4.Drugs and gastrointestinal disease

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Drugs and Gastrointestinal Disease:

Drugs and Gastrointestinal Disease

Outline :

Outline Peptic ulcer disease Gastro-oesophagel reflux disease (GORD) Diarrhoea and constipation Nausea and vomitting Inflammatory bowel disease Irritable bowel syndrome

Objectives :

Objectives Understand the classes of drugs used in the treatment of major GIT diseases metioned above Understand the group pharmacology (PK, mechanism of action, clinically significant adverse reactions and interactions Understand the clinical use of these drugs

Peptic Ulcer:

Peptic Ulcer Aims of treatment Relieve pain Heal the ulcer Prevent ulcer diathesis Pathopysiology Disruption of the balance between aggressive and protective factors in the upper GIT

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Two important factors disrupting balance between acid/peptic attack and mucosal resistance: Helicobacter pylori infection Non-steroidal antiinflammatory drugs (NSAIDs) H. pylori Stimulates increased gastrin release and thereby increased acid secretion Causes direct damage to the mucosa further disrupting physiological balance NSAIDs Impair mucosal resistance but do not alter acid secretion

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H. pylori infection Present in almost all patients with duodenal ulcer Present in most patients with gastric ulcer Now clear that eradication of H. pylori infection is associated with prolonged remission from peptic ulcer disease and perhaps with permanent cure Recognition of the role of H. pylori in peptic ulcer disease and development of effective erradication treatements have had enormous impact on the approach to the patient with peptic ulceration

Drugs used in the Treatment of Peptic Ulcer:

Drugs used in the Treatment of Peptic Ulcer Antiacids Drugs that inhibit gastric acid secretion H 2 -receptor anatagonists Proton pump inhibitors Synthetic prostaglandin analogues

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Drugs that do not directly inhibit gastric acid secretion Chelated salts of bisthmus Sucralfate Drug combinations to eradicate H. pylori

Antiacids :

Antiacids Mechanism of action They are weak alkalis and therefore, partly neutralise free acid in the stomach May also stimulate mucosal repair mechanisms around ulcers (possibly by stimulation of local prostaglandin release

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Pharmacokinetics Principally salts of magnesium or aluminium and are not absorbed from the GI to any appreciable extent Some, such as sodium bicarbonate, are absorbed Adverse effects Absorbable antiacids should not be administered in the long term Antiacids with high sodium content should be avoided in patients with impaired cardiac function or chronic liver disease

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Drug interactions Antiacids may reduce the absorption of a number of different drugs from the gut These include: digoxin, phenothiazines, and tetracyclines Clinical use Antiacids are mainly used for symptomatic relief in patients with peptic ulcer, GORD and non-ulcer dyspepsia They can accelerate healing of peptic ulcer when given frequently and in high doses Suitable acids are aluminium hydroxide and magnesium trisilicate

Drugs that inhibit gastric acid secretion:

Drugs that inhibit gastric acid secretion H 2 -receptor antagonists Four such agents available on the market: cimetidine, ranitidine, nizatidine, and famotidine Mechanism of action Competitive inhibition at the H 2 -receptor Reduce acid secretion by parietal cells especially at night and in fasting state Less effective in reducing food stimulated acid secretion

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Pharmacokinetics Well absorbed following oral administration Relatively short half-lives and are excreted largely unchanged by the kidneys Adverse effects Cimetidine weakly anti-androgenic in humans (may cause impotence or gynaecomastia) Cimetidine or ranitidine may cause reversible mental confusion (especially in sick elderly patients) Some potentially serious cardiac dysarrhythmias have occured following iv injectiins of H2-receptor antagonists

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Drug interactions Cimetidine inhibits oxidative drug metabolism by the liver Interacts with many drugs but only three are of clinical importance (phenytoin, theophylline, and warfarin) These drugs metabolised in the liver and have narrow therapeutic indices Cimetidine slow metabolism of these drugs and may induce toxicity No clinically relevant drug interactions have been reported with the other H 2 -receptor antagonists

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Clinical use Can heal DUs and benign GUs Can be effective (higher doses) in some patients with GORD (milder grades of severity) Important that patients are advised to have nothing firther by mouth after dosing No proven value in patient with upper GI haemorrhage Propylaxis in some critically ill patients in an effort to prevent stress-related mucosal haemorrhage Without H. Pylori eradication peptic ulcer relapse common after stopping treatment (need long-term maintenance treatment

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Proton pump inhibitors: omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole Mechanism of action These are irreversible inhibitors of the proton pump on the parietal cell membrane Proton pump: an enzyme (H+/K+ -ATPase) that actively secretes H+ into the gastric lumen, responsible for final step in acid secretion Blocking the proton pump causes marked (but temporary, supression of gastric acid secretion to any stimulus including food

