Peptic ulcer is a major health problem. It is a wound inside the stomach or duodenum. It occurs due to localized destruction of the inner wall (mucosa) of the stomach (gastric ulcer) pr the upper part of the small intestine (duodenal ulcer). It is usually associated with the hyperacidity. The causes of peptic ulcer are complex.
Major factors in the genesis of peptic ulcer are: (a) increased acid and pepsin secretion, (b) decreased gastroduodenal epithelial and mucosal resistance, (c) Helicobactor pylon infection. Excessive smoking and excessive use of alcohol, tea, coffee and certain drugs like corticosteroids, phenylbutazone, iridomethacin, reserpine, etc. may also be responsible for peptic ulcer. Important symptom is sharp, penetrating and burning type of pain in the upper part of the abdomen which may be aggravated by food.
Some drugs used in Peptic Ulcer, which are used to treat peptic ulcer, act by reducing the gastric acid. It is, therefore, worthwhile to know the important physiological features of gastric acid secretion. Gastric add is secreted by the parietal cells in gastric mucosa due to stimulation of proton pump (HK ATPase pump). The basolateral membrane of these cells contain receptors for the three main stimulants of acid secretion, namely gastrin (from antral C-cells), histamine (from enterochromaffin-like cells) and acetylcholine (from vagal efferents). Histamine binds to H2 receptors and increases intracellular cAMP by activating adenylyl cyclase enzyme; acetylcholine and gastrin cause increase in cytosolic In turn both cAMP and cytosolic Ca activate protein kirtases which stimulate acid secretion from H÷K ATPase pump.
Gastric acid secretion is stimulated in three phases:
• Cephalic phase: Sight, smell or taste of the food stimulates acid secretion via vagus.
• Gastric phase: Amino acids and peptides in the food stimulate C-cells of antrum to release gastrin which binds to the parietal cell receptors. Due to this, there occurs increase in cytosolic Cat which stimulates protein kinases to promote acid secretion through an HK ATPase pump (proton pump) into the lumen of the stomach.
• Intestinal phase: Gastric acid secretion starts due to luminal distention and nutrient assimilation of food in the intestine.
Gastric acid production is inhibited by somatostatin hormone which is released by Dcells of gastric mucosa in response to H-. It acts either by decreasing histamine release from enterochromaffin-like cells (ECL) or by decreasing gastrin release from C-cells. Secretin and cholecystokinin are other hormonal factors which provide negative feedback to gastrin release in response to raised gastric H concentration.
Anti-Peptic Ulcer drugs
1. Antacids: These are classified into two groups of drugs used in Peptic Ulcer:
i. Non-absorbable antacids: (a) Aluminium salts such as aluminium hydroxide, aluminium phosphate, dihydroxy aluminium aminoacetate and aluminium carbonate. (Dose: 200—600 mg every hour during acute attacks).
(b) Magnesium salts such as magnesium trisilicate, magnesium hydroxide (milk of magnesia), magnesium oxide and magnesium carbonate (Dose: 250— 500 mg every hour during the acute attacks). (c) Calcium carbonate.
ii. Absorbable antacid such as sodium bicarbonate act as drugs used in Peptic Ulcer.
Mode of action: They neutralize gastric hydrochloric acid and prevent activation of pepsin. Aluminium also binds pepsin. The trisilicate salt of magnesium and aluminium hydroxide form protective coating over ulcer surface by forming hydrated silicon gel.
Use: Antacids mainly provide symptomatic relief by reducing acid irritation of ulcers and to a lesser extent promote healing.
Adverse reactions of drugs used in Peptic Ulcer: Although sodium bicarbonate causes rapid relief from pain, it is not used clinically because it causes systemic alkalosis, gastric distension, rebound acidity and milk alkali syndrome. Aluminium salts induce constipation, phosphate depletion on prolonged use and aluminium encephalopathy on prolonged use in presence of renal failure. Magnesium salts produce diarrhoea and hypermagnesaemia in the presence of renal failure. Calcium salts cause constipation, milk alkali syndrome, rebound acidity and perforation of ulcer due to production of carbon dioxide. Clinically, aluminium and magnesium salts are used in combination to counteract the side effects of each other.
Interactions of drugs used in Peptic Ulcer:
a. Sodium containing antacidreduces the antihypertensive effect of drugs.
b. Aluminium decreases the absorption of digoxin, tetracycline, isoniazid, iron salts and prednisolone.
c. Magnesium retards the absorption of tetracycline, digoxin and dicoumarol.
d. Calcium carbonate containing antacid decreases the absorption of scopolamine, glycopyrrolate, and propantheline, which are used to control excessive salivation in dentistry.
