peptic ulcer by b chaitra amin

PEPTIC ULCER

BY

CHAITHRA AMIN B1ST M.PHARM

DEPT OF PHARMACOLOGY

• Peptic ulcer is a lesion in the lining ( mucosa )of the

digestive tract, typically in the stomach or duodenum, caused

by the digestive action of pepsin and acid secreted by

stomach.

• Occurs in the part of the GIT. Which is exposed to gastric acid

and pepsin, i.e. the stomach and duodenum.

INTRODUCTION

• It results probably due to an imbalance between the two

factors

• 1. Aggressive (acid , pepsin, bile and H.pylori )

• 2. Defensive ( gastric mucus and bicarbonate secretions,

PGs, innate resistance of the mucosal cells )

• In gastric ulcer generally acid secretion is normal or low.

• In duodenal ulcer acid secretion is high in half of the patients

but normal in the rest.

Pathogenesis of peptic ulcer• Acid and Pepsine • Helicobacter pylori • NSAIDs • Motility disturbance • Stress • Ischemia• Hypergastrinemic

Syndromes• Hyperhistaminic Syndromes• Alcohol• Tobacco

Regulation of gastric acid secretion

• The terminal enzymes H+K+ATPase which secretes H+ ions

in the apical canaliculi of parietal cells can be activated by

histamine, Ach and gastrin acting via their own receptors

located on the basolateral membrane of these cells.

• Histamine acting through H2 receptors, plays the dominant

role, because the other two, gastrin and Ach partly directly

and to a greater extent indirectly by releasing histamine from

‘ histaminocytes’ located in the oxyntic glands.

• While H2 receptors activate H+K+ATPase by generating cAMP,

muscarinic and gastrin receptors appear to function through the

phospholipase C IP3 – DAG pathway that mobilizes intracellular Ca+2.

• The cAMP mediated proton pump activation also involves ca+2.

• The secretomotor response to gastrin and cholinergic agonists is

expressed fully only in the presence of cAMP generated by H 2

activation.

• Histamine participates in the acid response to gastrin, ACh at more

than one levels, and H2antagonists suppress not only histamine, but

also Ach and in fact any other gastric secretion stimulus.

• Gastrin is secreted from the antrum in response to rise in antral pH,

food constituents and vagally mediated reflexes. The dominant

muscarinic receptor mediating vagal responses is of theM1 subtype.

• Vagus releases Ach in close proximity to histaminocytes and gastrin

secreting cells.

• Prostaglandins have been ascribed a ‘cytoprotective’ role in the

gastric mucosa by augmenting mucus and bicarbonate secretion, as

well as other actions.

• PGE2, produced by gastric mucosa, inhibits acid secretion by

opposing cAMP generation ( in parietal cells ) and gastrin release

( from antral cells )

symptoms• Epigastric pain after meal or during meal• Upper dyspeptic syndrome – loss of appetite,

nausea, vomiting.• Vomiting brings relief • Reduced nutrition• Loss of weight• Oral flatulence, bloating, distension and intolerance of

fatty food • Heartburn • Pain radiating to the back

1. Reduction of gastric acid secretion

2. Neutralization of gastric acid ( antacids )

3. Ulcer protectives

4. Anti- H.Pylori drugs

APPROACHES FOR THE REDUCTION OF PEPTIC ULCER

1. H2 Antihistamins : cimetidin, rantidine, famotidine,

roxatidine.

2. Proton pump inhibitors : omeprazole, lansoprazole,

pantoprazole, rabeprazole, esomeprazole.

3. Anticholinergics : pirenzepine, propantheline,

oxyphenonium.

4. Prostaglandin analogue : misoprostol.

Reduction of gastric acid secretion

Neutralization of gastric acid (antacids)

1. Systemic : sodium bicarbonate, sod. Citrate

2. Nonsystemic : magnesium hydroxide,

mag.Trisilicate, aluminium hydroxide gel, calcium

carbonate

Ulcer protectivesSucralfate , colloidal bismuth subcitrate (CBS)

Anti H-pylori drugsAmoxicillin, clarithromycin, Metronidazole, trinidazole,

tetracycline.

Eg: Cimetidine ,ranitidine etc

• First class of highly effective drugs

• Their interaction with H2 receptors has been found to be

compititive. Cimetidine was the first H2 blocker to be

introduced clinically and is described as prototype, though

other H2 blockers are commonly used now.

1. H2 Antagonists

1. H2 Blockade : Cimetidine and other H2 antagonists block histamine-

induced gastric secretion, cardiac stimulaton,uternine

relaxation,bronchial realaxation.Attenuate Fall in BP due to histamine,

especially the late phase response seen with high doses.

