An overview of Diarrhea's etiologies, pathophysiology, treatment.

1. DIARRHEA
ASSIGNMENT
Submitted to,
Dr. Sreeja P A
Head, Dept. of Pharmacy Practice
Sanjo College of Pharmaceutical Studies
Submitted By,
Ameena Kadar K A
First sem M P harm
Dept. of Pharmacy Practice
Sanjo College of Pharmaceutical studies

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DIARRHEA
 Diarrhea is defined as the increased passage of loose or watery stools relative to
the person's usual bowel habit.
 It may be accompanied by anorexia, nausea, vomiting, abdominal cramps or
bloating.
 It is not a disease but a sign of an underlying problem such as an infection or
gastro-intestinal disorder.
 It is an abnormal frequent passage of loose stools or passage of stools with
increased frequency, fluidity and weight or increased stool water excretion.
 It can range from an acute self-limiting episode to severe chronic illness.
 According to WHO, it is 3 or more loose or watery stools in a 24 hour
period.
 In pathological terms, it occurs due to passage of excess water in feaces.
 This may be due to:
•Decreased electrolyte and water absorption.
• Increased secretion by intestinal mucosa.
• Increased luminal osmotic load.
• Inflammation of mucosa and exudation into lumen.
TYPES OF DIARRHEA
1. On the basis of Duration
 Acute diarrhea; Diarrhea lasts for less than 14 days
 Chronic diarrhea; Diarrhea lasts for more than 14 days.
2. On the basis of Clinical
 Acute Watery diarrhea; It lasts for several hours or days and occurs in condition
like cholera.

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 Acute Bloody diarrhea; Diarrhea with blood in stool, with or without mucus is
known as Dysentery.
ETIOLOGY
1) Infection
o Bacteria: Shigella, E.coli, Salmonella, Staphylococcus.
o Virus: Influenza, Adenovirus, Enterovirus, Rotavirus.
o Parasites: Giardia lamblia, Entamoeba histolytica and Amoeba.
o Fungi: Candida albicans.
2) Drugs
o Antibiotics
o Iron supplements
3) Dietary Causes
o Food Poisoning
o Food Allergies
o Over eating
o Eating of stale foods.
4) Surgical conditions
o Appendicular abscess.

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Table.1: Examples of medicines known to cause diarrhea (defined as very
common [>10%] or common [1–10%])

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PATHOPHYSIOLOGY
There are numerous causes of Diarrhea, but in almost all cases, this disorder is a
manifestation of one of the 4 basic mechanisms is:
 Osmotic Diarrhea
 Secretory Diarrhea
 Inflammatory and infectious Diarrhea
 Diarrhea associated with Deranged motility.
CLINICAL PRESENTATION OF DIARRHEA
a) History: Number and description of stools per day, body weight, fluid intake,
frequency of urination etc.
b) Physical examination: To assess degree of dehydration.
c) Stool examination: Helps to identify Micro-organisms
d) Blood test: Hematocrit, BUN, WBC, serum sodium, serum bicarbonate,
serum chloride.

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PRINCIPLES OF MANAGEMENT
Therapeutic measures may be grouped into:
(a) Treatment of fluid depletion, shock and acidosis. (Non-
pharmacological)
(b) Maintenance of nutrition (Non-pharmacological)
(c) Drug therapy
(d) Prevention of diarrhea.

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(a) Treatment of fluid depletion, shock and acidosis.
 Rehydration
 In majority of cases, this is the only measure needed.
 Rehydration can be done orally or I.V.
 Intravenous rehydration: It is needed only when fluid loss is severe, i.e. >
10% body weight, (if not promptly corrected, it will lead to shock and death)
or if patient is losing > 10 ml/kg/ hr, or is unable to take enough oral fluids due
to weakness, stupor or vomiting.
 The recommended composition of i.v. fluid (Dhaka fluid) is:
 NaCl 85 mM = 5 g
 KCl 13 mM = 1 g
 NaHCO3 48 mM = 4 g,
 In 1L of Water or 5% of Glucose solution.
 Volume equivalent to 10% BW should be infused over 2–4 hours; the
subsequent rate of infusion is matched with the rate of fluid loss. In most cases,
oral rehydration can be instituted after the initial volume replacement.
 Oral rehydration: Advent of oral rehydration therapy (ORT) is considered a
major advance of recent times.
 If the fluid loss is mild (5–7% BW) or moderate (7.5–10% BW) ORT can be
instituted from the very beginning.
Rationale of ORS composition
 The sodium and water absorption by the small bowel is very much enhanced by
the addition of glucose to the oral fluid.

