DRUGS ACTING ON GASTROINTESTINAL

TRACT
By Lalisa

21-Feb-24 1
 Major function of GIT include;
 Digestion and absorption of food,

In addition ,its endocrine system and neural network has an

integrative role

Major GIT disorders include PUD, constipation, nausea and

vomiting, etc…

Medicines for treating these gastrointestinal disorders

comprise some 8% of all prescriptions

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 Drugs used for constipation
• Constipation
– Normal stool frequency on a Western diet is at least 3
times a week
– Decreased frequency, difficulty in initiation or
passage, passage of firm or small-volume feces, or a
feeling of incomplete evacuation.
• Causes
– Lack of dietary fiber, drugs, hormonal disturbances,
neurogenic disorders, and systemic illnesses.
– In most cases no specific cause is found.
 Drugs used for constipation;
Laxatives or Purgatives or Cathartics)
 LAXATIVES : Used in the treatment of constipation,
poison removal, preparation of bowel for surgery
and for removal of parasites after anthelementics
• Laxatives cause the evacuation of formed fecal
material from the rectum. while
• Cathartics cause evacuation of unformed, usually
watery fecal material from the entire colon.
• These drugs promote defection by different mechanism
and cause evacuation of fluid feces.
• Can soften the stool, increase stool volume and facilitate
evacuation from the rectum.
• Since constipation being a common problem, these drugs
are widely used.
 classified of Laxatives
 basis of their MOA into:-
1. Bulk – forming laxatives
2. Osmotic laxatives (saline purgatives)
3. Emollient laxatives (stool softeners)
4. Stimulant or irritant laxatives(Cathartics )
 GIT cont’d
1. BULK FORMING LAXATIVES
• MOA:- Indigestible, hydrophilic Colloids that absorb
water, forming a bulky, emollient gel that distends colon
& promotes peristalsis. which aids evacuation of feaces.
• Natural: psylium, methylcellulose
• Synthetic fiber: polycarbophil
• Bacterial digestion of the fiber in colon bloating and
flatus
– NB Adequate fluid intake must be maintained to avoid intestinal
obstruction.

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 GIT cont’d
2. STOOL SOFTNERS/SURFACTANT AGENTS/Emollient laxatives
• Change surface tension of fluids in the bowel - this has an emulsifying effect on
feces, making them retain more water and hence softer - easier to pass out
• Glycerine suppositories.
• Docusate oral or enema
• Liquid paraffin
– Oily, liquid substance
– Not used anymore
• Absorbs the fat soluble vitamins in the gut, and therefore you
loose your fat soluble vitamins

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3. OSMOTIC LAXATIVES GIT cont’d
• They act by maintaining a volume of fluid in the bowel by osmosis,
being hypertonic. Produce watery stool
• Soluble but not absorbable, resulting in increased stool liquidity
• treatment/prevention of acute/chronic constipation, respectively
• Nonabsorbable sugar: sorbitol & lactulose(synthetic disaccteride,
galactose – fructose)
♦ metabolized by colonic bacteria → severe flatus & cramp
• Nonabsorbable salt: magnesium oxide/ milk of magnesia
♦ MgSO4, Mg(OH)2, Na2SO4,
♦ hypermagnesemia in renal insufficient patient if used for
prolonged period
• High dose of osmotically active agents produce purgation within 1-
3hs
• Balanced polyethylene glycol: lavage solution containing PEG are
used for complete colonic cleansing prior to GI endoscopy
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4. STIMULANT LAXATIVES/ CATHARTICS GIT cont’d

• Direct stimulation of the enteric nervous system and colonic fluid

and electrolyte secretion

• Long term: dependency & destruction of myenteric plexus; atony

• Useful in neurologically impaired and in bed bound patients in

long term care facility

• Anthraquinone derivatives
-Aloe, senna & cascara: bowel movement in 6-8hs after p.o.
- cause brown pigmentation of colon “melanosis coli”

