Peptic ulcer treatment

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pharmacotherapy of peptic ulcer , antiulcer drugs

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  • Cl- ion is actively transported from cytoplasm of to lumen of canaliculus & Na+ ions are actively transported out of canaliculus into cytoplasm of parietal cells. These 2 effects create a negative potential of -40mV to -70mV in canaliculus which in turn causes diffusion of K+ in the canaliculus and also smaller na+, thus in effect kcl and little nacl enters the canaliculusWater dissociates to forms H+ and OH- ions in the cell cytoplasm, H+ ions are actively secreted into the canaliculus in exchange of k+ ions, this active exchange is catalysed by h+k+ Atpase. In addition Na+ ions are actively reabsorbed by separate sodium pump. Thus most of the na and potassium that had diffused into cell are reabsorbed and H+ takes their place in canaliculus. HCL is then secreted outward through open end of canaliculus into lumen of gland
  • This is the diagrammatic representation of the parietal cell, the final enzyme which secretes H+ ions into the apical canalciuli of the parietal cells is H-K Atpase, this can be activayed by Histamine, gastrin and ach via the receptors which are present on the basolateral surface of the parietal cells, out of these 3 histamine which acts through H2 receptors plays an important role because the other 2 gastrin and ach act partly directly and to greater extent indirectly by releasing histamine from paracrineEnterochromaffin cells also known as histaminocytes these histaminocytes have receptors for Ach and gastrin, H2 receptors activate H2 receptors by generating cAMP, muscarinic and gastrin receptors appear to function through Phospholipase C, IP3, DAG pathway. That mobilizes ca2+. The CAMP mediated proton pump activation also involves cA2+ . The secretomotor response to gastrin and cholinergic agonists is expressed fully only in presence of cAMP generated by H2 activation. H2 Antagonists not only supress histamine induced gastric secretion but also gastrin a
  • Therapy is directed at ↓ing acid secretion, enhancing host defense or eliminating aggressive factors; i.e., H. pylori
  • Calcium carbonate
  • These are the first class of highly effective drugs for acid peptic disease, 4 H2 antagonists cimetidine, ranitidine, famotidine and roxatidine, structural similarity to histamine competitively inhibit their interaction on histamine H2 receptors
  • Basal, psychogenic, neurogenic, gastric The volume of pepsin content and intrinsic factor secretion are also reduced but no vitamin B12 deficiency occurs even after prolonged use Usual ulcer healing doses produce 60-70% inhibiton of 24 hr acid output They also have antiulcerogenic property, stress ulcers and nsaid induced ulcers can also be prevented They do not have any action on gastric motility or les Highly selective, no action on H1 or H3 receptors
  • All drugs are absorbed orally adequatelyPreparations: available as tablets, injectionsAnd also in severe hepatic insufficiency. Elderly
  • Peptic ulcers: All four agents are equally effective in promoting healing of duodenal and gastric ulcers. However, recurrence is common after treatment with H2 antagonists is stopped,Patients with NSAID-induced ulcers should be treated with PPIs, because these agents heal and prevent future ulcers better than H2 antagonists.Acute stress ulcers: These drugs are useful in managing acute stress ulcers associated with major physical trauma in high-risk patients in intensive care units. They are usually injected intravenously.Gastroesophageal reflux disease: Low doses of H2 antagonists, recently released for over-the-counter sale, appear to be effective for prevention and treatment of heartburn (gastroesophageal reflux). However, about 50 percent of patients do not find benefit, and PPIs are now used preferentially in the treatment of this disorder. Because H2-receptor antagonists act by stopping acid secretion, they may not relieve symptoms for at least 45 minutes. Antacids more efficiently, but temporarily, neutralize secreted acid already in the stomach. Finally, tolerance to the effects of H2 antagonists can be seen within 2 weeks of therapy.
