PHARMACOLOGY OF THE

G.I.T.

By MUTIBO
Objectives.
 Classify drugs acting on the G.I.T
 Explain the mechanisms of action of drugs acting
on the G.I.T
 Explain the indications, contra-indications, adverse
reactions and precautions of various drugs acting
on G.I.T
 Describe the drugs used in the treatment of Peptic
ulcer disease.

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Intro.
 Drugs acting on the GIT Can be classified into various groups
namely:
1) Drugs stimulating GIT motility/Antispasmodics
2) Laxatives
3) Ant diarrhoeal Agents
4) Drugs used for the treatment of irritable bowel syndrome
5) Anti Emetic agents
6) Drugs used in treating inflammatory bowel disease
7) Local preparations for anal and rectal disorders
8) Drugs used in acid – peptic diseases
 
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1.Antispasmodics

 Drugs that can selectively stimulate gut motor function

(prokinetic agents) have significant potential clinical
usefulness.
 Agents that increase lower esophageal sphincter pressures
may be useful for GERD.
 They include:
 Cholinomimetic Agents
 Metoclopramide & Domperidone
 Macrolides
 Stool Surfactant Agents (Softeners)
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Cholinomimetic Agents
 Cholinomimetic agonists such as bethanechol stimulate
muscarinic receptors on muscle cells and at myenteric plexus
synapses
 Bethanechol was used in the past for the treatment of GERD
and gastroparesis. Owing to multiple cholinergic effects and
the advent of less toxic agents, it is now seldomly used
 Acetylcholinesterase inhibitor neostigmine can enhance
gastric, small intestine, and colonic emptying.
 Intravenous neostigmine has enjoyed a resurgence in clinical
usage for the treatment of hospitalized patients with acute
large bowel distention
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Metoclopramide & Domperidone
 Metoclopramide and domperidone are dopamine
receptor antagonists. Within the gastrointestinal tract
activation of dopamine receptors inhibits cholinergic
smooth muscle stimulation; blockade of this effect is
believed to be the primary prokinetic mechanism of
action of these agents.
 These agents increase esophageal peristaltic
amplitude, increase lower esophageal sphincter
pressure, and enhance gastric emptying but have no
effect on small intestine or colonic motility.
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Cont.
 Metoclopramide and domperidone also block dopamine
receptors in the chemoreceptor trigger zone of the medulla (area
postrema),resulting in potent antinausea and antiemetic action.
Clinical Uses
 Gastroesophageal Reflux Disease

 Impaired Gastric Emptying

 Nonulcer Dyspepsia

 Prevention of Vomiting

 Postpartum Lactation Stimulation

 Clears gastric contents in emergency anaesthesia

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Cont.
Adverse Effects
 The most common adverse effects of metoclopramide involve the

central nervous system.

 Restlessness

 Drowsiness

 Insomnia

 Anxiety

 agitation occur in 10–20% of patients, especially the elderly.

 Extrapyramidal effects (dystonias, akathisia, parkinsonian features)

due to central dopamine receptor blockade occur acutely in 25% of

patients given high doses and in 5% of patients receiving long-term
therapy
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Macrolides
 Macrolide antibiotics such as erythromycin directly
stimulate motilin receptors on gastrointestinal smooth
muscle and promote the onset of a migrating motor
complex.
 The group members include erythromycin, azithromycin,
clarithromycin, miocomycin, spectinomycin,
roxithromycin and ketolides (telithromycin)
 Intravenous erythromycin (3 mg/kg) is beneficial in
some patients with gastroparesis; however, tolerance
rapidly develops.

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Stool Surfactant Agents (Softeners)

 These agents soften stool material, permitting water

and lipids to penetrate.
 They may be administered orally or rectally.
 Common agents include docusate (oral or enema)
and glycerin suppository.

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2.Laxatives

 Laxatives are commonly used to accelerate the movement of

food through the gastrointestinal tract.
 These drugs can be classified on the basis of their mechanism
of action as irritants or stimulants of the gut, bulking agents,
and stool softeners.
 They all have a risk of being habit-forming. Laxatives also
increase the potential of loss of pharmacologic effect of poorly
absorbed, delayed-acting, and extended-release oral
preparations by accelerating their transit through the intestines.
 They may cause electrolyte imbalances when used chronically.

