PEPTIC ULCERPEPTIC ULCER

Definitions: Definitions: Stomach or duodenal mucosal Stomach or duodenal mucosal lesionslesions

Occurrence:Occurrence: due to imbalance between due to imbalance between aggressive factors and mucosal protective aggressive factors and mucosal protective mechanisms.mechanisms.

PEPTIC ULCERPEPTIC ULCER

Aggressive factorsAggressive factors

Pepsin secretion - acid secretion Pepsin secretion - acid secretion

Protective factorsProtective factors

Prostaglandins (E2 & I2 )Prostaglandins (E2 & I2 )

Mucus/bicarbonate secretionMucus/bicarbonate secretion

Mucosal blood flowMucosal blood flow

Rapid turnover of gastric mucosaRapid turnover of gastric mucosa

Risk factorsRisk factors H Pylori infectionsH Pylori infections AlcoholAlcohol SmokingSmoking DietDiet Drugs (NSAIDs, corticosteroids).Drugs (NSAIDs, corticosteroids). StressStress Genetic factorsGenetic factors Diseases (Zollinger Ellison Syndrome).Diseases (Zollinger Ellison Syndrome).

SYMPTOMS:SYMPTOMS:

Nausea – Vomiting – AnorexiaNausea – Vomiting – Anorexia Upper abdominal pain.Upper abdominal pain.

Weight loss.Weight loss. Heart burn.Heart burn.

COMPLICATIONS:COMPLICATIONS:

Gastrointestinal hemorrhageGastrointestinal hemorrhage Chronic iron deficiency anemia Chronic iron deficiency anemia

Pyloric stenosisPyloric stenosis PerforationPerforation

Gastric secretionsGastric secretions

1.1. Pepsinogens Pepsinogens (Chief cells).(Chief cells).

2.2. HCl and intrinsic factor HCl and intrinsic factor (Parietal cells).(Parietal cells).

3.3. Gastrin Gastrin (G-cells).(G-cells).

4.4. Mucus, bicarbonate Mucus, bicarbonate (mucus-secreting cells).(mucus-secreting cells).

Regulation of Gastric secretionsRegulation of Gastric secretions

1.1. Histamine Histamine (local hormone)(local hormone)

2.2. Acetylcholine Acetylcholine (neurotransmitter).(neurotransmitter).

3.3. Gastrin Gastrin (hormone).(hormone).

AIMS OF ULCER TREATMENTAIMS OF ULCER TREATMENT

Promotion of ulcer healing.Promotion of ulcer healing. Symptomatic relief of pain.Symptomatic relief of pain.

Prevention of recurrence (relapse).Prevention of recurrence (relapse). Prevention of complicationsPrevention of complications

DRUG TREATMENT OF PEPTIC ULCERDRUG TREATMENT OF PEPTIC ULCER

I. Gastric hyposecretory drugsI. Gastric hyposecretory drugs..

H2 receptor blockersH2 receptor blockers Muscarinic receptor blockers Muscarinic receptor blockers Proton pump inhibitorsProton pump inhibitors

II. Eradication of H. pylori infectionsII. Eradication of H. pylori infections

To prevent relapseTo prevent relapse

DRUG TREATMENT OF PEPTIC ULCERDRUG TREATMENT OF PEPTIC ULCER

III. Mucosal cytoprotective agentsIII. Mucosal cytoprotective agents.. SucralfateSucralfate Colloidal bismuthColloidal bismuth Prostaglandin analoguesProstaglandin analogues

IV. Neutralizing agents (antacids). IV. Neutralizing agents (antacids).

Gastric hyposecretory drugsGastric hyposecretory drugs

H2 receptor blockersH2 receptor blockers Muscarinic receptor blockers Muscarinic receptor blockers Proton pump inhibitorsProton pump inhibitors

• Decreasing gastric acidity can reduce Decreasing gastric acidity can reduce absorption of ketoconazole & iron absorption of ketoconazole & iron preparation, digoxin.preparation, digoxin.