  • Extremely safe drugs and well toleratedHeadache, dizziness, bowel upset, dry mouthCNS: Confusion, restlessness, Convulsions and coma rarely in elderly patients and in those with renal impairment,especially with large doses infused IV Bolus IV – release histamine – bradycardia, arrhythmia, cardiac arrest, so it should be given by slow iv.Cimetidine hasantiandrogenic action. Displaces DHT from its itscytoplasmic receptors, increases plasma prolactin. And inhibits metabolism of estradiol by liver. High doses given for prolonged periods have produced gynaecomasti, loss of libido impotence and temporary decrease in sperm count Transient elevation of plasma aminotransferases but hepatotoxicity is rare Displaces DHT from its cytoplasmic receptor , ↑prolactin secretion and inhibits degradation of estradiolby liverAntacids
  • Metabolism of propranolol and diazepam is also retarded When H2 blockers used concurrently a gap of 2 hr should be allowed
  • The only significant action of PPI is dose dependent supression of gastric acid secretion without cholinergic or gastric blockade. It is a powerful inhibitor of gastric acid: can totally abolish HCL secretion both resting as well as stimulated by food without much action on pepsin, intrinsic factor, juice volume or gastric motility
  • irreversible inhibition of PPI and new PP synthesis takes time (24 to 48 hour suppression of acid secretion, despite the much shorter plasma half-lives of the parent compounds)They should be administered 30 min before food in morning Plateau state is attained after 4-5 days of dosingbecause an acidic pH in the parietal cell acid canaliculi is required for drug activation, and food stimulates acid production Given on an empty stomach because food affects absorptionConcomitant use of other antisecretory drugs - H2 receptor antagonists – reduces action Metabolites of these agents are excreted in urine and fece
  • Gerd : more complete inhibiton of gastric acid secretion and rapid relief of symptoms, more effective than h2 blockers in healing the lesions , drug of choice in patients with chronic symptoms stage 2 or stage 3 Peptic ulcers: complete healing even those ulcers not healed by h2 blockers drug of choice for NSAID induced ulcers integral part of H Pylori regimen and drug of choice for NSAID induced ulcers
  • Vitamin B12 deficiencyHypergastrinemia which may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and may promote the growth of gastrointestinal tumors (carcinoid tumors )
  • Prostaglandins PGE2 AND I2 produced in the gastric mucosa have protective role : by Have an ill defined cytoprotective action Most important action appears to be their ability to reinforce the mucous layer covering gastric duodenal mucosa buffered by hco3-
  • Antacids are weak bases that neutralize the gastric acid raise the intra gastric pH. Peptic activity is indirectly reduced at higher pH They do not reduce acid production, rather the agents that raise the antral Ph >4 EVOKE reflex gastrinreleasemore acid is secreted especially in patients with hyperacidity and duodenal ulcer “acid rebound occurs and gastric motility is increased The potency of the antacid is generally expressedin terms of ANC
  • Sodium bicarbonate is water soluble acts instantaneously, but the duration of action is short, it is a potnet neutralizer ANC= 12 meq, Ph can raise above 7 also Demerits: absorbed systemically: large doses will induce alkalosis Produces co2 in stomachAcid rebound Increase in sodium load may worsen edema and CHFUse of sodium bicarbonate is restricted to casual treatment of heart burn , provides quick symptomatic relief other uses are to alkalanize the urine and treat acidosisSodium citrate is having properties similar to sodium bicarbonate ANC= 10 but co2 not evolved
  • Capsules & Tablets:PowdersChewable tabletsSuspensionsEffervescent granules and tabletsAlso idecrease the absorption of fluoroquinolones, ,nitrofurantoinThese drugs should be given 2 hrs after giving antacids
  • This drug is aluminium salt of sulfated sucrose Astringent action: precipitates surface protein at ulcer base and acts as a physical barrier preventing acid, bile and pepsin from coming in contact with ulcer base Delays gastric emptying and causes gastric PG synthesis – protective actionThere is also some evidence to suggest that it enhnces PGE synthesis and HCO3-synthesis
  • because increased gastric pH may be a factor in the development of nosocomial pneumonia in critically ill patients, sucralfate may offer an advantage over proton pump inhibitors and H2 receptor antagonists for the prophylaxis of stress ulcers. Due to its unique mechanism of action, sucralfate also has been used in several other conditions associated with mucosal inflammation/ulceration that may not respond to acid suppression, including oral mucositis (radiation and aphthous ulcers) and bile reflux gastropathy.
