Antidiarrhoeal Agents

Diarrhoea
 Diarrhoea = increased stool liquidity and/or stool
weight.
 Associated with increased frequency (>3/day), perianal
discomfort, urgency, incontinence
 Causes:
 Infection (Salmonella, Shigella, Campylobacter,
Clostridium, E. coli)
 Toxins

 Anxiety

 Drugs…

 In healthy adults: discomfort and inconvenience

 In children (particularly malnourished) a principal cause
of death due to excessive loss of water and minerals
Pathophysiology
 Water and electrolytes are absorbed as well as secreted in the
intestine
 Jejunum: freely permeable to salt and water (passive)
secondary to nutrient (glucose, amino acids, etc.) absorption
 Ileum and colon: active Na+K+ATPase mediated salt absorption
occurs, primarily in the mature cells lining the villous tips, water
follows isoosmotically
 In addition glucose facilitated Na+ absorption takes place in the
ileum by Na+-glucose cotransporter; one Na+ ion is transported
along with each molecule of glucose absorbed
 This mechanism remains intact even in severe diarrhoeas
 Absorption of Cl¯ and HCO3¯ is passive (paracellular) as well
as by exchange of HCO3 ¯ for Cl¯ (transcellular)
 Bicarbonate is absorbed also by the secretion of H+ (similar to
that in proximal tubule of kidney) and Na+ accompanies it
 K+ is excreted in faecal water by exchange with Na+, as well
as by secretion into mucus and in desquamated cells
 The osmotic load of luminal contents plays an important role
in determining final stool water volume
 Inhibition of Na+K+ATPase and structural damage to mucosal
cell (by Rota virus) causes diarrhoea by reducing absorption
 Stimuli enhancing cAMP or cGMP cause net loss of salt and water, both
by inhibiting NaCl absorption in villous cells and by promoting anion
secretion (Na+ accompanies) in the crypt cells
 Many bacterial toxins, e.g. cholera toxin, exotoxin elaborated by
Enterotoxigenic E. coli (ETEC), Staph. aureus, Salmonella, etc.
activate adenylyl cyclase which enhances secretion that reaches its
peak after 3–4 hours and persists until the stimulated cells are shed in
the normal turnover, i.e. 36 hours after a single exposure.
 Prostaglandins (PGs) and intracellular Ca2+ also stimulate the
secretory process
 Diarrhoea associated with carcinoid (secreting 5-HT) and medullary
carcinoma of thyroid (secreting calcitonin) is mediated by cAMP.
 Excess of bile acids also cause diarrhoea by activating adenylyl cyclase.
 Treatment of Diarrhoea
Treatment:
Major causes:
1. Maintain fluid & electrolyte balance
1. Infection
2. Antibacterial agent (if required)
2. Food
3. Antidiarrheal agents
3. Drugs
• Intraluminal agents
4. Anxiety
• Antimotility agents
5. Toxins
• Anti secretory /Antiinflammatory agents
Treatment of Diarrhoea

 Three approaches to the treatment of severe acute

diarrhea:

 Maintenance of fluid and electrolyte balance

 Use of antimicrobial agents

 Use of non-antimicrobial antidiarrhoeal agents

 Maintenance of fluid and electrolyte
balance

 Oral rehydration is the first priority

 In the ileum there is co-transport of Na+ and glucose across the
epithelial cell
 Glucose enhances Na+ absorption and thus water uptake
 Amino acids have a similar effect
 Preparations of sodium chloride and glucose for oral use are
available in powder form, ready to be dissolved in water before
use
 Rehydration
 Intravenous rehydration
 Needed when fluid loss is
severe > 10% BW
 If patient is loosing > 10
ml/kg/hr
 Volume 10% BW to be
infused over 2-4 hrs
 Oral rehydration
 Should be either isotonic or
hypotonic
 Molar ratio of glucose > Na+
but n.g.t. 110 mM
 K+ and HCO3 to be provided
to make up for the losses in
stools
DRUG THERAPY

 It consists of:
 (i) Specific antimicrobial drugs.
 (ii) Nonspecific antidiarrhoeal drugs.
 ANTIMICROBIALS
 Limited role as :
 (i) Bacterial pathogen is responsible for only a fraction of cases.
 (ii) Even in bacterial diarrhoea, antimicrobials alter the course of
illness only in selected cases.
 (iii) Antimicrobials may prolong the carrier state
 Antimicrobials are of no value in noninfective causes, such as:
 (i) Irritable bowel syndrome (IBS)
 (ii) Coeliac disease
 (iii) Pancreatic enzyme deficiency
 (iv) Tropical sprue (except when there is secondary infection)
 (v) Thyrotoxicosis.
 (vi) Rotavirus
 (vii) Salmonellosis
 Use of anti-infective agents
 Not necessary in simple gastroenteritis since most infections
are usually viral in origin, and those that are bacterial generally
resolve without antibacterial drug therapy
 Campylobacter sp. is the commonest bacterial organism
causing gastroenteritis
 Severe infections may require Ciprofloxacin
 Chemotherapy may be necessary in some types of enteritis
(e.g. typhoid, amoebic dysentery and cholera)
Use of non-antimicrobial antidiarrhoeal
agents