• Caster oil: hydrolysed in small intestine to ricinoleic acid-irritant

that stimulates motility.
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• Clinical Application of Laxative
– For severe constipations
– Adjuvant with Anthelmintic ( Niclosimide )
– For Pre surgery especially Castor oil
– For Hemorrhoid – rectal vein dilation
– For geriatric patients
– For removal of Ingested poison
• All laxatives are contra indicated to
– Pregnant women
– Hypertensive patient
– Children less than 3 years except Glycerin
 Antidiarrhoeals
• In diarrhea there is a frequent passing of liquidy
stool (feces) with or without mucous and blood.
• Diarrhea can be caused by enteric infections,
inflammations, food toxins, malnutrition, and
drugs (like reserpine, guanethidine, broad
spectrum antibiotics, synthetic PGs,
metoclopramide and purgatives).
• Specific chemotherapy will be required for
infective diarrhea, while
• non – specific measure is taken for non – specific
diarrhea.
 GIT cont’d
TREATMENT OF DIARRHOEAS
• Therapeutic measures:
– treatment of fluid depletion, shock, and acidosis
– maintenance of nutrition
– drug therapy
• Rehydration
– Intravenous rehydration in severe fluid loss [10% body
weight]
– Oral rehydration if the fluid loss is mild
• Antimicrobials are of no use in diarrhea due to non infective
causes
• Antimicrobials are useful only in severe disease
• Travellers diarrhea:mostly due to C.pylori, virus
[cotrimoxazole, norfloxacin, doxycycline, erythromycin]

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 Non – specific anti-diarrhoeal measures are:
1. re-hydration therapy
• oral re-hydration therapy
– administering glucose and electrolyte solutions orally.
– replace fluid and electrolyte misbalance in patients with
watery diarrhea
– Oral rehydration salts (ORS) are recommended by WHO
– ORS – formulation consists of NaCl (3.5g), KCl (1.5g),
sodium citrate (2.9g) and glucose (20g) to be dissolved in
one litter of water and used with in 24hr after
reconstitution.
• IV re-hydration therapy
– Used when oral rehydration is not adequate or the patient
is severely dehydrated
– RL, NaCl, D5W;
 Non Specific
2. Adsorbents.
– Kaolin, pectin and chalk were used because of their ability to
adsorb toxins. Their antidiarrheal effects are small and hence
they are rarely used.
– Bismuth subsalicylate has been proposed to exert local anti –
inflammatory effect (because of salicylate), apart from adsorbent
action.
3. Anti-motility agents
– drugs reduce peristalsis & increase reabsorption of water by
delaying intestinal transit time. increase tone of rectal sphincter.
– No narcotics Eg. - Diphenoxylate and loperamide,
– Narcotics (Morphine & Codeine was used earlier,
– The antimotility effect of all these drugs is due to inhibition of
Ach release through presynaptic opioid receptors in the enteric
plexus.
• N.B. These agents are contraindicated in infants and
children because of danger of induction of paralytic ileus.
 Emetics and antiemetics
A. Emetics
– Emesis (vomiting) is a complex physiological
process that ultimately results in the forceful
expulsion of the contents of the stomach.
• Nausea vs. Vomiting
– Nausea: an awareness of discomfort that may or
may not proceed vomiting
– decreased gastric tone and peristalsis
– Vomiting: is the ejection or expulsion of gastric
contents through the mouth, often requiring a
forceful event.
 Emetics,…
• Causes of Nausea & Vomiting
– a/ Drug induced emesis: chemotherapy , Opioids,
Cholinomimetics, Cardiac, glycosides, Emetine, morphine,
L-Dopa, Bromocriptinen, High doses of estrogen
– b. Bacterial & viral toxin.
– c. During early pregnancy
– d. CNS related: Motion sickness , migraine
• Emetics: agents that induce reflex vomiting.
– The drugs that produce vomiting are called emetics,
– main therapeutic uses are to treat swallowed poisons.
– Ipecac : a mixture of alkaloids: ipecacuanha plant.
– The most commonly used drugs for this purpose are Ipecac
syrup and apomorphine.
– Sometimes drugs like mustard (1 tea spoonful in water),
hypertonic sodium or copper sulphate (300mg along with
water) are used.
 GIT cont’d

• Drugs which causes nausea and vomiting

– Apomorphine (and Bromocriptine)
· Acts on the D2 receptor in the CTZ to
cause vomiting
– Cisplatin
· causes release of serotonin in the gut

