CHAPTER

Gastrointestinal
8
Drugs

DRUGS FOR PEPTIC ULCER

Introduction
• Ulcers  a breach in the mucosa of alimentry tract that extends through submucosa into
mucularis mucasea or deep.
• Peptic ulcers  areas of degeneration and necrosis of gastrointestinal mucosa exposed to
acid-peptic secretions.

ULCER
MUCOSA
MUCOSA

SUBMUCO
SA SUBMUCO
SA
MUSCULARIS
PROPRIA MUSCULARIS
PROPRIA

SERO
SA SERO
SA

Types
• 2 types 
1. Gastric ulcer
2. Duodenal ulcer

Clinical Features
1. Dyspepsia (upper abdominal pain or discomfort)
2. Epigastric pain
3. Nausea
4. Vomiting
5. Heart burn

Etiology
• Imbalance between  Mucosal Damaging factors/ Aggressive factors and Defense
mechanisms
 DR. PRIYANKA SACHDEV

Aggressive forces Defensive forces

• Gastric Acid  Bicarbonate
• Pepsin  Mucus
• H. Pylori  Prostaglandins

Excess activity of acid

↓
Acid induces damage
Activates pepsin
↓
Pepsin hydrolyzes mucosal protein
↓
Mucosal erosion
↓
Peptic ulcer

Gastric acid secretion

• Acid is secreted from parietal cells

Cell types Substance secreted Function of secretion

Parietal cells HCL Kills microbes and activates pepsinogen
Intrinsic factor Binds vit. B12 to allow it's absorption
Chief cells Pepsinogen Protein digestion
Gastric lipase Fat digestion
G cells Gastrin Stimulates gastric acid secretion
ECL cells Histamine Stimulates gastric acid secretion
Mucus-neck cells Mucus and bicarbonate Protects stomach epithelium from acid
D cells Somatostatin Inhibits gastric acid secretion

Major secretagogues
1. Histamine  through H2 receptors
2. Acetylcholine  through M3 receptors
3. Gastrin  through CCK2 receptors

• Their receptors are located on basolateral membrane of paraietal cells.

• They stimulate proton pump to exchange potassium with H ions for formation of HCl

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Physiology of Gastric acid formation and Secretion

Food
↓
Release of 
Gastrin from G cells
Ach from ENS ganglionic cell
↓
Gastrin acts on cck2 receptor of ECL
cell
Ach acts on M receptor of ECL cell
(Indirect mechanism)
↓
Release of histamine fron ECL cell
↓
Histamine acts on H2 receptor of
parietal cell
↓
Generation of cAMP
↓
Activate H+K+ATPase (Proton pump)
↓
Acid release in lumen of stomach

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 DR. PRIYANKA SACHDEV

• Out of these 3 secretogogues  Histamine  plays a dominant role

• Other two  Acetylcholine and Gastrin act indirectly  by releasing histamine from
enterochromaffin-like (ECL) cells and only partly by direct action.

Remember
1. H2 receptors  activate H+K+ATPase by generating cAMP
2. M3 and CCK2 receptors  function through phospholipase C → IP3–DAG pathway

Prostaglandin
Prostaglandin
↓
Acts through EP3 receptor
↓
Cytoprotective role
↓
Inhibits gastric acid secretion
Protects by stimulating mucus secretions
H. Pylori

H. Pylori

Inhibit somatostatin, which causes Inhibit mucus formation

inhibition of gastrin

Increases gastrin concentration

Increases acid Break the defense

APPROACH FOR TREATMENT OF PEPTIC ULCER

4 approaches
1. Decrease/ inhibit secretion of acid in stomach.
2. Neutralize gastric acid by antacids.
3. Protect the ulcer by forming a layer over it
4. Kill H. pylori associated with peptic ulcer disease

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Classification

Drugs for Peptic ulcer

Gastric acid secretion Inhibitors
H2 Antagonist PPI Anticholinergics Prostaglandin
Analogue
Drugs
MOA
Pharmacokinetics
Uses
Adverse effects
Interactions

Drugs for Peptic ulcer

Gastric acid Neutralizer Protect ulcer Kill H. pylori
Antacid Ulcer Anti H.pylori drugs
protectives
Drugs
MOA
Pharmacokinetics
Uses
Adverse effects
Interactions

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 DR. PRIYANKA SACHDEV

GASTRIC ACID SECRETION INHIBITORS

H2 ANTAGONIST
Drugs
• Cimetidine  first H2 blocker and prototype
• Ranitidine
• Famotidine
• Roxatidine
• Nizatidine
• Loxatidine

MOA
H2 Antagonists
↓
Competitive blockers of H2 receptor on parietal cells
↓
Inhibit gastric secretion

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Remember
• These drugs reduce basal acid secretion with little effect on stimulated acid secretion (Contrast
PPIs inhibit both basal as well as stimulated acid secretion).
• Volume, pepsin content and intrinsic factor secretion are reduced, but most marked effect is on
acid (Contrast PPIs have no effect on volume, pepsin content and intrinsic factor secretion.
• 60–70% inhibition of 24 hr acid output
• No effect on motality
• They have been surpassed by proton pump inhibitors (PPIs)

Pharmacokinetics
 Cimetidine 
 Absorbed orally
 Bioavailability is 60–80% due to first pass hepatic metabolism.
 Absorption is not interfered by presence of food in stomach.
 Crosses placenta and reaches milk
 About 2/3 of a dose is excreted unchanged in urine and bile
 Elimination t½ is 2–3 hr

Uses
1. Peptic ulcer
2. Stress ulcers and gastritis
3. Zollinger-Ellison syndrome
4. Gastroesophageal reflux disease (GERD)
5. Prophylaxis of aspiration pneumonia

1. Peptic ulcer
 Duodenal ulcer
 H2 blockers produce rapid and marked pain relief (within 2–3 days)
 60–85% ulcers heal at 4 weeks
 70–95% ulcers at 8 weeks

 Gastric ulcer
 Healing rates obtained in gastric ulcer are somewhat lower
 50–75% heal at 8 weeks

• PPI are DOC for peptic ulcer

2. Stress ulcers and gastritis

• Acutely stressful situations like hepatic coma, severe burns and trauma, prolonged surgery,
prolonged intensive care, renal failure, asphyxia neonatorum, etc. are associated with gastric
erosions and bleeding.
• H2 blockers are DOC

3. Zollinger-Ellison syndrome
• It is a gastric hypersecretory state due to a rare tumour of G cells secreting gastrin.

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• H2 blockers in high doses control hyperacidity and symptoms in many patients

• PPIs are DOC
• Definitive treatment is surgical.

4. Gastroesophageal reflux disease (GERD)

• H2 blockers afford symptomatic relief and facilitate healing of esophageal erosions, but are less
effective than PPIs
• Indicated only in mild or stage-1 cases of GERD

5. Prophylaxis of aspiration pneumonia

• H2 blockers given preoperatively (preferably evening before also) reduce the risk of aspiration of
acidic gastric contents during anaesthesia and surgery.
• Now PPI are DOC

Adverse effects
1. CNS effects  Headache, dizziness,confusional state (Delirium), restlessness, convulsions,
coma, headache dizziness, hallucination
2. GIT  Bowel upset , dry mouth
3. CVS  Bolus i.v. injection can cause histamine release -> arrhythmias and cardiac arrest.
4. Liver  Transient elevation of plasma aminotransferases
5. Cimetidine (but not other H2 blockers) 
 Antiandrogenic effects due to inhibition of binding of testosterone to
receptor and reduced metabolism of estrogen.
 Enhanced release of prolactin  loss of libido, impotence,
gynecomastia and galactorrhea.