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 However, dehydration can be successfully treated with oral fluids containing
glucose, once the initial hypovolemia is corrected by 2-4 liters of IV fluid
replacement.
 Mild to moderate dehydration and acidosis due to diarrhea can be corrected in
3-6 hours by oral therapy alone.  In many cases it is a lifesaving measure.
 The treatment should continue even when diarrhea is not controlled.
 The ORT has many advantages:
(1) It is far less expensive than IV fluids.

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(2) No expertise is needed to administer the fluid.
(3) The solution need not be sterile and can be prepared on spot with components
purchased from the local bazaar, and plain water available at home.
(4) It can be given by family members and non-professionals as well as by health
workers.
 It capitalizes on the intactness of glucose coupled Na+ absorption, even when
other mechanisms have failed or when intestinal secretion is excessive, because
the secreted fluid lacks glucose and cannot be reabsorbed.
 The composition of oral rehydration salt/solution (ORS) has been debated. 
 The general principles are:
(a) It should be isotonic or somewhat hypotonic, i.e. total osmolarity 200–310
mOsm/L (diarrhea fluids are approximately isotonic with plasma).
(b) The molar ratio of glucose should be equal to or somewhat higher than Na+
(excess glucose will be utilized in absorbing Na+ present in the intestinal
secretions in addition to that present in ORS itself), but not exceed 110 mM.
(c) Enough K+ (15–25 mM) and bicarbonate/ citrate (8–12 mM) should be
provided to make up the losses in stool.
 In 2002, a new formula low Na+ low glucose ORS was released by the WHO.
 The new formula ORS has proven as effective and as safe in cholera as well,
but there is some risk of hyponatremia in adults with cholera.
 The WHO and UNICEF have recommended replacement of standard (310
mOsm/L) ORS formula by the new (245 mOsm/L).
 Potassium is an important constituent of ORS, since in most acute diarrheas K+
loss is substantial.

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 The base (bicarbonate, citrate, and lactate) is added to correct acidosis due to
alkali loss in stools.
 It may independently promote Na+ and water absorption. However, relying on
the ability of the kidney to restore acid-base balance, acidotic states have been
managed without an exogenous base.
 Base free ORS has been found to be equally effective in rehydrating, but
correction of acidosis is slower. Thus, there is a trend to consider base as a
nonessential constituent of ORS, but if present it may be beneficial, especially
in severe cases with over acidosis.
 Administration of ORT:
 Patients are encouraged to drink ORS at ½–1 hourly intervals.
 Initially 5–7.5% BW volume equivalent is given in 2–4 hours (5 ml/kg/hr in
children). Thirst due to volume depletion provides an adequate driving force.
 In a weak child who refuses to drink ORS at the desired rate, it can be given by
intra-gastric drip; restoring hydration within 6 hours should be aimed.
 ORT is not designed to stop diarrhea, but to restore and maintain hydration,
electrolyte and pH balance until diarrhea ceases, mostly spontaneously.
 Non-diarrhea uses of ORT:
(a) Post-surgical, post burn and post-trauma maintenance of hydration and nutrition
(in place of I.V. infusion).
(b) Heat stroke.
(c) During changeover from intravenous to enteral alimentation.

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Cereal-based oral rehydration solution (CORS):
o Nature of ORS has provided foods containing starches such as cereals and roots
which have low osmolality in solution.
o Studies have indicated that ORS in which rice and other food sources of starch
are substituted for glucose effectively replace lost fluids, decrease vomiting,
and reduce the severity of diarrhea.
o Glucose based ORS does not decrease and may slightly increase the stool
volume.
o The cereal (rice) based solutions, on the other hand, is equally effective in
reducing volume losses, and may also shorten the duration of illness.
o Rice contains a low molecular weight fraction which has a direct effect on the
chloride channel.
o Physiologically, cereal-based ORS are identical to their glucose based
counterparts.  The dominant component in the cereals is starch from rice, corn,
wheat, potato, sorghum, millet or even plantain.
o Starch is a large polymer of glucose that, on exposure to amylase in the
intestine, is digested into smaller polymers that are then split by maltase into
glucose at the intestinal brush border.
o This digestive process supplies a larger number of glucose molecules for
transfer of sodium ions from lumen into the blood, while generating less
luminal osmotic ―back drag‖ than would the direct ingestion of an equivalent
amount of glucose.
o The cereal proteins also provide small peptides and amino acids which also
facilitate the absorption of additional sodium ions. Of course, the presence of
sufficient digestive enzyme is essential for the success of such solutions.
Zinc supplemented ORS:

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 Zinc supplementation is also considered as an adjunct therapy in diarrhea
because zinc maintains the GI mucosal integrity.
 It is also imparts local immunity.
 Deficiency of zinc has been shown to worsen diarrhea.  Moreover diarrhea
itself leads to zinc deficiency.
 Hence, UNICEF&WHO have proposed zinc supplemented ORS.
 This ORS also has shown to reduce duration of diarrhea and the stool
frequency.
 In children less than 6 month, 10 mg/day of zinc and for the older children 20
mg/day of zinc is advocated.
 All children with acute diarrhea should be given Zinc supplementation along
with ORS and continued for the next 10–14 days.
 The mechanism of benefit of Zinc in diarrhea is not known.
 In vitro studies have suggested that Zinc could reduce fluid secretion in the
intestine by indirectly inhibiting cAMP dependent Cl¯ transport across the
mucosa through an action on the basolateral membrane K+ channels.
 It could also strengthen the immune response and help regeneration of intestinal
epithelium.
 Zinc can be administered to children by dissolving Zinc sulfate dispersible
tablets.
(b) Maintenance of Nutrition.
 Contrary to traditional view, patients of diarrhea should not be starved.
 Fasting decreases brush border disaccharides enzymes and reduces absorption
of salt, water and nutrients; may lead to malnutrition if diarrhea is prolonged or
recurrent.

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 Feeding during diarrhea has been shown to increase intestinal digestive
enzymes and cell proliferation in mucosa.
 Simple foods like breast milk or ½ strength buffalo milk, boiled potato, rice,
chicken soup, banana, sago, etc. should be given as soon as the patient can eat.
 Avoiding fats, high fiber foods and alcohol generally improves patient comfort.
(c) Drug Therapy.
 Drugs used in diarrheas may be categorized into:
1. Specific antimicrobial drugs
2. Probiotics
3. Nonspecific antidiarrheal drugs.
4. Drugs for inflammatory bowel disease (IBD).

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1. ANTIMICROBIALS IN DIARRHOEA
 One or more antimicrobial agent is almost routinely prescribed to most patients of
diarrhea. However, such drugs have a limited role in the overall treatment of
diarrheal diseases; the reasons are:
 Bacterial pathogen is responsible for only a fraction of cases.
 Even in bacterial diarrhea, antimicrobials alter the course of illness only in selected
cases.
 Antimicrobials may prolong the carrier state.
 Diarrhea patients can be broadly placed in one of the two categories:
(a) Noninvasive diarrhea: Abundant watery diarrhea lacking mucus or blood,
usually dehydrating with frequent vomiting, but little or no fever. These are
generally caused by adhesive but noninvasive entero-toxigenic bacteria such
as cholera, ETEC, Salmonella enteritis or by Rota virus and other viruses
which stimulate massive secretion by activating cAMP in intestinal mucosal
cell. ORS and non- antimicrobials are the main therapy.
(b) Invasive diarrhea: Slightly loose, smaller volume stools, frequently with
mucus and/or blood, mild dehydration, usually attended with fever and
abdominal pain, but not vomiting. These symptoms are indications of
mucosal invasion, generally caused by entero-invasive organisms like
Shigella, enteropathogenic E. coli (EPEC), Campy. jejuni, Salmonella
typhimurium, Yersinia enterocolitica, E. histolytica, Clostri. difficile.
Antimicrobials are needed in many of these.
A. Antimicrobials are of no value:
 In diarrhea due to non-infective causes, such as:
(i) Irritable bowel syndrome (IBS)
(ii) Coeliac disease

