ANTI-ULCER DRUGS

RVS Chaitanya

Koppala

PEPTIC ULCER

An Ulcer is …

Erosion in the lining of the stomach or the first part of the small intestine, an area called the duodenum.

Ulcers damage the mucosa of the alimentary tract, which extends through the muscularis mucosa into the sub mucosa or deeper.

Ulcers that form in the stomach are called gastric ulcers; in the duodenum, they are called duodenal ulcers. Both types are referred to as peptic ulcers.

PEPTIC ULCERPEPTIC ULCER

PATHOGENESIS OF PEPTIC ULCER DISEASEIMBALANCE:

AGGRESSIVE FACTORS Acid Pepsin Helicobacter pylori NSAIDS

DEFENSIVE FACTORS Prostaglandins Mucosal blood flow Mucous gel layer HCO3

Epithelial junctions Regeneration of the epithelial layer

Epidermal growth factor

APPROACHES FOR THE TREATMENT OF ULCER1. Reduction of gastric acid secretion

A) H2 antihistaminics: Cimetidine, ranitidine, famotidine, roxatidine

B) Proton pump inhibitors: Omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dexrabeprazole

C) Anti cholinergic drugs: Pirenzapine, propantheline, oxyphenomium

D) Prostaglandin analogue: misoprostol

2. Neutralization of gastric acidA) Systemic : Sodium bicarbonate, sodium citrateB) Non systemic: Magnesium hydroxide, mag trisilicate, aluminium hydroxide gel, magaldrate, calcium carbonate

3. Ulcer protective : Sucralfate, colloidal bismuth subcirtrate

4. Anti H-pylori drugs:Clarithromycin, metronidazole, amoxicillin, tinidazole, tetracycline

PHYSIOLOGY OF GASTRIC ACID SECRETION Gastric acid secretion is a complex, continuous process in which multiple central and peripheral factors contribute to a common endpoint secretion of H⁺ by parietal cells.

Neuronal(acetylcholine,Ach),paracrine(histamine), and endocrine (gastrin) factors all regulate acid secretion.

Their specific receptors (M3,H2,and CCK2 receptors, respectively)are on the basolateral membrane of parietal cells in the body and fundus of the stomach.

The H2 receptor is a GPCR that activates the Gs- adenyl cyclase –cyclic AMP-PKA pathway.

Ach and gastrin signal through GPCRs that couple to the Gq-PLC-IP3-Ca2+ pathway in parietal cells .

In parietal cells , the cyclic AMP and the Ca2+

dependant pathways activate H+,K+-ATPase (the proton pump), which exchanges hydrogen and potassium ions across the parietal cell membrane

PATHOPHYSIOLOGY

HISTAMINE ANTAGONIST Cimetidine .Histamine antagonists inhibit the action of histamine on the acid-producing cells of the stomach and reduce stomach acid

HISTAMINE ANTAGONIST First class of highly effective drugs for acid peptic disease but surpassed by proton pump inhibitors

Cimetidine was the first to introduce in the market and described as prototype

Pharmacological actions:1.H2 blockade: Block histamine induced gastric secretion, cardiac stimulation, uterine relaxation

No effect on H1 responses because they are selective

2. Gastric secretion:Marked inhibition of gastric secretionAll phase are suppressed dose dependently.Secretory response to not only histamine but also Ach, gastrin, insulin, alcohol, food are attenuated

The volume, pepsin content and intrinsic factor secretion are reduced

They don’t have any direct action on gastric or oesophageal motility or on LES tone

PHARMACOKINETICS Adequately absorbed orally, Bioavailability is 60-80% Undergoes first pass metabolism No interference by presence of food Crosses placenta and reaches milk Poor BBB penetration About 2/3 of dose is excreted unchanged in urine/bile Elimination t1/2 is 2-3hr Dose reduction is needed in renal failure

CIMETIDINESIDE EFFECTS; It include constipation, diarrhea, fatigue, headache, insomnia, muscle pain, and vomiting.

Major side effects: Bowel upset,

Dry mouth,Rashes, Gynaecomastia, Impotence, Loss of libido, Decrease in sperm count

USES: It is used in treatment of Duodenal ulcer, Gastric ulcer, Stress ulcer, GERD, Zollinger ellison syndromeProphylaxis of aspiration pneumonia

PROTON PUMP INHIBITORS  Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme (H+K+ATPase) system of the gastric parietal cells.

The proton pump is the terminal stage in gastric acid secretion

PROTON PUMP INHIBITORS(OMEPRAZOLE) Prototype member of this category Overtaken H2 blockers for acid peptic disorders Dose dependant suppression of gastric secretion No anticholinergic/ antihistaminergic Powerful inhibitor of gastric acid secretion both resting and as well as stimulated

No much action on pepsin, juice volume and gastric motility

MECHANISM OF ACTION Inactive at neutral pH, but at <5 it rearranges to two charged cationic forms

React covalently with SH groups of H+K+ATPase enzyme and inactivate it irreversibly

After absorption if diffusion and concentrate in parietal cell and then in acidic pH of canaliculi

Binds tighly covalently with enzyme of parietal cell confer high degree of selectivity

Acid secretion resumes only when new H+K+ATPase molecules are synthesized

PHARMACOKINETICS All PPIs are administered enteric coated Oral bioavailability is 50% due to acid lability Food interferes with absorption Should be taken 1 hour prior to meal Highly plasma protein binding Metabolised byCYP2C19 and CYP3A4 Plasma t1/2 is1 hour Metabolites are excreted in urine No dose modification is required in any impairment

Uses Peptic ulcer Bleeding peptic ulcer Stress ulcer GERD Zollinger Ellison syndrome Aspiration pneumonia

Adverse effects Nausea, loose stools, headache, abdominal pain, muscle and joint pains Rashes Leucopenia Hepatic dysfunction Gynecomastia and erectile dysfunction (lately observed)

HELICOBACTER PYLORI

1981 - Robin Warren, M.D., an Australian pathologist, discovered numerous bacteria living in tissue taken during a stomach biopsy.