Interactions
Cimetidine
↓
Inhibits cytochrome P-450 isoenzymes
↓
Inhibits the metabolism of many drugs
↓
Accumulate to toxic levels

• e.g. theophylline, phenytoin, carbamazepine, phenobarbitone, sulfonylureas, metronidazole,

warfarin, imipramine, lidocaine, nifedipine, quinidine.

Substrate /Object drug

• C - Cyclosporin, CCB
• T - Tacrolimus
• S - Statins
• C - Cisapride
• A - Amiodaron, Astemizole

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• N - Navirs (Protease inhibitors)t

Enzyme Inhibitors
• Vitamin - Valproate
• K - Ketoconzole
• Cannot - Cimetidine
• Cause - Ciprofloxacin
• Enzyme - Erythromycin
• Inhibition - INH

Ranitidine Versus Cemetidine

• Ranitidine several desirable advantages over cemetidine
1. 5 times more potent
2. No antiandrogenicide effects
3. Less penetration to brain (less CNS effects)
4. Less effect on metabolism of other drugs

Remember
• Cimetidine  least potent H2 blocker.
• Famotidine  most potent H2 blocker.
• All H2 blockers are competitive blockers except famotidine (competitive - noncompetitive) and
loxatidine (non competitive).
• Nizatidine  anticholinesterase activity  cause bradycardia and increased gastric emptying.
• Nizatidine  negligible first pass metabolism  100% bioavailability).
• All H2 blockers except famotidine inhibits gastric first pass metabolism of ethanol.
• Absorption of cimetidine is not affected by food

PROTON PUMP INHIBITORS (PPI)

Drugs
• Omeprazole  prototype
• Esomeprazole
• Lansoprazole
• Pantoprazole
• Rabeprazole
• Dexrabeprazole

Introduction
• Ultimate mediator of acid secretion is proton pump i.e. H+K+ ATPase  so inhibitors block
ultimate stage
• PPIs have overtaken H2 blockers for acid-peptic disorders.

MOA
• Omeprazole is inactive at neutral pH

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 DR. PRIYANKA SACHDEV

Omeprazol taken orally enteric coated (e.c.) tablet

↓
Absorbed systematically from intestine
↓
Subsequent diffusion into parietal cell
↓
At pH < 5 it rearranges to two charged cationic forms
(a sulphenic acid and a sulphenamide configurations)
↓
React covalently with SH groups of H+K+ATPase enzyme
↓
Inactivate it irreversibly
( two molecules of omeprazole react with one molecule of the enzyme)
↓
Decreased acid secreation

Remember
• They decrease a basal acid secretion by 90-95%.
• There is reduction in acid secretion but no change in volume, secretion of pepsin,intrinsic factors
and gastric motility.

Pharmacokinetics
1. All PPIs are administered orally in enteric coated (e.c.) form to
protect them from molecular transformation in the acidic gastric
juice.
 e.c. tablet or granules filled in capsules should not be broken
or crushed before swallowing.

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 Esomeprazole, lansoperazole and pantoperazole can also be given intravenously

2. PPI are prodrugs

 On reaching the parietal cells, active moiety, i.e. sulfenamide is formed and gets trapped
which inhibits H+, K+ ATPase irreversibly.

3. PPI
• Short half life  1.5 hours
• Long Duration of action  lasts for 24 to 48 hours
 This is due to irreversible inactivation of proton pump
 Until new proton pumps are synthesized and incorporated into the luminal membrane of
parietal cells.

4. Because not all proton pumps are inactivated with first dose of medication as not all proton
pumps are active simultaneously
 Maximal suppression of acid requires several doses of proton pump inhibitors, i.e. 2 to 5
days of therapy is required before the full acid-inhibiting potential is reached.

5. Bioavailability of all PPIs is reduced by food

 They should be taken in empty stomach
 Followed 1 hour later by a meal to activate the H+K+ ATPase and make it more susceptible
to the PPI.

Uses
1. Peptic ulcer
2. Stress ulcers and gastritis
3. Zollinger-Ellison syndrome
4. Gastroesophageal reflux disease (GERD)
5. Prophylaxis of aspiration pneumonia

1. Peptic ulcer
• Omeprazole 20 mg OD is equally or more effective than H2 blockers.
 Relief of pain is rapid and excellent.
 Faster healing has been demonstrated with 40 mg/day
 Duodenal ulcers heal (over 90%) at 4 weeks.
 Gastric ulcer generally requires 4–8 weeks.
 Continued treatment (20 mg daily or thrice weekly) can prevent ulcer relapse
 DOC for peptic ulcer

2. Stress ulcers
• Intravenous pantoprazole/ rabeprazole is as effective prophylactic (if not more) for stress ulcers
as i.v. H2 blockers

3. Zollinger-Ellison syndrome
• Omeprazole is more effective than H2 blockers in controlling hyperacidity in Z-E syndrome.
• 60–120 mg/day or more (in 2 divided doses) is often required for healing of ulcers
• PPIs are DOC
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 DR. PRIYANKA SACHDEV

• Definitive treatment is surgical.

4. Gastroesophageal reflux disease(GERD)

• Omeprazole produces more complete round-the-clock inhibition of gastric acid resulting in rapid
symptom relief
• It is more effective than H2 blockers in promoting healing of esophageal lesions.
• PPIs are DOC for GERD

5. Aspiration pneumonia
• PPIs are preferred to H2 blockers for prophylaxis of aspiration pneumonia due to prolonged
anaesthesia.

Adverse effects
1. Nausea, loose stools, abdominal pain
2. Muscle and joint pain, dizziness
3. Rashes
4. Hepatic dysfunction
5. On prolonged treatment  atrophic gastritis

Interactions
1. Interferes with activation of clopidogrel by inhibiting CYP2C19.
2. Omeprazole inhibits oxidation of certain drugs: diazepam, phenytoin and warfarin levels may be
increased.

Remember
• PPIs given for 
 4 weeks for duodenal ulcer
 8 weeks for gastric ulcers.
• Refractory ulcer 
 Duodenal ulcers that fail to heal after 8 weeks
 Gastric ulcers that fail to heal after 12 weeks.

• Lansoprazole  most potent PPI

• Rabeprazole  longest acting PPI
• Pantoprazole  can also be given intravenously
• Lansoprazole  safest PPI in pregnancy
• Omeprazole and esomeprazole  enzyme inhibitors and may decrease the metabolism of
diazepam.
• Lansoprazole  enhances the metabolism of theophylline.

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ANTICHOLINERGICS

Drugs
• Pirenzapine
• Propantheline
• Oxyphenonium

MOA
Anticholinergics
↓
Inhibiting M3 receptors on gastric mucosa
↓
Decrease gastric acid secretion

Not preferred because

1. Exhibit a weak antisecretory effect as compared to H2 blockers.
2. Decrease basal acid secretion by 40-45%.
3. In doses need to reduce acid secretion there are typical anticholinergic adverse effects like
dryness of mouth, blurring of vision, tachycardia, urinary retention and glaucoma, therefore they
are not preferred.
4. Reduce volume of gastric juice without raising its pH

PROSTAGLANDIN ANALOGUE

Drugs
• Misoprostol (PGE1 analogue)
• Enprostil (PGE2 analogue)

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 DR. PRIYANKA SACHDEV

• Rioprostil (PGE2 analogue)

MOA
• Cytoprotective antisecretory activity action
1. Inhibiting acid secretion
2. Inhibit gastrin release
3. Promoting mucus as well as HCO3¯ secretion
4. Increase mucosal blood flow
5. Ability to reinforce the mucus layer covering gastric and duodenal mucosa which is buffered
by HCO3 ¯ secreted into this layer
• Reduction in 24 hour acid production is less than H2 blockers

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Uses
• Misoprostol (PGE1 analogue) is used for prevention and treatment of NSAID induced ulcer
• But DOC is PPI

Adverse effects
• Abdominal cramps
• Diarrhea
• Headache
• Fever
• Potential for abortion

• It is seldom employed now because PPIs are more effective, more convenient, better tolerated
and cheaper.