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(iii) Pancreatic enzyme deficiency
(iv) Tropical sprue (except when there is secondary infection)
(v) Thyrotoxicosis.
 Rotavirus is an important pathogen of acute diarrhea, especially in children in
developed countries.
 Along with other diarrhea causing viruses, it is not amenable to chemotherapy.
 Salmonella food poisoning is generally a self-limiting disease.
 Antibiotics have been widely used, but may be harmful rather than beneficial.
B. Antimicrobials are useful only in severe disease (but not in mild cases):
 Salmonella food poisoning is generally a self-limiting disease.
 Antibiotics have been widely used, but may be harmful rather than beneficial.
 Treated patients have been found to pass organisms in stool for longer periods
than untreated patients.
 However, very severe illness or that in infants/elderly or immuno-compromized
patients may be treated with ciprofloxacin or azithromycin or I.V.
ceftriaxone.
 Travellers’ diarrhea: mostly due to ETEC, Campylobacter or virus:
cotrimoxazole, norfloxacin, doxycycline reduce the duration of diarrhea and
total fluid needed only in severe cases.
 RIFAXIMIN is a minimally absorbed oral rifamycin (related to rifampin)
active against E. coli and many other gut pathogens.
 It is recently approved by US-FDA for the empiric treatment of travellers’
diarrhea caused by non-invasive strains of E.coli.
 A review of data from controlled trials using rifaximin 200 mg TDS for 3 days
has rated it to be superior to placebo, and as effective as ciprofloxacin in

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reducing duration of travellers’ diarrhea, irrespective of whether the causative
pathogen was identified or not.
 It has also been used in diarrheal phase of IBS as well as for prophylaxis before
and after gut surgery.
 A higher strength (550 mg) tablet is marketed for reducing risk of hepatic
encephalopathy recurrence by suppressing NH3 forming gut bacteria.
 The tolerability profile of rifaximin is similar to placebo.
 Side effects are: Flatulence, Abdominal pain, Defecation urgency, Headache.
 Because of poor absorption, systemic toxicity is not expected.
 Clinical experience with rifaximin is limited, and efficacy for empirical
treatment of diarrhea is still to be convincingly established against local strains
of the bacteria.
 EPEC: is less common, but causes Shigella like invasive illness.
 Cotrimoxazole, or a fluoroquinolone or colistin may be used in acute cases
and in infants.
 Shigella enteritis: only when associated with blood and mucus in stools may be
treated with ciprofloxacin or norfloxacin.
 Co-trimoxazole and ampicillin are alternatives, but many strains are resistant
to these.
 Non-typhoid Salmonella enteritis is often invasive; severe cases may be treated
with a fluoroquinolone, cotrimoxazole or ampicillin.
 Yersinia enterocolitica: common in colder places, not in tropics.
Cotrimoxazole is the most suitable drug in severe cases; ciprofloxacin is an
alternative.

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C. Antimicrobials are regularly useful in all cases:

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BRIEF DESCRIPTION OF ANTIMICROBIAL AGENTS IN DIARRHEA
 NORFLOXACIN; A synthetic fluoroquinolone with broad-spectrum
antibacterial activity against most gram-negative and gram-positive bacteria.
MOA: The bactericidal action of Norfloxacin results from inhibition of the
enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are
required for bacterial DNA replication, transcription, repair, and recombination.
 CIPROFLOXACIN; It is a second generation fluoroquinolone that has
spawned many derivative antibiotics. It is formulated for oral, intravenous,
intratympanic, ophthalmic, and otic administration for a number of bacterial
infections. The first ciprofloxacin containing product was FDA approved on 22
October 1987.
MOA: Ciprofloxacin acts on bacterial topoisomerase II (DNA gyrase) and
topoisomerase IV. Ciprofloxacin's targeting of the alpha subunits of DNA
gyrase prevents it from supercoiling the bacterial DNA which prevents DNA
replication.
 OFLOXACIN; A synthetic fluoroquinolone (fluoroquinolones) antibacterial
agent that inhibits the supercoiling activity of bacterial DNA gyrase, halting
DNA replication.
 RIFAXIMIN; It is a semisynthetic, rifamycin-based non-systemic antibiotic,
meaning that the drug will not pass the gastrointestinal wall into the circulation
as is common for other types of orally administered antibiotics. It has multiple
indications and is used in treatment of traveller's diarrhea caused by E. coli;
reduction in risk of overt hepatic encephalopathy recurrence; as well as
diarrhea-predominant irritable bowel syndrome (IBS-D) in adult women and
men. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals.
MOA: Acts by inhibiting RNA synthesis in susceptible bacteria by binding to