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 GIT cont’d
B. ANTI EMETICS
• Main area responsible for vomiting is the vomiting center
• It receives input from many areas:
– Chemoreceptor trigger zone -picks up circulating chemical
in the blood
– Vestibular apparatus
– vagal afferents from the gut
– Direct input from gut (reflex)
• Receptors involved in the emetic response
· On the CTZ: 5HT3, D2
· On the vagal afferents: 5HT3
· In the vomiting center: Muscarinic, H1 receptors

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Anti emetics
1. Dopamine receptor antagonists: Eg, Phenothiazines:
Chlorpromazine, promethazine, metoclopramide, domperidone
– These drugs block D2 receptors in CTZ.
– Metoclopramide and domperidone also act peripherally by stimulating
gut motility (prokinetic action)
2. Antimuscarinic agents: e.g. Hyoscine (but not atropine)
– inhibit muscarinic receptors centrally (CTZ and vomiting center) and
peripherally on stomach – duodenum
– Dosage forms. Tablets, injections and transdermal patches
3. Antihistaminic agents
– Eg. dimenhydrinate, diphenhydramine, doxylamine, cyclizine,
meclizine.
– They antagonize H1 – receptors and are specifically useful in motion
sickness.
4. 5-HT3 receptor antagonists. E.g. Ondansetron
– These drugs reduce CTZ dopamine activity by blocking the 5 – HT
hetroreceptors modulating dopamine synthesis and release.
5. Others E.g. - synthetic Cannabinoid (nabilone) and glucocorticoids.
 GIT cont’d
ANTI EMETIC DRUGS CHOICE

1. Motion Sickness
 Promethazine
• H1 antagonist, antimuscarinic actions
• Used as a sedative in children
• Effective at preventing motion sickness (since the vestibular
afferents input in the vomiting center which has H1 and
Muscarinic receptors
• Not used for the driver [drowsy]

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Hyoscine (scopolamine)-anti-cholinergic.
Available as oral, subcutaneous, and transdermal

Can be used as a patch behind the ear

suppresses nerve traffic in neuronal pathway from vestibular

apparatus of inner ear to vomiting center

 common side effects are dry mouth, blurred vision, drowsiness

more severe side effects include urinary retention,

constipation, and disorientation

21-Feb-24 22
 GIT cont’d
2. CTZ Mediated Vomiting

• Prochlorperazine
– phenothiazine, D2 antagonist
– Has no antipsychotic effects
– Useful as an antiemetic as well as for dizziness
– Has minor anticholinergic effects (it may work in motion
sickness, however, the above drugs are preferred)
– blocks D2 receptors elsewhere (e.g. substantia
nigra)cause extrapyramidal effects
– Chlorpromazine can also be used as an antiemetic,
although it tends to be very sedative

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 GIT cont’d
• Metoclopromide
– D2 antagonist, weak 5HT3 antagonist
– Increases motility of the gut in the upper regions
– Useful because when someone is nauseous, there
is often gastric stasis
– helps absorption of drugs as it stimulates gastric
emptying

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 GIT cont’d

3. Vomiting associated with vagal afferents (gut disorders,

heart, gut irritants - all stimulate the 5HT3 receptor on
the vagal afferents)
• Ondansetron
– Most effective drug available for suppressing nausea and vomiting caused
by cisplatin and other highly emetogenic anticancer drugs.
– 5HT3 antagonist
– Effective in patients receiving cancer chemotherapy (radiation or cisplatin
– stimulate the release of serotonin in the gut)
– Can also be used for CTZ nausea

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 Clinical use of antiemitics
– Nausea and Vomiting

– For motion sickness- Dimenhydranate

– Morning sickness- Promethazine or Metoclopromide

(Plasil )

– Infection and chemo irritant – Metoclopromide (Plasil )

– Hyper emesis - Gravis medris is disease that occur in

pregnant time.
 GIT cont’d
DRUGS FOR PEPTIC ULCER

• Ulcer: Breakdown of the protective mucosal

layer
– Common sites: Duodenum & Stomach
– Pain is due to:
· Acid acting on the erosion
· Increase in the motility of the gut, causing increased
intramural tension (antimotility agents decrease the pain)

