1. Treatment of peptic ulcer

2. Introduction
A peptic ulcer, also known as peptic ulcer disease (PUD), is the most common ulcer of an area of the GIT.
70–90% of such ulcers are associated with Helicobacter pylori, a rod-shaped bacterium that lives in the acidic environment of the stomach
Ulcers can also be caused or worsened by drugs such as aspirin, ibuprofen, and other NSAIDs.

3. Pathophysiology
In normal acid/pepsin attack is balanced by mucosal defences
Increased attack by hyperacidity
Weakened mucosal defence – the major factor (H. pylori related)
Three factors increase the gastric acid secretion:
Ach
Gastrin
Histamine

4. Pathogenesis Three major factors are recognized:
Infection with helicobacter pylori
Increased hydrochloric acid secretion
Inadequate mucosal defense against gastric acid

5. Treatment approach Eradicating the H. pylori infection
Reducing secretion of gastric acid with the use of H2-receptor antagonists or PPIs, and/or
Providing agents that protect the gastric mucosa from damage, such as misoprostol and sucralfate.
If patients are unable to tolerate the above therapies, neutralizing gastric acid with nonabsorbable antacids is an option.

6. 1. Treatment of H. pylori Infection
H. pylori produces large amounts of the enzyme urease. Urease breaks down urea to carbon dioxide and ammonia (which neutralizes gastric acid).
H. pylori penetrate the mucus layer of host stomach and adhere the surface of gastric mucosal epithelial cells.
Produce ammonia from urea by the urease, and the ammonia neutralize the gastric acid to escape from elimination and form infectious focus.

7. ANTIBIOTICS
Triple therapy include PPI+ Amoxicillin+ clarithromycin for 7-14 days
If the patient has penicillin allergy use metronidazole instead of amoxicillin
If failed; use Quadruple therapy which consist of a PPI, combined with bismuth and two antibiotics (e.g. metronidazole and tetracycline ) given for days.

8. 2. Acid secretion inhibitors
H2 – Histamine receptor blockers
Cimetidine, Famotidine, Nizatidine, Ranitidine
Mechanism of action:
Antagonists at the histamine H2 receptor. So inhibit histamine-driven production of HCL.
These drugs are effective acid secretion suppressors
Because they act on only one of the pathways, they are not able to suppress gastric acid secretion completely, even at high dosages.

9. Therapeutic Uses
Healing of gastric and duodenal ulcers. Eradication of Helicobacter pylori infection
Reflux esophagitis.
Prophylaxis against stress ulcer in an ICU patient.
Nocturnal acid breakthrough. (there is high acid secretion throughout the night) is mainly mediated by histamine. H2 receptor blockers are more effective for nocturnal acid secretion as opposed to food stimulated acid secretion
Use famotidine, nizatidine, or ranitidine in preference to cimetidine.
These drugs are pregnancy category B.

10. Contraindications and Cautions
H2 receptor antagonists can mask symptoms and delay the diagnosis of gastric malignancy.
They are not effective in acute hematemesis; they do not improve outcome.
Adverse effects
The most common are: diarrhea, altered liver function, rash, headache and dizziness
Cimetidine blocks androgen receptors and may cause gynecomastia, loss of libido and impotence.
Cimetidine also causes hyperprolactinemia

11. Interactions
Cimetidine inhibits hepatic metabolism by P450 enzymes.
It can therefore increase the plasma concentrations of several drugs, in particular warfarin, theophylline, benzodiazepines and phenytoin.
Nizatidine, famotidine, and ranitidine do not do this.

12. Proton pump inhibitors (PPI)
Lansoprazole
Omeprazole
Rabeprazole
Pantoprasole
Esomeprosole
Mechanism of action:
Irreversible inhibitors of the H+/K+ ATPase (proton pump).
These drugs bind irreversibly to the H+/K+ ATPase, located in the secretory cannaliculi of parietal cells.

13. The drug must be absorbed into the blood stream to do this; it does not act directly from the stomach lumen.
It also requires an acid environment to be activated; this provides a negative feedback mechanism and inhibition of acid production reduces the activation of the PPI.
The H+/K+ ATPase is the final common pathway of gastric acid secretion, so these drugs are powerful antacids.
Once a PPI binds irreversibly to H+/K+ ATPase , a new protein has to synthesized to replace the inactivated H+/K+ ATPase

14. Therapeutic Uses
Healing of gastric and duodenal ulcers.
Reflux esophagitis.
Patients with Barrett's esophagus(they also will require regular endoscopic follow-up).
Eradication of Helicobacter pylori infection, in combination with antibacterial drugs.
Treatment of Zollinger-Ellison syndrome.
High-dose intravenous omeprazole has been used in patients with high-risk bleeding duodenal ulcer.

