Topic: Treatment of Peptic Ulcer

Prepared by: Usman Saleem

Semester : 4th

Group : 10th

What is Peptic Ulcer ?A peptic ulcer disease or PUD is an ulcer

(defined as mucosal erosions equal to or greater than 0.5 cm) of an area of the gastrointestinal tract exposed to the acid and pepsin secretion

Gastritis is the precursor to PUD and it is clinically difficult to differentiate the twoStomach (called gastric ulcer)Duodenum (called duodenal ulcer)Esophagus (called Esophageal ulcer)Meckel's Diverticulum (called Meckel's Diverticulum

ulcer)

Duodenal Vs Gastric Ulcers Duodenal

Age: 25-75 years Gnawing or burning upper

abdomen pain relieved by food but reappears 1-3 hrs after meals

Worse pain when stomach empty

Bleeding occurs with deep erosionHematemesisMelena

Gastric

Age: 55-65 years Relieved by food but pain

may persist even after eating

Anorexia, wt loss, vomiting Infrequent or absent

remissions Small % become cancerous Severe ulcers may erode

through stomach wall

ProglumideACh

PGE2Histamine Gastrin

Adenyl cyclase

_ +

ATP cAMP

Protein Kinase (Activated)

Ca++

+

Ca++

Proton pump

KK+ H+

Gastric acid

Parietal cellLumen of stomach

AntacidOmeprazole

Ranitidine

H2M3

Misoprostol

_

__

_

+

PGE receptor

+

+

Gastrin receptor+

+

+

Gastroesophageal Reflux Disease (GERD)Common and GI motility disorderAcidity of Gastric contents – most common

factorAcid contents reflux back into esophagusIntense burning, sometimes belchingCan lead to esophagitis, esophageal ulcers,

and stricturesBarrett’s esophagus

Commonly associated with obesityImproves with lifestyle management

Why Ulceration Occurs? High [H+] in the gastric lumenRequire defense mechanisms to protect

oesophagus and stomachOesophagus – LESStomach: a number of mechanisms

Mucus secretion: slows ion diffusionProstaglandins: I2 and E2 (alcohol, aspirin,

and other drugs)Bicabonate ionsHigh Blood Flow (nitric oxide)

Because of Imbalance

Imbalance primarily between Aggressive factors and Defensive factors:

Aggressive

factors, e,g,

acid, pepsin,

bile etc.

Defensive

factors, e.g.

mucus,

HCO3, PG

What may contribute imbalance ?Helicobacter pyloriNSAIDsEthanolTobaccoSevere physiologic stress (Burns, CNS trauma,Surgery, Severe medical illness)Steroids

Drugs For Treatment of Peptic Ulcer

Classification1. Acid Neutralizing agents: (ANTACIDS)

• Systemic: Sodium Bicarbonate and Sod. Citrate• Nonsystemic: Magnesium hydroxide, Mag. Treisilicate,

Aluminium hydroxide gel, Magaldrate and calcium carbonate

2. Reduction in Gastric acid secretion: H2 antihistamines: Cimetidine, Ranitidine,

Famotidine, Nizatidine and Roxatidine Proton pump inhibitors: Omeprazole,

Lansoprazole Pantoprazole, Rabeprazole and Esomeprazole

Anticholinergics: Pirenzepine, Propantheline and Oxyphenonium

Prostaglandin analogue: Misoprostol

Classification – contd.3. Ulcer protectives: Sucralfate, Colloidal

Bismuth sudcitrate4. Anti-H. pylori Drugs: Amoxicillin,

Clarithromycin, metronidazole, tinidazole and tetracycline

AntacidsAntacids Mechanism of Action Mechanism of ActionPromote the gastric mucosal defense Promote the gastric mucosal defense

mechanisms:mechanisms:Secretion of:

-Mucus: Protective barrier against HCl.-Bicarbonate: Helps buffer acidic properties of HCl.-Prostaglandins: Prevent activation of proton pump.

Antacids DO NOT prevent the over-production of acid.

Acids NEUTRALIZE the acid once it’s in the stomach.

Drug EffectsDrug EffectsReduction of pain associated with acid-related Reduction of pain associated with acid-related

disorders.disorders.

Raising gastric pH from 1.3 to 1.6 neutralizes 50% of gastric acid.

Raising gastric pH point from 1.3 to 2.3 neutralizes 90% of the gastric acid.

AntaciAntacidd

Antacids – cont…

Duration of action :30 min when taken in empty stomach2 hrs when taken after a mealSide effects :Al3+ antacids – constipation (As they relax gastric

smooth muscle & delay gastric emptying)Mg2+ antacids – Osmotic diarrhoea .In renal failure Al3+ antacid – Aluminium toxicity & Encephalopathy

AntacidsCapsules & Tablets:PowdersChewable tabletsSuspensionsEffervescent granules and tablets

AntacidsAntacidsMagnesium salts:Magnesium salts:

Forms: carbonate hydroxide, oxide, trisilicate. Commonly cause a laxative effect. Usually used with the other agents to counteract this effect. Dangerous when used with renal failure-the Failing kidney

cannot excrete magnesium, resulting in accumulation. Example :magnesium hydroxide(MOM);combination products

such as Maalox,aluminium & magnesium.

