Drugs Used In PUD

SHAHEEN LIPIKA QUAYUM

 GASTROINTESTINAL DISORDERS
•Gastroesophageal Reflux Disease (GERD)
•Peptic Ulcer Disease (PUD)
•Duodenal Ulcer
•Nausea

•Emesis

•IBS

•Diarrhoea

•Constipation
 PEPTIC ULCER
Aggressive factors
Pepsin secretion - acid secretion

Protective factors
Prostaglandins (E2 & I2 )
Mucus/bicarbonate secretion
Mucosal blood flow
Rapid turnover of gastric mucosa
Risk factors
• H Pylori infections
• Alcohol
• Smoking
• Diet
• Drugs (NSAIDs, corticosteroids).
• Stress
• Genetic factors
• Diseases (Zollinger Ellison Syndrome).
 Because of Imbalance

• Imbalance primarily between

Aggressive factors and Defensive
factors:
• What may contribute imbalance ?
• •Helicobacter pylori
• •NSAIDs
• •Ethanol
• •Tobacco
• •Severe physiologic

• stress (Burns, CNS trauma,

• Surgery, Severe medical illness)
• Steroids
Gastric secretions
1. Pepsinogens (Chief cells).
2. HCl and intrinsic factor (Parietal cells).
3. Gastrin (G-cells).
4. Mucus, bicarbonate (mucus-secreting cells).
Regulation of Gastric secretions
1. Histamine (local hormone)
2. Vagus (Acetylcholine neurotransmitter).
3. Gastrin (hormone).
 Summary of Acid Reduction therapeutics

H+ Cl-
 Classification
• [Link] Neutralizing agents: (ANTACIDS)
• Systemic: Sodium Bicarbonate
• Nonsystemic: Magnesium hydroxide, Mag. Treisilicate,
Aluminium hydroxide gel,
• Others-simethicone

• [Link] in Gastric acid secretion:

• •H2 antagonist: Cimetidine, Ranitidine, Famotidine,
Nizatidine and Roxatidine
• •Proton pump inhibitors: Omeprazole, Lansoprazole
• Anticholinergics: Pirenzepine, Propantheline
and Oxyphenonium
• •Prostaglandin analogue: Misoprostol
[Link] protectives: Sucralfate(sucrose Al
Phosphate) , Colloidal Bismuth compound
• [Link]‐ H. pylori Drugs: Amoxicillin,
Clarithromycin, metronidazole, & tetracycline
 ANTACID
• Antacids are weak bases that react with gastric
hydrochloric acid to form a salt & water, thereby
diminishing gastric acidity.
• Because pepsin is inactive at a pH greater than 4,
antacids also reduce peptic activity.
• They have other actions as well, such as reduction of H.
pylori colonization & stimulation of prostaglandin synthesis
• Antacids act by two ways • Chemical neutralization
(systemic antacids act by this mechanism) • Physical
adsorption (non systemic antacids act by this mechanism)
• They can produce healing of duodenal ulcers but are less
effective for gastric ulcers.
 Antacid (objectives)
• Very rapidly acting & neutralizes acid within few
minutes
• More sustained effect
• Minimum adverse effect achieved by using combination
preparation due to lower dose of each component
• Bowel function not changed as in combination one
component antagonizes side effect of another (laxation
versus constipation)
• Prevents acid reflux to the lower part of oesophagus
• Can be effective in promoting healing of duodenal ulcer
• Types of antacids
• Systemic: it is that antacid which is absorbed in
systemic circulation & produces metabolic alkalosis
NaHCO3 , Na citrate, Na acetate
• Nonsystemic: those antacids which are not absorbed in
systemic circulation, not disturb the acid base balance
of the body & not produce metabolic alkalosis
Buffer: those antacids which does not make the pH
of stomach alkaline. This keeps the pH of stomach within
3.5-4
Al (OH)3 gel, Al (PO4) gel, Mg trisilicate
Non-buffer: those antacids which make the pH alkaline
(> 5-6) Criteria of an ideal antacid . MgCO3, CaCO3 &
bismuth carbonate (triple carbonate)
 NaHCO3 (baking soda)
Advantage
• Cheap • Available • Rapidly neutralizes gastric acid so
there is rapid relief of pain • No constipation or diarrhea •
Easy to swallow
• Disadvantage • Shorter duration of action • Produces
rebound acidity • Improved renal function leads to
metabolic alkalosis • CO 2 production causes distention of
abdomen • Rebound acidity • Mechanism of systemic
alkalosis
• When NaHCO3 is administered it neutralizes HCl •
NaHCO3 + HCl NaCl + H2O + CO2
• On the other hand, HCO3 which is secreted
normally by mucosa will be absorbed in the
systemic circulation & shift the acid base
balance towards alkaline. So, there will be
development of metabolic alkalosis
• which is characterized by: • Loss of appetite •
Weakness • Mental confusion
 Antacids
Weak basic part In the form of OH, Responsible for
oxide, HCO3 trisilicate neutralization of acid