2. Gastric secretion : Markedly inhibited. All phases of secretion are

suppressed dose-dependently, but the basal nocturnal secretion is

suppressed completely. Secretory responses to not only histamine but

all other stimuli i.e Ach , gastrin, food, alcohol are seen.

PHARMACOLOGICAL ACTIONS

• Absorbed orally , bioavailibility is 60-80%.

Absorption not interfered by presence of food in

stomach.

• Cross placenta and reaches milk

• Dose reduction- in case of renal failure.

Pharmacokinetics

• CNS effects like confusional state, restlessness, convulsions

and coma have occurred infrequently in elderly persons with

renal impairment with large doses infused i.v

• Headach, dizziness, bowel upset, dry mouth, rashes.

• Cemetidine - Anti androgenic action.Increases plasma

prolactin and inhibit degradation of estradiol by liver.

• High dose for long time - gynaecomastia, loss of libido,

impotence and temporary decrease in sperm count

Adverse effects

Used in conditions in which it is profitable to suppress gastric

acid secretion.

1. Duodenal ulcer

2. Gastric ulcer

3. Stress ulcers and gastritis

4. Zollingers-Ellison syndrome

5. Gastroesophagel reflux disease

Uses

• These are the most effective drug, both for symptomatic relief

as well as for healing of easophagal lesions. Gastric pH is

maintained for 18 hours a day.

• This level of acid suppression can only be achieved by PPIs.

Therefore these are the drug of choice for all stages of GERD

patients. Rapid relief and 80% lesion heal in 4-8 weeks.

2.PROTON PUMP INHIBITORS

• It is the member of substituted benzimidazoles which inhibits

final step in gastric acid secretion and overtaken by H2

blockers for acid- peptic disorders. Powerful inhibitor of

gastric acid can totally abolish HCL secretion.

• Omeprazole is inactive at neutral pH, but at pH<5 rearranges

to 2 charged cationic forms (sulphanic acid and sulphenamide

configurations )

Eg: omeprazole

• That react covalently with SH groups of H+K+ATPase enzyme

and inactivate it irreversibly , especially when two molecules

of omeprazole react with one molecule of the enzyme.

• After diffusing into parietal cell from blood, it get

concentrated in the acidic pH of the canaliculi because the

charged forms generated there are unable to diffuse back.

• Moreover , it gets tightly bound to the enzyme. These features

and the specific delocalization of H+K+ATPase to the apical

membrane of the parietal cells confer high degree of

selectivity of action to omeprazole.

• Acid secretion resumes only when new H+K+ATPase

molecules are synthesized.

• The oral absorption is about 50% because of instability at acidic

pH. Bioavailibity of PPIs can be reduced by food. Should be taken

in empty stomach . Inhibition of HCL secretion occurs within 1 hr

reaches maximum at 2 hr.

• All PPIs produce 80-98% suppression of 24 hour acid output with

conventional doses.

• Because of long lasting acid suppression , hypergastrinemia has

been observed. This found to increase proliferation of parietal cells

in rats but not in humans.

Pharmacokinetics

1. Peptic ulcer : faster healing , omeprazole 20 mg OD is equally or more effective than H2 blockers.

2. GERD disease: inhibition of gastric acid resulting in rapid symptoms relief and is more effective than H2blockers in promoting healing of esophageal lesions . Omeprazole 20-60 mg daily twice.

3. Bleeding peptic ulcer : PPI therapy profoundly inhibit bleeding.

Uses of PPIs

• Abdominal pain• Headache, dizziness,rashesh.• Hepatic dysfunction• Muscle and join pain• On prolonged use atrophic gastritis

Drug interaction• Inhibits oxidation of certain drugs like Diazepam, phenytoin.• Clarithromycin inhibits omeprazole metabolism and increases

its plasma concentration.

Adverse effects

• PGE2 and PGI2 are in the gastric mucosa and appear to serve a

protective role by inhibiting acid secretion and promoting

mucous secretion. In addition , PGs inhibit gastrin production ,

increase mucosal blood flow and probably have an ill-defined

cytoprotective action.

• Natural PGs have very short t ½ . Number of stable PG

analogues which exert action for hours rather than minutes

have developed for use in peptic ulcer.

3.Prostaglandin analogue

• Misoprostol is commercially available drug. It inhibits acid

output dose dependently. However, reduction in 24 hrs acid

production is less than H2 blockers because of shorter duration

action.

