DRUGS USED IN

GASTROINTESTINAL TRACT
KILEMI MITHEU
Daystar
Gastrointestinal tract-Introduction
❖ Comprises of several organs with distinct
functions-esophagus, stomach, small
intestines, colon, pancreas, gallbladder, liver
❖ Two Main functions are;
➢ Assimilation of nutrients
➢ Elimination of waste
 Classification of GIT drugs
1. Drugs used in Acid Peptic disease
2. Drugs stimulating motility
3. Laxatives
4. Anti emetics
5. Inflammatory bowel disease(IBD) drugs
6. Anti-diarrhoeal
7. Pancreatic supplements
8. Bile acid therapy for gallstones
 Acid peptic disease
• Acid-peptic diseases include gastroesophageal
reflux, peptic ulcer (gastric and duodenal), and
stress-related mucosal injury.
• In all these conditions, mucosal erosions or
ulceration arise when the caustic effects of
aggressive factors (acid, pepsin, bile) overwhelm
the defensive factors of the gastrointestinal
mucosa (mucus and bicarbonate secretion,
prostaglandins, blood flow, and the processes of
restitution and regeneration after cellular injury).
• Over 90% of peptic ulcers are caused by
infection with the bacterium Helicobacter
pylori or by use of non steroidal anti
inflammatory drugs (NSAIDs).
 Drugs used in acid-peptic disease
Divided into 2 classes
❖Agents that reduce intra-gastric acidity
1. Antacids
2. H2 receptor antagonists
3. Proton pump inhibitors
4. Anti cholinergic/anti muscuranic agents
❖Agents that promote mucosal defense
1. Sucralfate
2. Prostaglandin analogs
3. Bismuth compounds
 Acid peptic disease
• Enhanced HCl secretion is the primary factor in
the pathophysiology and pain of acid peptic
diseases.
• Treatment can be accomplished using drugs that;
➢Decrease gastric acid secretion
➢Neutralize the acid after it has been released
➢Providing agents that protect the gastric mucosa from
damage.
➢Use of antibiotics.
 PHYSIOLOGY OF ACID SECRETION
• The gastric epithelium secretes several
substances-hydrochloric acid (HCL) from the
parietal cells, digestive enzymes from the
peptic cells, and mucus from the mucus-
secreting cells.
• The acid and the enzymes convert food into a
thick semi-liquid paste called chyme, while
mucus protects the stomach from its own
corrosive secretions
 …..cntd
• The parietal cells contains receptors for
gastrin (CCK-B), histamine (H2), and
acetylcholine (muscarinic, M3).
• When acetylcholine or gastrin bind to the
parietal cell receptors, they cause an increase
in cytosolic calcium, which in turn stimulates
protein kinases that stimulate acid secretion
from a H+/K+-ATPase (the proton pump) on
the canalicular surface.
 ....cntd
• Peptic ulceration results from the breach in
the mucosal lining the alimentary tract caused
by acid and enzyme attack.
• Unprotected mucosa rapidly undergoes
autodigestion leading to a range of damage
Inflammation or Gastritis, necrosis,
haemorrage, and perforation as the erosion
deepens.
Regulation of HCl Secretion
 (1).AGENTS THAT REDUCE
INTRAGASTRIC ACIDITY
A) ANTACIDS
• Antacids have been used for centuries in
the treatment of patients with dyspepsia
and acid-peptic disorders.
• Antacids largely have been replaced by
more effective and convenient drugs.
 ANTACIDS
• However, antacids continue to be used
commonly by patients as nonprescription
remedies for the treatment of intermittent
heartburn and dyspepsia.
• Antacids are weak bases that react with
gastric hydrochloric acid to form a salt and
water.
• Their principal mechanism of action is
Reduction of intragastric acidity
 (I) Sodium bicarbonate
Example: baking soda, Alka Seltzer
• MOA-reacts rapidly with hydrochloric acid (HCl)
to produce carbon dioxide and sodium chloride,
Na cl & CO2
• Formation of carbon dioxide results in gastric
distention and belching.
• ADR-May cause metabolic alkalosis when given in
high doses to patients with renal insufficiency.
Sodium chloride absorption may exacerbate fluid
retention in patients with heart failure,
hypertension, and renal insufficiency.
 (II) Calcium carbonate
Example: Tums, Os-Cal
MOA-reacts with HCl to form carbon
dioxide and calcium chloride (CaCl2).
ADR-calcium carbonate may cause
belching or metabolic alkalosis.
 ….cntd
NOTE :Excessive doses of either sodium
bicarbonate or calcium carbonate with
calcium-containing dairy products can
lead to hypercalcemia, renal
insufficiency, and metabolic alkalosis
(milk-alkali syndrome).
 (III) Magnesium hydroxide
(VI) Aluminium hydroxide
MOA-react slowly with HCl forming chlorides and
water.
No gas is generated= no belching.
• Are more efficient in neutralizing the acid hence
no metabolic alkalosis.
• Unabsorbed mg salts cause osmotic diarrhoea,
AL salts cause constipation thus commonly co-
administered in proprietary formulations.
• Mg & AL-excreted through the kidneys hence
contraindicated for long term use in pts with
renal insufficiency.
 Antacids ……..Drug interactions
❖All antacids may affect the absorption of other
medications by binding the drug (reducing its
absorption) or by increasing intragastric pH so
that the drug’s dissolution or solubility
(especially weakly basic or acidic drugs) is
altered.
❖ Antacids should not be given within 2 hours
of doses of tetracyclines, fluoroquinolones,
itraconazole, and iron.
 B) H2-Receptor antagonists
H2 antagonists in clinical use:
• Cimetidine
• Ranitidine
• Famotidine
• Nizatidine.
 H2-RECEPTOR ANTAGONISTS
• The 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.