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3.Antidiarrheals

Increased motility of the gastrointestinal tract and decreased absorption of

fluid are major factors in diarrhea.
 In all patients presenting with diarrhoea, it is important to identify and
eliminate the cause where possible.
If the cause is unclear, symptomatic relief may be helpful. The drugs used
will depend upon the cause of diarrhoea.
 Antidiarrheal drugs include:-

a) antimotility agents

b) Adsorbents

c) drugs that modify fluid and electrolyte transport .

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Cont.
Antimotility agents
 Two drugs that are widely used to control diarrhea are

diphenoxylate and loperamide.

 Both are analogs of meperidine and have opioid-like actions on the

gut, activating presynaptic opioid receptors in the enteric nervous

system to inhibit acetylcholine release and decrease peristalsis. At
the usual doses, they lack analgesic effects.
 Side effects include drowsiness, abdominal cramps, and dizziness.

 Because these drugs can contribute to toxic megacolon, they should

not be used in young children or in patients with severe colitis.

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Cont.

Diphenoxylate
1)

 This is an opiate derivative. It is combined with atropine in the preparation

lomotil.

 It is more expensive than codeine phosphate and probably better.

Loperamide
2)

 Loperamide is synthetic opiate with some anti-cholinergic activity.

 It may cause dizziness or dry mouth.

 The usual dose is 2mg three or four times daily.

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Cont.
Adsorbents
 Adsorbent agents, such as bismuth subsalicylate, methylcellulose, and

aluminum hydroxide are used to control diarrhea.

 Presumably, these agents act by adsorbing intestinal toxins or

microorganisms and/or by coating or protecting the intestinal mucosa.

 They are much less effective than antimotility agents. They can

interfere with the absorption of other drugs.

Agents that modify fluid and electrolyte transport
 Bismuth subsalicylate, used for traveler's diarrhea, decreases fluid

secretion in the bowel.

 Its action may be due to its salicylate component as well as its coating

action.

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4.Irritable bowel syndrome

 This common condition is the most frequent cause of chronic, recurrent

abdominal pain.
 It may also cause upset of bowel habit with diarrhoea, constipation or both.
 The pathophysiology is poorly understood.
 There are abnormal motility patterns in the bowel and patients may be
unduly sensitive to distension or contraction of viscera smooth muscle.
 Some patients’ diets are deficient of fibre.
 There is a relationship between psychological stress and symptoms in some
patients.

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Cont.

Drugs used include;

oMebeverine;

 An antispasmodic agent which does not have significant

anticholinergic effects. It is useful in relieving symptoms in some

patients at a dose of 135mg two or three-times daily.

oEnteric coated capsules of peppermint oil;

 These are useful in relieving gut spasm in some patients. The capsules

may cause heartburn if bitten into.

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5.Anti Emetic agents

 Nausea and vomiting may be manifestations of a wide variety of conditions,

including adverse effects from medications; systemic disorders or infections;
pregnancy; vestibular dysfunction; central nervous system infection or
increased pressure; peritonitis; hepatobiliary disorders; radiation or
chemotherapy; and gastrointestinal obstruction, dysmotility, or infections.

However, a useful abbreviation for remembering causes of nausea and
vomiting is VOMIT.
Vestibular
Obstruction or drugs like Opiates)
Mind
Infection (Irritation of gut)
Toxins (Taste and other senses)

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 Pathophysiology of Emesis

Cancer chemotherapy
Cerebral cortex
Opioids Smell
Sight Anticipatory emesis
Thought

Chemoreceptor Vestibular
Vomiting Centre
Trigger Zone Motion nuclei
(medulla) sickness
(CTZ) Muscarinic, 5 HT3 & Muscarinic
(Outside BBB) Histaminic H1 Histaminic H1
Dopamine D2
5 HT3,,Opioid Chemo & radio therapy
Receptors Gastroenteritis

