Peptic ulcer— it refers to as ulcer in the lower oesophagus, stomach, duodenum, in jejunum after surgical anastomosis or rarely in ileum adjacent to Meckel's diverticulum. It is a chronic condition with neutral history of relapse and remission.
Importantsites— | o Lesser curvature of the stomach o First part of the duodenum |
*** the ratio between the gastric and duodenal ulcer is 4:1
*** as a whole male suffer more from the duodenal ulcer.
Othersites— | o Lower end of the oesophagus o Meckel's diverticulum o Jejunum after gastro-jejunal anastomosis |
Types of peptic ulcer— acute and chronic.
Acid-pepsin mixture—acid (HCl) and pepsin are secreted from the parietal and the peptic cells respectively. Pepsin can digest protein, only when the pH is sufficiently low (2-3), at higher pH (>5) pepsin becomes inactive and cannot digest protein. Therefore presence of HCl is necessary for the action of pepsin (proteolysis).
Acid-pepsin mixture does not digest gastric mucosa itself because—
In the gastric mucosa as well as in the first part of the duodenum there is a defense mechanism. In normal person it is adequate and there is no formation of ulcer. When the mechanism is weakened or the aggressive factor (acid-pepsin mixture) is strengthen peptic ulcer develops {Zollinger-Ellinson syndrome}
Components of the defense mechanism—
1. Gastric mucus
2. The HCO3- secretion from the gastric mucosal cells
3. Presence of tight junction in the epithelial cells of the stomach and duodenum
4. The blood circulation
*** gastric mucus forms a layer over the epithelium of the mucosa. Some mucosal cells of the pyloric region of the stomach secrets HCO3- which remains between the epithelial cells and the mucus. The pH of this spot is very high (6-7). Here pepsin loses its activity. We know pepsin molecules are large molecules which do not easily cross the thick sticky mucus layer. So, it appears that any condition that depolymerises the muco-polysaccharide molecules of the mucus lowers the defense mechanism by lowering the stickiness of the mucus. Loss of stickiness increases the permeability of pepsin. NSAID (aspirin) by inhibiting the secretion of PGE2 and PGI2 causes depolymerisation of the muco-polysaccharide polymers of mucus. The tight junctions of gastric and duodenal epithelium do not allow passage of anything through them. Aspirin due to high pH in the stomach is well absorbed and damages the tight junction and also inhibits the PG secretion within the cells. These two things weaken the defense mechanism.
*** Histamine, gastrin, Ach ↑ HCl secretion and PG and somatostatin ↓ HClsecretion.
Roles of prostaglandin on GIT—
o it increases mucus secretion
o it increases HCO3- secretion
o it increases the local blood supply
o it decreases HCl secretion by the parietal cells
*** aspirin inhibits PG secretion by blocking the cycloxegenase pathway.
Aggravating factors—
1. Acid-pepsin mixture
2. H. pylori—splits urea into ammonia and makes the environment highly alkaline causing damage of the epithelium
3. Alcohol
4. Smoking
Principles / Approaches of treatment of PUD—
o Neutralizing the acid
o Decreasing the secretion of acid
o Protection of the mucosa by using mucosal protecting drugs
o Using the prostaglandin analogue (used in drug induce ulcer)
Clinicalfeatures— | o Epigastric pain | o Heart burn |
o Night pain | o Loss of appetite | |
oWater brash | o Vomiting |
*** an ulcer is formed when there is an imbalance between acid pepsin secretion and gastric mucosal defense mechanism. The mucosal resistance constitutes the gastric mucosal barrier.