• Half-lives of the four agents range from 1.1 to
4 hrs.
 …..ctnd
• 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 severe hepatic
insufficiency.
 Pharmacodynamics
• Competitively inhibit H2 receptors at parietal
cells suppressing both basal and meal
stimulated acid secretion in a linear and dose
dependent fashion.
• The volume of both gastric acid and pepsin is
decreased.
• Are highly selective and have no effect on H1
and H3
 MOA
• H2 antagonists reduce acid secretion stimulated
by histamine as well as by gastrin and
cholinomimetic agents through two mechanisms.
i. Histamine released from ECL cells by gastrin or
vagal stimulation is blocked from binding to the
parietal cell H2 receptor.
ii. Direct stimulation of the parietal cell by gastrin
or acetylcholine has a diminished effect on acid
secretion in the presence of H2-receptor
blockade.
 ..…Cont
• Agents are effective in inhibiting nocturnal
acid secretion which is largely dependent on
histamine.
• They have a modest impact on meal
stimulated acid secretion ( stimulated by
gastrin , Ach & histamine)
• Serum half lives is 1.1-4hrs
 H2-Receptor antagonists
indications
1. Gastroesophageal reflux disease
(GERD).
2. Peptic ulcer disease
3. Non ulcer dyspepsia
4. Prevention of bleeding from stress-
related gastritis
 Adverse Effects
• H2 antagonists are extremely safe drugs.
• Adverse effects occur in less than 3% of patients
and include diarrhea, headache, fatigue, myalgia,
and constipation.
• Mental status changes ie confusion,
hallucinations, agitation may occur with
administration of intravenous H2 antagonists,
especially inpatients in ICU who are elderly or
who have renal or hepatic dysfunction-
Cimetidine.
 Adverse Effects
• 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.
 Adverse Effects
• H2 antagonists cross the placenta. Therefore,
they should not be administered to pregnant
women unless absolutely necessary.
• The H2 antagonists are secreted into breast
milk and may affect nursing infants.
• Rapid intravenous infusion may cause
bradycardia and hypotension through
blockade of cardiac H2 receptors; intravenous
injections should be given over 30 minutes.
 Drug Interactions
• Cimetidine interferes with hepatic cytochrome
P450 drug metabolism pathways, including those
catalyzed by CYP1A2,CYP2C9, CYP2D6, and
CYP3A4.
• The half-lives of drugs metabolized by these
pathways example benzodiazepines,
theophylline, and warfarin may be prolonged-
dosage require adjustment.
• Ranitidine binds 4–10 times less than cimetidine
to cytochrome P450.
• Negligible interaction occurs with nizatidine and
famotidine.
 Drug Interactions….
• H2 antagonists compete with creatinine
and certain drugs example, procainamide
for renal tubular secretion.
• Cimetidine, Ranitidine, and nizatidine
inhibit gastric first-pass metabolism of
ethanol, especially in women. Increased
bioavailability of ethanol could lead to
increased blood ethanol levels.
 C) PROTON-PUMP INHIBITORS (PPIs)
• Most widely used agents due to their
outstanding efficacy and safety.
• All are substituted benzimidazoles resembling
H2 receptor antagonists.
Include:
• Esomeprazole
• Pantoprazole
• Lansoprazole
• Rabeprazole
• Omeprazole
• Dexlansoprazole
 PPIs
• Proton pump inhibitors (PPIs) are prodrugs that
require activation in an acid environment.
• After absorption into the systemic circulation,
the prodrug diffuses into the parietal cells of the
stomach and accumulates in the acidic secretory
canaliculi.
• PPIs are activated by proton-catalyzed formation
of a tetracyclic sulfenamide, trapping the drug so
that it cannot diffuse back across the canalicular
membrane.
 PPIs
• The activated form then binds covalently with
sulfhydryl groups of cysteine in the H+, K+-
ATPase, irreversibly inactivating the pump
molecule.
• Acid secretion resumes only after new pump
molecules are synthesized and inserted into the
luminal membrane, providing a prolonged (up to
24- to 48-hour) suppression of acid secretion,
despite the much shorter plasma half-lives (0.5-2
hours) of the parent compounds.
 PPIs
• All are available as oral preparations but
esomeprazole and pantoprazole as IV drugs also.
• Are lipophilic weak bases given as inactive
prodrugs.
• Oral products are formulated as delayed release
acid-resistant, enteric-coated capsules or tablets to
protect destruction in gastric lumen.
• Diffuse to acidified compartment (parietal cell
canaliculus), become protonated & conc. >1000x.
• Converts to reactive thiophilic sulfenamide cation
which form irreversible disulfide covalent bond
with H+/K+ ATPase inactivating it.
 PPIs-PK
• Food decreases their bioavailability by 50%.
• T1/2 of 1.5hrs though acid inhibition last
24hrs.
• They undergo rapid 1st pass and systemic
hepatic metabolism -dose adjustment in
severe liver impairment.
• Administer 1hr before meal-peak serum conc.
coincide with maximum proton pump
secretion.
• Have negligible renal clearance.
 PPIs
• 3-4days required before full acid inhibiting
potential is achieved.
• IV formulation as continuous infusion
/repeated bolus 1st 24-48hrs for max.
inhibition.
• PPIs are ideal drugs from a pharmacokinetic
perspective:
❖Have short serum t1/2
❖Concentrated & activated near their site of action
❖Have long duration of action
 PPIs-Pharmacodynamics
• PPIs inhibit both fasting & meal stimulated
acid by blocking (H+/K+ ATPase) pump.