15. Contraindications
PPIs can mask symptoms and delay the diagnosis of gastric malignancy
PPIs are not suitable for acute hematemesis.
PPIs are metabolized by the liver; dosage adjustment is not usually required, but take care in severe hepatic insufficiency.
In the USA, these drugs are pregnancy category C

16. Adverse Effects Well-tolerated.
The most common adverse effect is diarrhea, particularly with long-term use.
Other rare adverse effects include rash, liver enzyme abnormalities, and interstitial nephritis.
Long-term treatment with these drugs causes carcinoid tumors in the stomachs of laboratory animals, but has not been observed in clinical practice. Always consider whether maintenance treatment is required.
Concerns About the Effects of Proton Pump Inhibitors
One area of concern regarding the side effects of proton pump inhibitors is their effect on bone health. Studies have shown that people who take this class of medications have a higher risk of developing hip fractures than those who have never taken them. It’s thought that when these drugs reduce acid secretion by the stomach it results in less calcium being absorbed by the body. Calcium is, of course, needed to maintain healthy bones and help prevent fractures from occurring. It appears that the longer these drugs are taken, the greater the risk of hip fracture. This is of particular concern if you’ve been diagnosed with osteoporosis.
What Are Other Adverse Effects of Proton Pump Inhibitors?
Another of the important side effects of proton pump inhibitors is an increased risk of infection. It’s thought that acid secretion by the stomach helps to kill bacteria that could ultimately lead to infection if left unchecked. When proton pump inhibitors slow down acid secretion by the stomach, these bacteria are able to more easily survive and proliferate. It was shown in one study that taking proton pump inhibitors increases the risk of bacterial pneumonia.
What’s the Bottom Line?
If you’re at high risk for osteoporosis or have a history of pneumonia in the past, talk to your doctor about the negative side effects of proton pump inhibitors. Although this class of drugs is the most powerful for treating peptic ulcer and gastroesophageal reflux, there are other alternative medications that may work if your symptoms aren’t severe. If you do decide to take a proton pump inhibitor, take measures to get extra calcium in your diet, particularly if you’re a woman at high risk of osteoporosis.
Carcinoid tumors are noncancerous (benign) or cancerous (malignant) growths that sometimes produce excessive amounts of hormonelike substances, resulting in the carcinoid syndrome.
People with carcinoid tumors may have cramping pain and changes in bowel movements.
People with carcinoid syndrome usually have flushing and sometimes diarrhea.
Doctors measure the amount of a serotonin byproduct in a person's urine.
Imaging tests are needed to determine tumor location.
Sometimes tumors are removed surgically.
People may need to take drugs to control symptoms.
Carcinoid tumors usually originate in hormone-producing cells that line the small intestine or other cells of the digestive tract. They can also occur in the pancreas, testes, ovaries, or lungs. Carcinoid tumors can produce an excess of hormonelike substances, such as serotonin, bradykinin, histamine, and prostaglandins. Excess levels of these substances can sometimes result in a diverse set of symptoms called carcinoid syndrome. Carcinoid tumors use the amino acid tryptophan to produce the excess serotonin. Because tryptophan is normally used to make niacin (vitamin B3), people may develop a niacin deficiency, causing the disease pellagra (see Vitamins: Niacin Deficiency).
When carcinoid tumors occur in the digestive tract or pancreas, the substances they produce are released into a blood vessel that flows directly to the liver (portal vein), where enzymes destroy them. Therefore, carcinoid tumors that originate in the digestive tract generally do not produce symptoms unless the tumors have spread to the liver.
If the tumors have spread to the liver, the liver is unable to process the substances before they begin circulating throughout the body. Depending on which substances are being released by the tumors, the person will have the various symptoms of carcinoid syndrome. Carcinoid tumors of the lungs, testes, and ovaries also cause symptoms because the substances they produce bypass the liver and circulate widely in the bloodstream.