GASTRIC ACID NEUTRALIZER  ANTACID

Drugs

Antacids

Systemic Nonsystemic
Sod. bicarbonate Mag, hydroxide
Sod. citrate Mag. trisilicate
Alumin. hydroxide
Magaldrate
Cal. carbonate

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 DR. PRIYANKA SACHDEV

MOA
Antacids
↓
Basic substances
↓
Neutralize already secreted gastric acid
↓
Raise pH of gastric content

2. Peptic activity is indirectly reduced if pH rises above 4 because 

• Pepsin is secreted as a complex with an inhibitory terminal moiety that dissociates below pH
5.so optimum peptic activity is exerted between pH 2 to 4.

• Antacids do not decrease acid production rather 

Antacids
↓
Raise antral pH to > 4
↓
Evoke reflex gastrin release
↓
More acid is secreted
↓
Acid rebound

Potency of an antacid
• Acid neutralizing capacity (ANC)  It is defined as 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.

Pharmacokinetics
• Taken in empty stomach  acts for 30–60 min only, since in this time any gastric content is
passed into duodenum.
• Taken with meals  act for at the most 2–3 hr

Types
1. Systemic Antacids
2. Non-systemic antacids

1. Systemic Antacids
• Sodium bicarbonate
 It gets absorbed leading to systemic (metabolic) alkalosis
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 Hence not preferred as antacid.

2. Non-systemic antacids
• Aluminum and magnesium salts
 Insoluble salts
 Not absorbed significantly
 Do not disturb systemic pH.

Aluminum compounds
• Weak antacids
• Slow acting
• Inhibit motility so delays gastric emptying produces constipation.
• Inhibits phosphate absorption, increase in calcium resorption from bones  chronic use may
lead phosphate depletion syndrome hypercalcemia, hypercalciuria and osteomalacia.

Magnesium compounds
• Strong antacids
• Rapidly acting
• Increase GI motility  produce diarrhea.
• 5-10% of magnesium may get absorbed and then eliminated by kidney  magnesium salts are
contraindicated to a patient of renal insufficiency

Calcium Salts
• Strong antacid
• Rapidly acting
• Longer duration of action but not preferred owing to following problems
 Acid rebound: Calcium, in small intestine, increases release of gastrin and acid.
 Hypercalcemia.
 Milk alkali syndrome
 Constipation.
 Belching, abdominal discomfort and flatulence due to production of gas.

Antacid combinations
• Combination of Magnesium salts and aluminium salts has many
advantages
• Mag. salts  Fast , Alum. salts  slow
• Mag. salts  laxative, Alum. salts  constipation
• Mag./cal. salts  hasten Gastric emptying ,Alum. salts  delay Gastric
emptying  Gastric emptying is least affected

Interactions
• By raising gastric pH and by forming complexes  non-absorbable antacids decrease
absorption of many drugs 
 Tetracyclines
 Iron salts
 fluoroquinolones
 Ketoconazole
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 DR. PRIYANKA SACHDEV

 H2 blockers
 Diazepam
 Phenothiazines
 Indomethacin
 Phenytoin
 Isoniazid
 ethambutol
 Nitrofurantoin

Uses
• Antacids are now employed only for intercurrent pain relief and acidity
• Mostly self-prescribed by the patients as over counter preparations

Adverse effects
• Acid rebound
• Bowel upset

ULCER PROTECTIVES

Drugs
1. Sucralfate
2. Colloidal bismuth subcitrate (CBS;
Tripotassium dicitratobismuthate)

Sucralfate
• Sucralfate is an ulcer protective agent.

MOA

Sucralfate
↓
Basic aluminium salt of sulfated sucrose
↓
Polymerizes at pH < 4 by cross linking of molecules
↓
Forms a sticky gel-like consistency
↓
preferentially and strongly adheres to ulcer base (seen
endoscopically to remain there for ~ 6 hours)
↓
Acts as a physical barrier preventing acid, pepsin and
bile from coming in contact with the ulcer base.

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↓
Promotes healing

Remember
 Sucralfate 
 Minimally absorbed after oral administration.
 No acid neutralizing action
 Delays gastric emptying
 Action is entirely local.
 Viscous and gel like properties that are responsible for its action.
 This protective action is attributed to sucralfate only in acidic medium

Dose
• Ulcer healing dose of sucralfate is 1 g taken in empty stomach 1 hour before the 3 major meals
and at bed time for 4–8 weeks.

Interactions
• Antacids should not be taken with sucralfate because its polymerization is dependent on acidic
pH

Adverse effects
1. Constipation is reported by 2% patients.
2. It has potential for inducing hypophosphatemia by binding phosphate ions in the intestine.
3. Dry mouth and nausea

Uses
• Sucralfate is infrequently used now because of need for 4 large well-timed daily doses and
availability of simpler and more effective H2 blockers/PPIs.

Colloidal bismuth subcitrate (CBS)

• It is a colloidal bismuth compound
• Precipitates at pH < 5

MOA
1. Increase gastric mucosal PGE2, mucus and HCO3 production.
2. Precipitate mucus glycoproteins and coat the ulcer base.
3. Detach and inhibit H.pylori directly

Adverse effects
• Diarrhoea
• Headache
• Dizziness
• Blackening of tongue, dentures and stools

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 DR. PRIYANKA SACHDEV

ANTI H.PYLORI DRUGS

Introduction
• Helicobacter Pylori are gram-negative
bacteria

It attaches to surface epithelium beneath mucus

↓
High urease activity
↓
Urease split urea into ammonia
↓
Maintains a neutral microenvironment around bacteria
↓
Promotes back diffusion of H+ ions
↓
Ulcer

H. Pylori

Inhibit somatostatin, which causes Inhibit mucus formation

inhibition of gastrin

Increases gastrin concentration

Increases acid Break the defense

• It has been found as a commensal in 20–70%

normal individuals
• 70-90% of peptic ulcers are associated with H.
pylori.
• Eradication of H. pylori concurrently with H2
blocker/PPI therapy of peptic ulcer has been
associated with faster ulcer healing and largely
prevents ulcer relapse.

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• H. pylori infection can be detected by  urea breath test

1. All H. pylori positive ulcer patients should receive H. pylori eradication therapy.
2. In the absence of H. pylori testing, all cases with failed conventional ulcer therapy and
relapse cases must be given the benefit of H. pylori eradication.

Antimicrobials against H. pylori

1. Amoxicillin
2. Clarithromycin
3. Tetracycline
4. Metronidazole/Tinidazole

Combinations are used

• Any single antibiotic is ineffective.
• Resistance develops rapidly,
• Acid suppression by PPIs/H2 blockers enhances effectiveness of anti-H. pylori antibiotics, and
optimum benefits are obtained when gastric pH is kept >5 for at least 16–18 hours per day.
• Therefore combinations are used combination of one PPI and two anti H pylori

Therapies Used
A. Triple therapy  Regimen (LCA), Regimen (OAM)
B. Quadruple therapy  Regimen (OBTM)

A) Triple therapy
• A number of 3 drug regimens 
• Combination of one PPI and two anti H pylori for 1 or 2 weeks are being used
• 2 week regimens achieve higher (upto 96%) eradication rates, though compliance is often poor
due to side effects.

Regimen 1 (LCA)
• US-FDA approved regimen is:
1. Lansoprazole 30 mg
2. Clarithromycin 500 mg
3. Amoxicillin 1000 mg
• All given twice daily for 2 weeks.