  • Water soluble but precipitates at pH<5, it is not an antacid but heals 60% ulcer at 4 weeks and 80-90% at 8 weeksGastritis and non ulcer dyspepsia associated with H.Pylori are also improved by CBS120 mg taken ½ hour before major meals and at bed time for 4-8 weeks
  • Single antibiotic regimens not effective proton pump inhibitor or H2 receptor antagonist significantly enhances the effectiveness of H. pylori antibiotic regimens containing amoxicillin or clarithromycin. regimen of 10-14 days of treatment appears to be better than shorter treatment regimens; Fourth, poor patient compliance is linked to the medication-related side effects experienced by as many as half of patients taking triple-agent regimens, and to the inconvenience of three- or four-drug regimens administered several times per day. Packaging that combines the daily doses into one convenient unit is available and may improve patient compliance (Table 45–5). Finally, the emergence of resistance to clarithromycin and metronidazole increasingly is recognized as an important factor in the failure to eradicate H. pylori.
  • 80-92 % OF ERADICTAION RATE
  • Quadruple therapy x 14 days: Proton pump inhibitor twice a day + metronidazole 500 mg three times daily plus bismuth subsalicylate 525 mg + tetracycline 500 mg four times daily
  • Peptic ulcer treatment

    1. 1. Pharmacotherapy of Peptic ulcer
    2. 2. Objectives  Regulation of Gastric acid secretion  Classification of drugs used in peptic ulcer  Mechanism of action, Uses & Adverse effects, drug interactions of  H2 Blockers  Proton pump inhibitors  Antacids  Ulcer protectives  Drugs for eradication of H.pylori
    3. 3. Why Peptic ulcer occurs  Imbalance primarily between Aggressive factors and Defensive factors
    4. 4. Formation of HCL
    5. 5. Regulation of gastric acid secretion
    6. 6. Classification of drugs used in peptic ulcer 1. Drugs that inhibit gastric acid secretion 2. Drugs that neutralize gastric acid (Antacids) 3. Ulcer protectives 4. Anti H. pylori drugs
    7. 7. Classification (Contd.)  Drugs that inhibit gastric acid secretion  H2 receptor blockers: Cimetidine, Ranitidine, Famotidine  Proton pump inhibitors: Omeprazole, Pantoprazole, esomeprazole  Anticholinergics : Pirenzepine  Prostaglandin analogues: Misoprostol
    8. 8. Classification (Contd..)  Drugs that neutralize gastric acid (Antacids)  Systemic: • Sodium bicarbonate, sodium citrate  Non systemic: • Magnesium hydroxide, Mag. Trisilicate, Aluminium hydroxide gel, Magaldrate
    9. 9. Classification (Contd..)  Ulcer protectives  Sucralfate  Colloidal Bismuth Sulfate (CBS)  Anti H. pylori drugs  Amoxicillin, Clarithromycin, Metronidazole, Tinidazole, Tetracycline
    10. 10. H2 ANTAGONISTS
    11. 11. Mechanism of action  Competitively block H2 receptors on parietal cell & inhibit gastric acid production  Supress secretion of acid in all phases but mainly nocturnal acid secretion  Also reduce acid secretion stimulated by Ach, gastrin, food, etc.
    12. 12. Pharmacokinetics  Absorption is not interfered by food  Can cross placental barrier and reaches milk, Poor CNS penetration  The serum half-lives range from 1.1 to 4 hours;  Cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion.  Dose reduction needed in moderate to severe renal insufficiency
    13. 13. Bioavailability 80 50 40 >90 Relative Potency 1 5 -10 32 5 -10 Half life (hrs) 1.5 - 2.3 1.6 - 2.4 2.5 - 4 1.1 -1.6 DOA (hrs) 6 8 12 8 Inhibition of 1 0.1 0 0 CYP 450 Dose mg (bd) 400 150 20 150 Cimetidine Ranitidine Famotidine Nizatidine Comparison of H2 antagonists
    14. 14. H2 antagonists - Uses Promote the healing of gastric and duodenal ulcers  Duodenal ulcer – 70 to 90% at 8 weeks  Gastric Ulcer – 50 to 75%  NSAID ulcers induced ulcers  Stress ulcer and gastritis  GERD  Zollinger-Ellison syndrome  Prophylaxis of aspiration pneumonia