• Problems occurred by the usage of misoprostol are diarrhea,

abdominal crams, uterine bleeding, abortion.

• These are the basic substances which neutralize gastric acid

and raise pH of gastric contents. Peptic activity is reduced if

the pH rises above 4, because pepsin is secreted as a complex

with an inhibitory terminal moiety that dissociates below pH 5

. Optimum peptic activity is exerted between pH 2-4 .

• Antacids do no decrease acid production; rather, agents that

rise antral pH to >4 evoke reflex gastrin release more acid

is secreted especially in patients with hyperacidity; “ acid

rebound ” and gastric motility is increased.

4.ANTACIDS

Eg: SODIUM BICARBONATE :

• It is water soluble , acts instantaneously, but the duration of

action is short. It is a potent neutralizer, pH may rise above 7.

• However it has several demerits

a) Absorbed systemically , large doses will induce alkalosis.

b) Produces carbon dioxide in stomach which creates

discomfort, risk of ulcer perforation.

c) Acid rebound

a) SYSTEMIC ANTACIDS

• These are insoluble and poorly absorbed basic compounds ,

react in stomach to form the corresponding chloride salt. The

chloride salt again reacts with the intestinal bicarbonate so that

HCO3 is not spared for absorption so that no acid base

disturbance occurs. However small amount that are absorbed

have the same alkalinizing effect as NaHCO3.

b)Nonsystemic antacids

• Has low water solubility ; its aqueous suspension has low

concentration of OH- ions and thus low alkalinity. However it

reacts with HCL promptly and is an efficacious antacid.

• MILK OF MAGNESIA - 0.4 g / 5 ml suspension

Eg: Mag. hydroxide

By raising gastric pH and by forming complexes the non-

absorbable antacids decrease the absorption of many drugs

especially tetracycline, H2 blockers, diazepam,

indomethacin,isoniazid etc.

Drug interactions

• Gastroesophageal reflix: antacids afford faster symptom relief

than drugs which inhibit acid secretion, but donot provide

sustained benefit.

No longer used for healing peptic ulcer because they are needed

in large and frequent doses, are inconvenient can cause acid

rebound and bowel upset, and have poor patient acceptability.

Uses of antacids

Eg: SUCRALFATE : • It is a basic aluminum salt of sulfated sucrose. It strongly

adhere to ulcer base , especially duodenal ulcer. Precipitates

surface proteins at ulcer base and acts as a physical barrier

preventing acid, pepsin , bile from coming in contact with

ulcer base.

• Dose: ulcer healing dose is 1g , taken 1 hr before 3 major

meals and at bed time for 4-8 weeks.

5) Ulcer protectives

6) Anti H.pylori drugs• H.pylori is a gram negative

bacillus uniquely adapted to survival in the hostile environment of stomach.

• It attaches to the surface epithelium beneath the mucus, has high urease activity-produces ammonia which maintains the neutral microenvironment around the bacteria, and promotes back diffusion of H+ ions.

• Eradication of H.pylori concurrently with H2 blocker/ PPI

therapy of peptic ulcer has been associated with faster healing

and lower relapse rate. Antimicrobials that have been found

clinically effective against H.pylori are: amoxicillin,

clarithromycin, tetracycline and metronidazole.

• Bismuth is active against H.pylori and resistance does not

develop to it.

• Omeprazole monotherapy reduces the population of H.pylori

in gastric antrum, probably by altering the acid environment as

well as direct inhibitory effect.

• Rise in the intragastric pH enhances the anti- H.pylori action

of the antibiotics.

• US FDA approved regimen is : Lansoprozole 30 mg +

Amoxicillin 100 mg + Clarithromycin 500 mg all given twice

daily for 2 weeks.

• A 4 drug regimen ( PPI + Tetracycline + CBS + Metronidazole

) has also been advocated.

• Regimens are expensive, complex, side effects are frequent

and compliance is poor.

• Benefits of anti H.pylori drugs include lowering ulcer desease,

prevalence and prevention of gastric carcinoma.

• H.pylori vaccines are under development.

• Available anti H.pylori kit are PYLOMOX, LANSI KIT,

HELIBACT.

I. Relief of painII. Ulcer healing III. Prevention of complicationsIV. Prevension of relapse

ROLE OF DRUG IN PEPTIC ULCER DESEASE

References1. K.D Tripathi. Essential of medical

pharmacology. 6th ed. pg no: 627-37

2. Padmaja Udaykumar.medical

pharmacology. 4th ed. pg no: 359-68

3. Rang and dale's pharmacology. 6th ed.

pgno: 385-90

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