2. Anticholinergic agents:
i. Non-selective M1 and M2 receptor blockers like probanthine, oxyphenonium and dicyclomine.
ii. Selective M1 receptor blockers like pirenzepine and telenzepine. They have minimum effect on heart, intestine, and urinary bladder. So the adverse effects such as dryness of mouth, blurred vision and headache are less common.
Mode of action of drugs used in Peptic Ulcer: They act by reducing gastric acid secretion. They also inhibit gastric motility which may be helpful in ulcer healing.
Use: Since they have weak antisecretory éffett, they are used only as adjunct to other antiulcer drugs. Commonly used drug is pirenzepine. It is given in doses of 50 mg orally twice or thrice daily for 4—6 weeks.
Interactions drugs used in Peptic Ulcer: Non-selective anticholinergic drugs increase the absorption of digoxin, prednisolone, and phenytoin by delaying intestinal transit time.
3. Histamine 112 antagonists (cimetidine, ranitidine, famotidine, nizatidine, roxatidine): These drugs block histamine H2 receptors. They block histamine-mediated acid secretion from gastric parietal cells and also reduce gastrin and cholinergic acid secretion. They reduce both quantity and concentration of acid but have no effect on mucous secretion and gastric motility.
Uses: These are used in:
- Gastric and duodenal ulcers. They help in ulcer healing and prevent recurrence of ulcers.
- Gastric erosions with or without bleeding.
- Ref lux oesophagitis.
- Stress ulcers (burns).
- Zollinger-Ellison syndrome.
- Chronic gastritis.
- Chronic urticaria as they increase the effect of H1 antagonists.
- Protection of aspiration pneumonia. This is achieved by giving them preoperatively to decrease the risk of aspiration of gastric acid content.
Dosage:
Ranitidine: 150 mg twice daily or 300 mg at bedtime for 4—6 weeks.
Famatidine: 20 mg twice daily or 40 mg at bedtime for 4—6 weeks.
Roxatidine: 75 mg twice daily or 150 mg at bedtime.
Nizatidine: 150 mg twice daily or 300 mg at bedtime for 4—6 weeks.
Loxatidine: Recently developed powerful non-competitive l12 antagonist.
Side effects of drugs used in Peptic Ulcer: Cimetidine is no more used, due to gynecomastia and impotency which are produced in males by cimetidine because of its weak antiandrogenic activity. Cimetidine may produce mental confusion, hallucinations, drowsiness and convulsions also because it crosses blood— brain barrier.
Newer H2 blockers do not have antiandrogenic activity and have minimal access across the blood—brain barrier. They occasionally induce diarrhoea, headache, and vertigo, mild disorientation and skin rashes.
Interactions of drugs used in Peptic Ulcer: Cimetidine potentiates the toxicity of propranolol, diazepam, theophylline, imipramine, lignocaine, phenytoin, warfarin and phenobarbitone by inhibiting hepatic microsomal oxidase enzyme. However, in therapeutic doses newer H, antagonists have minimal hepatic enzyme inhibiting activity. They retard absorption of ketoconazole due to reduction in gastric acidity.
4. Proton pump inhibitors: They inhibit the so called proton pump by inhibiting the enzyme H÷K ATPase of the gastric parietal cells. The important members of this group are omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. All are prodrugs. Their active entity is a sulfonamide cation that is produced within gastric parietal cells. All are given orally except pantoprazole which can also be given i.v.
Uses:
These are used to treat gastric and duodenal ulcers, not responding to lI2 antagonists because there long-term use is likely to be hazardous.
- These are drug of choice for ZollingerEllison syndrome.
- Reflux oesophagitis.
- NSAIDs induced ulcerations and bleeding.
- For prevention of acid aspiration during general anaesthesia. For this purpose, these are given in doses of 40 mg oral an evening before surgery and further a 40 mg oral 6 hrs before surgery.
Doses: Therapeutic doses of these drugs are in range of 20 to 40 mg once daily for 4—6 weeks. However, for the treatment of Zollinger-Ellison syndrome, higher doses (in range of 60 to 120 mg daily) may be required to be given for longer period.
Side effects; During short-term therapy, it causes nausea, diarrhoea, pain in abdomen, dizziness, headache. They are generally mild and do not require reduction in doses.
During long-term therapy there occurs gastrin stimulated hyperplasia of gastric epithelium and bacterial overgrowth due to sustained decrease in gastric acidity which converts ingested nitrates into carcinogenic nitrosamines.
5. Dngs providing protection to mucosa:
i. Sucralfate: It is an aluminium containing salt of sucrose octasulfate.