H. pylori infection is clinically associated with the following—
oDuodenal ulcer | o Non-ulcer dyspepsia |
o Gastric ulcer | o Gastric β-cell lymphoma |
o Gastric cancer | oGastro-oesophageal reflux / oesophagitis |
Drugs used in peptic ulcer—
1.Drugs used for neutralization of acid—
Antacids— | a. Systemic—NaHCO3, CaCO3 b.Non-system—Al(OH)3, Mg(OH)2 |
Criteria for ideal antacid— | o Rapid onset of action. o Prompt relief. o Cost effective. o Less adverse effects. |
Systemic—after ingestion absorbed in the system and produce their systemic effect
ex—
NaHCO3 [Na causes hypernatraemia, HCO3- may cause metabolic alkalosis. Cheap and easily available]
CaCO3 [hypercalcaemia occurs → Milk-alkali syndrome]
Non-systemic—acts locally in the GIT and is not absorbed remarkably
ex—
Al(OH)3 [relaxes smooth muscle of the GIT causing constipation, binds with many substances like Tetracycline, PO4 etc. So there is chance of hypophosphatemia, Al(OH)3 + 3HCl = AlCl3 + 3H2O]
Mg(OH)2 [popularly called milk of magnesia because of its resemblance to milk, combines with HCl to form MgCl2 and H2O. MgCl2 is well absorbed and may produce sign symptoms of Mg-overload in patients suffering from kidney failure. It acts as a laxative]
Advantages and disadvantages of systemic antacids—
Advantages | Disadvantages |
Rapid onset of action | Cause transient metabolic alkalosis |
Very effective | Short duration of action |
Have carminative action | Cause belching, flatulence, abdominal distension |
Do not produce constipation and diarrhoea | May produce rebound acidity |
May cause milk-alkali syndrome | |
Interfere peptic digestion | |
Cause oedema and UBP due to Na+ retention | |
Long term use may cause renal damage | |
Hampers the acid-base balance |
Advantage and disadvantages of non-systemic antacids—
Advantages | Disadvantages |
Longer duration of action | Ca-compounds produce constipation, hypercalcaemia, milk-alkali syndrome |
Do not cause metabolic alkalosis | Mg-compounds produce diarrhoea |
Do not cause rebound acidity (except CaCO3) | Al-compounds produce constipation |
Do not hamper acid-base balance | Al and Mg compounds may interfere the absorption of other drugs |
Do not interfere pepsin activity | |
Has some demulcent and absorbent properties | |
Stimulate mucous secretion | |
Mg-salts possess laxative effects |
Commercial preparations of antacid contain this combination—
(this is the preferred preparation of antacid for treatment)
Al(OH)3 + Mg(OH)2 + Methyl-Poly-Siloxane Simethicone
Some points in favour of this compound—
A very rapidly acting antacid preparation which can achieve neutralization within few minutes.
More sustained effect.
One component antagonizes the side-effect of another (constipation versus laxation)
Methyl-Poly-Siloxane Simethicone is an anti-flatulent agent. This compound is believed to reduce gastric distension, belching and forms a coat on the ulcer.
*** antacid is given one hour after meal when the buffering power of food is ceased. If given in empty stomach then the effect lasts for only 20-40 minutes.
*** it is available in liquid and tablet formulations. tablet requires disintegration and dissolution time so liquid works quickly.
2.Drugs used for decreasing HCl secretion—
i. H2 receptor antagonist—Ranitidine, Cimetidine, Famotidine (also called H2 blocker)
ii. Proton pump inhibitor—Omeprazole, Lensoprazole.
*** these two drugs are not given combinedly but any one can be given with antacids.
*** not given together as their final mechanism is the same and both decrease HCl secretion.
H2 blocker—
H2 stands for Histamine. H2 blockers bind with the H2 receptors of the parietal cells of gastric mucosa and produce competitive drug antagonism thus inhibiting or decreasing the HCl secretion.
Drug | Half life | Liver metabolism | Excretion (unchanged) | Enzymic inhibition |
Cimetidine | 2 hrs | 40% | 60% | Yes |
Ranitidine | 2 hrs | 50% | 50% | Less |
Famotidine | 3 hrs | 25% | 75% | -- |
Nizatidine | 1 hr | 10% | 90% | -- |
Adverse effects of H2 blockers—
o Headache, dizziness, constipation, diarrhoea.
o Gynaecomastia (due to blocking of androgen receptor altered metabolism in men)
o Bradycardia.
o Drug interaction {Cimetidine is a liver enzyme inhibitor. It can cause drug interaction by interfering with the metabolism of other drugs. It inhibits the metabolism of other drugs like Warfarin, Phenytoin, Propranolol, Theophylline, Sulfonylureas etc. thus the plasma concentration of theses drugs are raised and there is a potential for increased effect}
Limitation of Cimetidine—
1.Cimetidine produces adverse effects such as GIT upset, Gynaecomastia, loss of livido or impotency.