• Std doses inhibit 90-98% of 24hr acid

secretion.
• Dexlansoprazole has a delayed release
preparation hence longer Tmax. & greater
AUC than rest.
 PPIs-Indications
• GERD
• Peptic ulcer disease
➢More rapid symptom relief & fast ulcer
healing than H2 antagonists.
➢>90% duodenal ulcers heal in 4wks, &
>90% gastric ulcers in 6wks.
 PPIs-Indication
a. H. Pylori ulcers- PPIs have direct
antimicrobial activity & raise intra-gastric PH.
b. NSAID associated ulcers
c. Prevention of re bleeding from peptic ulcers
• Non ulcer dyspepsia
• Prevention of stress related mucosal bleeding
• Gastrinoma & other hyper secretory
conditions
 PPIs-Adverse effects
• Are extremely safe
• Diarrhoea, headache &abdominal pain
reported in 1-5% of patients .
• Subnormal levels of Vit B12
• Osteoporosis –osteoclast/ca absorption
inhibited
• Life threatening hypomagnesemia with sec.
hypocalcemia.
 ….cntd
• Increased risk of enteric infections- 2-3x
risk of hosp/ community acquired c.
difficle infections, risk for enteric
infections shigella, salmonella, E.coli,
Campylobacter.
• Long term -small benign gastric fundic-
gland polyps.
 PPIs-Drug Interactions
• Alteration in absorption of other drugs due to
decreased acid production;
o Itraconazole
o Ketoconazole
o Digoxin
o Atazanavir
 PPIs-Drug Interactions
• Omeprazole may inhibit metabolism of
warfarin, diazepam & phenytoin.
• Esomeprazole decreases the metabolism of
diazepam.
• Lansomeprazole enhances clearance of
theophyline.
• Rabeprazole and pantoprazole have no
significant drug interactions
 D) Anticholinergic agents
• Pirenzipine-is an M1 selective muscarinic
antagonist.
• Inhibits gastric acid secretion at doses that don’t
affect other systems.
• It is used in combination with H2 receptor
antagonists.
• Pirenzipine & telenzipine are under investigation .
• Anti muscarinics now rarely used in PUD; provide
mild relief in travelers diarrhoea & self limited
conditions of hypermotility.
 Agents that promote mucosal
defense
a). Sucralfate
• A salt of sucrose complexed with sulfated
aluminium hydroxide with limited solubility.
• Forms a viscous paste in water or acidic solutions
that binds selectively to ulcers or erosions for up
to 6hrs.
• Less than 3% of intact drug absorbed, rest
excreted in faeces.
• Breaks down to sucrose sulfate(strongly –ve) &
aluminium salt.
 Pharmacodynamics
Mechanism of action – not clear;
• Sucrose sulfate -ve charged bind to +ve charged
proteins at ulcer base to form a physical barrier that
restrict further caustic damage.
• Binds to and inactivates pepsin & bile acids.
• Stimulates mucosal prostaglandin and bicarbonate
secretion.
Indications-Critically ill (ICU) to prevent upper GIT
bleeding
• Prevention of stress related bleeding
-Administer at least 1 hr before meals.
 Sucralfate-Adverse effects