Proton Pump InhibitorsProton Pump Inhibitors

Mechanism of actionMechanism of actionIrreversible inhibition of proton pump Irreversible inhibition of proton pump (H+/ K+ (H+/ K+ ATPase)ATPase) that is responsible for final step in that is responsible for final step in gastric acid secretion from the parietal cellgastric acid secretion from the parietal cell ..

PP inhibitors include:PP inhibitors include: OmOmperazoleperazole LansoLansoprazoleprazole PantoPantoprazoleprazole

Illustration of Gastric secretion by parietal cells

Pharmacokinetics:Pharmacokinetics:

They are prodrugs – taken orally.They are prodrugs – taken orally. are given as are given as enteric coated capsulesenteric coated capsules

They are rapidly absorbed from the intestine. They are rapidly absorbed from the intestine. They are They are activated in the acidic mediumactivated in the acidic medium of of

the secretory parietal cell canaliculus.the secretory parietal cell canaliculus. They are inactivated if (combined with H2 They are inactivated if (combined with H2

receptor blockers).receptor blockers).

Have long duration of action (> 12 h-24 h).Have long duration of action (> 12 h-24 h). Once daily dose is sufficient Once daily dose is sufficient Bioavailability is reduced by food.Bioavailability is reduced by food. Given 1 h before meal.Given 1 h before meal. Are metabolized in the liver by CytP450.Are metabolized in the liver by CytP450. They are more potent than H2 receptor They are more potent than H2 receptor

blockers blockers Inhibits basal and stimulated-acid secretion.Inhibits basal and stimulated-acid secretion. Dose reduction is required in severe liver Dose reduction is required in severe liver

failure.failure.

USESUSES

1. Zollinger Ellison syndrome (First choice).1. Zollinger Ellison syndrome (First choice).

2. Resistant severe peptic ulcer ( 4-8 weeks).2. Resistant severe peptic ulcer ( 4-8 weeks).

3. Reflux esophagitis.3. Reflux esophagitis.

4. Eradication of H. pylori.4. Eradication of H. pylori.

ADVERSE EFFECTSADVERSE EFFECTS

GIT disturbances: nausea, vomiting, diarrheaGIT disturbances: nausea, vomiting, diarrhea Achlorhydria.Achlorhydria.

HypergastrinaemiaHypergastrinaemia Gastric hyperplasia. Gastric hyperplasia.

Increased bacterial flora (nitrosamine)Increased bacterial flora (nitrosamine)

H2 receptor blockersH2 receptor blockers

Mechanism of actionMechanism of action They competitively and reversibly block to H2 They competitively and reversibly block to H2

receptors on the parietal cells thus reduce receptors on the parietal cells thus reduce gastric secretion. They include:gastric secretion. They include:

- CimeCimetidinetidine - RaniRanitidinetidine

- FamoFamotidine tidine - NizaNizatidinetidine

PharmacokineticsPharmacokinetics Good oral absorptionGood oral absorption Plasma half life (1-3 h).Plasma half life (1-3 h). Duration (4-12 h).Duration (4-12 h). First pass metabolism (50% Except First pass metabolism (50% Except

Nizatidine 100 % bioavailability).Nizatidine 100 % bioavailability). Given before meals.Given before meals. Metabolized by liver.Metabolized by liver. Excreted mainly in urine.Excreted mainly in urine. Cross placenta & excreted in milkCross placenta & excreted in milk

Pharmacological actionsPharmacological actions::

Inhibit histamine, gastrin, cholinergic drug -Inhibit histamine, gastrin, cholinergic drug -induced secretions.induced secretions.

Reduce basal and food-stimulated gastric Reduce basal and food-stimulated gastric secretion.secretion.

Reduce pepsin activity.Reduce pepsin activity.

Promote mucosal healing & decrease painPromote mucosal healing & decrease pain

USES:

• Duodenal Ulcer (6-8 weeks).

• Benign gastric ulcer (8-12 weeks).

• Reflux esophagitis

• Zollinger Ellison Syndrome (large doses).

• Pre-anesthetic medication (To prevent

aspiration pneumonitis).