Metalic cations Al,Mg,Na, Ca, K Responsible for

pharmacodynamic
property and adverse
effect
•Present day antacids combination of :Aluminium Hydroxide
Magnesium Hydroxide –milk of magnesia
simethicone- antiflatulent agent

•Duration of action : 30 min when taken in empty stomach and 2

hrs when taken after a meal
•Side effects :Aluminium antacids –constipation(As they relax gastric
smooth muscle & delay gastric emptying) –also hypophosphatemia
(by binding with po4- in gut which is non absorbable) and
osteomalcia
• Mg2+ antacids –Osmotic diarrhoea
 Therapeutic Questions

• Is it rational to combine Aluminium hydroxide

and magnesium hydroxide in antacid
preparations ?
• Interactions can be avoided by taking antacids 2 hrs before
or after ingestion of other drugs
– •Combination provides a relatively fast and sustained
neutralizing capacity(Magnesium Hydroxide –Rapidly
acting
– Aluminium Hydroxide ‐Slowly acting )

– •Combination maintains normal bowel

function(Aluminium Hydroxide –constipation
– Magnesium hydroxide –diarrhoea )
 Pharmacological action of Antacid
• Acid neutralization
• Prevent acid reflux to the lower part of
oesophagus
 Simethicone
• Simethicone is a silicone polymer.
• It is pharmacologicallly inert, repels water & helps in
proper dispersion of antacid in the gastric contents.
• Simethicone acts in the stomach & intestine by
changing the surface tension of gas bubbles,
enabling them to coalesce; thus, gas is freed &
eliminated more easily by belching or passing flatus.

• Simethicone may be used in combination with

antacid.
 • Has been used for the relief of the painful
symptoms of excess gas in the digestive tract.
Such gas is frequently caused by excessive
swallowing of air while eating foods that disagree,
& this may also lead to indigestion
• It has also been used in infantile colic but
evidence of benefit is uncertain
 Indication
Hyperacidity
Peptic ulcer disease
Gastritis
Reflux oesophagitis
Non-ulcer dyspepsia
 Adverse effect
• Systemic antacid(Na)-metabolic alkalosis

acid-base abnormality, dangerous for

cardiac & renal disease.
Non-systemic antacid-constipation(Al),
diarrhoea(Mg), Milk alkali syndrome(Ca)
 Drug interaction
• Antacid form complex with iron, tetracycline,
digoxin, ranitidine, fluroquinolones,
sulfonamides and antimuscarinic drugs.
• To avoid these, antacid should be taken 2
hours before or 2 hours after other drugs.
 H2 blocker
• Cimetidine, Ranitidine, Famotidine, Roxatidine,
Nizatidine and
– MOA: Reversible competitive inhibitors of H2receptor
– Highly selective, no action on H1or H3receptors
– All phases of gastric acid secretion
– Very effective in inhibiting nocturnal acid secretion (as
it depends largely on Histamine )
– Modest impact on meal stimulated acid secretion (as it
depends on gastrin, acetylcholine and histamine)
– No effect on motility
• Mechanism of action:
• Gastric parietal cell contains H2 receptor which is
responsible for HCl secretion. Having structural similarity
with histamine these drugs bind selectively &
competitively to H2 receptor on the basolateral
membrane of the parietal cell & block the action of
histamine .
• So there will be no secretion of acid
• Direct stimulation of the parietal cell by gastrin or
acetylcholine results in diminished acid secretion in the
presence of H2 receptor blockade
• It appears that reduced parietal cell cAMP levels
attenuate the intracellular activation of protein kinase by
gastrin or acetylcholine
 H2 blocker