Constipation in 2% of patients-Aluminium salt)

Pts with renal insufficiency-don’t use for long
period (small amounts of Al are absorbed).
Drug Interactions
Binds to other medications & impair their
absorption e.g. ciprofloxacin, digoxin,
phenytoin, theophyline, amitriptyline
 b). Bismuth compounds
• Include bismuth subsalicylate and
bismuth subcitrate potassium.
• Bismuth subsalicylate undergo rapid
dissociation in stomach & salicylate is
absorbed; minimal bismuth (1%)
absorbed but slowly excreted by renal
route.
 Bismuth compounds
MOA
• Coats ulcers and erosions creating a protective
layer against acid and pepsin.
• May stimulate PGs, mucus and bicarbonate
secretion.
• Reduces stool frequency & liquidity in acute
episodes of diarrhoea due to salicylate inhibition
of intestinal PGs and Cl- secretion.
• Direct antimicrobial effect-binds enterotoxins
• Direct antimicrobial activity against H. Pylori
 Indications
• Prevention & treatment of traveler's diarrhoea.
• Non specific Rx of diarrhea & dyspepsia.
• Eradication of H. pylori in combination with PPI,
tetracycline & metronidazole (mostly 2nd line
therapy).
1st line therapy H. pylori- tripple therapy with
• PPI
• Clarithromycin
• And amoxicillin or metronidazole BD x 14/7
 Drawbacks of triple therapy;
▪ Patient compliance
▪ Side effects in some pts- bismuth-darkening of
tongue and stool,
▪ Amoxycillin- pseudomembranous colitis, nausea,
vomiting, skin rash and allergic reactions.
▪ Tetracyclines- skin rash, rarely-anaphylaxis and
hepatotoxicity.
▪ Metronidazole –nausea, vomiting, diarrhoea,
altered taste sensation.
 Adverse Effects
1. Darkening/ blackening of the tongue, teeth &
stool-this may be confused with GIT bleeding

2. Prolonged use ;bismuth toxicity =ataxia,

headaches, confusion and seizures
(encephalopathy).