• Eradication of H. pylori infections.

Adverse Effects of H2 blockers:Adverse Effects of H2 blockers:

1.1. GIT disturbances:GIT disturbances: nausea, vomiting nausea, vomiting

2.2. CNS effects:CNS effects:

Headache, dizziness, confusion (elderly – Headache, dizziness, confusion (elderly – renal or hepatic dysfunction).renal or hepatic dysfunction).

3.3. CVS effectsCVS effects

Bradycardia and hypotension (rapid I.V.)Bradycardia and hypotension (rapid I.V.)

Cimetidine Cimetidine has other adverse effects:has other adverse effects:

4.4. Endocrine effectsEndocrine effects

Antiandrogenic actions (gynecomasteia – Antiandrogenic actions (gynecomasteia –

impotence)impotence)

Galactorrhea in women.Galactorrhea in women.

5.5. Cytochrome P450 inhibitorCytochrome P450 inhibitor: : decrease decrease metabolism of oral anticoagulant, phenytoin, metabolism of oral anticoagulant, phenytoin, benzodiazepines.benzodiazepines.

PrecautionsPrecautions

1.1. Maintenance dose (Relapse may occur).Maintenance dose (Relapse may occur).

2.2. Dose reduction in severe renal or hepatic Dose reduction in severe renal or hepatic failure and elderly.failure and elderly.

ANTICHOLINERGIC DRUGSANTICHOLINERGIC DRUGS

1. Non selective muscarinic blockers:1. Non selective muscarinic blockers:

Oxyphenonium, dicyclomineOxyphenonium, dicyclomine

- Decreased gastric motility Decreased gastric motility - Delayed gastric emptyingDelayed gastric emptying

- Heart burn- Heart burn

- Atropine like side effects.- Atropine like side effects.

2. Selective muscarinic blockers:2. Selective muscarinic blockers:

Pirenzepine - TelenzepinePirenzepine - Telenzepine Blocks M1 receptors on the parietal cells.Blocks M1 receptors on the parietal cells. Selectively inhibit gastric acid secretionSelectively inhibit gastric acid secretion No effect on gastric motilityNo effect on gastric motility Less side effects of cholinergic blockade.Less side effects of cholinergic blockade. No effect on CNS.No effect on CNS. Dose : 50 mg bid for 4-6 weeksDose : 50 mg bid for 4-6 weeks

UsesUses

1.Adjuvants to H2 receptor blockers.1.Adjuvants to H2 receptor blockers.

2. decrease nocturnal pain in peptic ulcer.2. decrease nocturnal pain in peptic ulcer.

Eradication Of H PyloriEradication Of H Pylori Is a bacteria that causes chronic inflammation Is a bacteria that causes chronic inflammation of the inner lining of the stomach.of the inner lining of the stomach. Produce enzymes (tissue damage), Produce enzymes (tissue damage), inflammation – ulcer.inflammation – ulcer. Duodenal ulcer - Gastric ulcer Duodenal ulcer - Gastric ulcer Risk factor for esophagus and stomach Risk factor for esophagus and stomach cancers.cancers. Eradication is important to prevent recurrence Eradication is important to prevent recurrence

of ulcer.of ulcer.

Helicobacter pylori in association with gastric mucosa

TreatmentTreatment

Combined therapy is usually used.Combined therapy is usually used.

– Clarithromycin, tetracycline, amoxicillinClarithromycin, tetracycline, amoxicillin

– Proton pump inhibitors or HProton pump inhibitors or H22 receptor receptor

blockers.blockers.

– Bismuth compoundsBismuth compounds

– Metronidazole.Metronidazole. Resistance may develop to antibiotics.Resistance may develop to antibiotics. Better eradication is obtained using Better eradication is obtained using proton proton

pump inhibitors & clarithromycin.pump inhibitors & clarithromycin.

TreatmentTreatment

The standard The standard first-line therapy is "triple therapy" consisting of proton pump inhibitors as omeprazole and the antibiotics clarithromycin and

amoxicillin .