    15. 15. Adverse effects  Headache, dizziness, bowel upset, dry mouth  CNS: Confusion, restlessness  Bolus IV – release histamine – bradycardia, arrhythmia, cardiac arrest  Cimetidine has antiandrogenic actions
    16. 16. Drug interactions  Cimetidine inhibits several CYP-450 isoenzymes and reduces hepatic blood flow, so inhibits metabolism of many drugs like theophylline, metronidazole, phenytoin, imipramine etc.  Antacids reduce the absorption of all H2 blockers
    17. 17. Proton Pump Inhibitors  Most effective drugs in antiulcer therapy  Prodrugs requiring activation in acid environment  Activated forms binds irreversibly to H+K+ATPase and inhibit it Omeprazole Pantoprazole Lansoprazole Esomeprazole
    18. 18. Mechanism of Action  Prodrugs inactive at neutral pH  At pH < 5 rearranges to two charged cationic forms (sulfenamide + sulphenic acid) that bind covalently with SH groups of H⁺K⁺ ATPase and inactivate it irreversibly  Also inhibits gastric mucosal carbonic anhydrase
    19. 19. Pharmacokinetics - PPI  Available as enteric coated tablets  They should be given 30 minutes to 1 hour before food intake  half life is very short and only 1-2 Hrs  Still the action persists for 24 Hrs to 48 hrs after a single dose  Action lasts for 3-4days even after stoppage of the drug
    20. 20. PPI – contd.  Therapeutic uses: 1. Gastroesophageal reflux disease (GERD) 2. Peptic Ulcer - Gastric and duodenal ulcers 3. Bleeding peptic Ulcer 4. Zollinger Ellison Syndrome 5. Prevention of recurrence of nonsteroidal antiinflammatory drug (NSAID) - associated gastric ulcers in patients who continue NSAID use. 6. Reducing the risk of duodenal ulcer recurrence associated with H. pylori infections 7. Aspiration Pneumonia
    21. 21. Comparative success of therapy with PPI and H2 antagonist
    22. 22. Adverse Effects  Nausea, loose stools, headache abdominal pain, constipation,  Muscle & joint pain, dizziness, rashes  Rare  Gynaecomastia, erectile dysfunction  Leucopenia and hepatic dysfunction  Osteoporosis in elderly on prolonged use  Hypergastrinemia
    23. 23. Drug interactions  Omeprazole inhibits the metabolism of warfarin, phenytoin, diazepam, and cyclosporine.  However, drug interactions are not a problem with the other PPIs.
    24. 24. PPI – Dosage schedule  Omeprazole 20 mg o.d.  Lansoprazole 30 mg o.d.  Pantoprazole 40 mg o.d.  Rabeprazole 20 mg o.d.  Esomeprazole 20-40 mg o.d
    25. 25. Proton Pump Inhibitors  Lansoprazole :  Partly reversible, more potent, slightly more against H pylori, Higher BA, rapid onset.  Pantoprazole:  More acid stable, I.V, CYP450 less affinity  Rabeprazole: claimed to most rapid  Es-omeprazole  Better intragastric pH , higher healing rates.
    26. 26. Muscarinic antagonists  Block the M1 class receptors  Reduce acid production, Abolish gastrointestinal spasm Pirenzepine and Telenzepine  Reduce meal stimulated HCl secretion by reversible blockade of muscarinic (M1) receptors on the cell bodies of the intramural cholinergic ganglia  Unpopular as a first choice because of high incidence of anticholinergic side effects (dry mouth and blurred vision)
    27. 27. Prostaglandin analogues- Misoprostol  Inhibit gastric acid secretion  Enhance local production of mucus or bicarbonate  Help to maintain mucosal blood  Therapeutic use:  Prevention of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)
    28. 28. Misoprostol  Doses: 200 mcg 4 times a day  ADRs:  Diarrhoea and abdominal cramps  Uterine bleeding  Abortion  Exacerbation of inflammatory bowel disease and should be avoided in patients with this disorder Contraindications: 1. Inflammatory bowel disease 2. Pregnancy (may cause abortion)
    29. 29. Antacids  Weak bases that neutralize acid  Also inhibit formation of pepsin (As pepsinogen converted to pepsin at acidic pH)  Acid Neutralizing Capacity:  Potency of Antacids  Expressed in terms of Number of mEq of 1N HCl that are brought down to pH 3.5 in 15 minutes by unit dose of a preparation (1 gm)