3. High doses of bismuth subsalicylate may lead

to salicylate toxicity.
 c). Prostaglandin Analogs
Misoprostol
MOA
• Acid inhibitory and mucosal protective
properties.
• Enhances mucosal blood flow.
• Stimulates mucus and bicarbonate
secretion.
• Inhibit acid production- binds to PG
receptors on the parietal cells.
 Misoprostol-Indications
❖NSAIDS induced ulcers
Adverse Effects
❖ -Diarrhoea and abdominal pain/cramps in 10-
20% of patients
❖ -Stimulates uterine smooth muscle
contractions;
❖ C/I in pregnancy, women of child bearing potential
unless PT-ve & effective FP
 (2).DRUGS STIMULATING
GASTROINTESTINAL MOTILITY
• Metoclopramide
• Domperidone
• Cholinomimetics- neostigmine
• Macrolides- erythromycin
 ….cntd
Metoclopramide and Domperidone
• Both are potent D2 receptor blockers.
• Activation of D2 receptors in the GIT inhibits
cholinergic smooth muscle stimulation.
• They also block the receptors in the CTZ zone
hence CNS effects.
• Used extensively to prevent vomiting and
enhance gastric motility
 ….cntd
Indication- disorders of gut movt e.g. irritable
bowel syndrome and tropical sprue
• Gastric paresis in diabetics
Adverse effects- restlessness, drowsiness,
insomnia, anxiety and agitation in 10-20% of pts
esp the elderly.
Galactorrhea, gyanaecomastia, impotence and
menstral disorders may also occur due to
elevated levels of prolactin
N/B Domperidone causes less CNS effects
 ….cntd
• Cholinomimetic agents e.g. Bethanechol
• Stimulate the M3 receptors on muscle cells
and myenteric plexus synapsess
• Used previously for GERD and gastric paresis
but now rarely used.
 ….cntd
• Acetylcholinesterase inhibitors e.g
neostigmine
• Enhances gastric, small intestine and colonic
emptying
• Drug is used IV in treatment of hospitalized
pts with acute large bowel distention.
 ….cntd
• Macrolides- erythromycin directly stimulates
motilin receptors on GIT smooth muscles.
• It is used in pts with gastroparesis but
tolerance develops rapidly.
• It may also be used in pts with acute upper
GIT haemorrhage to promote gastric emptying
of blood before endoscopy.
 (3).LAXATIVES
• Laxatives; are foods, cpds, or drugs taken to
induce bowel movements or to loosen the
stool, most often taken to treat constipation.
• Constipation: Abnormally infrequent and
difficult passage of feces through the lower GI
tract Symptom, not a disease.
• Disorder of movement through the colon
and/or rectum Can be caused by a variety of
diseases or drugs
62
 Groups of laxatives
• There are several types of laxatives.
• Some combine more than one active ingredient.
• Laxatives may be oral or in suppository form.
• Types of laxatives:
• Bulk-producing agents
• Osmotic laxatives
• Stool softeners / Surfactants
• Lubricants / Emollient
• Stimulant / Irritant
• Saline (consider a hydrating agent)

63
 Bulk forming
• High fiber
• Absorbs water to increase bulk
• Distends bowel to initiate reflex bowel activity
• Site of Action: Small and large intestine
• Onset of Action: 12 - 72 hours
• Examples: psyllium (Metamucil),
methylcellulose (Citrucel), Polycarbophil, Agar,
stercula, bran, ispeghula
64
 Osmotic laxatives
• Site of Action: Colon
• Onset of Action: 0.5 - 3 hours
• Examples: Glycine suppositories, Sorbitol,
Lactulose, and Polyethylene glycol (PEG).
• Lactulose works by the osmotic effect, which
retains water in the colon, lowering the pH
and increasing colonic peristalsis.
• Lactulose is also indicated in Portal-systemic
encephalopathy.
65
 Saline laxative
• Site of Action: Small and large intestine
• Onset of Action: 0.5 - 6 hours
• Saline laxatives draw fluid into the bowel from
nearby tissue. This softens stools and helps the
bowel move them out.
• Result: bowel distention, increased peristalsis,
and evacuation
• Examples: magnesium sulfate (Epsom salts),
magnesium hydroxide (MOM), magnesium
citrate, sodium phosphate (Fleet Phospho-Soda,
Fleet enema)
66
 Stimulant laxative
• They stimulate peristaltic action and can be
dangerous under certain circumstances.
• Long term use can lead to 'cathartic colon'.
• Stimulant laxatives act on the intestinal
mucosa, or nerve plexus.
• They also alter water and electrolyte
secretion.
• They should be used only in extreme
conditions.
67
 Cont.
• Castor oil may be preferred when more
complete evacuation is required
• Examples: castor oil, Senna A and B, cascara,
Bisacodyl
• Site of Action: Colon
• Onset of Action: 15min to 8 hours depending
the drug

68
 Lubricants / Emollient
• Stool softeners and lubricants
• Site of Action: Colon
• Onset of Action: 6 - 8 hours
• Lubricant laxatives work by coating the surface of
the stools. This helps the stools hold in water so
they move out of the body more easily
• (Lubricate the fecal material and intestinal walls)
• Examples: Stool softeners: docusate salts (Colace, Surfak)
– Lubricants: mineral oil

69
 Stool softeners / Surfactants
• Site of Action: Small and large intestine
• Onset of Action: 12 - 72 hours
• Examples: docustate (Colace, Diocto)
• Stool softeners help mix fluid into stools to soften
them.
• These cause water and fats to penetrate the
stool, making it easier to move along.
• Many of these quickly produce a tolerance effect
and so become ineffective with prolonged use.