Pharynx & GIT

5 HT3 receptors
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Classification
• Serotonin 5 HT3 Antagonists e.g ondansetron, dolasetron,
granesitron
• Dopamine D2 Antagonist e.g Metoclopramide,
phenothiazines, butyrophenols
• Anticholinergics e.g Hyoscine, atropine
• Antihistaminics H1e.g Cyclizine
• Glucosteroids e.g Dexamethasone
• Cannabinoids e.g nabilone
• Neurokinin 1 (NK1) Apretitant
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Metoclopramide
 Acts at dopamine receptors in stomach, upper GI,
CTZ
 Enhances gastric emptying, intestinal motility
 T max 1-2 hrs
 Crosses the BBB (extrapyramidal effects)> facial
muscle spasms, trismus, abn tongue movements)
 Agitation
 Hypotension, sinus tachycardia, SVT, sinus
brady>>>give over 1-2 min
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Cont.
Other D2 receptor antagonists
Neuroleptics:
 Antipsychotics with potent antiemetic property due to D2
antagonism
 Chlorpromazine, droperidol orally, parentrally, suppository
used for vomiting due to chemotherapy- induced emesis
but 5-HT3 antagonist replace them due to their side effects
 Side effects: extrapyramidal symptoms hypotension,
sedation, restlessness

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SEROTONIN ANTAGONISTS

 Potent antiemetics
 Even though 5 HT3 receptors are present in vomiting
centre & CTZ, the antiemetic action is restricted to emesis
caused by vagal stimulation.
 High first pass metabolism
 Excreted by liver & kidney
 No dose reduction in renal insufficiency but needed in
hepatic insufficiency
 Given once or twice daily – orally or intravenously.
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Cont.
 Ondansetron 32 mg / day
 Granisetron 10 mg / kg / day
 Dolasetron 1.8 mg / kg / day
Indications.
 Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy.
 Postoperative & postradiation nausea & vomiting
Adverse effects
 Excellent safety profile
 Headache & constipation
 All three drugs cause prolongation of QT interval, but more pronounced with
dolasetron.

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Cont.
H1 Antihistaminics
 Most effective drugs for motion sickness
 Drugs available
Meclizine, Cyclizine
Dimenhydrinate, Diphenydramine
Promethazine – Used in late pregnancy
Anticholinergics
 Scopolamine (hyoscine) – used as transdermal patch for motion sickness

Cannabinoids
 Dronabinol – used as adjuvant in chemotherapy induced vomiting.It is a
psychoactive substance
 Nabilone

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Cont.
Glucocorticoids
 Dexamethasone and methylprednisolone
 Highly effective in acute emesis alone or combined with
ondansetron.
 Used for vomiting by cytotoxic drugs.
Neurokinin1 (NK1) receptor antagonists
Aprepitant

 Is a substance P antagonists that acts by blocking neurokinin 1 receptors.

 Used in prevention of acute and delayed
chemotherapy-induced nausea and vomiting (CINV) and for prevention
of postoperative nausea and vomiting.

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In summary choice of Antiemetics

Motion sickness
 Hyoscine: For short Journey.
 Diphenhydramine: For Long Journey.
Vomiting with pregnancy (morning sickness)
avoid all drugs in the first trimester
 pyridoxine (b6)
 Promethazine ( late pregnancy).
Drug- induced vomiting (CTZ) uremia -gasteritis
 domperidone & metoclopramide
Vomiting due to cytotoxic drugs.
 Ondansetron
 D2- antagonists.
 Dexamethazone
 Nabilone .
Post operative vomiting
 Dopamine antagonists (Metoclopromide or Domperidone)
 Dexamethasone

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6.INFLAMMATORY BOWEL DISEASE

pathophysiology
 Ulcerative colitis and Crohn’s disease are chronic inflammatory conditions of

unknown aetiology.

 There is however increasing appreciation of the importance of alteration in mucosal

immune response to residence luminal bacteria.

 Both are characterized by episode of remission and relapse.

 Drug treatment is aimed at controlling inflammation and bringing about remission.

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Classification of drugs

1) Corticosteroids

2) Aminosalicylates

3) Azathioprine

4) Other immunosuppressants

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Corticosteroids

 Steroids are known to be of proven value in the treatment of acute relapses

of ulcerative colitis and Crohn’s disease.