Regimen 2 (OAM)
• National Formulary of India suggests a model H. pylori eradication regimen
1. Omeprazole 40 mg OD
2. Metronidazole 400 mg TDS
3. Amoxicillin 500 mg TDS
• All given twice daily for 1 weeks.

B) Quadruple therapy
• For eradication failure cases
• Combination of one PPI and CBS and two anti H pylori

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 DR. PRIYANKA SACHDEV

Regimen (OBTM)
1. Omeprazole 20 mg BD
2. CBS 120 mg QID
3. Metronidazole 400 mg TDS
4. Tetracycline 500 mg QID

DRUGS FOR GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Introduction
• Reflux is sensation of stomach contents coming back in foodpipe
• Patient complains of ‘heart-burn’, acid eructation, especially after a large
meal
• Aggravated by stooping or lying flat.

Etiology
Relaxation of lower esophageal sphincter
(LES) in the absence of swallowing
↓
Reflux of acid from stomach to lower
1/3rd of oesophagus
↓
Repeated reflux of acid gastric contents
into lower 1/3rd of esophagus
↓
Causes esophagitis, erosions, ulcers,
pain on swallowing, dysphagia, strictures,
and increases the risk of esophageal
carcinoma

• Though GERD is primarily a GI motility disorder, acidity of gastric contents is the most
important aggressive factor in causing symptoms and esophageal lesions.

Staging
• Stage 1: occasional heartburn (<3 episodes/ week), mostly only in
relation to a precipitating factor, mild symptoms, no esophageal
lesions.
• Stage 2: > 3 episodes/week of moderately severe symptoms,
nocturnal awakening due to regurgitation, esophagitis present or
absent.
• Stage 3: Daily/chronic symptoms, disturbed sleep,
esophagitis/erosions/stricture/extraesophageal symptoms like
laryngitis, hoarseness, dry cough, asthma.

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TREATMENT OF GERD

1. Proton pump inhibitors (PPIs)

2. H2 blockers
3. Antacids
4. Sodium alginate
5. Prokinetic drugs

1. PROTON PUMP INHIBITORS (PPI)

• Reduce acidity of gastric contents
• No effect on LES tone
• Most effective drugs, both for symptomatic relief as well as for healing of esophageal lesions
• Intragastric pH >4 for ~18 hr/day is considered optimal for healing of esophagitis.
• 80–90% esophageal lesions heal in 4–8 weeks
• PPIs  DOC for patients with all stages of GERD

2. H2 BLOCKERS
• Reduce acidity of gastric contents
• No effect on LES tone
• H2 blockers cause less complete acid suppression than PPIs, ie elevate intragastric pH to >4
for less than 8 hours in 24 hours
• H2 antagonists are indicated in stage-1 cases, or as alternative to PPIs in stage 2 or 3 cases.

3. ANTACIDS
• Used only for pain releif
• No longer employed for healing of esophagitis
• No effect on LES tone.

4. SODIUM ALGINATE
• Forms a thick frothy layer which floats on gastric contents like a raft may prevent contact of acid
with esophageal mucosa.
• No effect on LES tone.

5. PROKINETIC DRUGS
1. Metoclopramide
2. cisapride

MOA
1. By increasing LES tone
2. Improving esophageal clearance

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 DR. PRIYANKA SACHDEV

3. Facilitating gastric emptying,

• Do not affect gastric acidity or promote healing of esophagitis.
• Symptom control afforded by prokinetic drugs is much inferior to that by PPIs/H2 blockers.
• Prokinetic drugs are often coprescribed with PPI/H2 blocker therapy, but whether this improves
outcome is not clear

ANTIEMETIC AND PROKINETIC DRUGS

Emesis
• Vomiting  occurs due to stimulation of emetic (vomiting) centre
situated in the medulla oblongata.
• Close to vomiting centre are other visceral centre, including those for
respiration, salivation and vascular control, which give rise to the
prodromal sensations of vomiting.

 Motion sickness  Vomiting due to travelling

 Morning sickness  Vomiting in early pregnancy

 Sea sickness  Vomiting in sea

Pathways
• Multiple pathways can elicit vomiting
1. Chemoreceptor trigger zone (CTZ)
2. Nucleus tractus solitarius (NTS)
3. Cerebellum
4. Cortex higher centre

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1. Chemoreceptor trigger zone (CTZ)

• Located in area postrema
• Unprotected by BBB

• Expresses  dopamine D2, serotonin 5-HT3 , neurokinin NK1 (activated by substance P),
cannabinoid CB1 and opioid μ receptors

• Receives impulses arising in 

 GIT
 Bloodborne  drugs, mediators, hormones, toxins, etc. because it is unprotected by the
blood-brain barrier

2. Nucleus tractus solitarius (NTS)

• Protected by BBB

• Expresses  dopamine D2, serotonin 5-HT3 , neurokinin NK1 (activated by substance P),
histamine H1, cholinergic M receptors

• Receives impulses arising in 

 GIT

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Impulse from GIT

Cytotoxic drugs, radiation and other GI irritants
↓
Release 5-HT from enterochromaffin cells
↓
Acts on 5-HT3 receptors present on extrinsic primary afferent
neurones (PAN) of enteric nervous system
↓
These neurons send impulses to NTS and CTZ
↓
Acts on 5-HT3 receptors present on NTS and CTZ
↓
NTS and CTZ sends signals to vomiting centre
↓
Vomiting

Impulse from Blood

Inflammation
↓
5-HT released in large quantity / 5-HT released from platelets
by inflammatory mediators
↓
Spill into circulation
↓
Reach CTZ via vascular route also
↓
Acts on 5-HT3 receptors present on CTZ
↓
CTZ sends signals to vomiting centre
↓
Vomiting

3. Cerebellum
• Expresses  histamine H1, cholinergic M receptors

• Receives impulses arising in 

 Vestibular apparatus in inner ear

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Impulse from Vestibular apparatus

Body is rotated or equilibrium is disturbed or when

ototoxic drugs act
↓
Vestibular apparatus in inner ear is stimulated
↓
Sends impulse to cerebellum
↓
Acts on H1 and M receptors present on cerebellum
↓
Cerebellum sends signals to vomiting centre
↓
Vomiting

4. Cortex higher centres

 Receives impulses arising in 
 Various unpleasant sensory stimuli

Various unpleasant sensory stimuli

Bad odour, ghastly sight, severe pain as well as fear, recall of an obnoxious event,
anticipation of an emetic stimulus (repeat dose of cisplatin)
↓
Sends impulse to Cortex
↓
Cortex sends signals to vomiting centre
↓
Vomiting

Reduced gastric emptying

• Vomiting is accompanied by reduced gastric tone and peristalsis

In the emetic response 

1. LES, esophagus, fundus and body of stomach relax
2. Duodenum and pyloric stomach contract in a retrograde manner.
 Conditions that inhibit gastric emptying Predispose to vomiting
 Conditions that stimulates gastric emptying  Supress vomiting

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ANTIEMETIC DRUGS

Introduction
• Drugs used to prevent or suppress vomiting

Classification

Antiemetic Drugs
Anticholinergics H1 Neuroleptics Nk1 5-HT3
Antihistaminics Receptor Antagonists
Antagonists
Drugs
MOA
Pharmacokinetics
Uses
Drawbacks Interactions

ANTICHOLINERGICS

Drugs
• Hyoscine
• Dicyclomine

Hyoscine

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MOA

Hyoscine
↓
Block M receptor in cerebellum
↓
Block conduction of nerve impulses across a cholinergic link in pathway leading from vestibular
apparatus to vomiting centre
↓
Supress vomiting due to motion sickness
↓
Antiemetic action

Route
• A transdermal patch containing 1.5 mg of hyoscine, to be delivered
over 3 days has been developed.
• Applied behind the pinna, it suppresses motion sickness while
producing only mild side effects

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Uses
• Most effective drug for motion sickness.