Calcium salts:Calcium salts: Forms: many but carbonate is the most common. May cause constipation. Their use may result in kidney stones. Long duration of acid action may cause increase of gastric acid

secretion (hyperacidity bound) Often advertised as an extra source of dietary calcium. Example: Calcium carbonate

AntacidsAntacidsSodium Bicarbonate:Sodium Bicarbonate:

Highly soluble.Quick onset, but short duration.May cause metabolic alkalosis.Sodium content may cause problems in

patients with hypertension or renal insufficiency.

Aluminum salts:Aluminum salts:Forms: carbonate, hydroxide, phosphate.Have constipating effects.Often used with magnesium to counteract

constipation.Example: aluminum carbonate

Antacids & AntiflatulentsAntacids & AntiflatulentsAntiflatulents:Antiflatulents:

-Used to relieve the painful symptoms associated with gas.

-Several agents are used to bind or alter intestinal gas and are often added to antacid combination products.

OTC Antiflatulents:OTC Antiflatulents: -Activated charcoal.

-Simethicone: ｏ Alters elasticity of mucus-coated bubbles, causing them to break. ｏ Used often, but there are limited data to support effectiveness.

Antacids – Common additives

Simethicone – Decrease surface tension ,thereby reduce bubble formation Added to prevent reflux .Alginates - Form a layer of foam on top of gastric contents & reduce refluxOxethazaine – Surface anaesthetic

Antacid - Interactions

Adsorb drugs and form insoluble complexes that are not absorbed .

Clinical importance :

Interactions can be avoided by taking antacids 2 hrs before or after ingestion of other drugs .

AntacidsAntacidsSide effectsSide effectsMinimal and depend on the compound used:Minimal and depend on the compound used:Aluminum and Calcium:Aluminum and Calcium:

-Constipation

Magnesium:Magnesium:-Diarrhea

Calcium carbonate:Calcium carbonate:-Produce gas and belching; often combined with simethicone.

Histamine H2 Receptor AntagonistReversible competitive inhibitors of H2 receptor

Highly selective, No action on H1 or H3 receptors

Very effective in inhibiting nocturnal acid secretion ( as it depends largely on Histamine )

Modest impact on meal stimulated acid secretion (As it depends on gastrin, acetyl choline and histamine)

H2 AntagonistsCimetidine, Ranitidine, Famotidine,

Roxatidine, Nizatidine andMOA:

Reversible competitive inhibitors of H2 receptorHighly selective, no action on H1 or H3 receptorsAll phases of gastric acid secretionVery effective in inhibiting nocturnal acid secretion

(as it depends largely on Histamine )Modest impact on meal stimulated acid secretion (as it

depends on gastrin, acetylcholine and histamine)Volume of pepsin content and IF are also reducedVolume reduced by 60 – 70% - anti ulcerogenic effectNo effect on motility

H2 antagonistsKinetics:

All drugs are absorbed orally adequatelyBioavailability upto 80 %Absorption is not interfered by presence of

foodCan cross placental barrier and reaches milkPoor CNS penetration2/3rd of the drugs are excreted unchanged in

bile and urinePreparations: available as tablets,

injections

Cimetidine Ranitidine Famotidine Nizatidine

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

Duration of 6 8 12 8

action (hrs)

Inhibition of 1 0.1 0 0 CYP 450

Dose mg(bd) 400 150 20 150

H2 antagonists - UsesPromote the healing of gastric and duodenal

ulcers Duodenal ulcer – 70 to 90% Gastric Ulcer – 50 to 75% (NSAID ulcers)) Stress ulcer and gastritis GERD Zollinger-Ellison syndrome Prophylaxis of aspiration pneumonia UrticariaDoses:

• 300 mg/40 mg/150 mg at bed time of R, F, Rox respectively for healing

• Maintenance: 150/20/150 mg BD of R, F, Rox

ADVERSE EFFECTS

eadache, myalgia, fatigue, diarrhea or constipation

   CNS (Confusion, agitation ,hallucination)    ANTI – ANDROGEN (inhibits binding of

dihydrotestosterone to androgen receptors, increases serum prolactin level)

   Blood dyscrasias   Enzyme inhibitor   Cardio toxicity on i/v administration

Reversible abnormalities in liver chemistry

Proton Pump Inhibitors

Most effective drugs in antiulcer therapy

Irreversible inhibitor of H+ K+ ATPase

Prodrugs requiring activation in acid environment

Weakly basic drugs & so accumulate in canaliculi of parietal cell

Activated in canaliculi & binds covalently to extracellular domain of H+ K+ ATPase

Acid secretion resumes only after synthesis of new molecules

Proton Pump Inhibitors

Omeprazole.