17. The potential for drug interactions with these drugs is low.
Lansoprazole, omeprazole, and esomeprazole inhibit hepatic cytochrome P450 enzymes to some degree. This effect is not great, but may enhance the actions of warfarin and phenytoin.
PPI may decrease the absorption of vitamin B12 and other drugs that require acidity for their absorption e.g. digoxin

18. 3. Cytoprotective drugs for peptic ulcer disease
Mucosal protective agents
Colloidal bismuth
Sucralfate
Prostaglandins (enhance mucosal defense)
Misoprostol

19. A. Mucosal protective agents
I. Sucralfate
Mechanism of action:
Sucralfate is a sulfated polysaccharide that requires an acid pH to be activated.
It adheres to ulcer crater by binding to the necrotic tissue so acting as a barrier to acid, pepsin and bile.
The drug also promotes prostaglandin biosynthesis.
It promotes healing of peptic ulcers and reduces the recurrence rate.

20. Adverse effects:
Constipation, abdominal pain.
Systemic effects are negligible since the drug is not absorbed significantly from the gut.
Clinical uses:
Used to treat peptic ulcer and to prevent recurrence.
It is less effective than drugs that inhibit gastric acid secretion.

21. II. Bismuth compounds
Mechanism of action:
Bismuth subsalicylate and subcitrate likely act by the following mechanisms:
Binding to the ulcer, so coating and protecting it;
Inhibiting gastric and enteric secretions
Stimulate mucous and PG synthesis
Antimicrobial activity against organisms such as H. Pylori, C. Jejuni, E. coli and salmonella species.

22. Adverse effects:
Constipation and darkening of feces (mistaken sometimes for melena).
Large doses can cause fecal impaction and bismuth or salicylate toxicity.
Clinical uses:
In the multidrug regimen for the treatment of peptic ulcer.
For the treatment of mild infectious diarrhea (traveler’s diarrhea) or nonsyndromic, episodic diarrhea.

23. B. Prostaglandins Misoprostol Mechanism of action:
Misoprostol is a prostaglandin E1 analogue which activates prostaglandin receptors on:
Gastric epithelial cells (so leading to a cytoprotective effect on gastric mucosa by stimulating the secretion of mucus and bicarbonate);
Gastric parietal cells (so reducing acid and pepsin secretion).

24. Adverse effects:
Diarrhea (up to 30%), abdominal pain
Contraindications:
Pregnancy (FDA category X)
Clinical uses:
Mainly for the prevention (not for the treatment) of peptic ulcer in patients taking NSAIDs on a long-term basis.
It is not widely used now because of the need of multiple daily dosing and its adverse effects

25. 4. Antacids
Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water.
Although their principal mechanism of action is reduction of intragastric acidity, they may also promote mucosal defense mechanisms through stimulation of mucosal prostaglandin production.
A single dose of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours.
Antacids are the most rapidly acting acid suppressors because they react with acid instantaneous in the lumen of the stomach.

26. A. Sodium bicarbonate
Sodium bicarbonate (baking soda) reacts rapidly with HCl to produce carbon dioxide and NaCl.
Formation of carbon dioxide results in gastric distention and belching.
Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency.

27. B. Calcium carbonate
Calcium carbonate is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and CaCl2.
Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis.
Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, renal stones, and metabolic alkalosis (milk-alkali syndrome).

28. C. Magnesium hydroxide and aluminum hydroxide
Poorly absorbed and they react slowly with HCl to form magnesium chloride or aluminum chloride and water.
Because no gas is generated, belching does not occur.
Magnisium hydroxide has strong laxative effect white aluminium hydroxide has a constipating effect
Patients with renal insufficiency should not take these agents long-term.
Like CaCO3, Al(OH)3 is a phosphate binder and may also lead to hypophosphatemia with prolonged use.

29. Adverse Effects of Antacids
Change in bowel habits
AL & Ca based antacids cause constipation, while Mg-based causes diarrhea. Either combining or alternating compounds with these effects can treat this problem.
Cation absorption (Na, Ca, Mg, Al)
Increase Ca leads to systemic hypercalcaemia with formation of calculi and milk alkali syndrome especially in renal impairment.
Increased Mg++ causes muscle weakness and fatigue
Increased Na+ absorption leading to hypertension and edema.
AL binds phosphate and prevents its absorption leading to hypophosphatemia with muscle weakness and resorption of bone.
Rebound hypersecretion of HCl with Ca++ and NaHCO3 containing antacids.

30. Drug Interactions
Ca, AL and Mg, decrease absorption of tetracycline, Al (OH)3 decrease absorption of digoxin, isoniazid (INH), warfarin, anticholinergic drugs and iron.
The increase in gastric pH decrease the absorption of acidic drugs.
Systemic antacids increase excretion of drugs e.g. quinidine. 
Uses of Antacids
Symptomatic treatment of gastric, duodenal ulcer and GERD
Healing of duodenal ulcer (high dose)   

31. Good luck