 They may be given rectally, orally or intravenously depending on the extent

and severity of the condition.

 Steroids are of no value in ulcerative colitis in remission and should be

withdrawn once clinical remission is achieved.

 There is no good evidence that long-term steroids help in Crohn’s disease.

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Aminosalicylate

 These preparations are designed to deliver the drug at the distal gastrointestinal tract and include;
oMesalazine;

A controlled release preparation of 5-aminosalicylic acid (5-ASA)

oOsalazine;

2-molecules of 5-ASA linked by an azo bond that is split by colonic bacteria to release 5-ASA
within the colon.
oBasalazide;

A pro-drug of 5-ASA
oSulphasalazine;

Consists of 5-ASA linked to sulphapyridizine by an azo bond that is split in the colon by bacteria
azo-reductases.

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Cont.

Mechanism of Action
 5-ASA is thought to exert a local anti-inflammatory effect.

Adverse effects
 Blood dyscrasias

 Renal damage

 Watery diarrhoea ( Osalazine)

Clinical use
 These drugs are used in the management of mild to moderate ulcerative colitis and in the

maintenance of remission.

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Azathioprine

Mechanism of Action
 This is an immunosuppressive agent which may be useful in
controlling patients with severe inflammatory bowel disease
proving difficult to control on steroids and aminosalicylates.

Adverse effects
 Bone marrow suppression
 Reduction of immune response particularly to viral infection.
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Other immunosuppressants

 Include.
 Cyclosporin;
o Used in patients with severe ulcerative colitis that is not responding to parenteral corticosteroids

 Methotrexate;
o May induce remission in patients with Crohn’s disease that have either not been able to tolerate
or unresponsive to azathioprine
 Infliximab;
o A monoclonal antibody against tumour necrosis factor-α.
o It recently became available and is used in the treatment of severely active Crohn’s disease that
has not responded to corticosteroids, azathioprine or methotrexate.

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Drugs used in acid – peptic diseases

 Acid – peptic diseases include gastro – oesophageal

reflux, peptic ulcer (gastric and duodenal ulcer) and
stress related mucosal injury.
 In all these diseases mucosal erosions or ulcerations
occur when the damaging effects of aggressive
factors such as acid, pepsin, bile, NSAIDS and
helicobacter pyloric overwhelm the GIT mucosal
defence factors namely mucous and bicarbonate
secretion, prostaglandins, blood flow and the process
of restitution and regeneration after cellular injury
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Pathophysiology
 Prostaglandins produce mucous and HCO3 ions
which protect the tissue in the stomach by being
destroyed with hydrochloric acid and pepsin.
 Dyspepsia is the imbalance between the protective
mucosa and acid/pepsin.
 Peptic ulcer which is a defect beyond muscularis
mucosa will develop if there is an imbalance.
 NB -stress ulcers do not extent through the muscularis
mucosa.

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Cont.
 Two types of peptic ulcers
1) Duodenal ulcers which occur in the
first portion of the duodenum.
2) Gastric ulcers which usually occur
in the lesser curvature of the stomach.

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 Causes
 H. pylori - a spiral, urease producing flagellated
bacterium which lives between the mucus gel and
mucosa.
 Its production of urease, cytotoxins, proteases and other
compounds disturb the gel and increase tissue exposure
to acid and pepsin.
 H. pylori is seen in 95% of pts with duodenal ulcers and
80% of gastric ulcers.
 NB: only 10-20% of pts who are infected with H.
pylori will develop ulcers.

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Cont.
 NSAID’s - inhibit prostaglandins which in turn
increases tissue exposure to acid and pepsin.

 Zollinger-Ellison syndrome - is a gastrin secreting

tumor which creates such a high acid level it over
rides the protective gel.

 Cigarette smoking - inhibits bicarbonate ion

production and increases gastric emptying.

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Risk factors.
 Bile salts
 Emotional stress
 Type O blood
 Prolonged use of corticosteriods
 Caffeinated beverages
 NB: diet and alcohol are not predisposing
factors to the development of peptic
ulcers.