Drawbacks
1. It has a brief duration of action; so suitable only for short brisk journeys
2. Produces sedation
3. Dry mouth and other anticholinergic side effects
4. Has poor efficacy in vomiting of other etiologies.

Dicyclomine
• Use for prophylaxis of motion sickness and for
morning sickness.

H1 ANTIHISTAMINICS

Drugs
• Promethazine
• Diphenhydramine
• Dimenhydrinate
• Doxylamine
• Meclozine (Meclizine)
• Cinnarizine

Promethazine,diphenhydramine,dimenhydrinate
MOA
Promethazine,diphenhydramine,dimenhydrinate
↓
Block H1 receptor in cerebellum and NTS
Block M receptors (Weak anticholinergics)
↓
Antiemetic action

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Uses
• Protection of motion sickness for 4–6 hours
• Chemotherapy induced nausea and vomiting
(CINV).

Drawbacks
1. Produces sedation
2. Dry mouth and other anticholinergic side effects (they are also weak
anticholinergics)

Doxylamine
• It is a sedative H1 antihistaminic with prominent anticholinergic activity.
• Specifically promoted in India for morning sickness

Meclozine (meclizine)
• Less sedative
• Longer-acting
• Protects against sea sickness for nearly 24 hours.

Cinnarizine
• Additional MOA  acts by inhibiting influx of Ca2+ from
endolymph into vestibular sensory cells which mediates
labyrinthine reflexes

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• Use  Motion sickness

NEUROLEPTICS

Drugs
• Chlorpromazine
• Triflupromazine
• Prochlorperazine
• Haloperidol

MOA
1. Block D2 receptors in CTZ and NTS
2. Also Block M receptors  Additional antimuscarinic property
3. Also Block H1 receptors  Additional antihistaminic property

Uses
1. Drug induced and postoperative nausea and vomiting (PONV).
2. Disease induced vomiting: gastroenteritis, uraemia, liver disease, migraine, etc.
3. Malignancy associated and cancer chemotherapy (mildly emetogenic) induced vomiting.
4. Radiation sickness vomiting (less effective).
5. Morning sickness: should not be used except in hyperemesis gravidarum.

Remember
• Neuroleptics are less effective in motion sickness: vestibular pathway does not involve
dopaminergic link.

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Drawbacks
1. Sedation
2. Acute muscle dystonia

NK1 RECEPTOR ANTAGONISTS

Drugs
• Aprepitant
• Fosaprepitant

Aprepitant

MOA
Aprepitant
Also known as substance P antagonists
↓
Selective  high affinity NK1 receptor antagonist
↓
Block NK1 receptors in CTZ and NTS
(Receptor for substance P)
↓
Antiemetic action

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Pharmacokinetics
• Metabolized primarily by hepatic CYP 3A4
• Aprepitant is contraindicated in patients on cisapride or pimozide, in which life threatening QT
prolongation has been reported.

Uses
1. Antiemetic efficacy against high emetogenic cisplatin based chemotherapy.
 Greater additional protection was afforded against delayed vomiting than against acute
vomiting.
 It was particularly useful in patients undergoing multiple cycles of chemotherapy.
2. PONV

Drawbacks
• Weakness
• Fatigue
• Flatulence
• Rise in liver enzymes

Fosaprepitant
• Parenterally administered prodrug of aprepitant.

5-HT3 ANTAGONISTS

Drugs
• Ondansetron
• Granisetron
• Palonosetron
• Ramosetron

Ondansetron
• Blocks emetogenic impulses both at their peripheral origin and their central relay.

MOA
Ondansetron
↓
Blocks 5-HT3 receptors on 
Vagal afferents in gut
NTS and CTZ
↓
Antiemetic action

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Uses
• Ondansetron is DOC for 
1. Cytotoxic drug induce vomiting
• Ondansetron is more effective in acute vomiting after cisplatin
• Ondansetron alone is less effective in delayed vomiting (NK1 antagonist aprepitant is
given)
2. Prevention and treatment of postoperative nausea and vomiting (PONV)

Pharmacokinetics
• Oral bioavailability is 60–70%
• t½ is 3–5 hrs
• Duration of action is 8–12 hrs

Adverse effects
1. Most common side effect  headache and dizziness.
2. Mild constipation and abdominal discomfort
3. Hypotension, bradycardia, chest pain and allergic reactions are reported, especially after i.v.
injection.

Remeber
• Granisetron  10-15 times more potent than ondensetron and more effective during the
repeat cycle of chemotherapy.
• Palonasetron  maximum affinity for 5 HT3 receptor
• Palonasetron  most potent 5-HT3 blocker and longest acting

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• Ondansetron  shortest acting.

• Dolasetron  cause QT prolongation.
• Alosetron  withdrawn because of fatal GI side effects like constipation and ischemic colitis.
• Dolasetron, Tropisetron and Palonasetron  newer 5-HT3 antagonists.

PROKINETIC DRUGS

Drugs
• Metoclopramide
• Domperidone
• Cisapride,Mosapride, Itopride
• Tegaserod

Prokinetic Drugs
Metoclopramide Domperidone Cisapride Tegaserod
Introduction
MOA
Pharmacokinetics
Uses
Adverse effects
Interactions

Introduction
• Promote gastrointestinal transit
• Speed gastric emptying by enhancing coordinated propulsive motility.

Pathophysiology of gastrokinetic drugs

• Acetylcholine  major neurotransmitter in the GIT which is responsible for peristaltic
movement.
• Its secretion is affected by other neurotransmitter 
1. Activation of prejunctional excitatory 5-HT4 receptors increases release of Ach.
2. Activation of prejunctional inhibitory D2 and 5-HT3 receptors inhibits release of Ach.

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Prokinetic drugs act by

↓
5HT4 agonistic activity
D2 antagonistic activity
5-HT3 antagonistic activity

↓
Increase release of Ach
↓
Increase motility of GIT

METOCLOPRAMIDE
Introduction
• Metoclopramide (a benzamide, like procainamide1) is a prokinetic drug
MOA
1. 5-HT4 agonism in GIT
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2. D2 antagonism in GIT and CTZ / NTS

3. 5-HT3 antagonism in GIT and CTZ / NTS

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1. 5-HT4 agonism
Metoclopramide
↓
Stimulation of 5-HT4 receptor in GIT
↓
Enhances release of ACH from myenteric plexus
↓
Main prokinetic action is due to this action.

2. D2 antagonism
• Blockade of D2 receptor in GIT  responsible for prokinetic action
• Blockade of D2 receptor in CTZ / NTS  responsible for antiemetic effect

3. 5-HT3 antagonism
• Blockade of 5-HT3 receptor in GIT  responsible for
prokinetic action
• Blockade of 5-HT3 receptor in CTZ/NTS  responsible for
antiemetic effect
• Increases tone of lower esophageal sphincter (LES) 
GERD opposed
• Relax pylorus and first part of duodenum  speed gastric
emptying
• More prominent effect on upper GIT  increases gastric
peristalsis
• Less prominent effect on lower GIT -> increases intestinal
motility to some extent
• But has no significant action on colonic motility

Pharmacokinetics
• Metoclopramide is rapidly absorbed orally, enters brain, crosses placenta and is secreted in
milk.
• Plasma t½ is 3– 6 hours.
• Orally it acts in ½–1 hr, but within 10 min after i.m. and 2 min after i.v. injection.
• Action lasts for 4–6 hours.