Spiral urease-producing, Gram-negative bacteria always accompanied changes in the stomach lining

HELICOBACTER PYLORI Gram negative, Spiral bacilli Spirochetes Do not invade cells – only mucous Breakdown urea - ammonia Break down mucosal defense Chronic Superficial inflammation

SYMPTOMS OF H. PYLORI Abdominal pain

Feeling of Fullness Indigestion Feeling very hungry 1 to 3 hours after eating

Mild nausea Pain Starts 2/3 hours after meals, or in the middle of the night

SYMPTOMS Burning abdominal pain Haematemesis Melena Nausea or vomiting Unexplained weight loss Anorexia Abdominal fullness

DIAGNOSIS Endoscopy: Flexible tube fitted with camera is threaded down the esophagus in to stomach to see the ulcer by physician

Barium meal: Barium liquid is drunk making ulcer visible on X-ray

Test for diagnosing H.pyloriBreath test :by measuring the amount of co2 in exhaled breath.Blood test: by identifying H.pylori antibodies by ELISA test.Stool test :stool sample tested with H.pylori antigen.

ACETYL CHOLINE ANTAGONISTPIRENZEPINE

MECHANISM: It selectively block M1 muscaranic recptors and inhibits gastric secretion.

Because of their relatively poor efficacy, side effects, and risk of blood disorders, they are rarely used today

AGENTS THAT ENHANCE MUCOSAL DEFENSE

Prostaglandin Analogs:

prostaglandins are produced in the gastric mucosa and appear to serve a protective role by inhibiting acid secretion and promoting mucus

and bicarbonate secretion. In addition, PGs inhibits gastrin production, increase mucosal blood flow and probably have an ill defined cytoprotective action.

DRUGS: Misoprostol

MISOPROSTOL

MECHANISM: Misoprostol acts upon gastric parietal cells,

inhibiting the secretion of gastric acid via G-protein coupled receptor-mediated inhibition of adenylate cyclase, which leads to decreased intracellular cyclic AMP levels and decreased

pump activity at the apical surface of the parietal cell Side effects Diarrhea. Other common side effects include: abdominal pain,

nausea, flatulence, headache, dyspepsia, vomiting, and constipation.

ULCER PROTECTIVES SUCRALFATE MECHANISM: Sucralfate is a locally acting substance that in an acidic environment (pH < 4),

reacts with hydrochloric acid in the stomach to form a cross-linking, viscous, paste-like material capable of acting as an acid buffer for as long as 6 to 8 hours after a single dose.

It also attaches to proteins on the surface of ulcers, such as albumin and fibrinogen, to form stable insoluble complexes.

These complexes serve as protective barriers at the ulcer surface, preventing further damage from acid, pepsin, and bile.

Side effects The most common side effects seen are constipation. Less commonly reported include flatulence, cephalalgia (headache), xerostomia (dry mouth).

USES: It is used in treatment of Gastritis, Stress ulcers.

ANTACIDS Basic substances which neutralize the gastric acid and increase pH

Peptic activity is indirectly reduced if pH increase above 4 which dissociates below 5

Do not decrease acid production rather increase acid antral pH >4

Potency is generally expressed in term ANC Acid neutralizing capacity : no of mEq of 1N HCl that are brought to pH 3.5 in 15 mins by a unit dose of antacid

ANTACIDSYSTEMIC ANTACIDS

Sodium bicarbonate It is water soluble, acts instantaneously, but the duration of action is short. It is a potent neutralizer (1 g → 12 mEq HCl), pH may rise above 7. However, it has several demerits: (a) Absorbed systemically: large doses will induce alkalosis. (b) Produces CO2 in stomach → distention, discomfort, belching, risk of ulcer perforation. (c) Acid rebound occurs, but is usually short lasting.

NON SYSTEMIC ANTACIDS Insoluble and poorly absorbed basic substance react in stomach to form corresponding chloride salts

The chloride salts reacts with intestinal bicarbonate so that HCO3 in spread for absorption- no acid basic disturbances occurs

Magnesium hydroxide ( milk of magnesia) with 30mEq HCl

Magnesium trisilicate :mg salts are having laxative action generation osmotically active MgCl2 induced cholecystokinin hormone

Alluminium hydroxide:It ANC depends upon storage, it activity decline as storage time increasesAlum. hydrox. binds phosphate in the intestine and prevents its absorption—hypophosphatemia occurs on regular use. This may: (a) cause osteomalacia (b) be used therapeutically in hyperphosphatemia and phosphate stones. Small amount of Al3+ that is absorbed is excreted by kidney. This is impaired in renal failure—aluminium toxicity(encephalopathy, osteoporosis) can occur.

SODIUM BICARBONATE (ANTACID)

It is water soluble, acts instantaneously, but duration of action is short. It is a potent neutralizer, pH may raises above 7.

Adverse reactions It causes systemic alkalosis, gastric

distention, rebound acidity and milk-alkali syndrome

Uses It is restricted to casual treatment of

heartburn and to treat acidosis

CONCLUSION