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Clinical Features
 Epigastric pain - (gnawing, aching or burning) .
 Gastric ulcers usually develop pain shortly before
eating.
 Duodenal ulcers usually develop pain 2-3 hours after
eating and awaken patients at night. Pain can be
relieved by food.
 Physical exam of uncomplicated PUD, there may be
a finding of epigastric tenderness.

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Classification of drugs

Antacids
1)

Drugs that inhibit acid secretion;

2)

H2-receptor antagonists

Proton pump inhibitors

Synthetic prostaglandin analogues

Drugs that do not directly inhibit gastric acid secretion;

3)

Chelate salts of bismuth

Sucralfate

Drug combinations used to eradicate H. pylori

4)

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ANTACIDS

 Antacids have been used for treatment of patients with

dyspepsia and acid- peptic disorders for many years.
 Antacids are weak bases that react with HCL to form a
salt and water.
 The Hydroxide is the most common base, the other
bases being trinscilicate, carbonate and bicarbonate.
 The efficiency and adverse effects of antacids depend
on the metallic ion with which the base is combined.
 The common ones are aluminium, magnesium and
sodium.
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Cont.

Mechanism of Action
These drugs are weak alkalis, so they partly neutralize free acid in the stomach.


They may also stimulate mucosal repair around ulcers, possibly by stimulating


local prostaglandin release.

Pharmacokinetics
Most antacids (principally salts of magnesium or aluminium) are not absorbed


from the alimentary tract to any appreciable extent. Some, such as sodium

bicarbonate are absorbed.

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Cont.

Adverse effects
Antacids that contain aluminium tend to cause constipation, whereas those


containing magnesium tend to cause diarrhoea.

Sodium bicarbonate in large doses may alter acid base status causing


metabolic alkalosis and may promote formation of phosphate-containing renal

calculi.

Absorbable antacids should not be administered for a very long time.



Antacids with high sodium content should be avoided in patients with impaired


cardiac function or chronic liver disease.

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Cont.

Drug interaction

Antacids may reduce absorption of a number of different drugs from the gut.


 These include;

oDigoxin

oPhenothiazines

oTetracyclines

oIron containing haematinics

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Cont.

Clinical use and dosage

 For symptomatic relief of patients with;

oPeptic ulcer disease

oGastro-oesophageal reflux disease

oNon-ulcer dyspepsia ‘indigestion’

 For acceleration of healing of peptic ulcers but must be given

frequently and in high doses.

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INDIVIDUAL ANTACIDS

ALUMINIUM HYDROXIDE
 Aluminium hydroxide (ALOH) reacts with HCL to form aluminium chloride in turn

reacts with intestinal secretions to produce insoluble salts mainly phosphate.

 The chloride is released and reabsorbed hence systemic acid- base balance is not

altered.
Precautions 
 Dementia

 patients in dialysis

 poor renal function

 encephalopathy

Contraindications
 Renal failure

 hypophosphotaemia -impaired absorption due to phosphate binding

 appendicitis

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Cont.
Indications
 hyperacidity

 diarrhoea

 hyperphosphotaemia

preparations
 liquid antacid

 tablets

dose
 As a phosphate binding agent in renal failure 2000mg – 10000mg daily in divided

doses
 As antacid – 500mg QID and at bedtime

Common names
 Alluminium hydroxide

 Magnessium Oxide + hydroxide

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DRUGS THAT I NHIBIT GASTRI CACID SECRETION

H2-RECEPTOR ANTAGONISTS;

Currently there are 4-competitive H2-receptor antagonists.



They act at the H2-receptor found mainly on the parietal cells



These include;


Cimetidine

Ranitidine

Nizatidine

Famotidine

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Mechanism of Action

By competing with histamine at the H2 –receptor.



Act by reducing acid secretion by the parietal cell,



especially at night and in

fasting state (Basal Acid Output).

They are less effective in reducing food-stimulated acid



secretion.
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Pharmacokinetics

They are well absorbed orally.

They have relatively short half-lives and are

excreted largely unchanged by the

kidneys.