70
 (4). Antiemetic agents
Include;
a) 5H3 receptor antagonists-Ondansetron,
Granisetron and Tropisetron
Agents are used as anti emetics but also for
treatment of allergy.

71
 ..contd
Ondansetron- is used mainly to control vomiting
in chronic illnesses such as cancer.
-Is administered orally or as an IV.
-Is well absorbed and well distributed
MOA-Metabolised to inactive metabolites
excreted in urine.

72
 ..contd
b) Cannabinoids e.g Nobilone and Dronabinol
• Almost completely absorbed following oral
absorption.
• Undergo significant 1st pass metabolism
• Metabolites are excreted slowly in feaces and
urine
• Indications-as appetite stimulants and
antiemetic agents.
73
 ..contd
c) Substituted benzamides- metoclopramide and
trimethobenzamide.
Exert their antiemetic effects thro’ dopamine
receptor blockade.
The latter also has weak antihistaminic activity
Adverse effect-restlessness and parkinsonian
symptoms.

74
 ..contd
d) H1 antihistamines e.g diphenhydramine and
dimenhydrinate, meclizine.
-The latter causes less sedation and minimal
anticholinergic props.
-Is used for prevention of motion sickness and
treatment of vertigo due to labyrinth
dysfunction.

75
 ..contd
e) Hyoscine(scopolamine)
- A muscarinic receptor antagonist used for
treatment of motion sickness.
f) Phenothiazines e.g. Promethazine,
prochlorperazine and thiethylperazine
g) Antipsychotic agents-Droperidol

76
 (5).Inflammatory Bowel Disease
• Ulcerative colitis :Diffuse mucosal inflammation
limited to the colon; bloody diarrhoea, colicky pain,
urgency, tenesmus
• Crohn's disease: patchy transmural inflammation
May affect any part of GI tract
▪ S & S-abdominal pain, diarrhoea, weight loss
intestinal obstruction
systemic symptoms

77
 IBD drugs
▪ Aminosalicylates
▪ Corticosteroids
▪ Thiopurines
▪ Methotrexate
▪ Ciclosporin
▪ Infliximab

78
 Aminosalicylates
▪ Sulfasalazine-(5-aminosalicylic acid and sulfapyridine as
carrier substance)
▪ Others: Mesalazine (5-ASA), eg Asacol, Pentasa,
Balsalazide (prodrug of 5-ASA), Olsalazine (5-ASA dimer
cleaves in colon)
• Oral, rectal preparation
Indication-Maintaining remission, Active disease, May
reduce risk of colorectal cancer
▪ Adverse effect: 10-45%
▪ Nausea, headache, epigastric pain, diarrhoea,
hypersensitivity, pancreatitis, blood disorders, lung
disorders, myo/pericarditis
▪ Caution in renal impairment, pregnancy, breast
feeding
79
 Corticosteroids
• Anti-inflammatory agents for moderate to severe
relapses e.g. 40mg Prednisolone
• Inhibition of inflammatory pathways (↓IL
transcription, suppression of arachidonic acid
metabolism, lymphocyte apoptosis)
Adverse effect: Acne, moon face, oedema, Sleep,
mood disturbance, glucose intolerance, Cataracts,
osteoporosis, myopathy

80
 Thiopurines
Azathioprine, mercaptopurine
MOA-Inhibit ribonucleotide synthesis
Inducing T cell apoptosis by modulating cell signalling
Azathioprine metabolised to mercaptopurine and 6-
thioguanine nucleotides
Indication- Active and chronic disease, Steroid sparing
Adverse effect- Leucopaenia (myelotoxic), Monitor for
signs of infection, sore throat, Flu like symptoms
after 2 to 3 weeks, liver, pancreas toxicity

81
 Methotrexate
MOA-Inhibits dihydrofolate reductase and
probably inhibition of cytokine and eicosanoid
synthesis
Indication-Relapsing or active crohn desease
refractory or intolerant to AZA or
Mercaptopurine
• Monitor FBC, LFT
Adverse effect-GI, Hepatotoxicity, pneumonitis

