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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
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