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Drugs acting on the gastrointestinal tract

Drugs acting on the gastrointestinal tract. Prof. MUDr Jiřina Martínková PhD, 2006/2007. Drugs used to inhibit or neutralise gastric secretion.

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Drugs acting on the gastrointestinal tract

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  1. Drugs acting on the gastrointestinal tract Prof. MUDr Jiřina Martínková PhD, 2006/2007

  2. Drugs used to inhibit or neutralise gastric secretion to reduce acid secretion and peptic ulceration (both duodenal and gastric), reflux, oesophagitis (in which gastric juice causes damage to the oesophagus) Reasons why peptic ulcers develop: - increased mucosal irritation , mucosal-damaging mechanisms enhanced acidity (acid, pepsin,stress, alcohol, cigarette smoking…) - decreased mucosal-protecting mechanisms of the stomach - NSAIDs consumption PGS synthesis is diminished (PGE 1-2 stimulates mucus and bicarbonate secretion decreases acid secretion and causes vasodilation), PGI2 inhibits acid, stimulates mucus and bicarbonate secretion - infection of the stomach mucosawith Helicobacter pylori (chronic gastritis)

  3. Drugs used to inhibit or neutralise gastric secretion Fig. 1 Regulation of acid secretion by parietal cells is important in peptic ulcer. The secretion is an isotonic solution of HCl (150 mmol/L) with a pH less than 1. The Cl- is actively transported into canaliculi in the cells which communicate with the lumen of the gastric glands and thus with the lumen of the stomach. This Cl-secretion is accompanied by K+, which is than exchanged for H+ from within the cell by a PP. Carbonic anhydrase catalyses the combination of carbon dioxide and water to give carbonic acid, which dissociates into H+and bicarbonate ions. The latter exchanges across the basal membrane for Cl- Three main stimuli act on the parietal cells: - gastrin (a hormon) - ACH (a neurotransmitter) - histamine (a local hormone)

  4. GASTRIC PARIETAL CELL intersticial fluid M - muscarinic receptor PGR - prostaglandin E2 receptor ECHB –enterochromaffin cells Gs a Gi - G-proteins cAMP - cyclic AMP Ac - adenylyl cyclase PK - proteinkinase PGE - prostaglandins E C - synport carrier for Cl- a K+ P = antiport, which exchanges Cl- and HCO-3 PP = proton-pump bazolaterall membrane apical membrane

  5. Drugs used to inhibit or neutralise gastric secretion ANTACIDS HISTAMINE H2-RECEPTOR ANTAGONISTS PROTON-PUMP INHIBITORS TREATMENT OF HELICOBACTER PYLORI INFECTION DRUGS THAT PROTECT THE MUCOSA

  6. Drugs used to inhibit or neutralise gastric secretion ANTACIDS act by neutralising gastric acid and thus raising the gastric pH.This has the effect of inhibiting peptic activity, which practically ceases at pH 5.They vary widely in their potency The antacids in common use are salts of magnesium and aluminium: Magnesium trisilicate, aluminium hydroxide, alginates given 1 and 3 hours after each meal and at bedtime used indyspepsia symptomatic relief in peptic ulcer, A. can be effective in promoting healing of duodenal ulcers, their benefit in gastric ulcers is less clear oesophageal reflux

  7. Drugs used to inhibit or neutralise gastric secretion HISTAMINE H2-RECEPTOR ANTAGONISTS The histamine H2-antagonists competitively inhibit histamine action at all H2 –receptors, their main clinical use is as inhibitors of gastric acid secretion. They inhibit histamine - gastrin - and ACH-stimulated acid secretion: both basal and food stimulated by 90% and promote healing of duodenal ulcers Relapses are likely to follow when treatment with H2 –receptors antagonists is stopped Drugs: (cimetidin- a CYP450 inhibitor) ranitidine famotidine Adverse effects: diarrhea, dizziness, muscle pain, transient rashes

  8. Drugs used to inhibit or neutralise gastric secretionPROTON-PUMP INHIBITORS Inhibit the terminal step in the acid secretory pathway – the proton pump which results in markedly inhibition of both basal and stimulated gastric acid secretion Being weak bases, they accumulate in the acid environment of the canaliculi of the stimulated parietal cells where they are activated. This preferential accumulation in areas of very low pH, such as occur uniquely in the secretory canaliculi of gastric parietal cells, results in a specific effect on these cells Given orally (as capsules containing enteric-coated granules) they are absorbed and distributed into the parietal cells and then accumulate in the canaliculi (a single daily dose affects acid secretion for 2-3 days)

  9. Drugs used to inhibit or neutralise gastric secretion PROTON-PUMP INHIBITORS omeprazole lanzoprazole pantoprazole Adverse effects (not very common) headache, diarrhea, rashes… used in: - peptic ulcer - reflux oesophagitis - as one component of therapy for Helicobacter pylori infection - Zollinger-Ellison syndrome (a rare condition caused by gastrin-secreting tumours)

  10. Drugs used to inhibit or neutralise gastric secretion TREATMENT OF HELICOBACTER PYLORI INFECTION H.pylori is implicated in the production of gastric and, more particularly, duodenal ulcers and is a risk factor for gastric cancer Combination therapy with three drugs is employed to eradicate H.pylori like: omeprazole + amoxicillin+ metronidazole or omeprazole + clarithromycin + amoxicillin (tetracycline) + bismuth chelates Elimination of the bacillus can produce long-term remission of ulcers but reinfection can occur

  11. Drugs used to inhibit or neutralise gastric secretion DRUGS THAT PROTECT THE MUCOSA enhance the mucosal protection mechanisms and/or provide a physical barrier over the surface of the ulcer Bismuth chelate has: toxic effects on the bacillus mucosal-protecting effects: coating the ulcer base, adsorbing pepsin, enhancing local PG synthesis, stimulating bicarbonate secretion Adverse effects: nausea, vomiting, blackening of the tongue and faeces used:as one component of therapy for H.pylori infection

  12. Drugs used to inhibit or neutralise gastric secretion DRUGS THAT PROTECT THE MUCOSA Sucralfate A complex of aluminium hydroxide and sulfated sucrose, which in the presence of acid acquires a strong negative charge and binds to positively charged groups in protein forms complex gels with mucus - decreasing mucus degradation and H+ions diffusion stimulates bicarbonate secretion and PGs production Adverse effects: Constipation (in 15% of patients treated) Less common: dry mouth, headache, rashes S.reduces the absorption of a number of other drugs including: fluorochinolone antibiotics, theophylline, tetracycline, digoxin…

  13. Drugs used to inhibit or neutralise gastric secretion DRUGS THAT PROTECT THE MUCOSA Misoprostol A stable analogue of PGE1 which inhibits gastric acid secretion, both basal and stimulated by food or histamine by a direct action on the parietal cells. It increases mucosal blood flow and augments the secretion of mucus and bicarbonate Adverse effects: diarrhea, abdominal cramps, uterine contractions used to prevent gastric damage that can occur with chronic use of NSAIDs

  14. URINARY BLADDER - INNERVATION Symp (L1-L4) parasymp (S2-S4) motor innervation (L2 – S2)

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