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Cont.
 Four H2 antagonists are in clinical use:
cimetidine,ranitidine, famotidine, and nizatidine.
 All four agents are rapidly absorbed from the intestine.
 Cimetidine,ranitidine, and famotidine undergo first-
pass hepatic metabolism resulting in a bioavailability of
approximately 50%.
 Nizatidine has little first-pass metabolism.
 The serum half-lives of the four agents range from 1.1
to 4 hours

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Cont.
 H2 antagonists are cleared by a combination of
hepatic metabolism, glomerular filtration,and renal
tubular secretion.
 Dose reduction is required in patients with
moderate to severe renal (and possibly severe
hepatic) insufficiency.
 In the elderly, there is a decline of up to 50% in
drug clearance as well as a significant reduction in
volume of distribution.

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Pharmacodynamics
 The H2 antagonists exhibit competitive inhibition at the parietal
cell thereby suppressing basal and meal stimulated acid secretion
 They are highly selective and do not affect H1 or H3 receptors
 H2 antagonists reduce acid secretion stimulated by histamine as
well as by gastrin and cholinomimetic agents through two
mechanisms.
 First, histamine released from ECL(enterochromaffins) cells by
gastrin or vagal stimulation is blocked from binding to the parietal
cell H2 receptor.
 Second, direct stimulation of the parietal cell by gastrin or
acetylcholine has a diminished effect on acid secretion in the
presence of H2-receptor blockade.
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Cont.
 The potencies of the four H2-receptor antagonists
vary over a 50-fold range
 When given in usual prescription doses however,all
inhibit 60–70% of total 24-hour acid secretion.
 H2 antagonists are especially effective at inhibiting
nocturnal acid secretion (whichdepends largely on
histamine), but they have a modest impact on meal-
stimulated acid secretion (which is stimulated by
gastrin and acetylcholine as well as histamine).

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Clinical Uses
 H2-receptor antagonists continue to be prescribed
but proton pump inhibitors are steadily replacing
H2 antagonists for most clinical indications.
 Gastroesophageal Reflux Disease (GERD)
 Peptic Ulcer Disease
 Nonulcer Dyspepsia

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Adverse effects.
 H2 antagonists are extremely safe drugs. Adverse effects
occur in less than 3% of patients and include diarrhea,
headache, fatigue, myalgias, andconstipation.
 Some studies suggest that intravenous H2 antagonists (or
proton pump inhibitors) may increase the risk of
nosocomial pneumonia in critically ill patients.
 Mental status changes (confusion, hallucinations,agitation)
may occur with administration of intravenous H2
antagonists, especially in patients in the intensive care unit
who are elderly or who have renal or hepatic dysfunction.

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Cont.
 Cimetidine inhibits binding of dihydrotestosterone
to androgen receptors,inhibits metabolism of
estradiol, and increases serum prolactin levels.
 When used long-term or in high doses, it may
cause gynecomastia or impotence in men and
galactorrhea in women.

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Drug Interactions
 Cimetidine interferes with several important hepatic
cytochrome P450 drug metabolism pathways,
including those catalyzed by CYP1A2, CYP2C9,
CYP2D6, and CYP3A4
 Hence, the half-lives of drugs metabolized by these
pathways may be prolonged. Ranitidine binds 4–10
times less avidly than cimetidine to cytochrome P450.
 Negligible interaction occurs with nizatidine and
famotidine.

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Cont.
Cimetidine inhibits oxidative drug metabolism by the liver, thereby interacting with


many drugs especially;

o Phenytoin
o Theophylline
o Warfarin

These drugs have a narrow therapeutic index and Cimetidine will slow their


metabolism and may induce toxicity.

 Food interference reduce the pharmacological effect by stimulating the gastric
acid secretion through gastrin and vagal activity. This is due to the fact that

H2-receptor antagonists are less effective in reducing food-stimulated acid

secretion.