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Pharmacokinetics Administered as delayed release preparations Bioavailability of omeprazole limited after the first dose increases with repeated once daily dosing reaching plateau by aroung the 5 th day Short elimination half-lives (1 –2 h) but prolonged pharmacological effect Converted in the liver to inactive metabolites

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Adverse effects Mild and infrequent No serious life-threatening adverse effects have been encountered Drug interactions Omeprazole reduces the clearance and prolongs the elimination of diazepam, phenytoin, and warfarin through inhibition of their hepatic matabolism No clinically important drug interactions have been reported with the other proton pump inhibitors

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Clinical use Treatment of severe, erosive oesophagitis Treatment and prophylaxis of NAIDs-induced ulcers Used in combination with antibiotics in the eradication of H. Pylori Treatment of Zollinger-Ellison syndrome Intravenous preparations are also used, in combination with endoscopic treatment, for the treatment of bleeding peptic ulcers

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Synthetic prostaglandins: misoprostol Mechanism of action Not fully understood However, prostaglandins are weak inhibitors of gastric acid secretion when given in pharmacological doses Shown in animal studies to prevent or limit experimental damage of the gastric or duodenal mucosa (‘cytoprotection’) from variety of noxious stimuli Cytoprotection demonstrable at doses below those required for inhibition of gastric acid secretion

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Pharmacokinetics Misoprostol has a short plasma half-life May act on the stomach both locally and sytemically Adverse effects Self-limiting mild diarrhoea in 40 % of patients May cause abortion, should not be given to women of child-bearing age

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Clinical use Mainly used to prevent gastric mucosal damage and GUs in patients on NSAIDs (200µg twice to four times daily) Misoprostol should be considered for those patients who genuinely require to take NSAIDs and who have a past history of peptic ulcer or upper GI bleeding

Drugs that do not directly inhibit gastric acid secretion:

Drugs that do not directly inhibit gastric acid secretion Chelated salts of bismuth: tripotassium, dicitrato bismuthate Mechanism of action Not fully understood However, bismuth salts do supress H. pylori infection and thus reduce the hypersecretion of acid induced by the infection

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Bismuth salts may form an insoluble protective layer over the ulcer base preventing further damage by acid and pepsin They may also stimulate local prostaglandin production Pharmacokinetics Small quantity of bismuth is absorbed following oral administration Urinary excretion continues for over 2 weeks after stopping a course of treatment

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Adverse effect Liquid preparations should be avoided because: unpleasant smell and taste; and discolours the tongue Liquid or tablet preparation may colour faeces black Not recommended for continous or repeated administaration as long-term consequences of bismuth absorption are unknown

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Clinical use Main use of bismuth-containing compounds is as part of drug combination against H. pylori When combined with metronidazole and another antibiotic such as tetracycline, can eradicate infection in 80 – 90 % of patients within 2 weeks However, frequent doses are necessary and compliance may be a problem

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Sucralfate (sucrose aluminium octasulphate) Mechanism of action Exact mechanism unknown May act by coating ulcer bases or stimulating local prostagladin release Does not directly affect acid secretion Like bismuth salts it supresses H. pylori infection Probably supresses H. Pylori by interfering withability of the organism to bind to mucosal epithelial cells

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Clinical use Sucralfate is indicated for the treatment of DU and benign GU Should not be used in patients with chronic renal failure because of the risk of aluminium absorption and toxicity Pharmacokinetics Sucralfate acts locally; only small amounts of aluminium are absorbed Drug interaction Sucralfate can reduce absorption of a number of different drugs, including phenytoin and tetracycline

Gastro-oesophageal reflux disease:

Gastro-oesophageal reflux disease Aims of treatment To relieve symptoms To heal lesions of oesophagitis To prevent complications Pathophysiology Functionally incompetent lower oesophageal sphincter that relaxes inappropriately, at times other than during swallowing

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This allows excessive reflux of gastric contents, containing acid and pepsin into the oesophagus Acid material remains in contact with the mucosa for prolonged periods Gastric acid secretion is usually normal Some patients have delayed gastric empyting

Drugs used in the treatment of GORD:

Drugs used in the treatment of GORD Antiacids and antiacid/alginate preparations Antiacids in combination with an alginate are though to provide a protective coating to the lower oesophagus, preventing contact with refluxed gastric contents Drugs that inhibit gastric acid secretion H 2 -receptor antagonists: they may have to be given in much higher doses than in peptic ulcer (e.g. Ranitidine, 300mg 6-hourly)

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Proton pump inhibitors: they are highly effective in treating all grades of GORD and are superior to H2-receptor antagonists in controlling symptoms and in healling oesophagitis Drugs that act on oesophageal and/or gasric motility (metoclopramide, domperidone) May be effective in patients with mild grades of GORD They have weak tonic effect on the lower oesophageal sphincter May improve oesophageal clearance and may also improve gastric emptying Metoclopramide is not recommended for long-term use because of CNS adverse effects

Diarrhoea and constipation:

Diarrhoea and constipation Diarrhoea Drugs used depend on the cause of the diarrhoea Irritable bowel syndrome Mebeverine is an antispasmodic agent without significant anticholinergic effects It is useful in relieving symptoms in some patients

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Enteric-coated capsules of pappermint oil are useful in relieving gut spasms in some patients Pancreatic insufficiency A preparation of exogenous pancreatic enzymes containing trypsin, lipase and amylase is given for patients with chronic pancreatic exocrine insufficiency (e.g. Chronic pancreatitis, cystic fibrosis) H2-receptor antagonists may be given also inorder to prevent denaturation of pancreatic enzymes by gastric acid

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Drugs used in non-specific diarrhoea Codeine phosphate Morphine Diphenoxylate Loperamide Drugs used in non-specific constipation Drugs that increase faecal bulk: non-absorbable polysaccharides as in bran, ispaghulia or sterculia, agents of choice where treatment is likely prolonged

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Stimulant laxatives: stimulate intenstinal motility (myenteric nerve plexus), e.g. senna and bisacodyl Stool softners: liguid paraffin best known agen, acts by lubricating faeces aiding passage along the bowel; long-term use can cause malabsorption of fat soluble vitamins; not indicated for infants as inhalation of the liquid may produce lipoid pneumonia Osmotic laxatives: agents that retain water in the bowel; increase faecal bulk and mositen faeces (e.g. Lactulose and salts of magnesium

Nausea and vomiting:

Nausea and vomiting Treatment aims Establish underlying cause and give specific treatment Give symptomatic treatment Pathophysiology Vomiting controlled by two separate brain centers (vomiting center and chemoreceptor trigger zone) Trigger zone may be activated endogenously or exogenously by toxins or drugs e. g. opiates

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Activation of the trigger zone stimulates the vomiting center Act of vomiting controlled by vomiting center mainly through vagal action The vomiting center has afferent input from the gut, higher cortical centers and the vestibular apparatus Muscarinic receptors and histamine H1-receptors are highly concentrated around the area of the vomiting center

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Drugs used in treatment of vomiting Anticholinergic drugs: hyosine Antihistamines: promethazine Dopamine antagonists: phenothiazines (chlorpromazine, prochlorperazine); metoclopramide; domperidone Cannabinoids: nabilone Serotonin antagonists: ondansetron

Inflammatory bowel disease:

Inflammatory bowel disease Treatment aims To obtain remission in periods of relapse To prolong periods of remission Pathophysiology Ulcerative colitis and Crohn’s disease are chronic inflammatory conditions of unknown aetiology There is increasing appreciaition of the importance of alterations in the mucosal immune responses to resident luminal bacteria

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Both diseases are characterised by episodes of remission and relapse The aim of drug treatment is to control inflammation and bringing about remission Treatment also depends on psychological support, correction of nutritional deficiencies, and possibly surgery

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Drugs used in the treatment of inflammatory bowel disease Corticosteroids Proven value in the treatment of acute relapses of ulcerative colitis and Crohn’s disease Route of administration dependent on severity of disease (oral, rectal or iv) Budesonide, a synthetic corticosteroid with extensive first pass metabolism (less systemic side effects) An oral controlled release formulation of budesonide is used for terminal Crohn’s disease

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Steroids are of no value in ulcerative colitis in remission and should be withdrawn when clinical remission is achieved No good evidence that long-term steroids help Crohn’s disease Aminosalicylates Preparations designed to deliver the drug to the distal GI Mesalazine (a controlled release preparation of 5-aminosalicylic acid) Olsalazine (two molecules of 5-ASA linked by an azo bond that is split by colonic bacteria to release 5-ASA within the colon

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Balsalazide, a prodrug of 5-ASA Sulphasalazine consists of 5-ASA linked to sulphapyridine by an azo bond that is split in the colon by bacterial azo-reductases Mechanism of action It is thought that 5-ASA exerts a local anti-inflammatory effect. Adverse effects Blood dyscrasias, renal damage, and (with olsalazine) waterly diarrhoea Clinical use Used in the management of mild-moderate ulcerative colitis and in the maitenance of remission

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Azathioprine Mechanism of action An immunosupressive agent which may be useful in improving control in patients with severe IBD proving difficult to control on steroids and aminosalicylates Adverse effects May cause bone marrow supression May reduce the immune responses particularly to viral infection Clinical use Patients to report to their doctor immediately if develop symptoms such as sore throat or bleeding tendency and blood counts shoud be checked regularly

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Other immunosupressants Use is restricted to physicians with experience in their use Ciclosporin: used in patients with severe ulcerative colitis not responded to parenteral corticosteroids Methotrexate: may induce remission in patients with Crohn’s disease not able to tolerate or are unresponsive to azathioprine Infliximab: a monoclonal antibody against TNF-α, has recently become available and is used for severe active Crohn’s disease that has not responded to corticosteroids, azathioprine or methotrexate