82
 Cyclosporin
MOA-Inhibitor of calcineurin, preventing clonal
expansion of T cell subsets
Indication-Active and chronic disease, Steroid
sparing
Adverse effect-Tremor, paraesthesiae, malaise,
headache, abnormal LFT
▪ Gingival hyperplasia, hirsutism
▪ Major: renal impairment, infections,
neurotoxicity
N/B- monitor BP, FBC, renal function
83
 Infliximab
• Anti TNF-α monoclonal antibody
• Potent anti inflammatory effects
Indication-Fistulising CD
• Severe active CD refractory/intolerant of
steroids or immunosuppression
• iv infusion
Adverse effect-Infusion reactions, Sepsis
▪ Reactivation of Tb, increased risk of Tb

84
 (6)Anti diarrheal drugs
Acute diarrhea
• Sudden onset in a previously healthy person
• Lasts from 3 days to 2 weeks
• Self-limiting
• Resolves without sequelae

85
 ….cntd
Chronic diarrhea
• Lasts for more than 3 weeks
• Associated with recurring passage of diarrheal
stools, fever, loss of appetite, nausea,
vomiting, weight loss, and chronic weakness

86
 Causes of diarrhea
• Bacterial • Tumors
• Viral • Diabetes
• Addison’s disease
• Drug induced
• Hyperthyroidism
• Nutritional • Irritable bowel
• Protozoal syndrome

Chronic diarrhea
87
 Pharmacotherapy of diarrhea
• Reserved for pts with persistent symptoms.
• Nonspecific antidiarrheal agents do not address
the underlying pathophysiology and their function
is to provide symptomatic relief
• They act by decreasing intestinal motility and
should be avoided in acute diarrhea caused by
invasive organisms.
• They may mask the clinical picture, delay
clearance of organisms, and increase the risk of
systemic invasion by the organisms.
88
 Opioids
• Decrease bowel motility and relieve
rectal spasms
• Decrease transit time through the bowel,
allowing more time for water and
electrolytes to be absorbed
• Examples: codeine, loperamide,
diphenoxylate

89
 Loperamide.
• A piperidine butyramide derivative with mu-receptor
activity.
• Orally active antidiarrheal agent and 40 to 50 times
more potent than morphine as an antidiarrheal agent.
MOA-It increases mouth-to-cecum transit times.
• Increases anal sphincter tone, an effect that may be of
therapeutic value in pts with anal incontinence.
• Antisecretory activity against cholera and some E. coli
toxins, by acting on Gi-linked receptors & countering
the rise in cAMP generated in response to toxins.

90
 PK
• It acts quickly after an oral dose, peak plasma levels
achieved in 3 to 5 hrs.
• T1/2 11 hrs & undergoes extensive hepatic
metabolism.
• Poor CNS penetration
Adult dose is 4 mg followed by 2 mg after each
subsequent loose stool, up to 16 mg per day.
• Discontinue the drug if no clinical improvement within
48hrs.
N/B-Not recommended for children younger than 2 yrs.

91
 Indication
• Traveler's diarrhea, used either alone or in
combination with antimicrobial agents e.g.
fluoroquinolone).
• Chronic diarrheal disease.
• Overdosage, can result in CNS depression
(especially in children) and paralytic ileus.
• Caution in patients with active inflammatory
bowel disease involving the colon because of
the risk of toxic megacolon.
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 Diphenoxylate and Difenoxin
PK
• Diphenoxylate and its active metabolite difenoxin
(diphenoxylic acid) are piperidine derivatives
(structurally related to meperidine).
• More potent than morphine as anti-diarrhea.
• Absorbed readily after oral administration
• Peak plasma levels achieved within 1 to 2 hrs.
• Diphenoxylate is rapidly deesterified to difenoxin,
which is eliminated with a half-life of about 12 hrs.

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 ….cntd
• Both drugs can produce CNS effects when
used in higher doses (40 to 60 mg per day) and
thus have a potential for abuse and/or
addiction.
• Other opioids used for diarrhea include
codeine (in doses of 30 mg given three or four
times daily).