Uses
1. As an antiemetic
2. Gastrokinetic
3. Dyspepsia
4. GERD

1. As an antiemetic 

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 Effective for many types of vomiting— postoperative, drug induced, disease associated
(especially migraine), radiation sickness, etc
 But is less effective in motion sickness.
 Though no teratogenic effects have been reported, metoclopramide should be used for
morning sickness only when not controlled by other measures.

2. Gastrokinetic: To accelerate gastric emptying:

(a) When emergency general anaesthesia has to be given and the patient has taken food less
than 4 hours before.
(b) To relieve postvagotomy gastroparesis associated gastric stasis.

3. Dyspepsia
 Metoclopramide may succeed in stopping persistent hiccups

4. GERD
 Metoclopramide may benefit milder cases of GERD, but is much less effective than PPIs/H2
blockers.
 Used as adjuvant to acid suppressive therapy.

Adverse effects
1. Sedation, dizziness, loose stools, muscle dystonia (especially in children) are main side effects.
2. D2 - blocking action cause extrapyramidal symptoms (Akathsia, Parkinsonism) and
hyperprolactinemia (galactorrhea, gynacomastia).

Interactions
• Levodopa  By blocking DA receptors in basal ganglia, it abolishes the therapeutic effect of
levodopa

DOMPERIDONE

Introduction
• It is a D2 receptor antagonist

MOA
• D2 antagonism in GIT and CTZ
 Blockade of D2 receptor in GIT  responsible for prokinetic action
 Blockade of D2 receptor in CTZ  responsible for antiemetic effect

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It does not cross blood brain barrier

1. Exerts antiemetic effect, because CTZ lies out side the BBB
2. No extrapyramidal side effects and hyperprolactinemia (in contrast to metoclopramide)
3. It can be given with levodopa  Domeperidone decreases levodopa induced vomiting (by
acting on CTZ) without interfering its therapeutic effects

Pharmacokinetics
• Domperidone is absorbed orally.
• Bioavailability is only ~15% due to first pass metabolism.
• Plasma t½ is 7.5 hr.

Uses
• Same as metaclopromide

Adverse effects
• Less than with metoclopramide.
1. Dry mouth, loose stools, headache, rashes, galactorrhoea are generally mild.
2. Cardiac arrhythmias have developed on rapid i.v. injection

CISAPRIDE

Introduction
• It is a prokinetic with little antiemetic property.

MOA
1. 5-HT4 agonism in GIT Stimulation of 5-HT4 receptor in GIT enhances release of ACH from
myenteric plexus
2. Weak 5-HT3 antagonistic activity in GIT  suppresses inhibitory transmission in myentric
plexuses  enhances release of ACH from myenteric plexus

• No D2-antagonistic activity

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Pharmacokinetics
• Cisapride is primarily inactivated by CYP3A4
• Plasma t½ of ~ 10 hours.

Uses
1. GERD
2. Dyspepsia
3. Impaired gastric emptying
4. Chronic constipation

Adverse effects
1. At high concentrations, cisapride blocks delayed rectifying K+ channels in heart—prolongs Q-Tc
interval and predisposes to torsades de pointes/ventricular fibrillation  Banned
2. Ventricular arrhythmias and death, mainly among patients who took CYP3A4 inhibitors like
azole antifungals, macrolide antibiotics, antidepressants

Misapride
• Similar to cisapride, but does not cause QT prolongation.

TEGASEROD

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MOA
• Selective 5-HT4 agonist in GIT with no action on 5-HT3 receptor (contrast cisapride also has
weak 5-HT3 antagonistic action).
• It mainly augments colonic motility along with promotion of gastric emptying and intestinal
transit, and less effect on LES tone.

Use
1. Constipation
2. Irritable bowel syndrome

Remember

Motion sickness
• Anticholinergic  Hyoscine (scopolamine) and H1 antihistaminic drugs are more effective in
motion sickness.
a) Anticholinergics  Hyoscine (Scopolamine) Dicyclomine
b) H1 antihistaminic  Promethazine, cyclizine, meclizine, cinnarizine, etc.

Morning sickness
H1 antihistaminic is preferred

1. Combination of doxylamine (an antihistaminic) with pyridoxine is preferred.

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2. Promethazine is an alternative to doxylamine

Chemotherapy induced nausea and vomiting

• Cisplatin is most common culprit causing chemotherapy induced nausea and vomiting.
• Cytotoxic drugs and radiation cause cellular damage which leads to release of 5-HT from
intestine and activation of emetogenic 5-HT3 receptors.
• Therefore, 5-HT3 receptor antagonists (e.g. ondenstron) are the DOC for this condition.
• Cisplatin can induce vomiting within 24 hours or after 2 days.
 DOC for early vomiting  Ondensetron
 DOC for delayed vomiting  Aprepitant (substant P antagonist)

Post-operative nausea and vomiting (PONV)

• Prevention of PONV
 For high risk patients, propofol is the drug of choice for induction and maintenance.
 As prophylaxis droperidol or metoclopramide or ondansetron can be given before surgery.
• Control of PONV
 All the mentioned antiemitic drugs can be used.

DRUGS FOR CONSTIPATION

Constipation
• A stool frequency of once in 2 days to 2–3 times per day is
considered normal by different individuals
• Constipation is infrequent production of hard stools requiring
straining to pass, or a sense of incomplete evacuation.
• Constipation is a symptom rather than a disease.

Etiology
• Various aspects of patient’s lifestyle may contribute:
(a) Misconception about the normal/necessary frequency, amount or consistency of stools.
(b) Inadequate fibre in diet, less fluid intake.
(c) Lack of exercise, sedentary nature of work.
(d) Irregular bowel habits, rushing out for job

Types
1. Spastic constipation (irritable bowel):
• Excessive tone of colonic muscles which
narrows cavity and the forward movement
of faeces is retarded
• The stools are hard, rounded, stone like
and difficult to pass.
2. Atonic constipation (sluggish bowel):
• Due to advanced age, debility or laxative
abuse.

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DRUGS FOR CONSTIPATION

1. Laxative or aperient:
 Milder action
 Elimination of soft but formed stools.

2. Purgative or cathartic:
 Stronger action
 Resulting in more fluid evacuation.

• Many drugs in low doses act as laxative and in larger doses as purgative

Classification

Drugs for constipation

Bulk Purgatives Stool Stimulant Stimulant
Softener Purgatives Purgatives
Drugs
MOA
Uses
Adverse effects
Contraindications

Overall MOA
• All Purgatives /Luxative increase water content of faeces by:

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Purgatives /Luxative
↓
Hydrophilic or osmotic action
↓
Retaining water and electrolytes
in the intestinal lumen
↓
Increase volume of colonic
content
↓
Make it easily propelled

Purgatives /Luxative
↓
Acting on intestinal mucosa
↓
Decrease net absorption of water and electrolyte
↓
Increase volume of colonic content
↓
Make it easily propelled

Purgatives /Luxative
↓
Increasing propulsive activity of colon (Primary effect)
↓
Allowing less time for absorption of salt and water (secondary effect)
↓
Make it easily propelled

BULK PURGATIVES

Drugs
• Dietary fibre: bran
• Psyllium (Plantago)
• Ispaghula
• Methylcellulose

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Dietary fibre: bran

• Dietary fibre is the plant cell wall that resists digestion,
consist of cellulose, lignin, polysaccharides like pectin
and hemicellulose
• Bran is the residual product of flour industry which
consists of ~40% dietary fibre.