2.Cimetidine is a liver enzyme inhibitor (cyt-P450) and so causes drug interaction by interfering with metabolism of other drugs.
Proton pump inhibitor— Omeprazole, Lensoprazole.
These drugs inhibit the H+-K+-ATPase enzyme system of the gastric parietal cells. This enzyme normally catalyzes the exchange of H+ for K+ at the cell membrane. This is the final stage of acid secretory process, called the pump.
Therefore these drugs antagonize all stimulation (histamine, gastrin, Ach mediated) of the gastric secretion.
o They stimulate both basic and stimulated acid secretion.
o Given as enteric coated granules.
o The drug is rapidly metabolized.
o A single dose of 20mg Omeprazole ↓ acidity by 90% in 24 hours.
Adverse effects—
o Headache, diarrhoea, constipation, rash,
o Hypergastrinemia (G-cell ↑ gastrin secretion→ ↑ HCl secretion. Potentially it may be carcinogenic).
o Prolong use may cause prolong achlorhydria, rapid proliferation of the gastric epithelium forming carcinoid tumor ultimately. It may also cause overgrowth of the gastric bacterial flora.
3.Mucosal protective agents / cytoprotective agents—
Sucralfate, Colloidal Bismuth, Misoprostol (PG analogue).
Misoprostol—
It is a PG analogue. It is similar to the endogenous prostaglandin.
Mechanism—
1.Maintains the vascular integrity of gastric mucosa.
2.They promote the mucous secretion.
3.They prevent back diffusion of H+ ion.
4.It encourages the self replication / regeneration of the gastric mucosa.
5.They inhibit Histamine induced secretion of acid.
Adverse effects—
1.In pregnancy—it may cause abortion.
2.Diarrhoea.
3.It is expensive.
Sucralfate—this is also a mucosal protective agent but acts in a different way.
Basically it has sucrose-Al(OH)3, when it enters into the GIT it interacts with the protein molecules of ulcer base and produce an ulcer coat, thus protecting from the further damage from the acid-pepsin. It cannot be given simultaneously with antacid. So there may be at least a gap of 30min.
It can reduce absorption of Theophylline, warfarin, ciprofloxacin, digoxin, so bioavailabilty of these drugs will be less.
Bismuth colloid / colloidal bismuth—
This drug is also mucosal protective agent and provides coat on the ulcer.
To some extent it can—
o Reduce the gastric HCL secretion.
o Help in eradication of H. pylori.
o Stimulates the PGE secretion.
o Reduce pepsin secretion.
o Decrease H+ ion back diffusion.
o It causes blackening of the tongue.
4.Antibiotic regimens for H. pylori eradication—
| OCM / LCM Omeprazole 40mg once/day Or Lensoprazole 30 mg 12 hourly + Clarithromycin 500mg 12 hourly + Metronidazole 400mg 12 hourly This has 90% efficacy and 1st line regimen | OAC / LAC Omeprazole 40mg once/day Or Lensoprazole 30 mg 12 hourly + Amoxicillin 500mg 12 hourly + Clarithromycin 500mg 12 hourly This has 85-90% efficacy and 1st line regimen |
OAM / LAM Omeprazole 40mg once/day Or Lensoprazole 30 mg 12 hourly + Amoxicillin 500mg 12 hourly + Metronidazole 400mg 12 hourly This is a 2nd line regimen | BAM Bismuth (CBs) 125mg 6 hourly + Amoxicillin 500mg 12 hourly + Metronidazole 400mg 12 hourly This is a 2nd line regimen. |
*** Omeprazole is given to make the environment less acidic as H. pylori lives better in acidic environment.
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