6. 1) Drug for reducing acid
secretion
i) Proton Pump inhibitors(PPIs):
• Proton pump H+, K+ ATPase is membrane bond enzyme
than plays an important role in final step of gastric acid
secretion.
• Hence PPIs are most the most powerful inhibitors of
gastric acid secretion
• Prototype: Omeprazole.
• Eg:- Lansoprazole, pantoprazole and rabeprazole.
7. MOA
Mechanism of action: These
are prodrug and activated to
sulphenamide at acidic pH.
The activated form bind
covalently with proton pump
and irreversibly inactivates
it.
Hence it decreases the
secretion of HCl from parietal
cell of stomac.
PARIETAL
CELL
8. Pharmacokinetic
• Bioavailability: more than 80%
• Plasma t ½: 1-2 hours.
• metabolized in liver via liver enzymes
• Excretion via urine
• Inhibition of HCl occur within 1 hr and reached maximum
at 2 hrs.
• At least Given 30 minutes before food(empty stomach)
• Acid Labile hence administered as enteric coated
formulation.
• Given as oral solid dosage form(tablet and capsule)
• Pantoprazole and lansoprazole also available in IV.
9. Uses
• Peptic ulcer:
• Standard dose is omeprazole 20 mg OD and lansoprazole
30 mg OD
• Faster healing demonstrate with 40 mg/day.
• Duodenal ulcer requires 4 weeks to heal and gastric
ulcer generally requires 4-8 weeks.
• Continued treatment 20 mg daily or thrice weekly can
prevent ulcer relapse.
• PPIs are integral component of anti H pylori therapy and
drug of choice of NSAIDs induce gastric/duodenal ulcer.
10. Cont..
• Stress ulcer: IV pantoprazole/rabeprazole is effective
for stress ulcer
• Gastroesophagul reflux disease(GERD): PPIs are drug of
choice
• Omeprazole 20 mg BD daily for 8-12 weeks is needed.
• Zollinger Ellison syndrome:
• It is characterize by hypergastrinaemia with multiple peptic
ulcer. Omeprazole or lansoprazole is treatment of choice.
Higher doses(60-120mg in divided dose) of PPIs are required
for healing ulcers. Surgery is definitve treatment whereas for
inoperable cases, prolonge therapy is recommended.
11. Adverse effects
• Generally well tolerated.
• Headache, diarrhea, abdominal pain,
• dizziness(3-5%), rashes(1.5%)
• No harmful effects of PPIs during pregnancy are
known.
• PPIS Should not use of for very long period as it
may cause achlorhydria,(Complete inhibition of
HCl)
12. Drug Interactions
• PPIs may interfere with absorption of ketoconazole,
digoxin and iron by decreasing gastric acid
secretion.
• Omeprazole may inhibit metabolism of warfarin,
diazepam, phenytoin etc.
• Pantoprazole has no such interaction and can safely
administered with these drugs.
13. ii) H2 receptor blocker(antagonist)
Prototype drug: Cimetidine
Other: Ranitidine, famotidine
Mechanism of action:-
It completely block the H2 receptor on
parietal cell and inhibit gastric acid production. They
mainly suppress nocturnal acid secretion.
They also reduce acid secretion stimulated by Ach ,
gastrin and food.
14. Pharmacokinetic
• Cimetidine
• Administered orally.
• bioavailability is 60-80%
• It crosses placenta and reaches milk,
• About 2/3 of adose is excreted unchanged in urine and
bile
• Metabolize in liver
• Dosage and Indication (uses)
• For ulcer healing-400 mg BD or 800 mg at bed time
• orally; maintenance-400 mg at bed time (h.s)
• for stress ulcer- 50 mg/hr i.v. infusion.
15. Cont.
Side effect
• Headache, dizziness, bowel upset, dry mouth, rashes.
• CNS effects like confusional state, restlessness, convulsions
and coma have occurred infrequently in elderly patients.
• In those with renal impairment, especially with large doses
infused i.v. bolus i.v. injection can release histamine caused
bradycardia, arrhythmias and cardiac arrest, hence It
should always be given by slow infusion.
• Cimetidine (but not other Hz blockers) has antiandrogenic
action (displaces dihydrotestosterone from its cytoplasmic
receptor), increases plasma prolactin and inhibits
degradation of estradiol by liver.
• High doses give for long periods have produced
gynaecomastia, loss of libido, impotence and temporary
decrease in sperm count.
16. cont
Drug Interaction:
• Cimetidine inhibits several cytochrome P-450 isoenzymes
and reduces hepatic blood flow.