MOA
• 3 Mechanisms 

It
absorbs water in the intestines
↓
Swells
↓
Increases water content of faeces
↓
softens it
↓
Facilitates colonic transit

Dietary fibre supports bacterial growth in colon

↓
Bacterial degradation of pectins, gums, etc.
↓
Osmotically active products are formed in colon
↓
Retain water
↓
Softens faeces
↓
Facilitates colonic transit

Dietary fibre bind bile acids

↓
Increase their excretion

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↓
so stimulate their synthesis from cholesterol in liver
↓
So decrease plasma cholesterol
Uses
1. First line approach for simple constipation.
2. Prolonged intake reduces rectosigmoid intraluminal pressure and helps to relieve symptoms of
irritable bowel syndrome (IBS)
3. Chronic diverticulosis
4. Useful when straining at stools has to be avoided.

Drawbacks
1. Unpalatable
2. Large quantity (20–40 g/day) needs to be ingested
3. Full effect requires daily intake for at least 3–4 days.
4. It does not soften faeces already present in colon or rectum.So bran is useful for prevention of
constipation, but not for treating already constipated subjects.
5. Flatulence may occur.

Contraindications
1. Patients with gut ulcerations
2. Adhesions
3. Stenosis
4. when faecal impaction is a possibility

Psyllium (Plantago) and Ispaghula

• Contain natural colloidal mucilage which forms a gelatinous mass
by absorbing water.
• Refined ispaghula husk 3–8 g is freshly mixed with cold milk, fruit
juice or water and taken once or twice daily.
• It should not be swallowed dry (may cause esophageal impaction).
• It acts in 1–3 days.

Methylcellulose
• A semi-synthetic, colloidal, hydrophilic derivative of cellulose that remains largely unfermented
in colon.
• It takes up water to swell (about 25 times).
• A dose of 4–6 g/day is satisfactory in most individuals.

STOOL SOFTENER

Introduction
• Also known as Surfactants / Emollients

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Drugs
• Docusates (Dioctyl sodium sulfosuccinate : DOSS)
• Liquid paraffin

Docusates (Dioctyl sodium sulfosuccinate: DOSS)

MOA
• 2 mechanisms 
Stool Softener
↓
Emulsify colonic contents
↓
Increase penetration of water into feces
↓
Soften stools
↓
Make it easily propelled

Stool Softener
↓
Acts on intestinal mucosa
↓
Decrease net absorption of water and electrolyte
↓
Increase volume of colonic content
↓
Make it easily propelled
Uses
Mild laxative  indicated when straining at stools must be avoided.

Side effects
• It is bitter
• Cramps and abdominal pain can occu
• Liquid preparations may cause nausea.
• Hepatotoxicity on prolonged use

Liquid paraffin
• It is a viscous liquid; a mixture of petroleum hydrocarbons
• Indigestible and non absorbable
• It is pharmacologically inert.
• Takes 2–3 days for action

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STIMULANT PURGATIVES

Drugs

Stimulant purgatives

Diphenylmethanes Anthraquinones 5-HT4 agonist Fixed oil

(Emodins
Prucalopride
Phenolphthalein Castor oil
Senna
Bisacodyl Cascara sagrada
Sod. picosulfate

MOA
• 2 mechanisms 
Stimulant Purgatives
↓
Act on myenteric plexuses of intestine
↓
Directly increase motility

(a) Inhibiting Na+K+ATPase of villous cells— impairing electrolyte and water absorption.
(b) Stimulating adenylyl cyclase in crypt cells— increasing water and electrolyte secretion.
(c) Enhancing PG synthesis in mucosa which increases secretion.
(d) Increasing NO synthesis which enhances secretion

Increase volume of colonic content

↓
Make it easily propelled
Adverse effects
1. Hypokalaemia
2. Routine and long-term use must be discouraged, because it can produce colonic atony

Contraindication
1. They can reflexly stimulate gravid uterus, therefore are contraindicated during pregnancy
2. Subacute or chronic intestinal obstruction

Diphenylmethanes
 Phenolphthalein
 It is a litmus-like indicator which is in use as purgative

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 It turns urine pink if alkaline

 About 15% is absorbed and eliminated by kidney so urine becomes pink or red if it is
alkaline.
 It has a prolonged effect owing to enterohepatic circulation

 Bisacodyl
 Intestinal enzymes convert bisacodyl in to the active disacetyl metabolite.
 Available as enteric coated preparation that has to be. swallowed with out chewing or
crushing
 Also used in suppository form, which may produce burning sensation in rectum

Anthraquinones
 Senna and Cascara
 Plant purgatives contain anthraquinone glycosides, also called emodins.
 Unabsorbed in the small intestine, they are passed to the colon where bacteria liberate the
active anthrol form
 Take 6–8 hours to produce action.
 Taken by lactating mothers, the amount secreted in milk is sufficient to cause purgation in
the suckling infant

Prucalopride
• It is a selective 5-HT4 receptor agonist
• It activates 5-HT4 receptors on intrinsic enteric neurones to enhance intestinal contractions

Castor oil
• Obtained from the seeds of Ricinus communis.
• In small intestine, pancreatic lipase converts it into glycerol and ricinoleic acid.
• Ricinoleic acid irritate the mucosa and stimulate intestinal contractions
• Onset of action is in 1-3 hours since the site of action is small intestine.

OSMOTIC PURGATIVES

Introduction
• Osmotic Purgatives are solutes that are
1. Not absorbed in the intestine
2. They retain water osmotically

MOA
Osmotic Purgatives
↓
Osmotic action
↓
Retaining water osmotically in intestinal lumen

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↓
Increase volume of colonic content
↓
Make it easily propelled
Uses
1. First line approach for simple constipation.
2. Useful when straining at stools has to be avoided.
3. Hepatic encephalopathy 
• Patients have reduced capacity to detoxify ammonia produced by colon bacterias
• Lactulose causes reduction of blood NH3 concentration by 25–50%.
• The breakdown products of lactulose are acidic—lower the pH of stools.
• Ammonia produced by bacteria in colon is converted to ionized NH4+ salts that are not
absorbed.

Adverse effects
• Flatulence
• Cramps
• Abdominal discomfort
• Nausea and vomiting
• Diarrhea

VALID INDICATIONS OF LAXATIVES

1. Functional constipation
• Spastic constipation (irritable bowel)
 First choice laxative is dietary fibre or bulk forming agents taken over weeks/months.
 Stimulant purgatives are Contraindicated

• Atonic constipation (sluggish bowel):

 Non-drug measures like plenty of fluids, exercise, regular habits and reassurance should be
tried.
 In resistant cases a bulk forming agent should be prescribed. In case of poor compliance or
if the patient is not satisfied—bisacodyl or senna may be given once or twice a week for as
short a period as possible.

2. Bedridden patients
• Myocardial infarction, stroke, fractures, postoperative
• Bowel movement may be sluggish and constipation can be anticipated.
(a) To prevent constipation: bulk forming agents on a regular schedule; docusates, lactulose
and liquid paraffin are alternatives.
(b) To treat constipation: Enema (soap-water/ glycerine) is preferred; bisacodyl or senna may
be used.
3. To avoid straining at stools
• Hernia,cardiovascular disease, eye surgery) and in perianal afflictions (piles, fissure, anal
surgery)

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 DR. PRIYANKA SACHDEV

• It is essential to keep the faeces soft.

• Bulk forming agent, lactulose or docusates.

4. Preparation of bowel
• For surgery, colonoscopy, abdominal X-ray
• Bowel needs to be emptied of the contents including gas.
• Saline purgative, bisacodyl or senna may be used

5. After certain anthelmintics

• Saline purgative or senna may be used to flush out the worm and the anthelmintic drug.

CONTRAINDICATIONS OF LAXATIVES

1. Undiagnosed abdominal pain, colic or vomiting.

2. Organic (secondary) constipation due to stricture or obstruction in bowel,
hypothyroidism,hypercalcaemia, malignancies and certain drugs, e.g.—opiates, sedatives,
anticholinergics including antiparkinsonian, antidepressants and antihistaminics, oral iron,
clonidine, verapamil and laxative abuse itself.
3. Primary cause should be treated in these cases.