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Proton Pump Inhibitors
 Since their introduction in the late 1980s, these efficacious acid
inhibitory agents have assumed the major role for the treatment
of acid-peptic disorders.
 Proton pump inhibitors (PPIs) are now among the most widely
prescribed drugs worldwide due to their outstanding efficacy
and safety.
 Five proton pump inhibitors are available for clinical use:
omeprazole, lansoprazole,rabeprazole, pantoprazole, and
esomeprazole.
 All are substituted benzimidazoles that resemble H2 antagonists
in structure but have a completely different mechanism of action

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Clinical use

Treatment of duodenal & gastric ulcers

Treatment and prophylaxis of NSAID-induced ulcers

Combination with antibiotics in the eradication of H. pylori.

Treatment of Zollinger-Ellison syndrome.

Intravenous-treatment of bleeding peptic ulcers in

combination with endoscopic treatment.

Nmtc series MUTIBO

Mechanism of Action

These drugs are irreversible inhibitors of the proton pump on the parietal cell

membrane.

The proton pump is an enzyme (H+ / K+ - ATPase) that actively secretes H+ into

the gastric lumen. It is therefore responsible for the final step in the process of

acid secretion.

Blocking this enzyme causes a marked but temporary suppression of gastric acid

secretion to any stimulus, including food.

Nmtc series MUTIBO

Pharmacodynamics
 Proton pump inhibitors inhibit both fasting and
meal-stimulated secretion because they block the
final common pathway of acid secretion, the proton
pump.
 In standard doses, proton pump inhibitors inhibit
90–98% of 24-hour acid secretion

Nmtc series MUTIBO

Pharmacokinetics

These drugs are administered as delayed release preparations.

The bioavailability of omeprazole after the first dose is limited, but

increases with the repeated once-daily dosing to reach a plateau by around

the fifth day.

These drugs have short elimination half-lives of 1-2 hours but a prolonged

pharmacological effect and are converted in the liver to inactive

metabolites.

Nmtc series MUTIBO

Adverse effects

These are mild and infrequent and include;

o Diarrhoea
oSkin rash
oHeadache

o Blood dyscrasias
o Gynaecomastia
 No serious life threatening adverse effects have
been encountered
Nmtc series MUTIBO
Drug interaction

Omeprazole reduces the clearance and

prolongs the elimination of diazepam, phenytoin
and warfarin through inhibition of their hepatic
metabolism.
No clinically important drug interactions have
been reported with the other
proton-pump inhibitors
Nmtc series MUTIBO
Dose

oOmeprazole; 20mg daily

oLansoprazole; 30mg daily

oRabeprazole; 20mg daily

oPantoprazole; 40mg daily

oEsomeprazole; 20mg or 40mg daily.

90% of duodenal ulcers will heal within 4-weeks



In gastric ulcers, treatment recommendation is 8-weeks to achieve 90%



healing.

Nmtc series MUTIBO

Prostaglandin Analogs
 The human gastrointestinal mucosa synthesizes a number of
prostaglandins the primary ones are prostaglandins E and F.
 Misoprostol, a methyl analog of PGE1 , has been approved

for gastrointestinal conditions.

Pharmacokinetics
 Misoprostol has a short plasma half-life.
 It may act on the stomach both locally and systemically.
Nmtc series MUTIBO
Mechanism of action

Their mechanism of action is not fully understood.

They are thought to have ‘cytoprotection’ properties thereby protecting the

gastric and duodenal mucosa from damage.

PGE2 and PGI2 are the major prostaglandins synthesized by the gastric mucosa.
Misoprostol is thought to prevent gastric injury by cytoprotective effects that

include stimulation of mucin and bicarbonate secretion and increased mucosal

blood flow.
Since NSAIDs diminish prostaglandin formation by inhibiting

cyclooxygenase, synthetic prostaglandin analogs offer a logical approach to

reducing NSAID-induced mucosal damage .

Nmtc series MUTIBO

Cont.
Adverse effects

oDiarrhoea in up to 40% of patients; this is usually self limiting.

oAbortifacient potential; misoprostol and other prostaglandins should be

avoided in expectant mothers.

Clinical use and dosage

 Prevention of gastric mucosal damage; This is the main indication

especially in patients on NSAIDs

Dose; 200mg once daily

Nmtc series MUTIBO
Sucralfate
Chemistry & Pharmacokinetics
 Sucralfate is a salt of sucrose complexed to sulfated

aluminum hydroxide.
 In water or acidic solutions it forms a viscous,

tenacious paste that binds selectively to ulcers or

erosions for up to 6 hours.