• It inhibits the metabolism of many drugs so that they can
accumulate to toxic levels, e.g. theophylline,phenytoin,
carbamazepine, phenobarbitone, sulfonylureas,
metronidazole, warfarin, imipramine, lidocaine, nifedipine,
quinidine
• Metabolism of propranolol and diazepam is also retarded
• Antacids reduce absorption of all H2 blockers.
• When used concurrently a gap of 2hr should beallowed.
• Ketoconazole absorption is decreased by cimetidine
(probably by other H2 blockers
17. Cont..
• Ranitidine
• 5 times more powerful than cimetidine
• longer duration of action with greater 24 hr acid
suppression
• Dosage of Ranitidine: 150 mg BD(twice daily) in empty
stomach
Uses:
• For ulcer healing 300 mg at bed time or 150 mg BD;
• for maintenance 150 mg at bed time.
• Parenteral dose-- 50 mg i.m. or slow i.v. inj every 6-8 hr
(rapid i.v injection can cause hypotension), 0.1-0.25
mg/kg/hr by i.v.
• Side effect: Overall incidence of side effects is lower:
headache, diarrhoea constipation, dizziness have an
incidence similar to placebo
18. Cont..
• Famotidine: Similar to ranitidine. It is more potent than ranitidine (5-8
times).
• NO antiandrogenic effect , does not cross BBB, does not inhibit hepatic
microsomal P450enzyme.
• The oral bioavailability of famotidine is 40-50% and it is excreted by the
kidney.
• About 70% excrete in unchanged form.
Dosage:
• Famotidine: 10-20 mg BD in empty stomach 40 mg at bed time or 20 mg
BD (for healing);
• at bed time
• for maintenance; upto 40-80 mg/dav in syndrome;
• parenteral dose 20 mg i.v. 12 hourly
• Side effect
• Incidence of adverse effect is low: only headache, dizziness, bowel
ups.rarely disorientation and rash have been reported.
19. General comparison
Cimetidine: Ranitidine
H2 blocker(competitive) H2 blocker(competitive)
Less potent More potent
Short duration of action (6-8 hr) Longer duration of action(24 hrs)
Has antiandrogenic effect hence cause
menstrul irregularities and galactorrhoea in
womena and gynaecomastia, oligospermia
and impotence in men
No antiandrogenic
Enzyme inhibitors and increase plasma
concentration of phenytoin, digoxin warfarin
theophylline propranolol. etc
Does not inhibit enzyme
Cross BBB (blood brain barrier) and produce
CNS side effect confusion
Does not cross BBB
20. Contd..
• Therapeutic uses:
1) Peptic ulcer: Commonly used drug in peptic ulcer. It
produce symptomatic relief within days and ulcer healing
within weeks.
• Duration of treatment for duodenal ulcer is 4-6 weeks.
• Gastric ulcer:- 6-8 wks
21. Cont..
2) GERD: In GERD it is e ffective and produce
symptomatic relief. PPIs are more effective than H2
blocker.
3) Stress ulcer: I.V H2 blocker are used.
4) H2 blocker are used preoperatively before
anesthesia in emergency surgery to reduce risk of
acid pneumonia.
22. iii) Anticholinergic agent
• Pirenzepine, Propantheline ,Oxyphenonium
• These are not generally used in clinical practice.
• Less effective than H2 blocker
• MOA: Selectively blocker M1 receptor, inhibit acid
and pepsin secretion.
• Poorly penetrate BBB so no CNS side effects.
23. 2) Drugs to Neutralize
acids.(Antacids)
• Antacids are weak bases that neutralize gastric acid
and thus raise gastric pH.
• They do not affect acid production.
• Ideal Properties of an antacid.
• It should be insoluble and capable of neutralizing acid.
• It should not liberate CO2
• It should be non absorbable
• It should not disturb acid base balance of the body.
24. Types of antacids
• Systemic: Sodium bicarbonate, sodium citrate
• Sodium bicarbonate is very effective and rapidly neutralize
gastric acid.
• Have short duration of action.
• It is highly water soluble and rapidly absorb from gut.
• 1 g neutralize 12 mEq HCl
• Side effects:
• Sodium bicarbonate cause alkalosis and sodium overload
so it should be avoided in patient with hypertension and
congestive cardiac failure
• It release CO2 that can cause abdominal distention and
belching.
• Cause rebound acidity
• Sodium citrate : It has Properties similar to sod. Bicarbonate.
1 g neutralizes 10 mEq HCI. C02 is not evolved
25. Cont.
• Non systemic: Magnesium hydroxide, magnesium
trisilicate, aluminium hydroxide, calcium carbonate.
• There is no systemic alkalosis.