DRUGS FOR DIARRHOEA

Introduction
• WHO definition  3 or more loose or watery stools in a 24 hour period.
• However it is the recent change in consistency of stools rather than the number of stools that is
more important feature.
• This may be due to:
1. Decreased electrolyte and water absorption.
2. Increased secretion by intestinal mucosa.
3. Increased luminal osmotic load.
4. Inflammation of mucosa and exudation into lumen.

Types
1. Osmotic Diarrhea —increase in poorly absorbed substances, which are osmotically active like
carbohydrates and fats.
2. Secretory Diarrhea —increase in secretion of fluid and electrolytes in lumen due to toxins, bile
salt and mucosal abnormality.
3. Transit Disorders —hypermotility that leads to abnormality in contact of luminal contents with
mucosal surface.
TREATMENT OF DIARRHEA

A. Treatment of fluid depletion, shock and acidosis  Rehydration

B. Drug therapy
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 PHARMACOLOGY PROF BUSTER

A) REHYDRATION

1. Oral Rehydration Therapy

2. Intravenous Rehydration

1. Oral Rehydration Therapy

• With introduction of oral rehydration by WHO it is
established that oral rehydration treatment can be safely
and successfully used in treating acute diarrhoeas due to
all aetiologies, in all age groups, and in all countries.

Aim
• To prevent dehydration and reduce mortality.

Principle
• Oral fluid therapy is based on the observation that glucose given orally enhances the intestinal
absorption of salt and water, and is capable of correcting the electrolyte and water deficit.

Composition
• Since January 2004, the new ORS formulation is the only one procured by UNICEF.
• India was the first country in the world to launch this ORS formulation since June 2004.
• Treatment is Home based

Composition (grams)
Sodium chloride 2.6
Potassium chloride 1.5
Sodium citrate 2.9
Glucose 13.5
Total 20.5

Osmolar concentration (mmol/litre)

Sodium 75
Potassium 20
Chloride 65
Citrate 10
Glucose 75
Total 245

Estimated amount of ORS

• If the child’s weight is known, the amount of ORS solution required for rehydration during the
first four hours may be calculated by setting the deficit at approximately 75 ml/kg.
• If the child’s weight is not known, the approximate deficit may be determined on the basis of
child’s age, although this procedure is less accurate.
• As a general guide, after each loose stool, give 
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 DR. PRIYANKA SACHDEV

 children under 2 years of age : 50-100 ml

 children aged 2 up to 10 years : 100-200 ml
 older children and adults : as much fluid as they want
• Try to give the estimated required amount within a 4-hour period.

2. Intravenous Rehydration
• Intravenous infusion is usually required only for the initial rehydration of severely dehydrated
patients who are in shock or unable to drink
• Such patients are best transferred to the nearest hospital or treatment centre.

Solutions recommended by WHO for intravenous infusion

(a) Ringer’s lactate solution (Hartmann’s solution) : best commercially available solution. It
supplies adequate concentrations of sodium and potassium and the lactate yields bicarbonate
for correction of the acidosis. It can be used to correct dehydration due to acute diarrhoeas of all
causes
(b) Diarrhoea Treatment Solution (DTS)
(c) Normal saline

Dose
• The recommended dose of the IV fluid to be given is 100 ml/kg, divided as follows
Age First give 30 ml/kg in Then give 70 ml/kg in
Infants (under 12 1 hour 5 hours
months)
Older 30 minutes 2½ hours

B) DRUG THERAPY

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 PHARMACOLOGY PROF BUSTER

ANTIMICROBIAL DRUGS

A. Antimicrobials are of no value

B. Antimicrobials are useful only in severe disease (but not in mild cases)
C. Antimicrobials are regularly useful

A. Antimicrobials are of no value

• In diarrhoea due to noninfective causes, such as:
1. Irritable bowel syndrome (IBS)
2. Coeliac disease
3. Pancreatic enzyme deficiency
4. Tropical sprue
5. Thyrotoxicosis

B. Antimicrobials are useful only in severe disease (but not in mild cases)
1. Travellers’ diarrhoea: cotrimoxazole, norfloxacin, doxycycline
2. EPEC: Cotrimoxazole, or a fluoroquinolone or colistin
3. Shigella enteritis: ciprofloxacin or norfloxacin,Cotrimoxazole and ampicillin
4. Nontyphoid Salmonella enteritis: fluoroquinolone, cotrimoxazole or ampicillin.
5. Yersinia enterocolitica:Cotrimoxazole

C. Antimicrobials are regularly useful in

1. Cholera: Tetracyclines , Cotrimoxazole ,Ampicillin and erythromycin
2. Campylobacter jejuni: Norfloxacin and other fluoroquinolones
3. Clostridium difficile: metronidazole, while vancomycin given orally is an alternative.
4. Amoebiasis : metronidazole, diloxanide furoate,

PROBIOTICS
• Microbial cell preparations, either live cultures or lyophillised powders, that are intended to
restore and maintain healthy gut flora
• Organisms most commonly used are  Lactobacillus sp., Bifidobacterium, Streptococcus
faecalis, Enterococcus sp. and the yeast Saccharomyces boulardii, etc
• Convincing evidence of their efficacy is lacking
• Natural curd/yogurt is an abundant source of lactic acid producing organisms, which can serve
as probiotic.

ANTISECRETORY DRUGS

Racecadotril
• Prodrug
• Rapidly converted to thiorphan, an enkephalinase inhibitor.

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 DR. PRIYANKA SACHDEV

MOA
Racecadotril
↓
Inhibits enkephalinase
↓
Prevents degradation of endogenous enkephalins (ENKs)
↓
Enhanced ENK
↓
Lowering mucosal cAMP
↓
Decreases intestinal hypersecretion, without affecting motility
↓
Treats diarrhea

Uses
• Secretory diarrhoeas

Adverse effects
• Nausea
• Vomiting
• Drowsiness
• Flatulence

DRUGS FOR INFLAMMATORY BOWEL DISEASE (IBD)

Introduction
• IBD is a chronic relapsing inflammatory disease of the ileum, colon, or both, that may be
associated with systemic manifestations.
1. Ulcerative colitis (UC)
2. Crohn’s disease (CrD)

5-Amino salicylic acid (5-ASA) compounds

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 PHARMACOLOGY PROF BUSTER

Sulfasalazine (Salicylazosulfapyridine)

• It is a compound of 5-aminosalicylic
acid (5-ASA) with sulfapyridine linked
through an azo bond

MOA
Sulfasalazine
↓
Having low solubility, it is poorly absorbed from ileum
↓
Azo bond is split by colonic bacteria
↓
Release 5-ASA and sulfapyridine
↓
Sulfapyridine inhibits both COX and LOX
↓
Decreased PG and LT production
↓
Exerts a local antiinflammatory effect

Uses
• First line of treatment in mild to moderate UC and CD

Corticosteroids
• Prednisolone (40–60 mg/day) is highly effective in controlling symptoms as well as in inducing
remission in both UC and CrD.
• DOC for severe exacerbations
• Corticosteroids are generally used for short term, and discontinued after remission is induced.

Immunosuppressants
• Because of long latency of response, they are not suitable for acute flare ups of the disease, but
have good remission maintaining rates
• Azathioprine, 6-MP Can be used for the induction and maintenance of remission of U.C. and
C.D.
• Methotrexate  Can be used in CD, but has no use in U.C.
• Anti TNF-a (Infliximab, adalimumab, certolizumab, etanercept)  Can be used in CD.
• Cyclosporine  Used in severe U.C., which is refractory to glucocorticoids.

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