 Antimotility agents
 Intraluminal agents
 Adsorbents & Absorbents: to absorb excessive

secretions
 Agents that modify fluid and electrolyte transport

 Bulk-forming agents – psyllium, hydrophilic mucilloid

(Metamucil)
 Anti-inflammatory agents
 Salicylates – decrease local inflammatory responses

 Decrease GI motility and secretions (COX inhibition)

Antimotility agents
 The main pharmacological agents that decrease motility are
 Opiates

 Muscarinic receptor antagonists

 Agents in this group are seldom employed as primary

therapy for diarrhoea because of their actions on other
systems

 Small doses of atropine are used combined with

diphenoxylate
Antimotility agents: Opioid Drugs
 Most commonly
 Adverse effect of the opioid (constipation) is exploited
 All reduce gut motility by acting on opiate receptors to
reduce Ach release by GI neurons that stimulate
contraction
 All may have unwanted effects including constipation,
abdominal cramps, drowsiness and dizziness
 Should not be used in young children

 Codeine: Morphine cogener; Metabolised to morphine

by CYP2D6
 Diphenoxylate
 Loperamide
Diphenoxylate
 It is a synthetic opioid, chemically related to pethidine
 Used exclusively as constipating agent; action is similar to
codeine
 The antidiarrhoeal action is most prominent, but because it is
absorbed systemically and crosses bloodbrain barrier—CNS
effects do occur.
 Atropine is added in subpharmacological 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
 Loperamide (Imodium)
 It is an opiate analogue with major peripheral μ opioid and
additional weak anticholinergic property
 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. The duration of action is longer
(12 hr) than codeine and diphenoxylate.
 Loperamide also inhibits secretion It improves faecal continence by
enhancing anal sphincter tone.
 Adverse effects: Abdominal cramps and rashes are the most
common side effects
 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:
contraindicated in children < 4 yr.
 Adsorbents
 Preparations:kaolin, pectin, chalk, charcoal, methyl
cellulose and activated attapulgite (magnesium aluminium
silicate)
 Kaolin: naturally occurring hydrated magnesium aluminum silicate
(attapulgite)
 Pectin is an indigestible carbohydrate derived from apples
 These agents may act by
 adsorbing microorganisms or toxins

 by altering the intestinal flora

 by coating and protecting the intestinal mucosa

 Useful in acute diarrhea but are seldom used on a chronic basis

 Usual dose is 1.2-1.5 g after each loose bowel movement
(maximum: 9 g/d)
 Kaolin-pectin formulations are not absorbed and have no
significant adverse effects except constipation
 They should not be taken within 2 hours of other medications
(which they may bind).
 Antisecretory: 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.
 Racecadotril decreases intestinal hypersecretion, without affecting
motility, by lowering mucosal cAMP due to enhanced ENK action.
 It is indicated in the short-term treatment of acute secretory
diarrhoeas.
 In contrast to loperamide/diphenoxylate, it is not contraindicated in
children.
 Side effects : nausea, vomiting, drowsiness, flatulence.
 Dose: 100 mg (children 1.5 mg/kg) TDS for not more than 7 days.
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 tumours, and for
refractory diarrhoea
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
 It has some prophylactic value in travellers’ diarrhoea; (probably
due to weak antibacterial action also), but it is rather
inconvenient to carry and take
Traveler's Diarrhea

 Occurs with very high frequency in travelers to

some specific foreign countries
 Caused most commonly by toxigenic E. coli (45-
70%)
 Other frequent causative agents include:
 Campylobacter
 Salmonella
 Shigella
 Viruses and parasites
Treatment of Traveler’s Diarrhea
 Rehydration
 Bismuth subsalicylate (Pepto-Bismol)
 1-2 tablets every eight hours for eight doses

 Has both a weak antibacterial & an anti-inflammatory

action
 Generally controls diarrhea within 24 hr

 Side Effects and Toxicities of Pepto-Bismol

 Binds tetracyclines including doxycycline which is often
used for prophylaxis of malaria
 Turns stools and tongue black

 Contains salicylate, can cause ringing in ears, and is

additive with aspirin (C/I in pts allergic to aspirin)
 Can cause GI impaction in debilitated patients
Treatment of Traveler’s Diarrhea

 Loperamide: 4 mg loading dose plus 2 mg per stool with a

max of 16 mg/day (i.e., 8 tablets)
 Antimicrobial agents are only appropriate when:
 the diarrhea is severe,

 the patient is febrile,

 bloody diarrhea is present, and/or

 the infection is persistent

 Current best antimicrobial choices:

 Ciprofloxacin (Cipro) or Ofloxacin (Floxin) in adults or

 Trimethoprim-sulfamethoxazole (Bactrim) in children

 Treat with ABs up to 3 days or until symptoms resolve

Prophylaxis of Traveler’s
Diarrhea

 Bismuth Subsalicylate: reduces TD incidence from

61% to 23%
 Antimicrobial Agents:
 The same agents used to treat diarrhea can be

given for prophylaxis.

 Don’t use ABs for more than three weeks!

 Routine use of ABs for prophylaxis should be

discouraged.
 Many physicians provide ABs & loperamide to

travelers for use if symptoms appear