Drugs Acting OnDrugs Acting On

Gastrointestinal TractGastrointestinal Tract

Professor Kassim Al-Saudi,

M.B.,Ch.B.,Ph.D.

OBJECTIVESOBJECTIVES Identify classes of drugs used to improve GI

function. Identify uses and varying actions of these

drugs. Identify how these drugs are absorbed,

distributed, metabolized, and excreted. Identify drug interactions and adverse

reactions to these drugs. Be familiar with drug-induced hepatotoxicity

DRUGS AND THE GI DRUGS AND THE GI SYSTEMSYSTEM Classes of drugs used to improve GI

function include:

Peptic ulcer drugs Antiemetic and emetic drugs Antidiarrheal drugs Laxative drugs

Peptic Ulcer•The term “peptic ulcer” refers to an ulcer in the lower Oesophagus, stomach, duodenum (commonly), jujenum and ileum (rarely)

• Gastric and duodenal ulcers may be acute

or chronic

• Acute ulcer shows no evidence of fibrosis

• Both penetrate the muscularis mucosae

• Erosions do not penetrate the muscularis

mucosae

AetiologyAetiology::

1- Infection – Helicobacter pylori (Gm –ve)

- 50% Industrialized

- 90% Developing (Childhood)

- Majority symptoms free

- 90% of DU patients and 70% of GU

patients are infected with H. pylori

2- Acid and Pepsin secretion

3- Mucosal defensive mechanism

Pathogenesis of UlcersPathogenesis of Ulcers

Aggressive Aggressive FactorsFactors

Acid, pepsinAcid, pepsin Bile saltsBile salts Drugs (NSAIDs)Drugs (NSAIDs) H. pyloriH. pylori

Defensive FactorsDefensive Factors Mucus, bicarbonate Mucus, bicarbonate

layerlayer Blood flow, cell renewalBlood flow, cell renewal ProstaglandinsProstaglandins PhospholipidPhospholipid Free radical scavengersFree radical scavengers

Therapy is directed at enhancing host defense or eliminating aggressive factors; i.e., H. pylori.

Aim of TreatmentAim of Treatment

Relief Symptoms Heal Ulcer Prevent recurrence Prevent complications

Lifestyle measuresLifestyle measures

Raise the head of the bed Decrease fat intake Avoid certain foods Avoid lying down for 3 hours after eating Stop smoking Lose weight if appropriate

PEPTIC ULCER DRUGSPEPTIC ULCER DRUGS

Aimed at either eradicating H. pylori or Aimed at either eradicating H. pylori or restoring balance between acid and restoring balance between acid and pepsin secretions and the GI mucosal pepsin secretions and the GI mucosal defense.defense.

These drugs include: systemic antibiotics, These drugs include: systemic antibiotics, antacids, Histamine-2 (H2)-receptor antacids, Histamine-2 (H2)-receptor antagonists, proton pump inhibitors, and antagonists, proton pump inhibitors, and other peptic drugs such as misoprostol other peptic drugs such as misoprostol and sucralfate.and sucralfate.

Eradication of H. pylori

Tests For Initial Diagnosis of Tests For Initial Diagnosis of InfectionInfection

Urea Breath Test and Stool AssayUrea Breath Test and Stool AssayNon-invasive, sensitive and specificNon-invasive, sensitive and specific

SerologySerologyO.K. for initial diagnosisO.K. for initial diagnosisFair sensitivity and specificityFair sensitivity and specificity

Endoscopy Not necessary for diagnosisEndoscopy Not necessary for diagnosis

Who Should Be Treated For Who Should Be Treated For H. pyloriH. pylori Infection Infection??

Patients who have documented Patients who have documented H. pylori H. pylori infection infection and:and:Definitely had or has a duodenal or stomach ulcerHave had stomach lymphoma or family hx of stomach

cancer Consider treatment if:

Presence of “severe histologic” gastritis and H. pylori infection

Ulcer-like dyspepsia in the absence of an ulcer or prior to endoscopy in a young patient

FDA-Approved Treatment FDA-Approved Treatment Regimes for Regimes for H. pyloriH. pylori Infection Infection

Omeprazole 20 mg BID + Clarithromycin 500 mg BID + Amoxicillin 1 g BID for 10 days

Lansoprazole 30 mg BID +Clarithromycin 500 mg BID + Amoxicillin 1 g BID for 10 days

Bismuth subsalicylate (Pepto Bismol) 525 mg QID + Metronidazole 250 mg QID + Tetracycline 500 mg QID X 14 days + H2 receptor antagonist x 4 wks

Known Factors Which Determine Success of H. pylori Therapy

Patient compliance or non-complianceMedicine complications or side effects

Antimicrobial resistance of infecting H. pylori strains Duration of Therapy Correct dosing

Clearance of H. pylori infection is not equivalent to eradication.