    30. 30. Systemic antacids  Sodium Bicarbonate:  Potent neutralizing capacity and acts instantly  ANC: 1 gm = 12 mEq  DEMERITS:  Systemic alkalosis  Distension, discomfort and belching – CO2  Rebound acidity  Sodium overload
    31. 31. Non systemic antacids  Insoluble and poorly absorbed basic compounds  React in stomach to form corresponding chloride salt  The chloride salt again reacts with the intestinal HCO3- so that HCO3- is not spared for absorption
    32. 32. Non systemic Antacids  Magnesium hydroxide (ANC 30 mEq)  Aqueos suspension is called Milk of magnesia  Magnesium trisilicate (ANC 10 mEq)  Aluminium Hydroxide (ANC 1-2.5mEq/g) (Magaldrate – hydrated hydroxy magnesium aluminate)
    33. 33. Non systemic antacids  Duration of action : 30 min when taken in empty stomach and 2 hrs when taken after a meal  Adverse effects:  Aluminium antacids – constipation (As they relax gastric smooth muscle & delay gastric emptying) – also hypophosphatemia and osteomalcia  Mg2+ antacids – Osmotic diarrhoea  In renal failure Al3+ antacid – Aluminium toxicity & Encephalopathy
    34. 34. Miscellaneous drugs  Simethicone: Decrease surface tension thereby reduce bubble formation - added to prevent reflux  Alginates: Form a layer of foam on top of gastric contents & reduce reflux  Oxethazaine: Surface anaesthetic
    35. 35. Chemical reactions of antacids with HCl in the stomach
    36. 36. Drug interactions  By raising gastric pH & forming insoluble complexes ↓ absorption of many drugs  Tetracyclines, iron salts, H2 Blockers, diazepam, phenytoin, isoniazid, ethambutol
    37. 37. Sucralfate – ulcer protective  Aluminium salt of sulfated sucrose  MOA:  In acidic environment ( pH <4) it polymerises by cross linking molecules to form sticky viscous gel that adheres to ulcer crater - more on duodenal ulcer  Astringent action and acts as physical barrier  Dietary proteins get deposited on this layer forming another coat
    38. 38. Sucralfate – contd.  Concurrent antacids avoided, (as it needs acid for activation)  Uses:  Prophylaxis of Stress ulcers  Bile reflux gastritis  Topically – burn, bedsore ulcers, excoriated skins  Dose: 1 gm 1 Hr before 3 major meals and at bed time for 4-8 weeks  ADRs: Constipation, hypophosphatemia  Drug interactions : adsorbs many drugs and interferes with their absorption
    39. 39. Colloidal Bismuth Subcitrate (CBS)  Mechanism of action  CBS and mucous form glycoprotein bi complex which coats ulcer crater  ↑ secretion of mucous and bicarbonate, through stimulation of mucosal PGE production  Detaches H.pylori from surface of mucosa and directly kills them
    40. 40. Colloidal Bismuth subcitrate  Dose: 120 mg 4 times a day  Adverse effects  blackening of tongue, stools, dentures  Prolonged use may cause osteodystrophy and encephalopathy  Diarrhoea, headache, dizziness
    41. 41. Eradication of H.pylori No acid No ulcer OLD TESTAMENT No HP No ulcer NEW TESTAMENT
    42. 42. H. pylori  Gram (-) rod  Associated with gastritis, gastric & duodenal ulcers, gastric adenocarcinoma  Transmission route fecal-oral  Secretes urease → convert urea to ammonia  Produces alkaline environment enabling survival in stomach  Higher prevalence in Low SES
    43. 43. Who are they ? Barry J Marshall J. Robin Warren Nobel Laureates of Medicine – 2005 Discovery of H. pylori & its role in peptic ulcer
    44. 44. Triple Therapy The BEST among all the Triple therapy regimen is: Omeprazole / Lansoprazole - 20 / 30 mg bd Clarithromycin - 500 mg bd Amoxycillin / Metronidazole - 1gm / 500 mg bd Given for 14 days followed by P.P.I for 4 – 6 weeks Short regimens for 7 – 10 days not very effective
    45. 45. Other 2 weeks regimen(mg)  Amoxicillin 750/ + Tinidazole 500 +omeprazole 20 mg/ lansoprazole 30 mg BD  clarithromycin 250 + Tinidazole 500/amoxicillin 1000 + lansoprazole 30 mg BD
    46. 46. Thank You

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