Mode of action of drugs used in Peptic Ulcer:
- It becomes highly viscous gel in acid pH of the stomach. The gel binds to proteins in the ulcer crater and forms a protective coating. Due to this, it checks the diffusion of H ions and pepsin.
- It prOtects parietal cells by increasing endogenous prostaglandin synthesis.
- It attenuates peptic activity by binding with pepsin.
- It also binds with bile salts and provides an ideal physical barrier. Thus it protects ulcer site from offensive intraluminal acid.
Uses:
- Chronic gastric and duodenal ulcer
- Chronic gastritis.
Since sucralf ate is effective only in acid medium, it should not be given along with antacids, omeprazole or H2 antagonists. It effectively prevents ulcer recurrence.
Dose: 1 gm 6 hourly or 2 gm 12 hourly. Side effects: It may cause constipation, nausea, dyspepsia, headache, itching and swelling of skin due to allergy. Rarely aluminium toxicity may occur in renal failure.
ii. Carbenoxalone: It is extracted from roots of the plant liquorice. It increases mucus and promotes healing by increasing endogenous prostaglandin levels. However, this drug has little or no place in the treatment of peptic ulcer because it retains water and salt causing high blood pressure. Spironolactone (an aldosterone antagonist) reduces the ulcer healing effect of carbenoxolone.
iii. Prostaglandins: Prostaglandins (PGE2 and PGI2) maintain gastroduodenal mucosal integrity. Hence their reduction (endogenous PG levels) leads to mucosal damage and ulceration. Natural PGs have transient effects. Hence synthetic analogues are used. They are:
• Misoprostol (methyl ester of 15 methyl PGE1),
• Enprostil (dehydro-PGE2, derivative),
• Rioprostil (methyl PGE1, derivative),
• Arboprostil (15-methyl PGE2), and
• Trimoprostil (trimethyl-li deoxy derivative of PGE2)
Out of these, misoprostal is available
for clinical use. It is given in doses of
200 ag four times a day.
Mode of action:
• They strengthen the so-called mucus bicarbonate barrier by increasing secretion of mucus and bicarbonate.
• They prevent acid assault on mucosa by increasing phospholipid content of surface epithelium.
• They accelerate ulcer healing by increasing mucosal repair and restitution.
• They have protective effect on parietal cells of the stomach by increasing mucosal blood flow.
Uses:
• Chronic gastritis
• Duodenal ulcer
• NSAIDs induced ulceration and bleeding
Side effects: Diarrhoea, abdominal pain, nausea, dysmenorrhea are fairly common. PGs are contraindicated in pregnancy because they stimulate uterine muscles and can cause abortion or premature labour.
6. Anti-Helicobacter pylon drugs: H. pylon is a gram-negative bacillus. It has uniquely adopted to survival in the hostile environment of stomach. It attaches to the surface epithelium beneath the mucus. It has high urease activity. So it produces ammonia which maintains a neutral micro-environment around the bacteria and promotes back diffusion of Ft ions.
It is now well know that Helicobacter pylon infection is one of the most important etiological factors for peptic ulcer. So it is appropriate to treat H. pylon in patients with peptic ulcer or low-grade mucosa associated lymph oil tissue (MALT) lymphoma. Single drug regimens are not advocated due to the potential for the development of antibiotic resistance. This is particularly true to macrolides and nitroimidazoles, which are the key antimicrobials in the multi-drug regimes for H. pylon. At present, dual treatment combining a proton pump inhibitor(PPI) with either clarithromycin or amoxicillin are also not used because of unacceptable low eradication rates.
Comments
Although bismuth based triple therapy consisting of colloidal bismuth subcitrate, tetracycline and metronidazole for 2 weeks is cheap, well investigated having high cure rate, it is not used in developing countries because 80—90% of H. pylon strains are resistant to metronidazole. So triple therapies in drugs used in Peptic Ulcer with a combination of a proton pump inhibitor and 2 antibiotics have largely replaced the use of the classical bismuth based triple therapy in almost all countries. A new group of triple regimen has been developed which replaces proton pump inhibitor with ranitidine bismuth citrate. This regimen causes less acid suppression and also provides additional antimicrobial action of bismuth. In an attempt to achieve 100 % eradication of H. pylon, a quadruple therapy combination has been developed. The major advantages of this regimen over the classical triple therapy are:
a. High and consistent eradication rate
b. A 1 week treatment offering a cure rate similar to the classical triple therapy.
c. A significant reduction in complications seen with the 2 weeks bismuth based triple therapy.
d. This regimen is also recommended as the rescue line therapy when the first line therapy fails.
[Source: Principles of Pharmacology for Dental Students]
