. could cause kidney stones. long use may cause hyperacidity rebound due to increased gastric acid secretion. often advertised as an extra source of dietary calcium
• Antacids can be sodium salts eg bicarbonate. Highly soluble, quick onset, short duration. may cause metabolic alkalosis. sodium content can cause problems for patients with hypertension or renal insufficiency.
• antacids can be aluminium salts eg carbonate, hydroxide, phosphate. have constipating effects. often used with magnesium to counteract constipation.
• Histamine H2 receptor antagonists:

  •prevent Peptic ulcers & GORD

  • Histamine H2 receptor antagonists inhibit binding

  • High affinity for the H2 receptor (e.g. cimetidine with a Kd of 42 nM)

  •Decrease both basal acid secretion and food stimulated acid secretion by

  90%), but also promote healing of duodenal ulcers.

  Cimetidine, Ranitidine

  Their use has declined with the availability of the proton pump inhibitors.
• PPIs inc. omeprazole (prilosec), lansoprazole (prevacid) and pantoprazole (protonix). central sulfur atom. act by irreversibly blocking the H+/K+ ATPase (gastric proton pump) in the gastric parietal cells. THis is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen. They are prodrugs --> need to be converted into active compound by acid-catalysed activation (prevents side effects in other areas of the body as only stomach has enough acid)
• Benzimidazoles are protonated at acidic pH on their pyridine nitrogen into sulfenamides (active) (closes ring). Steals cystseine residue to block action of proton pump
• the sulfenamide-SH group interaction is irreversible enzyme inhibition. covalently bind to cysteine residues of the proton pump (p-type ATPases). However, they may bind to glutathione --> loss of inhibitory action
• PPIs bind on Cys 813, 822, 321 (pantoprazole only does 813 though)
• Non proton pump ATPases remain unaffected by PPIs, so other tissues don't get effected. This is because they are too compact to access their cysteine
• Resting PPs are present in cytoplasmic tubules (pH=5). upon stimulation; they move to be inserted into secretory canaliculli (pH=1). activation of PPIs occurs only in the secretory canaliculli. PPIs are effective on stimulated proton pumps, not on resting proton pumps.
• Drug elimination alone is not important for proton pump recovery (irreversible inhibitors). PPI half life in plasma = short = 0.5-3h. recovery half life = 15h omeprazole. rate of turnover of proton pumps is important since binding of PPIs to PPs is covalent. Half life of PPs is 48h >> 15h recovery. Difference explained by reactivation of blocked PPs by GSH in a sulfide exchange reaction. Varies in strength from one PPI to another.
• PPIs have 87.2% market share of anti-peptic ulcer drugs
• PPI use >12 weeks inc. risk of premature death (discovered 2015). Inc. risk CAD, gastric cancer, chronic kidney disease.
• Eradication with a 1-2 week regimen of triple therapy of h. pylori promotes rapid and long-term healing of peptic ulcers. Testing is routine practice.
• Triple therapy = PPI + amoxicillin and metronidazole/clarithromycin
• h. pylori = antibacterial resistant at low pH. PPI raise pH to 6 at high dose = > response
• Stomach lining is protected by mucous-secreting cells in the gastric mucosa and bicarbonate ions secreted and trapped in the mucous, creating a gel-like protective barrier that maintains the mucosal surface at pH 6-7 in the face of the lumen's 1-2pH.
• Locally produced 'cytoprotective' prostaglandins stimulate the secretion of mucous and bicarbonate - NSAIDs might inhibit this process. Could contribute to peptic ulcers.
• Cephalic phase → the sight, smell, taste or thought of food.

  Processed by brain → activate enteric neurons via parasympathetic preganglionic neurons travelling in vagus nerve
• Gastric phase → food bolus in stomach stimulates acid secretion

  Stretch sensed by mechanoreceptors → enteric neurons → parietal cell (reflex arc)

  Peptides and amino acids in food stimulate g cells to release gastrin

  Food raises pH, reduces somatostatin secretion
• Intestinal → chyme enters duodenum → negative feedback loops prevent chyme becoming too acidic. Neural + hormonal reflexes. CCK, secretin, GLP-1 and GIP act as enterogastrones. Enterogastrones inhibit stomach processes including acid secretion.