94
 Anticholinergics
• Decrease intestinal muscle tone and
peristalsis of GI tract
• Result: slowing the movement of fecal
matter through the GI tract
• Quaternary amines eg hyoscine
butylbromide (Buscopan) less lipid
soluble and thus less well absorbed than
atropine

95
 …cntd
Indication-angle-closure-glaucoma, mysthenia,
paralytic ileus, pyloric stenosis and prostatic
enlargement
Adverse effect- constipation, transient
bradycardia, reduced bronchial secretions,
urinary urgency etc
• Others are belladonna alkaloids (Donnatal)
 Intestinal flora modifiers

• Bacterial cultures of Lactobacillus organisms

work by:
– Supplying missing bacteria to the GI tract
– Suppressing the growth of diarrhea-causing
bacteria
• Example: L. acidophilus (Lactinex)

97
 Adsorbents

• Coat the walls of the GI tract

• Bind to the causative bacteria or toxin, which
is then eliminated through the stool
• Examples: bismuth subsalicylate (Pepto-
Bismol), kaolin-pectin, activated charcoal,
attapulgite (Kaopectate)

98
 a2 Adrenergic Receptor Agonists.
• clonidine can interact with specific receptors on
enteric neurons and enterocytes.
• Thereby stimulating absorption and inhibiting
secretion of fluid and electrolytes and increasing
intestinal transit time.
• These agents may have a special role in diabetics
with chronic diarrhea, in whom autonomic
neuropathy can lead to loss of noradrenergic
innervation.

99
 ….cntd
• Oral clonidine (beginning at 0.1 mg twice a
day) has been used in these patients;
• Clonidine also may be useful in patients with
diarrhea caused by opiate withdrawal.
• Side effects such as hypotension, depression,
and perceived fatigue may be dose limiting in
susceptible patients.

100
 Octreotide and Somatostatin.
• Octreotide- An octapeptide analog of somatostatin
• Effective in severe secretory diarrhea due to hormone-
secreting tumors of the pancreas and GIT.
MOA-: inhibition of hormone secretion e.g. serotonin
and other GI peptides (e.g., gastrin, VIP, insulin,
secretin, etc.).
• T1/2 1 - 2 hrs and is administered either SQ or IV as a
bolus dose.
• Its initial therapy is 50 - 100 mg, given SQ bd or tds,
with titration to a max dose of 500 mg tds..

101
• Octreotide has been used in
chemotherapy-induced diarrhea,
diarrhea associated with HIV and
diabetes.
• Its greatest utility is in the "dumping
syndrome" seen in pts after gastric
surgery and pyloroplasty.
• In this condition, it inhibits the release of
hormones (triggered by rapid passage of
food into the small intestine).
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 Indication
• Variceal Bleeding.
• Intestinal Dysmotility. Has conflicting effects on GI
motility, e.g. inhibition of motor activity and colonic
tone.
• However, it can also induce phase III activity of the
migrating motor complex in the small bowel to
produce longer and faster contractions than those
occurring spontaneously.
Use in Pancreatitis. Both somatostatin and
octreotide inhibit pancreatic secretion and have
been used for the prophylaxis and treatment of
acute pancreatitis.
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 OTHER AGENTS
• Calcium channel blockers e.g. verapamil and
nifedipine reduce motility and may promote
intestinal electrolyte and water absorption.
• Constipation is a significant side effect of these drugs.
• Rarely used because of their systemic effects.
• Chloride channel blockers- effective
antisecretory agents in vitro but too toxic for
human use and hence not used.
• Calmodulin inhibitors, which include
chlorpromazine, also are antisecretory.
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 (7) Pancreatic supplements
• Pancrelipase and Pancreatin
-Agents are well tolerated but excessive
amounts may cause diarrhoea and abdominal
pain
-Hyperuricosuria and renal stones may also
occur due to high purine content in these
agents.

105
 (8).GALL STONE THERAPY
• Ursodiol –a naturally occurring bile acid.
– Well absorbed when given orally
– Undergoes extensive enterohepatic recirculation
– Has a serum half life of 100hrs
– Drug decreases the cholesterol content of bile
– Is used for dissolution of small cholesterol gall
stones

106
Summary
 References
1. Goodman & Gilman's: The pharmacological
basis of therapeutics - 11th Ed. (2006) :
2. Katzung B.G : Basic and clinical pharmacology.
11th edition
3. Katzung B.G, Masters S.B, Trevor A.J (2012) :
Basic and clinical pharmacology. 12th edition,
Tata MacGraw Hall.
4. Bennet P.n, Brown M.J (2008): Clinical
Pharmacology . 10th Edition, Churchill
Livingstone.
 Thank you
Thank you