Pharmacology of Anti Ulcer drugs

1. ANTI-ULCER AGENTSPrepared by
S.SUDHAKAR
Asst.Professor
Annamacharya College of Pharmacy

4. Gastric Acid Secretion
3 Interdependent pathways stimulate parietal
cell HCl and Intrinsic Factor secretion.
– Neurocrine: ACETYLCHOLINE delivered
from VAGAL post-ganglionic nerves to
muscarinic receptors on the basolateral
parietal cell membrane.
---Endocrine: GASTRIN secreted by antral
G-CELLS reaching parietal cell receptors
via the blood stream.
– Paracrine: HISTAMINE secreted by
adjacent ECL- CELLS to bind H-2 receptors
on the parietal cell. Paracrine is the
dominant pathway

11. ANTIULCER AGENTS
 Drugs used in the treatment of
ulcer are called as antiulcer
 The goals of antiulcer therapy
are
 Relief of pain
 Ulcer healing
 Prevention of complications
 Prevention of relapse
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12. 5

13.  H2 ANTAGONISTS
 Highly effective drugs for treatment of ulcer
 But surpassed by PPI
 Pharmacological actions
 H2 blockade
 Highly selective to H2: no effect on H1 receptor
 Block histamine induced gastric secretion,cardiac
stimulation, uterine relaxation and bronchial relaxation
 At high dose they attenuate fall in BP
 Gastric secretion
 All phases (basal, psychic, neurogenic, gastric) of secretion are
suppressed dose dependently
 But the basal nocturnal acid secretion is suppressed more
Completely (Therefore, it is better to be given before night sleep)
 Secretory responses to not only histamine but also to ACh,
gastrin, insulin, alcohol, food induced Volume, pepsin
content and intrinsic factor secretion are reduced
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Drugs: Cimetidine
Ranitidine
Famotidine
Nizatidine
Roxatidine
M.O.A.
They competitively and reversibly block
H2 receptors on the parietal cells.

14.  Most marked effect is on acid secretion
 Vit B12 absorption is not interfered
 60–70% inhibition of 24 hr acid output
 No direct effect on gastric or esophageal motility
 Pharmacokinetics
 Absorbed orally (BAB 60–80%)
 Absorption is not interfered by food
 Crosses placenta and reaches milk but don’t cross BBB
 Metabolized by oxidation
 2/3 excreted unchange in urine and bile
 Dose reduction is needed in renal failure
 t½ is 2–3 hr
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15.  Adverse effects
 well tolerated but AE occurs in < 5% and are generally mild.
 Headache, dizziness, bowel upset, dry mouth, rashes.
 Cimetidine had antiandrogenic action, increase Prl and inhibits
degradation of estradiol
 Gynaecomastia, loss of libido, impotence and temporary
decrease in sperm count.
 Transient elevation of plasma aminotransferases;
but hepatotoxicity is rare.
 Drug Interaction
 Cimetidine inhibits several cytochrome P-450 isoenzymes
 e.g. Theophylline, Phenytoin, Carbamazepine, Phenobarbitone,
Sulfonylureas, Metronidazole, Warfarin, Imipramine, Lidocaine,
Nifedipine, Quinidine
 Reduces hepatic blood flow
 Antacids reduce absorption of all H2 blockers
 Ketoconazole absorption is decreased by H2 blockers due
to reduced gastric acidity. 8
Gynecomastia
(Male)
Galactorrhea
(Female)
Due to inhibition of
dihydrotestosterone binding to
androgen receptor