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Causes of peptic ulcer GIT cont’d
• Imbalance b/n protective and aggressive factors
• Defensive factors; mucus, bicarbonate, sub mucosal
blood flow and prostaglandins.
• Aggressive factors;
 H. pylori
 Excess HCL or pepsin secretion
 Stress
 NSAIDs
 Alcohol, smoking, spicy foods etc
• PUD = Aggressive factor – defensive factor
• Treatment strategy;
 decrease aggressive factors or increase defensive factors

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21-Feb-24
Mechanisms of HCL secretion and Major Drug targets for PUD 30
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 PUD treatment
• Therapeutic goal
– alleviate Symptoms,
– Promote healing,
– Prevent complications (hemorrhage, perforation,
obstruction) and Prevent recurrences
• Drug groups in PUD
• Proton pump inhibitors
• Histamine H2-receptor antagonists
• Antacids
• Gastric protectants
 Antacids
o Weak bases that neutralize acid
o Also inhibit formation of pepsin (As pepsinogen
converted to pepsin at acidic pH)
o Present day antacids :
Aluminium Hydroxide
Magnesium Hydroxide
o OTC drug for symptomatic relief of dyspepsia

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 Duration of action :
o 30 min when taken in empty stomach
o 2 hrs when taken after a meal
o Side effects :
Al3+ antacids – constipation (As they relax gastric
smooth muscle & delay gastric emptying)
Mg2+ antacids – Osmotic diarrhoea .
In renal failure Al3+ antacid – Aluminium toxicity
&
Encephalopathy

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 Drug interaction of antacids;
oAdsorb drugs and form insoluble complexes that are not absorbed .

Clinical importance :
o Interactions can be avoided by taking antacids 2 hrs before or after ingestion
of other drugs .
o rational to combine aluminium hydroxide and magnesium hydroxide in
antacid preparations
 Combination provides a relatively fast and sustained
neutralising capacity .
(Magnesium Hydroxide – Rapidly acting
Aluminium Hydroxide - Slowly acting )
 Combination preserves normal bowel function.
(Aluminium Hydroxide – constipation
Magnesium hydroxide – diarrhoea )

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Histamine H2 Receptor Antagonist
Reversible competitive inhibitors of H2 receptor
Highly selective, No action on H1 or H3 receptors
Very effective in inhibiting nocturnal acid secretion ( as
it depends largely on Histamine )
Modest impact on meal stimulated acid secretion (As it
depends on gastrin, acetyl choline and histamine)

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 comparison of the different H2 receptor antagonists
Cimetidine Ranitidine Famotidine Nizatidine
Bioavailability 80 50 40 >90

Relative Potency 1 5 -10 32 5 -10

Half life (hrs) 1.5 - 2.3 1.6 - 2.4 2.5 - 4 1.1 -1.6

Duration (hrs) 6 8 12 8

Inhibition of CYP 450 1 0.1 0 0

Dose mg(bd) 400 150 20 150

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 H2 Blockers–Side effects & Interactions
 Extremely safe drugs
 Cimetidine inhibits CYP450 & increases conc. of Warfarin,
Theophylline, Phenytoin, Ethanol
 CNS- Mental status change (confusion, agitation, hallucination)
in i.v. H2 antagonist
 Endocrine effect: cimetidine inhibits binding of
dihydrotestosterone, inhibits metabolism of estradiol, increase
prolactin [gynecomasia, impotence in male; galactorrhea]
 Cross the placenta &secreted into breast milk

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 Drug interaction:
 cimetidine interfere hepatic cytochrome P450 drug
metabolism pathways
 warfarin,
 theophylline,
phenytoin, lidocaine, quinidine, propranolol, TCAs,
several benzodiazepines,
CCBs, sulfonylureas, metronidazole, and ethanol

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 Proton Pump Inhibitors (PPIs)
 Most effective drugs in antiulcer therapy
 Irreversible inhibitor of H+ K+ ATPase
 Prodrugs requiring activation in acid environment
 Weakly basic drugs & so accumulate in canaliculi of parietal cell
 Activated in canaliculi & binds covalently to extracellular
domain of H+ K+ ATPase
 Acid secretion resumes only after synthesis of new molecules
 Since they require acid for activation - given 1 hr before meals
 Other acid suppressing agents not coadministered

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 Examples of PPIs and their doses;
Omeprazole 20 mg o.d.
Esomeprazole 20 - 40 mg o.d.
Lansoprazole 30 mg o.d.
Pantoprazole 40 mg o.d.
Rabeprazole 20 mg o.d.