• Kinetics: All drugs are absorbed orally adequately

• Bioavailability upto 80 %
• Absorption is not interfered by presence of food
• Can cross placental barrier and reaches milk
• Poor CNS penetration
• 2/3rdof the drugs are excreted unchanged in bile and urine

•Preparations: available as tablets, injections

Adverse Effects of H2 blockers:
1. GIT disturbances: nausea, vomiting
2. CNS effects:
Headache, dizziness, confusion (elderly –
renal or hepatic dysfunction).
3. CVS effects
Bradycardia and hypotension (rapid I.V.)
Cimetidine has other adverse effects:
4. Endocrine effects
 Antiandrogenic actions (gynecomasteia –
impotence)
 Galactorrhea in women.

5. Cytochrome P450 inhibitor: decrease metabolism

of oral anticoagulant, phenytoin, benzodiazepines.
 H2 antagonists ‐Uses

• Promote the healing of gastric and duodenal ulcers

• Duodenal ulcer –70 to 90%
• Gastric Ulcer –50 to 75% (NSAID ulcers))
• Stress ulcer and gastritis
• GERD (gastro-oesophageal reflux disease)
• Zollinger‐Ellison syndrome ( a gastrin secreting tumour or hyperplasia
of islets cells in pancreas causes overproduction of gastric acid)
• Prophylaxis of aspiration pneumonia
• Urticaria

• Doses:
• For ulcer healing-300 mg at bed time or 150 mg BD
RANITIDINE-NDMA-N-nitrosodimethylaine-
cancer
• Famotidine - Similar to ranitidine in its
pharmacologic action, but it is 20-50 times
more potent than cimetidine, & 3-20 times
more potent than ranitidine
• Drug interaction:
• Cimetidine inhibits cytochrome P450 & can retard
metabolism (& thus potentiate the action) of Phenytoin,
lignocaine, digoxin, propranolol, nifedipine,
phenobarbitone, benzodiazepines, oral anticoagulants &
TCA
• Except for famotidine, all these agents inhibit the gastric
first-pass metabolism of ethanol , bioavailability of
ethanol could lead to increase blood ethanol levels
• Drugs such as ketoconazole, which depends on an acidic
medium for gastric absorption, will not be efficiently
absorbed if taken with one of these antagonists
 Proton Pump Inhibitors

Mechanism of action
Irreversible inhibition of proton pump (H+/ K+ ATPase)
that is responsible for final step in gastric acid secretion
from the parietal cell.