REGIMENDOSEDURATION

BismuthMetronidazole

Tetracycline

525 mg qid250 mg tid500 mg qid

2 weeks

omeprazoleMetronidazole

Clarithromycin

20 mg bid500 mg bid500 mg bid

1 week

omeprazoleAmoxacillin

Clarithromycin

20 mg bid500 mg qid500 mg bid

1 week

omeprazoleBismuth

MetronidazoleAmoxacillin or /

Tetracycline

20 mg bid525 mg qid500 mg qid

500 mg qid

week

Mucosal protective agentsMucosal protective agents..

1.1. SucralfateSucralfate

2.2. Prostaglandin analogues.Prostaglandin analogues.

3.3. Colloidal bismuthColloidal bismuth

Sucralfate Sucralfate Sucrose octaphosphate + aluminium hydroxideSucrose octaphosphate + aluminium hydroxide

Mechanism of actionMechanism of action

1.1. In acidic pH, sucralfate dissociates In acidic pH, sucralfate dissociates into its components.into its components.

2.2. The negatively charged sucrose The negatively charged sucrose octaphosphate binds with positively octaphosphate binds with positively charged protein molecules found in charged protein molecules found in damaged mucosa (Coat over the ulcer).damaged mucosa (Coat over the ulcer).

3.3. Promote ulcer healing.Promote ulcer healing.

4.4. Inhibition of pepsin.Inhibition of pepsin.

3.3. Stimulation of mucosal protective Stimulation of mucosal protective mechanisms (mucous and bicarbonates mechanisms (mucous and bicarbonates secretion).secretion).

KineticsKinetics Orally, poor systemic absorption.Orally, poor systemic absorption.

Duration (6 h).Duration (6 h). Excreted in feces.Excreted in feces.

Avoid co-administration of antacid or H2Avoid co-administration of antacid or H2 blocker.blocker.

Bette taken on empty stomach.Bette taken on empty stomach.

Therapeutic UsesTherapeutic Uses Benign gastric and duodenal ulcer.Benign gastric and duodenal ulcer.

Chronic gastritis.Chronic gastritis.

Adverse effectsAdverse effects Constipation and dry mouth.Constipation and dry mouth.

Interferes with absorption of some drugs Interferes with absorption of some drugs tetracycline, theophyline, Tricyclic tetracycline, theophyline, Tricyclic antidepressant.antidepressant.

2. Misoprostol2. Misoprostol Prostaglandin Analogues (PGE1 )Prostaglandin Analogues (PGE1 )

HCL secretion.HCL secretion. Promote tight junction of gastric cellsPromote tight junction of gastric cells

prevent back diffusion of HCL.prevent back diffusion of HCL. mucous and bicarbonate secretion.mucous and bicarbonate secretion.blood flow of mucosa improve healing of ulcer.blood flow of mucosa improve healing of ulcer.

KineticsKinetics

Orally, 30 min.Orally, 30 min.

is converted into active metabolite.is converted into active metabolite.

Excreted in urine- must be taken 3-4 times/day.Excreted in urine- must be taken 3-4 times/day.

Therapeutic usesTherapeutic uses Prevention of NSAIDS-induced peptic ulcer.Prevention of NSAIDS-induced peptic ulcer.

AdverseAdverse Effects Effects Abdominal cramps (sever colicky pain).Abdominal cramps (sever colicky pain). Diarrhea.Diarrhea. Uterine contraction dysmenorrhea orUterine contraction dysmenorrhea or abortion.abortion. Vaginal bleeding.Vaginal bleeding.

3. Colloidal Bismuth compounds3. Colloidal Bismuth compounds

Bismuth subcitrateBismuth subcitrate

Tripotassium dicitrato bismuthate.Tripotassium dicitrato bismuthate.

Mechanism of ActionMechanism of Action

1.1. It forms a precipitate with mucous cover the ulcer It forms a precipitate with mucous cover the ulcer with a protective coat that prevent effect of HCl.with a protective coat that prevent effect of HCl.