Drugs Affecting Gastric Acid Drugs Affecting Gastric Acid SecretionSecretion

PROTON PUMP PROTON PUMP INHIBITORSINHIBITORS

Disrupt chemical binding in stomach cells to reduce acid production, lessening irritation and allowing peptic ulcers to heal.

These drugs include: Omeprazole (Prilosec) Rabeprazole (Aciphex) Pantoprazole (Protonix) Lansoprazole (Previcid) Esomaprazole (Nexium)

PROTON PUMP INHIBITORSPROTON PUMP INHIBITORS

Pharmacokinetics:Pharmacokinetics: Given orally in enteric-coated form to Given orally in enteric-coated form to

bypass the stomach and are dissolved and bypass the stomach and are dissolved and absorbed in the small intestine.absorbed in the small intestine.

Highly protein-bound and are extensively Highly protein-bound and are extensively metabolized by the liver; eliminated in the metabolized by the liver; eliminated in the urine.urine.

PROTON PUMP INHIBITORSPROTON PUMP INHIBITORS

Pharmacodynamics:Pharmacodynamics: Block the last step in the secretion of Block the last step in the secretion of

gastric acid by combining with hydrogen, gastric acid by combining with hydrogen, potassium, and adenosine triphosphate in potassium, and adenosine triphosphate in the parietal cells of the stomach.the parietal cells of the stomach.

PROTON PUMP INHIBITORSPROTON PUMP INHIBITORS

PharmacotherapeuticsPharmacotherapeutics:: Indicated for:Indicated for: Short term treatment of gastric ulcersShort term treatment of gastric ulcers Active duodenal ulcers and peptic ulcers Active duodenal ulcers and peptic ulcers

(H. pylori)(H. pylori) Erosive esophagitisErosive esophagitis GERDGERD Hypersecretory statesHypersecretory states

PROTON PUMP INHIBITORSPROTON PUMP INHIBITORS

Drug interactions:Drug interactions: May interfere with the metabolism of May interfere with the metabolism of

diazepam, phenytoin, and warfarin.diazepam, phenytoin, and warfarin. May also interfere with drugs that depend May also interfere with drugs that depend

on gastric pH for absorption.on gastric pH for absorption.

Adverse reactions:Adverse reactions: Abdominal pain, diarrhea, nausea, and Abdominal pain, diarrhea, nausea, and

vomitingvomiting

Pharmacological therapy – Pharmacological therapy – PPIsPPIs

Significantly more effective than H2RAs for Significantly more effective than H2RAs for both symptom resolution and healing of both symptom resolution and healing of erosive esophagitiserosive esophagitis

Also effective in more severe cases of Also effective in more severe cases of GERDGERD

Most patients respond well to standard Most patients respond well to standard therapy, but some require prolonged and/or therapy, but some require prolonged and/or high-dose treatmenthigh-dose treatment

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case

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2 4 6 8 10Weeks of treatment

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PPIs

H2RAs

Placebo

p < 0.0005

PPIs are the most effective PPIs are the most effective drugs for the initial drugs for the initial treatment of GERDtreatment of GERD

H2-RECEPTOR H2-RECEPTOR ANTAGONISTSANTAGONISTS

Commonly prescribed anti-ulcer drugs Commonly prescribed anti-ulcer drugs include:include:

Cimetidine (Tagamet)Cimetidine (Tagamet) Ranitidine (Zantac)Ranitidine (Zantac) Famotidine (Pepcid)Famotidine (Pepcid) Nizatidine (Axid)Nizatidine (Axid)

H2-RECEPTOR H2-RECEPTOR ANTAGONISTSANTAGONISTS

Pharmacokinetics: Absorbed rapidly and completely except for

famotidine; food and antiacids may reduce absorption; distributed widely throughout the body; metabolized by the liver; excreted primarily in the urine.