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the beta-subunit of bacterial deoxyribonucleic acid (DNA)-dependent
ribonucleic acid (RNA) polymerase enzyme. This binding blocks translocation,
which stops transcription.
 COTRIMOXAZOLE; It is used to treat certain bacterial infections; It also is
used to treat 'travelers' diarrhea. Cotrimoxazole is a combination of
trimethoprim and sulfamethoxazole and is in a class of medications called
sulfonamides.
MOA: Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by
competing with P-aminobenzoicacid (PABA). Trimethoprim blocks the
production of tetrahydrofolic acid from dihydrofolic acid by binding to and
reversibly inhibiting the required enzyme, dihydrofolate reductases. Thus, it
blocks the two consecutive steps in the biosynthesis of nucleic acids and
proteins essential to many bacteria.
 TETRACYCLINE; It is a broad spectrum polyketide antibiotic produced by
the Streptomyces genus of Actinobacteria.
MOA: It exerts a bacteriostatic effect on bacteria by binding reversible to the
bacterial 30S ribosomal subunit and blocking incoming aminoacyl tRNA from
binding to the ribosome acceptor site. It also binds to some extent to the
bacterial 50S ribosomal subunit and may alter the cytoplasmic membrane
causing intracellular components to leak from bacterial cells.
 ERYTHROMYCIN; It is a bacteriostatic antibiotic drug produced by a strain
of Saccharopolyspora erythraea (formerly Streptomyces erythraeus) and
belongs to the macrolide group of antibiotics which consists of Azithromycin,
Clarithromycin, Spiramycin and others. It was originally discovered in 1952.
Erythromycin is widely used for treating a variety of infections, including those
caused by gram-positive and gram-negative bacteria. It is available for

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administration in various forms, including intravenous, topical, and eye drop
preparations.
MOA: Erythromycin acts by inhibition of protein synthesis by binding to the
23S ribosomal RNA molecule in the 50S subunit of ribosomes in susceptible
bacterial organisms. It stops bacterial protein synthesis by inhibiting the
transpeptidation/translocation step of protein synthesis and by inhibiting the
assembly of the 50S ribosomal subunit.
 METRONIDAZOLE; It is a commonly used antibiotic, belonging to the
nitroimidazole class of antibiotics. It is frequently used to treat gastrointestinal
infections as well as trichomoniasis and giardiasis, and amebiasis which are
parasitic infections. Metronidazole has been used as an antibiotic for several
decades, with added antiparasitic properties that set it apart from many other
antibacterial drugs, allowing it to treat a wide variety of infections. It is
available in capsule form, tablet form, and topical form, and suppository
preparations for the treatment of various infections.
MOA: The exact mechanism of action of metronidazole has not been fully
established, however, it is possible that an intermediate in the reduction of
metronidazole which is only made by anaerobic bacteria and protozoa, binds
deoxyribonucleic acid and electron-transport proteins of organisms, blocking
nucleic acid synthesis.
2. PROBIOTICS IN DIARRHEA
These are microbial cell preparations, either live cultures or lyophilized powders,
that are intended to restore and maintain healthy gut flora or have other health
benefits. Diarrheal illnesses and antibiotic use are associated with alteration in the
population, composition and balance of gut micro flora. Decolonization of the gut

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by nonpathogenic, mostly lactic acid forming bacteria and yeast is believed to help
restore this balance. Organisms most commonly used are— Lactobacillus sp.,
Bifidobacterium, Streptococcus faecalis, Enterococcus sp. and the yeast
Saccharomyces boulardii, etc. Several reviews and meta-analysis of clinical trials
have suggested that probiotics significantly reduce antibiotic-associated diarrhoea,
acute infective diarrhoea and risk of traveller’s diarrhoea. While probiotics appear
to be useful adjuncts to conventional therapy of acute infectious diarrhoea,
convincing evidence of their efficacy is lacking. This prevents them from being
accepted as a standard component of diarrhoea therapy. Stronger evidence of
efficacy has emerged against antibiotic-associated diarrhoea, but there is no
justification yet for routine use of probiotics along with antibiotics. Natural
curd/yogurt is an abundant source of lactic acid producing organisms, which can
serve as probiotic. For all practical purposes, probiotics are safe, Infections and
acidosis caused by probiotics are very rare, though caution may be prudent in
immune-compromised patients.
Mechanism of Probiotics in the Treatment of Diarrhoea:
a. Protect the intestine by competing with pathogens for attachment.
b. Strengthening tight junctions between enterocytes.
c. Enhancing the mucosal immune response to pathogens.