16. USES:
 Duodenal ulcer
 Reduce rapid and marked pain relief (within 2–3 days)
 60–85% ulcers heal at 4 weeks and 70–95% ulcers at 8 weeks
 50% relapse within 1 year
 Maintenance therapy reduces the relapse rate to 15–20%/year
 Reduce nocturnal secretion by single dose
 Gastric ulcer
 Healing rates are somewhat lower (50–75% at 8 weeks).
 Can heal NSAID associated ulcers less effective than PPIs
 Stress ulcers and gastritis
 Stressful situations associated with gastric erosions & bleeding
 Intravenous infusion of H2 blockers effective in this condition
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17.  Zollinger-Ellison syndrome
 It is a gastric hypersecretory state due to a rare tumour
secreting gastrin.
 H2 blockers in high doses are effective
 But PPIs are the drugs of choice
 Definitive treatment is surgical
 Gastroesophageal reflux disease (GERD)
 Afford symptomatic relief
 But are less effective than PPIs
 Indicated in mild or stage-1 cases of GERD
 Prophylaxis of aspiration pneumonia
 Reduce the risk of aspiration of acidic gastric contents during
anaesthesia
 Other uses
 urticaria
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18. PROTON PUMP INHIBITORS
 Omeprazole
 PPI inhibits the inhibit the final step in gastric acid secretion
 PPI overtaken H2 blockers
 Powerful inhibitor of gastric acid (resting and sti. by food)
 Without much effect on pepsin, intrinsic factor, juice volume &
gastric motility.
 Omeprazole is inactive at neutral pH
 But at pH < 5 it rearranges to two charged cationic forms
(sulphenic acid and sulphenamide configurations)
MOA
 React covalently with SH groups of the H+K+ATPase enzyme
and inactivate it irreversibly
 Two molecules of omeprazole react with one molecule of enzyme
 Acid secretion resumes only when new H+K+ATPase molecules
are synthesized
 It also inhibits gastric mucosal carbonic anhydrase. 11
Drugs:
Omeprazole
Lansoprazole
Pantoprazole
Rabeprazole
Irreversible inhibition of Proton pump (H+ / K+ ATPase )

19.  PK
 All PPIs are administered orally in enteric coated form
 Oral BAB is ~50% due to acid liability
 BAB is reduced by food (taken in empty stomach or 1
hour later)
 Omeprazole is highly PPB
 Metabolized by CYP2C19 and CYP3A4 (pt1/2 is ~1 hr)
 Metabolites are excreted in urine
 No dose modification is required in elderly or in
patients with renal/hepatic impairment
 Because of its tight binding to target enzyme can be
detected in the gastric mucosa even after disappearance
from plasma
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 O/A 1hr, Cmax 2hrs, half maximal at 24 hr,
D/O 2-3 days
 Only active acid pump inhibited by PPI
 Antisecretory action increases on daily
dosing (plateau after 4 days)
 80–98% decrease of 24 hrs acid output
with conventional doses.
 Resumes gradually over 3–5 days of
stopping the drug.

20.  Adverse effects
 PPIs produce minimal AE
 Only 3-5 %
Nausea, loose stools, headache, abdominal pain,
muscle and joint pain and dizziness
 Rashes (1.5%)
 Leucopenia and hepatic dysfunction are infrequent.
 On prolonged treatment atrophic gastritis
 Harmful effects reported during pregnancy (advise to avoid)
 Drug interaction
 Omeprazole inhibits oxidation of Diazepam, Phenytoin and
Warfarin
 It interferes with activation of Clopidogrel by inhibiting CYP2C19.
 Clarithromycin inhibits omeprazole metabolism
 Decreases absorption of Ketoconazole and iron salts
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21.  Uses
 Peptic ulcer
 Omeprazole 20 mg OD, Faster healing at 40 mg/day
 Relief of pain is rapid and excellent.
 Duodenal ulcers heal even at 2 weeks & remaining at 4 weeks.
 Gastric ulcer generally requires 4–8 weeks
 Used in patients not responding to H2 blockers
 Continued treatment (20 mg/day or 3 weekly) can prevent ulcer
relapse
 Drugs of choice for NSAID induced gastric/duodenal ulcers.
 Healing may occur despite continued use of the NSAID
 But required high doses
 Switch over to COX-2 selective NSAID
 PPI are an integral component of anti-H. pylori therapy
 Bleeding peptic ulcer
 Acid enhances clot dissolution promoting ulcer bleed.
 Suppression of gastric acid has been found to facilitate clot formation
 Reduces blood loss and re-bleeding 13