Pharmacodynamics: Block histamine from stimulating the acid-

secreting parietal cells of the stomach.

H2-RECEPTOR ANTAGONISTS

Pharmacotherapeutics: Used therapeutically to: Promote healing of duodenal and gastric

ulcers. Provide long-term treatment of

pathological GI hypersecretory conditions. Reduce gastric acid production and

prevent stress ulcers.

H2-RECEPTOR H2-RECEPTOR ANTAGONISTSANTAGONISTS

Drug interactions:Drug interactions: Cimetidine inhibits metabolism of ethyl Cimetidine inhibits metabolism of ethyl

alcohol in the stomach resulting in higher alcohol in the stomach resulting in higher blood alcohol levels.blood alcohol levels.

Adverse reactions:Adverse reactions: Headache, diarrhea, and rashHeadache, diarrhea, and rash

Prevention of ulcers in NSAID Prevention of ulcers in NSAID UsersUsers

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5.2 5.7

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20

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Gastric Ulcer Duodenal Ulcer

Ranitidine 150 mg bidn = 215Omeprazole 20 mg qdn = 210

*

** p< 0.05

Antimuscarinic drugsAntimuscarinic drugsPirenzepine, telenzepinePirenzepine, telenzepine

• • M1 receptors antagonists :M1 receptors antagonists :Pirenzepine, telenzepine (a more potent analog), reduce gastric acid secretion with fewer adverse effects than atropine and others.

• • Contraindicated in some gastric ulcers as theyContraindicated in some gastric ulcers as they may slow gastric emptying and prolong themay slow gastric emptying and prolong the exposure of the ulcer bed to acid.exposure of the ulcer bed to acid.

ANTACIDS

Over-the-counter medications that include: Magnesium hydroxide and aluminum

hydroxide Sodium bicarbonate Calcium carbonate Simethicone

ANTACIDSANTACIDS

Pharmacokinetics:Pharmacokinetics: Work locally in the stomach by neutralizing Work locally in the stomach by neutralizing

gastric acid.gastric acid. Distributed throughout the GI tract; eliminated Distributed throughout the GI tract; eliminated

primarily in the feces.primarily in the feces.

Pharmacodynamics:Pharmacodynamics: Reduce the total amount of acid in the GI tract.Reduce the total amount of acid in the GI tract.

ANTACIDS

Pharmacotherapeutics: Prescribed to relieve pain and promote

healing in peptic ulcer disease. Also used to relieve symptoms of acid

indigestion, heart-burn, dyspepsia, or GERD. Also used to prevent stress ulcers, GI

bleeding, and hyperphosphatemia in kidney failure.

ANTACIDSANTACIDS

Drug interactions: All antacids can interfere with the All antacids can interfere with the

absorption of oral drugs given at the same absorption of oral drugs given at the same time.time.

Adverse reactions: Diarrhea, constipation, electrolyte Diarrhea, constipation, electrolyte

imbalances imbalances

Antacids

Mucosal Protective AgentsMucosal Protective Agents

Tripotassium dicitratobismuthate is a bismuth chelate effective in healing gastric & duodenal ulcers.

Low absorption has been reported

Colloidal Bismuth Subcitrate (CBS) is used in the management of gastric and duodenal ulcers, and in combination with two antibacterials for the eradication of H. pylori.

Bismuth Compounds:

Sucralfate

• It is a complex of aluminium hydroxide and sulphated sucrose but has minimal antacid properties.

• May act by protecting the mucosa from acid-pepsin attack in gastric and duodenal ulcers.

OTHER PEPTIC ULCER OTHER PEPTIC ULCER DRUGSDRUGS

MisoprostolMisoprostol (Cytotec) - Protects (Cytotec) - Protects against peptic ulcers caused by against peptic ulcers caused by NSAIDs by reducing the secretion of NSAIDs by reducing the secretion of gastric acid and by boosting the gastric acid and by boosting the production of gastric mucus.production of gastric mucus.

NSAID Use in the Arthritis NSAID Use in the Arthritis Patient with a History of Patient with a History of

Bleeding UlcerBleeding Ulcer

Treating H. pylori is likely to be of benefit if there was a duodenal ulcer;

test and treat for H. pylori is recommended. Use COX2 Inhibitor Add a PPI or Misoprostol