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3. NONSPECIFIC ANTIDIARRHEAL DRUGS
 These drugs can be grouped into:
A. Absorbants and adsorbants
B. Antisecretory drugs
C. Antimotility drugs
A. ABSORBANTS:
 These are colloidal bulk forming substances like ispaghula, methyl cellulose,
carboxy methyl cellulose which absorb water and swell.
 Modify the consistency and frequency of stools.
 But do not reduce the water and electrolyte loss.
 They are of value in selected conditions like diarrhoea phase of IBS, and to
increase the consistency of faeces in colostomy patients.

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 Ispaghula and other bulk forming colloids are useful in both constipation and
diarrhoea phases of IBS and reduce abdominal pain as well.
 Substances that do not ferment in colon are preferred for diarrhoea.
ADSORBANTS: Like kaolin (Hydrated magnesium aluminium silicate), pectin
(Indigestable carbohydrate), attapulgite (Magnesium aluminium phyllosilicate),
are believed to adsorb bacterial toxins in the gut and coat/protect the mucosa.
They were ones very popular ingredients of diarrhoea remedies, but are now
banned in India, because there is no objective proof of their efficacy.
B. ANTISECRETORY DRUGS:
RACECADOTRIL: This recently introduced prodrug is rapidly converted to
thiorphan, an enkephalinase inhibitor. It prevents degradation of endogenous
enkephalins (ENKs) which are mainly δ opioid receptor agonists. It decreases
intestinal hypersecretion, without affecting motility (motility appears to be
regulated through μ receptors) by lowering mucosal cAMP due to enhanced ENK
action.

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 It is indicated in the short term treatment of acute secretory diarrheas. In
contrast to loperamide/diphenoxylate, it is not contraindicated in children.
 The elimination t½ as thiorphan is 3 hr.
 Side effects are: Nausea, Vomiting, Drowsiness, Flatulence.
 Dose: 100 mg (children 1.5 mg/kg) TDS for not more than 7 days.
 BISMUTH SUBSALICYLATE: Taken as suspension (60 ml 6 hourly) it is
thought to act by decreasing PG synthesis in the intestinal mucosa, thereby
reducing Cl¯ secretion. They have astringent, adsorbent and antimicrobial
actions. They are devoid of serious toxicity. They also act against Helicobacter
pylori. It has some prophylactic value in travellers’ diarrhoea (probably due to
weak antibacterial action as well), but it is rather inconvenient to carry and take.
 ANTICHOLINERGICS: Atropinic drugs can reduce bowel motility and
secretion, but have poor efficacy in secretory diarrheas. They may benefit
nervous/drug (neostigmine, metoclopramide) induced diarrheas and provide
some symptomatic relief in dysenteries, diverticulitis.
 OCTREOTIDE: This somatostatin analogue has a long plasma t½ (90 min) as
well as potent antisecretory/ antimotility action on the gut. It has been used to
control diarrhoea in carcinoid and vasoactive intestinal peptide (VIP) secreting
tumors, and for refractory diarrhoea in AIDS patients, but needs to be given by
S.C. injection.
C. ANTIMOTILITY DRUGS
 These are opioid drugs which increase small bowel tone and segmenting
activity, reduce propulsive movements and diminish intestinal secretions while
enhancing absorption.
 They afford only symptomatic relief in diarrhoea.

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 The major action appears to be mediated through µ opioid receptors located on
enteric neuronal network, but direct action on intestinal smooth muscle and
secretory/ absorptive epithelium has also been demonstrated.
 The δ receptors are believed to promote absorption and inhibit secretion, while
the μ receptors enhance absorption and decrease propulsive movements.
 They increase resistance to luminal transit and allow more time for the
absorptive processes.
CODEINE; this opium alkaloid has prominent constipating action at a dose of 60
mg TDS.
 The antidiarrheal effect is attributed primarily to its peripheral action on small
intestine and colon.
 It does have central effects, but dependence producing liability is low.
 Side effects are: Nausea, Vomiting, and Dizziness.
 Diphenoxylate : (2.5 mg) + atropine (0.025 mg)
 Dose: 5–10 mg followed by 2.5–5 mg 6 hourly.
 It is a synthetic opioid, chemically related to pethidine; used exclusively as
constipating agent; action is similar to codeine.
 The antidiarrheal action is most prominent, but because it is absorbed
systemically and crosses blood-brain barrier—CNS effects do occur.
 Atropine is added in sub pharmacological dose to discourage abuse by taking
several tablets.
 Abuse liability is rated low, and overdose will produce disturbing atropinic side
effects.
 It has caused respiratory depression, paralytic ileus and toxic megacolon in
children.  Contraindicated below 6 years of age.