22.  High dose i.v. PPI therapy (Pantoprazole 40–120 mg/day or
Rabeprazole 40–80 mg/day)
 i.v. followed by oral PPI reduces recurrence of bleeding
 Stress ulcers
 i.v. Pantoprazole/ Rabeprazole is as effective prophylactic for stress
ulcers as i.v. H2 blockers
 GERD
 Omeprazole produces more complete round-the-clock inhibition
 Rapid symptom relief
 More effective than H2 blockers in healing of esophageal lesions
 PPIs are the drugs of choice
 Higher doses than for peptic ulcer or twice daily
 Zollinger-Ellison syndrome
 Omeprazole is more effective than H2 blockers
 60–120 mg/day or more (in 2 divided doses)
 Inoperable cases have been treated for >6 years
 Aspiration pneumonia
 Alternative to H2 blockers
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23.  ANTACIDS
 These are basic substances which neutralize gastric acid & raise
pH
 Peptic activity is indirectly 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 to 4
 Antacids do not decrease acid production, even reflex gastrin
release
 Acid rebound occurs & gastric motility is increased
 Potency of an antacid expressed as acid neutralizing capacity
(ANC)
 Number of mEq of 1N HCl that are brought to pH 3.5 in 15 min
(or 60 min in some tests) by a unit dose of the antacid
preparation
 Rate at which the antacid dissolves and reacts with HCl
 Single dose of any antacid act in empty stomach acts for 30–60
min, with meals antacids may act for at the most 2–3 hr
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24.  Systemic Antacids
 Sodium bicarbonate
 Water soluble
 Fast O/A but short D/A
 It is a potent neutralizer (1 g → 12 mEq HCl)
 pH may rise above 7
 Use only in heartburn, alkalinize urine and to treat acidosis
Some disadvantages
 Absorbed systemically (alkalosis)
 Produces CO2 in stomach (distention, discomfort, belching)
 Acid rebound occurs
 Increases Na+ load (worsen edema and CHF)
 Sodium citrate
 Properties similar to sod. Bicarbonate
 1 g neutralizes 10 mEq HCl; CO2 is notevolved.
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25.  Non-systemic Antacids
 Insoluble and poorly absorbed basic compounds
 React in stomach to form the corresponding chloride salt
 chloride salt again reacts with the intestinal bicarbonate so that
HCO3¯ is not spared for absorption
Drugs: Aluminium hydroxide, Magnesium trisilicate, Magaldrate
 Aluminium hydroxide gel
 It is a bland, weak and slowly reacting antacid
 On keeping it slowly polymerizes to variable extents into still
less reactive forms.
 Thus, the ANC of a preparation gradually declines on storage.
 1–2.5 mEq/g.
 Al3+ ions relax smooth muscle, mucosal astringent, delays
gastric emptying
 Alum. Hydrox causes constipation
 Alum. hydrox. binds phosphate in intestine & prevents its
absorption
 Causes hypophosphatemia
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26. Magnesium trisilicate
• Does not disturb acid base balance.
• SiO2 forms a gelatinous coating over gastric mucosa.
• MgCl2 & MgCO3 cause diarrhea.
• Mg salts & Al salts are commonly administered together to minimize
effect on bowel movement.
Magaldrate
• Hydrated complex of Al-Mg hydroxide sulfate.
• Reacts with HCl & releases Al(OH)3 & Mg(OH)3.
Calcium carbonate
• Powerful antacids with fast action.
• Raises gastric pH above 7.
• Causes belching due to release of CO2.
• Excessive doses with milk causes hypercalcemia, renal insufficiency
& metabolic alkalosis called milk-alkali syndrome.
• Acid rebound is marked as CaCl2 itself is gastrin stimulant.
• Causes constipation due to Ca-stereate.
Magnesium hydroxide
• Efficacious, neutralizes HCl
promptly.
• Elevates gastric pH up to 7.
• Acid rebound is mild & brief.
• MgCO3 causesdiarrhea.
• Belching does not occur as CO2
is not generated.
• Given along with Al(OH)3.