• Generally combination of antacids are used due to several
bgenefits:
• Aluminium salt cause constipation and magnesium
cause diarrhea so combination of these two can
counteract adverse effect of each other.
• Magnesium hydroxide has rapid onset of action and
aluminium hydroxide act slowly, so combined produce
rapid and sustain effects.
• Dose of individual antacid is reduce so decrease in
systemic toxicity.
26. Cont..
Magnesium hydroxide
• It has low water solubility: its aqueous suspension (milk of
magnesia) has low concentration OH- ions and thus low alkalinity
• Acid neutralizing capacity( ANC) :1 g neutralize 30mEq HCI.
Magnesium trisilicate : It has low solubility
ANC= 1 g can react with 10 mEq of acid
Magaldrate: I
It is a hydrated complex of hydroxymagnesium aluminate that
initially reacts rapidly with acid and releases alum hydrox. which
then reacts more slowly
• Acid neutralizing capacity is estimated to be 28 mEq Hcl /g.
27. CONT
Aluminium hydroxide gel
It is a bland, weak and slowly reacting antacid.
ANCs; usually it varies from 1-2.5 mEq/g.
Calcium carbonate:
• It is a potent and rapidly acting acid neutralizer (1 g -) 20 mEq HCl),
but ANC of commercial preparations is less and variable due to
differing particle size and crystal structure.
Uses:
• Antacids are employed only for inter current pain relief and acidity,
for non ulcer dyspepsia and minor episodes of heartburn
• Antacids are 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, afford little nocturnal protection
28. Cont..
GERD: Antacids afford faster symptom relief than drugs which
inhibit acid secretion, but do not provide sustained
benefit. May be used off and on for acid eructation and
heartburn
Side effects:
Magnesium hydroxide may produce diarrhea whereas
aluminium hydroxide may produce constipation and
phosphate depletion
Calcium carbonate may produce hypercalcemia and
hypercalciuria
Interaction:
Antacid increase pH of stomach and form insoluble and
non absorbable complexed with many drugs- iron,
tetracycline, fluoroquinolones, ketoconazole etc.
29. 3) Mucosal protective agents
i) Prostaglandin(PG) analogues:
Natural prostaglandin are very short acting.
• Misoprostol is synthetic PG analogue is effectively orally for
prevention and treatment of NSAID induced gastric and
duodenal ulcer.
Mechanism of action (MOA):
• It increase mucus and bicarbonate secretion and also
increase mucosal blood flow. (Cytoprotective effect)
• Reduction in 24 hrs acid production is less than H2 blockers
because of shorter duration of action (3 hr)
• Ulcer healing rates comparable to cimetidine have been
obtained in 4-8 weeks, but misoprostol is poorer in
relieving ulcer pain. Some patients may even complain of
increased pain during the first week of therapy.
30. Cont..
Dosage: 200 ug QID
Side effect: Diarrhea , abdominal cramp, uterine bleeding,
abortion.
(Hence patient acceptability is very low)
• Contraindication (CI):- In pregnancy as it may cause uterine
contraction.
• Uses: The primary use of PG analogues is in the prevention
and treatment of NSAID associated gastrointestinal injury and
blood loss.
31. Cont.
ii) Ulcer protective
Sucralfate: It is complex of aluminum hydroxide and sulfated
sucrose.
Mechanism of action: (MOA)
In acidic environment (pH <4) it undergo extensive
polymerization to form a sticky gel that adheres to ulcer base
and protect it by forming barriers against acid and pepsin
It precipitate proteins at ulcer base especially duodenal ulcer;
It has been seen endoscopically to remain there for - 6 hours.
It also stimulate release of PG and epidermal growth factor
locally so cytoprotective effect aswell.
It also increase mucus and bicarbonate secretion and enhance
mucosal defence.
32. Cont.
• Sucralfate has no acid neutralizing action, but delays gastric
emptying-its own stay in stomach is prolonged.
• Sucralfate is minimally absorbed after oral administration;
• Its action is entirely local.
• It is given orally on an empty stomach at least 1 hour before
meal.
• It is considered to superior in patients who continue to
smoke.
Dose: Available in tablets and suspension
• For ulcer healing : 1 g taken 1 hr before the 3 major meals
and at bed time for 4-8 week
33. Cont..
Other uses: Bile reflux, gastritis and prophylaxis stress ulcers.
• A topical formulation of sucralfate GEL is available for
application on
• bedsores, diabetic/radiation ulcers, excoriated skirn as a
protective
Side effects: constipation , dry mouth. N/V, headache and skin
rashes are less common.
Interaction: It reduce absorption of digoxin, tetracycline ,
ketoconazole, fluroquinolones etc.