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 LOPERAMIDE: It is an opiate analogue with major peripheral µ opioid and
additional weak anticholinergic property.
 As a constipating agent it is much more potent than codeine.
 Because of poor water solubility—little is absorbed from the intestines.
 Entry into brain is negligible—CNS effects are rare and occur only with high
doses; no abuse liability.
 Duration of action is longer (12 hr).
 It also inhibits secretion.
 Loperamide inhibits peristaltic activity by a direct effect on the circular and
longitudinal muscles of the intestinal wall. It is a non-selective calcium channel
blocker and binds to opioid mu-receptors.
 Direct interaction with calmodulin may be responsible for the antidiarrheal
action.
 Adverse effects: Abdominal cramps and rashes, Paralytic ileus, toxic
megacolon with abdominal distension is a serious complication in young
children—fatalities have occurred, probably due to absorption of toxins from
the intestines.
 It is contraindicated in children < 4 yr.
 Most effective and most suitable of the antimotility antidiarrheal drugs.
 Use in non-infective diarrhoea & mild traveller’s diarrhea.
 Contraindicated in infective diarrhea-delay the clearance of pathogen.
 Careful use in mild IBD.
 Can be used to induce short term constipation Eg; after anal surgery, reduce the
volume, fluidity and bag cleaning frequency in ileostomy/colostomy patients.
4. DRUGS FOR INFLAMMATORY BOWEL DISEASE (IBD)
 IBD is a chronic relapsing inflammatory disease of the ileum, colon, or both,
that may be associated with systemic manifestations.  It is idiopathic.

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 The two major types of IBD are:
 Ulcerative colitis (UC) - colon
 Crohn’s disease (CrD) any part of the GIT.
 The drugs used in UC and CrD are the same, but their roles and efficacy do
differ.
 Drugs used in IBD can be grouped into:
5-Amino salicylic acid (5-ASA) compounds
Corticosteroids
Immunosuppressant
TNFα inhibitors.
1. 5-AMINO SALICYLIC ACID (5-ASA) COMPOUNDS:
 SULFASALAZINE (Salicylazosulfapyridine): It is a compound of (5-ASA)
with sulfapyridine linked through an azo bond, and has a specific therapeutic
effect in IBD.
 Low solubility, it is poorly absorbed from the ileum.
 The azo bond is split by colonic bacteria to release 5-ASA and sulfapyridine.
The former exerts a local anti-inflammatory effect, the mechanism of which is
not clear.
 Though it inhibits COX and LOX, decreased PG and LT production appears to
play a minor role in the therapeutic effect.
 Inhibition of cytokine, PAF, TNFα and nuclear transcription factor (NFκB)
generation seems to be more important.
 A dose of 3–4 g/day induces remission over a few weeks in many patients, but
relapses are common after stoppage.

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 Maintenance therapy with 1.5–2 g/day has been found to postpone relapse in
majority, but not all cases.
 The primary value of sulfasalazine is in maintaining remission in UC, but not in
CrD, while corticosteroids are reserved to treat acute exacerbations.
 The sulfapyridine moiety only serves to carry 5-ASA to the colon without being
absorbed proximally. However, most of the released sulfapyridine is absorbed
in the colon and is responsible for adverse effects like rashes, fever, joint pain,
haemolysis and blood dyscrasias.
 Nausea, vomiting, headache, malaise and anemia are other frequent dose related
side effects.

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 Oligozoospermia and male infertility is reported.  It interferes with folate
absorption.
 Folic acid supplementation should always be given during its use.
 Sufasalazine has also been used as a disease modifying drug in rheumatoid
arthritis.
 The absorbed sulfapyridine moiety appears to be responsible for the therapeutic
effect.
MESALAZINE (MESALAMINE): 5-ASA compound.
 Primary use in preventing relapses of UC.
 Not effective orally.
 Better tolerated.
 Side effects: Nausea, Abdominal pain, Nephrotoxic, Enhance the gastric
toxicity of corticosteroids and hypoglycemic action of sulfonylureas.
 MOA: The MOA of mesalazine is not fully understood, it is believed to possess
a topical anti-inflammatory effect on colonic epithelial cells. Mucosal
production of arachidonic acid metabolites, both through the cyclooxygenase
pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e.,
leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with
chronic inflammatory bowel disease, and it is possible that mesalazine
diminishes inflammation by blocking cyclooxygenase and inhibiting
prostaglandin production in the colon.
 It also has the potential to inhibit the activation of Nuclear Factor kappa B
(NKkB) and consequently the production of key of pro-inflammatory cytokines.
 It has been proposed that reduced expression of PPAR gamma nuclear receptors
(gamma form of peroxisome proliferator-activated receptors) may be implicated
in ulcerative colitis.