Nmtc series MUTIBO

Mechanism of Action

The exact mechanism of ulcer healing by Sucralfate is unknown.

 Sucralfate consists of the octasulfate of sucrose to which Al(OH)3

has been added.

 In an acid environment (pH <4), sucralfate undergoes extensive

cross-linking to produce a viscous, sticky polymer that adheres to

epithelial cells and ulcer craters for up to 6 hours after a single dose.

This coats the ulcer base.

Nmtc series MUTIBO

Cont.
In addition to inhibiting hydrolysis of mucosal proteins by pepsin, sucralfate may

have additional cytoprotective effects, including stimulation of local production of

prostaglandins and epidermal growth factor.

It dose not directly affect acid secretion.

Like the bismuth salts, it suppresses H. pylori infection therefore reduces acid

hypersecretion stimulated by the infection.

It probably suppresses H. pylori by interfering with the ability of the organism to

bind to the mucosal epithelial cells.

Nmtc series MUTIBO

Clinical use and Dosage

Sucralfate is indicated for the treatment of duodenal ulcer and benign gastric


ulcer.

The usual dose is 1gm four-times daily or 2gm twice-daily.



Healing rates are comparable to those obtained with H2-receptor antagonists.



Sucralfate should not be used in patients with chronic renal failure because of


the risk of aluminium absorption and toxicity.

Nmtc series MUTIBO

Pharmacodynamics
 It is believed that the negatively charged sucrose
sulfate binds to positively charged proteins in the
base of ulcers or erosion,forming a physical barrier
that restricts further caustic damage and stimulates
mucosal prostaglandin and bicarbonate secretion.

Nmtc series MUTIBO

Cont.

Pharmacokinetics
 Sucralfate act locally; only small amounts of aluminium is absorbed.

Adverse effects
 Constipation

Drug interaction
 Sucralfate can reduce the absorption of a number of drugs, including

phenytoin and tetracyclines

Nmtc series MUTIBO

Bismuth Compounds
 Bismuth coats ulcers and erosions, creating a protective layer against acid and
pepsin.
 It may also stimulate prostaglandin, mucus, and bicarbonate secretion.

Clinical use
The main use of bismuth-containing compound is as part of a drug combination

against H. pylori.

This compound when combined with metronidazole and other antibiotic such as

tetracycline can eradicate infection in 80-90% of patients within 2-weeks.

Frequent doses however are necessary and compliance may be a problem

Nmtc series MUTIBO

Cont.

Mechanism of Action
The mechanisms by which bismuth salts heal ulcers are not fully understood.


They do not directly inhibit acid secretion, however they do suppress H. pylori


infection and thus reduce the hypersecretion of acid induced by the infection.

In addition they may form an insoluble protective layer over the ulcer base,


preventing further damage by acid-pepsin.

They may also stimulate local prostaglandin production.



Nmtc series MUTIBO

Cont.
Pharmacokinetics
A small quantity of bismuth is absorbed following oral administration.


Urine excretion of bismuth continues for over 2-weeks after stopping the course


of treatment.

Adverse effects
The liquid preparation should be avoided because of the unpleasant smell and


taste and the fact that it discolours the tongue.

The liquid or tablet preparation may colour the faeces black.



The long term consequence of bismuth absorption is unknown, therefore this



drug is not recommended for continuous or repeated administration.

Nmtc series MUTIBO

DRUG COMBINATIONS TO ERADICATE H. PYLORI.

Almost all patients with duodenal ulcer and many patients with gastric ulcer are


infected with H. pylori.

Successful eradication of this bacterium is associated with prolonged remission



from ulcer recurrence and possibly permanent cure.

Eradication of H. pylori usually requires both acid suppression and antibiotic treatment.


 If H. pylori positive then must be given antibiotics to prevent recurrence of ulcer. Usually

done with triple or quadruple treatment regimens.

Some antibiotics in regimens are metronidazole, tetracycline, amoxicillin, clarithromycin



plus a PPI

Nmtc series MUTIBO

Nmtc series MUTIBO