PP inhibitors include:
• Omperazole
• Lansoprazole
• Pantoprazole
• Proton Pump Inhibitors
•Most effective drugs in antiulcer therapy
•Prodrugs requiring activation in acid environment
•Block enzymes responsible for secreting HCl ‐binds
irreversibly to H+K+ATPase
•Prototype: Omeprazole
– •Examples:Lansoprazole
– Pantoprazole
– Rabeprazole
– Esomeprazole
 Mechanism of action
• The parietal cells of stomach secrete H+ with
the help of the enzyme H+K+ ATPase (proton
pump) present in its plasma membrane. This is
the final step in gastric acid secretion due to
any stimuli.
• PPI are inactive prodrugs, accumulate in the
parietal cells where they quickly get activated
in the acidic environment to sulfenamide
• The active form binds H+K+ATPase & thus inhibits
gastric secretion.
• The binding is irreversible & a single dose can
almost totally 90-95% inhibit gastric secretion.
• It requires 3-4 days of PPI therapy for maximum
efficacy to develop.
• The acid secretion resumes completely only after
3-4 days after stopping the PPI, when new
H+K+ATPase enzyme is synthesized.
 pharmacokinetics
• All PPI are given orally – as granules in enteric- coated or
delayed release capsule or tablets to avoid degradion by
the acid in the stomach.
• PPI are lipid soluble, weak bases and get rapidly absorbed
from the intestine.
• After the enteric coating is dissolved, the prodrug reaches
the parietal cell canaliculi because of its acidic nature.
• Though it also reaches other tissues, the concentration in
Parietal cell canaliculi 1000 times more as it gets trapped
• Though the t1/2 of omeprazole is 1-2 hr, the effect of a
single dose remains for 2-3 days because of its
accumulation in the parietal cell canaliculi( hit & run drug).
 pharmacokinetics
• Drugs are given as enteric coated capsules
• They are rapidly absorbed from the intestine.
• They are inactivated if (combined with H2
receptor blockers).
• They diminish90-98% of 24 hr acid secretion.
• Have long duration of action (> 12 h-24 h).
• Once daily dose is sufficient
• Bioavailability is reduced by food.
• Given 1 h before meal.
• Are metabolized in the liver by CytP450.
• They are more potent than H2 receptor blockers
• Inhibits basal and meal stimulated-acid secretion.
• Dose reduction is required in severe liver failure.
• They should be given 30 minutes to 1 hour before food intake because
an acidic pH in the parietal cell acid canaliculi is required for drug
activation, and food stimulates acid production
Concomitant use of other antisecretory drugs ‐H2 receptor antagonists
–reduces action
 INDICATION
Gastroesophageal reflux disease (GERD)
Peptic Ulcer ‐Gastric and duodenal ulcers
Bleeding peptic Ulcer
.
Zollinger ellison Syndrome
Prevention of recurrence of nonsteroidal
antiinflammatory drug (NSAID) ‐associated gastric
ulcers in patients who continue NSAID use.
Reducing the risk of duodenal ulcer recurrence
associated with H. pylori infections
Aspiration Pneumonia
 ADVERSE EFFECTS

• Achlorhydria.
• Hypergastrinaemia
• Gastric hyperplasia.
• Increased bacterial flora
•Prolong therapy causes ↓vit B12
•Carcinoid tumor
 Drug interaction
• Decreased gastric acidity may alter absorption of drugs
for which intragastric acidity affects drug bioavailability,
e.g., ketoconazole & digoxin
• Omeprazole may inhibit the metabolism of diazepam, &
phenytoin
• Esomeprazole also may decrease metabolism of
diazepam
• Lansoprazole may enhance clearance of theophylline
• Rabeprazole & pantoprazole have no significant drug
interactions
• Pantaprazole-ME inhibition is milder, oral
bioavailability higher, oral & IV infusion
available
• Rabeprazole-fastest onset of action, milder
inhibition of ME
• Esomeprazole –higher bioavilability >80%,
longer t1/2
• PPI –Dosage schedule
• Omeprazole 20 mg o.d.
• Lansoprazole 30 mg o.d.
• Pantoprazole 40 mg o.d.
• Rabeprazole 20 mg o.d.
• Esomeprazole 20 ‐40 mg o.d.
 Muscarinic antagonists
Atropine:

Pirenzipine, propanthiline, dicyclomine

– Block the M1 class receptors
– Reduce acid production
– Abolish gastrointestinal spasm

– (receptors on parietal cells are M3)

– Adverse effect (dry mouth and blurredvision)
• USES:

• Duodenal Ulcer (6-8 weeks).

• Benign gastric ulcer (8-12 weeks).
• Reflux esophagitis
• Zollinger Ellison Syndrome (large doses).
• Pre-anesthetic medication (To prevent
• aspiration pneumonitis).
• Eradication of H. pylori infections.
 Prostaglandin analogues
• Inhibit gastric acid secretion
• Exhibit ‘cytoprotective’ activity
• Enhance local production of mucus or
bicarbonate
• Promote local cell regeneration
• Help to maintain mucosal blood
• Prostaglandin analogues ‐Misoprostol
Therapeutic uses:

• Prevention of NSAID‐induced mucosal injury

• Misoprostol
• •Doses: 200 mcg 4 times a day (Misoprost)
– •ADRs:Diarrhoea and abdominal cramps
– Uterine bleeding
– Abortion
– Exacerbations of inflammatory bowel disease and
should be avoided in patients with this disorder

• Contraindications:
• Inflammatory bowel disease
• Pregnancy (may cause abortion)
 Ulcer-Healing Drugs
Mucosal Strengtheners
Sucralfate polymerizes below pH 4  a very
sticky gel that adheres strongly to the base of
ulcer craters.
Bismuthchelate(tripotassiumdicitratobismuthate
) acts similarly to sucralfate.
Strong affinity for mucosal glycoproteins,
especially in the necrotic tissue of the ulcer
craters, which become coated in a protective
layer of polymer-glycoprotein complex.
Bismuth may blacken the teeth and stools.
Bismuth and sucralfate must be given on an
empty stomach or they will complex with food
proteins.
• Sucralfate –ulcer protective
• Salt of sucrose and sulfated aluminium hydroxide
(basic aluminium salt)
– MOA:In acidic pH sucralfate polymerises to
form sticky , viscous gel that adheres to the
base ulcer ‐more on duodenal ulcer
– negetively charged sucralfate get attracted to
positively charged protein in ulcer base
– Dietary proteins get deposited on this layer
forming another coat
– It also stimulates gastric PG synthesis –
 Colloidal bismuth subcitrate
• May increase gastric mucosal PGE2,mucus & HCO3
production.
• May precipitate mucus glycoproteins and coat the ulcer
base
• Bismuth has direct antimicrobial effects & binds
enterotoxins, accounting for its benefit in preventing &
treating traveller’s diarrhoea
• May death and inhibit H. pylori directly
• Promote ulcer healing 4-8 weeks.
• BS dissociates in stomach-bismuth is excreted-black stool,
darkening of tongue, salicylate-absorb
• Drugs causing peptic ulcer:
• Non Steroidal Anti Inflammatory Drugs
(NSAIDs)
• Glucocorticoids
• Cytotoxic agents
 Eradication of Helicobacter pylori
• H. pylori is a bacterium (gm negative bacilli)
which may be responsible for pathogenesis of
peptic ulcer by • Direct damage of mucosa •
Inflammatory/immune mechanism • Altering
the gastric acid environment
Increase gastrin secretion probably by
ammonia production by urease • • May lead to
hypersecretory state in patient with duodenal
ulcer
• Triple Therapy
• The BEST among all the Triple therapy regimen is:
• Omeprazole / Lansoprazole -20 / 30 mg bd+
– Amoxycillin-1 gm bd and either:
– Clarithromycin -500 mg bd
– or
Metronidazole - 400 mg bd
• Given for 14 days followed by P.P.I for 4 –6 weeks
 Triple therapy
• Bishmuth chelate(2 tabs 4 times daily 4
weeks)
• Metronidazole (400 mg) (1 tab thrice daily 1st
week )
• Tetracycline (500 mg) (1 cap tds 1st week)
 Quadruple therapy
• CBS 120 mg QID+ tetracycline 500 mg QID+
metronidazole 400 mg TDS + Omeprazole 20
mg BD
• Another
• PPI + amoxicillin + clarithromycin +
metronidazole
• All twice daily for 2 weeks
• Why this combination of drugs?
• Amoxicillin acts on cell membrane
• Clarithromycin is a protein synthesis inhibitor
• Metronidazole –acts on anaerobic infection
• Delay develop the resistance
 Question
• Explain the disadvantages of systemic antacid
• What do you mean by triple therapy in PUD
• Explain the role of each component of triple
therapy in PUD
• Name the different groups of drugs that are
used in peptic ulcer disease
• Write down the mechanism of action of
proton pump inhibitor
• Enlist the drug used in H. pylori induced peptic
ulcer disease
• Write a regimen to eradicate H. pylori induced
PUD
• Mention the cytoprotective agents used in
PUD
• Explain the role of misoprostol in PUD
• Clinical uses of proton pump inhibitor
• Short notes-
• Lansoprazole, pantaprazole
THANK YOU
THANK YOU