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 PPI Side Effects;
 Extremely safe drugs
 Inhibit CYP 450 & hence metabolsim of warfarin,
phenytoin, etc
 Pantoprazole & Rabeprazole have no significant
interactions

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 Mucosal Protective Agents
Sucralfate
Misoprostol
Colloidal Bismuth compounds

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 Sucralfate;
Salt of sucrose complexed to sulfated aluminium
hydroxide
In acidic pH polymerises to viscous gel that adheres to
ulcer crater
Taken on empty stomach 1 hr. before meals
Concurrent antacids, H2 antagonist avoided
( as it needs acid for activation )

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 Misoprostol;
PGE2 analogue
Modest acid inhibition
Stimulate mucus & bicarbonate secretion
Enhance mucusal blood flow
Approved for prevention of NSAID induced ulcer
Diarrhoea & cramping abd. pain – 20 %
Not so popular as P.P.I are more effective &
better tolerated

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 PGE2 protects the stomach in a number of ways:

 limits the amount of gastric acid being released

It increases mucous secretion

It increases blood flow to the stomach

· Side effects:
· Colic and diarrhoea
· Dangerous in pregnancy  PGE2 contracts the uterus

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 Colloidal Bismuth Compounds
Coats ulcer, stimulates mucus & bicarbonate secretion
Direct antimicrobial activity against H.pylori
May cause blackening of stools & tongue
Not used for long periods – bismuth toxicity

Available compounds :
Bismuth subsalicylate – in USA
Bismuth sobcitrate – in Europe
Bismuth dinitrate
21-Feb-24 47
 TREATMENT OF PUD CAUSED by H PYLORI

H pylori is a gram negative bacilli that colonize itself in acidic environment of

stomach.

 Now generally considered to be a major cause of chronic gastritis.

 Eradication of H. pylori infection promotes rapid & long-term healing of ulcers.

 If a patient with PUD is positive for H Pylori, then it can be eradicated with a
1- or 2-week regimen of 'triple therapy'.

Triple theraoy comprises a PPI in combination with antibiotics amoxicillin or

metronidazole and clarithromycin.

In case of the 2-week regimen, bismuth-containing preparations are added.

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 Summary of drugs for PUD
1. PUD only
First Line
Ranitidine, 150 mg P.O. BID OR 300 mg at bedtime for 4 – 6 weeks.
Alternatives
Cimetidine, 400 mg P.O. BID, with breakfast and at night, OR 800 mg
at night for 4 - 6 weeks.
OR
Famotidine, 40 mg, P.O. at night for 4 – 6 weeks.
OR
Omeprazole, 20 mg P.O. QD for 4 weeks (DU) or 8 weeks.

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 2. PUD associated with H. pylori
First Line
Amoxicillin, 1g, P.O. BID

PLUS
Clarithromycin, 500mg P.O. BID

PLUS
Omeprazole, 20mg P.O. BID (OR 40mg QD), all for 7 - 14 days.

Alternative
Clarithromycin, 500mg P.O. BID
PLUS
Metronidazole, 500mg, P.O. BID

PLUS
Omeprazole, 20mg P.O. BID OR 40mg QD for 7 - 14 days .

21-Feb-24 51
 PUD Case
• 40 years old female patient present with chief compliant of
NV& Epigastric pain of three weeks duration she reported
brown color loose stool she has documented penicillin allergy
her P/E shows epigastric tenderness & v/s T 37.2OC, BP
128/80mmgh, p76bpm. Lab finding are HGB of 14mg/dl, hct41%
and fecal reagent test positive for Pylori and others within
normal ranges. The attending physician decide to put on
pylorus eradication therapy.
 Case
• What triple therapy is appropriate for this
patient.
A. Omeprazole 20mg BID + claritromycine500mg
BID + metronidazole 500mg BID for 14day
B. Omeprazole 20mg BID + claritromycine500mg
BID + Amoxicillin 1000mg BID for 14day
C. Omeprazole 20mg BID + Amoxicillin 1000mg BID
+ tetracycline 500mg BID for 14day
D. Omeprazole 20mg BID + Amoxicillin 1000mg BID
+ metronidazole 500mg BID for 14day