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 There is evidence that mesalazine produces pharmacodynamic effects through
direct activation of PPAR gamma receptors in the colonic/rectal epithelium as
well.
 Increased leukocyte migration, abnormal cytokine production, increased
production of arachidonic acid metabolites, particularly leukotriene B4, and
increased free radical formation in the inflamed intestinal tissue are all present
in patients with inflammatory bowel disease it is also believed that mesalazine
has in-vitro and in-vivo pharmacological effects that inhibit leukocyte
chemotaxis, decrease cytokine and leukotriene production and scavenge for free
radicals.
 OLSALAZINE: It consists of two molecules of 5-ASA coupled together by
azo bond. Poorly absorbed in the ileum.

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 BALSALAZIDE: This is 5-ASA linked to 4-aminobenzoyl-β-alanine as the
carrier which, unlike sulfapyridine, is inert. The 5-ASA is released in the colon,
and the carrier is poorly absorbed. It can be used as a safer alternative to
sulfasalazine.
2. CORTICOSTEROIDS:
 PREDNISOLONE: 40-60mg/day effective in controlling remission in both
UC and CD.
 Symptomatic relief starts within 3-7 days and remission is induced in 2-3
weeks.
 In severe cases with systemic manifestations I.V. Methylprednisolone 40- 60mg
12 to 24 hourly for few days.
 Hydrocortisone enema or foam can be used for topical treatment of proctitis.
 Generally used for short term.
 Neither effective nor suitable for maintaining remission.
IMMUNOSUPPRESSANTS:
 Long-term management of IBD, especially CrD.
AZATHIOPRINE: Purine antimetabolite.
 Indicated in steroid resistant, steroid dependent and severe cases of IBD.
 Side effects bone marrow hyper sensitivity.
 Dose 1.5-2mg/kg/day.
METHOTREXATE: Dihydrofolate reductase inhibitor. It acts faster than
azathioprine. Doses effective in IBD are higher than those for RA. Weekly
parenteral therapy is needed  Toxicity is more.
CYCLOSERINE: Potent immunosuppressant used in UC.

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 I.V. cycloserine usually controls symptoms in 7-10 days; bridge therapy for 2-3
months till azathioprine takes effects.
 Renal toxicity
 Poor efficacy in IBD.
TNF ALPHA INHIBITORS:
 Infliximab, Adalimumab, Certolizumab
 Indicated in severe active CrD, fistulating CrD and severe UC.
 Infused every 2-8 weeks, it decreases acute flareups and helps in fistula closure.
VACCINES
 Vaccines are a new therapeutic frontier in controlling infectious diarrheas,
especially in developing countries. An oral vaccine for cholera (Vaxchora®) is
licensed and available in the United States. The Advisory Committee for
Immunization Practices (ACIP) recommends the vaccine for adults aged 18-64
years old who are traveling to an endemic area. The vaccine can reduce the risk
of severe diarrhea by about 90%. Oral Shigella vaccine, although effective
under field conditions, requires five weekly oral doses and repeat booster doses,
thereby limiting its practicality for use in developing nations.

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RECOMMENDATIONS FOR TREATING ACUTE DIARRHEA

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RECOMMENDATIONS FOR TREATING CHRONIC DIARRHEA

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REFERENCES
1. Essentials of Medical Pharmacology by K D Tripathi, 8th edition, Page
No.727-737.
2. Pharmacology & Pharmacotherapeutics by R.S Satoskar ,Nirmala N.
Rege, S.D. Bhandarkar , 24th edition , Page No. 925-935.
3. Lippincott Illustrated Reviews Pharmacology by Karen Whalen, 7th
edition, Page No.1560-1564.
4. Pharmacotherapy: A Pathophysiologic approach, 11th
edition, Joseph T.
Dipiro et.al. Page No: 1602-1623.
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