Similarly since it require acidic environment(pH<4),
concurrent administration of antacid, PPIS, H2 blocker should
be avoided.
34. Bismuth containing preparations
• Colloidal bismuth sub citrate (CBS) Tripotassium dicitrato bismuthate
• It is a colloidal bismuth compound; water soluble and precipitates at
pH < 5 are most commonly used.
• It heal 60% ulcers at 4 weeks and 80--90% at 8 weeks.
MOA:
Not clear. They probably react with protein in base of ulcer and protect it
from peptic digestion. Also might stimulate secretion of prostaglandin,
mucus and bicarbonate.
• Also have anti H. pylori effect that is directly kill organism and prevent
relapse.
• The tablet should be chewed and swallowed.
• Most of CBS are excreted through faeces, and small amount is
absorbed and excreted in urine.
• 60% ulcers at 4 weeks and 80—90 % at 8 weeks
35. Cont..
• Dosage: 120 mg before meal.
• Usage: Presently occasionally as a component of
triple drug anti-H. pylori regimen, but not by itself
to heal peptic ulcer.
• Side effects: Nausea, vomiting, blackening of
tongue.
• Prolonged use of bismuth compound may cause
neurotoxicity
• Interaction: Milk and antacid not be taken
concomitantly
36. Anti H pylori agents
• H pylori is gram negative , rod shaped bacteria.
• Mechanism by which H. pylori cause mucosal
inflammation and damage are not clear. The ammonia
produce by urease activity may directly damage the
cells.
• UP to 90% patients of duodenal and gastric ulcer have
tested positive for H. pylori.
• Antimicrobials that have been found clinically effective
against H. pylori are: amoxicillin, clarithromycin,
tetracycline and metronidazole/ tinidazole.
• Resistance develop rapidly to metronidazole and
clarithromycin but not to amoxicillin and tetracycline.
• Amoxicillin should be avoided in patient with history of
penicillin allergy.
37. Cont..
• Bismuth (CBS) is active against H. pylori and
resistance does not develop to it, early combination
regimens included bismuth, but had poor patient
acceptability; are infrequently used now
Combination therapy is required( Triple (three
medicines)/ quadruple (4 medicine)) for eradication
The objective of combine therapy:
• To prevent or delay the development of resistant
• To prevent relapse
• To promote rapid ulcer healing
• To eradicate h pylori infection
38. Cont..
• Dosage Regimen
• Triple therapy: For 14 days
• Clarithromycin 500 mg
twice a day(BD)
• Amoxicillin 1gm BD/
metronidazole 500mg BD
• PPI (omeprazole 20 mg BD
or lansoprazole 30mg BD)
• The US-FDA approved
regimen is: lansoprazole
• 30 mg + amoxicillin 1000
mg + clarithromycin500 mg
all given twice daily for 2
weeks.
• It has achieved 86-92%
eradication rate.
39. cont
• Quadruple therapy for 2 weeks (4 regimens)
• PPI(omeprazole 20 mg BD or lansoprazole 30 mg BD)
• Tetracycline 500 mg QID (four times a day)
• Metronidazole 500 mg TID (Three times a day)
• Bismuth subsalicylate 525 mg QID.
After Eradication of H. pylori , PPIs/H2 blocker should be
continued for 6 more weeks to enhance ulcer healing.
• Higher failure rates (20-40%) of H. pylori eradication have
been reported from India.
• Also,5 year recurrence rate of H. pylori infection is higher.
Three week treatment is now being advocated
40. Life style management
• Discontinue NSAIDs and use
acetaminophen(paracetamol) for pain control if
possible.
• Smoking cessation
• Decrease alcohol consumption(as it may erode
protective mucosal line)
• Stress managment
• Maintain food hygiene
• Research shows diet containing high fibres and Vit
A might reduce development of duodenal ulcer
41. Surgical Intervention
• Indication of surgical intervention
• Gastric outlet obstruction not responsive to drug
• Failure to respond to maximal medical treatment with
severe symptom.
• Emergency indication: Perforation, hemorrhage
• Suspicious of malignancy
• Refractory ulcer
• .
42. Surgical Intervention:
• Surgical Invertention:
• Vagotomy: Cutting of vagus nerve to interrupt message sent
from brain to stomach to reducing acid secretion.
• Antrectomy: Remove of lower part of stomach (antrum)
which produce hormone that stimulate stomach to secrete
digestive juices.
• Pylorosplasty: the opening into duodenum and small
intestine (pylorus) are enlarged, enabling content to mass
more freely from stomach.
• Gastrectomy: surgical removal of the part of stomach. (To
treat stomach cancer &perforation)