Esomeprazole

Lansoprazole

Pantoprazole

Rabeprazole

Omeprazole - MOASubstituted Benzimidazole derivativeIts a Prodrug Diffuses into G. canaliculi = accumulationpH < 5 (proton catalyzed )= tetracyclic sulfenamide

+ sulphenic acidCovalent binding with sulfhydryl cysteines of H⁺K⁺ ATPaseIrreversible inactivation of the pump molecule(The charged forms cannot diffuse back across the

canaliculi) Acid suppressants regardless of stimulating factorsAlso inhibits gastric mucosal carbonic anhydrase

Poton Pump Inhibitors – KineticsGiven as enteric coated granules in capsule or

enteric coated tablets

Pantoprazole also given intravenously

Half life – 1.5 hrs

Since it requires acid for activation - given 1 hr before meals

Other acid suppressing agents not coadministered

PPI – contd. Drug Interaction:

Inhibits metabolism of Warfarin, Diazepam Therapeutic uses:

1. Gastroesophageal reflux disease (GERD)2. Peptic Ulcer - Gastric and duodenal ulcers3. Bleeding peptic Ulcer 4. Zollinger ellison Syndrome5. 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

Adverse Effects The most common are GIT troubles in

the form of nausea, abdominal pain, constipation, flatulence, and diarrhea

Subacute myopathy, arthralgias, headaches, and skin rashes

Prolonged use: Gynaecomastia, erectile dysfunction Leucopenia and hepatic dysfunction Vitamin B12 deficiency Hypergastrinemia which may predispose to rebound

hypersecretion of gastric acid upon discontinuation of therapy and may promote the growth of gastrointestinal tumors (carcinoid tumors )

PPI – Dosage scheduleOmeprazole 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.

Mucosal Protective Agents

Mucosal Protective Agents

Sucralfate

Misoprostol

Colloidal Bismuth compounds

Prostaglandin analogues

Inhibit gastric acid secretionExhibit ‘cytoprotective’ activityEnhance local production of mucus or

bicarbonatePromote local cell regenerationHelp to maintain mucosal blood

.

3- Cyto-Protective Agent ( Sucalfate)Sucralfate = complex of Aluminum Hydroxide

& Sulfated SucroseBinds to positively charged groups in proteins,

glycoproteins of necrotic tissue (coat ulcerated mucosa)

Not absorbed systemically Require acidic media to dissolve & coates the

ulcerative tissue so, it can not be given with H2-antagonist, PPIs, & antacids

.

3- Cyto-Protective Agent ( Sucalfate)Administration

Should not be given with food, give 1hr before or 3hr after meal

Dose: 1gm/ 4times daily or 2 gm/ 2times dailyMust be given for 6-8 weeksLarge tablet & difficult to swallow

.

3- Cyto-Protective Agent ( Sucalfate)Side Effects

Constipation; black stool & dry mouthIt is very safe in pregnancy

Prostaglandin analogues - MisoprostolActions:

Inhibit histamine-stimulated gastric acid secretion

Stimulation of mucin and bicarbonate secretionIncrease mucosal blood flow

(Reinforcing of mucous layer buffered by HCO3 secretion from epithelial cells)

Therapeutic uses:Prevent ion of NSAID-induced mucosal injury

(rarely used because it needs frequent administration – 4 times daily)

Misoprostol Doses: 200 mcg 4 times a day

(Misoprost) ADRs:

Diarrhoea and abdominal cramps Uterine bleeding Abortion Exacerbations of inflammatory bowel disease

and should be avoided in patients with this disorder

Contraindications:1. Inflammatory bowel disease2. Pregnancy (may cause abortion)

Colloidal Bismuth CompoundsCoats ulcer, stimulates mucus & bicarbonate

secretion

Direct antimicrobial activity against H.pylori

May cause blackening of stools & tongue

Not used for long periods – bismuth toxicity

Available compounds :Bismuth subsalicylate – in USA

Bismuth sobcitrate – in Europe

Bismuth dinitrate

The Mechanism & Side Effects of Various Acid Suppressive Medications

Drug Mechanism Common side effect

Antacid Neutralize acid Mg - diarrheaAl - constipationCa – constipation

H2 receptor antagonists

Block histamine receptor

Cytochrome 450 altered

metabolism of drugs

Prostaglandins

Agonist Diarrhea, cramps, abortion

H+/K+ ATPase inhibitors

Block acid pump Hypergastrinemiaenterochromaffin cell (ECL) hyperplasia

Sucrafate

Coat ulcerated mucosa

Constipation

Eradication of H.pylori

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

Triple Therapy – cont …

Bismuth subsalicylate – 2 tab qid

Metronidazole - 250 mg qid

Tetracycline - 500 mg qid

Some other Triple Therapy Regimens are

Ranitidine Bismuth citrate - 400 mg bd

Tetracycline - 500 mg bd

Clarithromycin / Metronidazole - 500 mg bd

Quadruple Therapy

Given when Triple Therapy fails

Omeprazole / Lansoprazole - 20 / 30 mg bd

Bismuth subsalycilate - 2 tabs qid

Metronidazole - 250 mg qid

Tetracycline - 500 mg qid

Drugs causing peptic ulcer

Non Steroidal Anti Inflammatory Drugs (NSAIDs)

Glucocorticoids

Cytotoxic agents

Stress induced ulceration after head trauma

Cushing’s ulcer

Stress induced ulceration after severe burns

Curling’s ulcer