27.  Drug interaction
 By raising gastric pH and by forming complexes, the non-absorbable antacids decrease the absorption of
many drugs, especially tetracyclines, iron salts, fluoroquinolones, etc.
 Stagger their administration by 2 hours.
 The efficacy of nitrofurantoin is also reduced by alkalinization of urine.
 Uses
 Antacids are no longer used for healing peptic ulcer, because they are needed in large and frequent doses
 Antacids are now employed only for intercurrent pain relief and acidity,
 Gastroesophageal reflux 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.
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28.  ANTI-H. PYLORI DRUGS
 H. pylori is a gram negative bacillus
 Attaches to the surface epithelium beneath the mucus
 Has high urease activity—produces ammonia—maintains a
neutral pH & promotes back diffusion of H+ ions
 Causes chronic gastritis, dyspepsia, peptic ulcer, gastric
lymphoma and gastric carcinoma
 H. pylori infection starts with a neutrophilic gastritis lasting
7–10 days which is usually asymptomatic.
 90% patients of duodenal and gastric ulcer had positive H. pylori
 Anti-H. pylori therapy + H2 blocker/PPI therapy
 Antimicrobials are Amoxicillin, Clarithromycin,
Tetracycline and Metronidazole/Tinidazole
 Single antibiotic is ineffective
 Resistance develops rapidly
(metronidazole/tinidazole and clarithromycin)
 CBC is active against H. pylori and resistance does not develop to
it21
 But poor patients acceptability

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30. 23
Anti H. pylori regimens

32.  ANTICHOLINERGICS
 Pirenzepine
 Selective M1 anticholinergic
 Used in Europe for peptic ulcer
 Gastric secretion is reduced by 40–50%
 No side effects
 It has not been used in India and USA.
 PROSTAGLANDIN ANALOGUE
 PGE2 serve a protective role by: Inhibiting acid
secretion
 Promoting mucus as well as HCO3¯ secretion
 Addition, PGs inhibit gastrin release, increase
mucosal blood flow
 Also have cytoprotective effect
 Natural PGs have very short t½
 Misoprostol longer acting synthetic PGE1
derivative
 Less effective then H2 blockers
 Dose: 200 μg QID
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33. Sucralfate – ulcer protective
• Aluminium salt of sulfated sucrose .
• MOA:
– In acidic environment ( pH <4) it polymerizes by cross linking molecules to form sticky
viscous gel that adheres to ulcer crater
– acts as acid resistant physical barrier.
– Dietary proteins get deposited on this layer forming another coat.
– May stimulate PGE2 synthesis & HCO3- secretion.
• Bind epithelial & fibroblast growth factors which promotes mucosal repair.
• SE: hypophosphataemia may occur.
• Concurrent antacids avoided.
• Uses:
– Prophylaxis of Stress ulcers
– Bile reflux gastritis
– Topically – burn, bedsore ulcers, excoriated skins
• Dose: 1 gm 1 Hr before 3 major meals and at bed time for 4-8 weeks .

34. Colloidal Bismuth Subcitrate (CBS)
• Mechanism of action
– CBS and mucous form glycoprotein bi complex which coats ulcer crater
– ↑ secretion of mucous and bicarbonate, through stimulation of mucosal PGE production
– Detaches H.pylori from surface of mucosa and directly kills them
• Dose: 120 mg 4 times a day
• Adverse effects
– blackening of tongue, stools, dentures
– Prolonged use may cause
osteodystrophy and encephalopathy
– Diarrhoea, headache, dizziness

35. ASSIGNMENT QUESTIONS
1. Define and classify antiulcer agents: describe Pharmacology of PPI in details
2. Write a short note on H2 receptor blocker
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