2.2. Promote healing of ulcer.Promote healing of ulcer.

3.3. Bactericidal effect against campylobacter pylori .Bactericidal effect against campylobacter pylori .

4.4. Decrease activity of pepsinDecrease activity of pepsin

5.5. Mucous & bicarbonate secretion.Mucous & bicarbonate secretion.

Adverse EffectsAdverse Effects

1.1. Black stool.Black stool.

2.2. Teeth discoloration.Teeth discoloration.

3.3. Encephalopathy (in renal dysfunction).Encephalopathy (in renal dysfunction).

USESUSES

1.1. Triple therapy for eradication of H. pylori.Triple therapy for eradication of H. pylori.

2.2. Benign gastric & duodenal ulcer.Benign gastric & duodenal ulcer.

3.3. Traveller’s diarrheaTraveller’s diarrhea

Drugs That Neutralize HCL (Antacids)Drugs That Neutralize HCL (Antacids)

Drugs used to relief gastric pain associated Drugs used to relief gastric pain associated with hypersecretion of HCL. with hypersecretion of HCL.

Mechanism of ActionMechanism of Action Neutralization of HCL.Neutralization of HCL.

Inhibition of pepsin (inactive at PH 5).Inhibition of pepsin (inactive at PH 5).

Therapeutic UsesTherapeutic Uses

1.1. relief pain of peptic ulcer.relief pain of peptic ulcer.

2.2. Dyspepsia.Dyspepsia.

I - Systemic AntacidsI - Systemic Antacids

Sodium bicarbonate Sodium bicarbonate

NaHCO3 + HCL NaHCO3 + HCL NaCL + CO2. NaCL + CO2.

Disadvantages Disadvantages

1. Rebound hyperacidity.1. Rebound hyperacidity.

2.2. Stomach distension due to CO2 liberation Stomach distension due to CO2 liberation pain sensation. pain sensation.

3. Sodium load 3. Sodium load salt and water retention salt and water retention

( # in cardiac patients).( # in cardiac patients).

4. Systemic alkalosis. 4. Systemic alkalosis.

Calcium CarbonateCalcium Carbonate

CaCO3+HCL CaCO3+HCL CaCl2 + H2O + CO2 CaCl2 + H2O + CO2

DisadvantagesDisadvantages

11 . .Liberation of CO2 Liberation of CO2 stomach distension stomach distension

22 . .10%10% is absorbed is absorbed hypercalcemia hypercalcemia..

33 . .Rebound hyperacidityRebound hyperacidity..

44 . .Milk alkali syndrome (hypercalcemia, renal Milk alkali syndrome (hypercalcemia, renal failure)failure)..

II – Non Systemic AntacidsII – Non Systemic Antacids

11 . .Aluminum Hydroxide GelAluminum Hydroxide Gel

2. Magnesium Trisilicate 2. Magnesium Trisilicate

Al (OH)3 + HCL Al (OH)3 + HCL HCL3 + H2O HCL3 + H2O..

AdvantagesAdvantages

1.1. Longer duration of action.Longer duration of action.

2.2. Gradual neutralization of HCL Gradual neutralization of HCL No No rebound hyperacidity.rebound hyperacidity.

3.3. Adsorbs pepsin.Adsorbs pepsin.

4.4. Minimal change in acid base balance.Minimal change in acid base balance.

5.5. No stomach distentionNo stomach distention

DisadvantagesDisadvantages

Al (OH)3Al (OH)3

1.1. Constipation.Constipation.

2.2. Drug interaction: Drug interaction: absorption of absorption of tetracycline, digoxin, iron.tetracycline, digoxin, iron.

Magnesium TrisilicateMagnesium Trisilicate

1.1. DiarrheaDiarrhea

2.2. CNS depression (renal failure).CNS depression (renal failure).

Alginates (Gaviscon)Alginates (Gaviscon)

Combine with antacids in reflux esophagitis Combine with antacids in reflux esophagitis to increase adherence of mucus to to increase adherence of mucus to esophageal mucosa.esophageal mucosa.