ANTIDIARRHOEALS

BY DR.UMA NARAYANAMURTHY,ASSISTANT PROFESSOR,

DEPARTMENT OF PHARMACOLOGY

Diarrhea: defined as 3 or more loose or watery stools in a 24 hour period.In other words it is due to passage of excess water in faeces which may be due to 1.Decreased water and electrolyte absorption2.Increased secretion by intestinal mucosa3.Increased luminal osmotic load4.Inflammation of mucosa and exudation into lumen

Most patients with sudden onset of diarrhea have a benign self-limited illness requiring no treatment or evaluation.

Principles of management

• Treatment of fluid depletion, shock and acidosis

• Maintainence of nutrition• Drug therapy• Based upon severity and nature of diarrhea

management is carried on

Intravenous rehydration

• When fluid loss is severe• Components:NaClKClNaHCO3Ringer lactate commonly recommended iv

fluid

Acute diarrheaOral rehydration solution is the cornerstone for patients with acute illnesses resulting in significant diarrhea

Rehydration. WHO ORS:1.Sodium chloride: 3.5g2.Sodium bicarbonate: 2.5g OrTrisodium citrate: 2.9g3.Potassium chloride 1.5g4.Glucose: 20g5.Potable water: 1 literRice based physiological solutions.Rationale of ORS

ORT

• Administration• Non-diarrhoeal uses• Zinc in pediatric diarrhoea

Home solution:

½ tsp salt (3.5g)

1 tsp baking soda (2.5g NaHCO3)

8 tsp sugar (40g)

8 oz orange juice (1.5g KCl)

1 L water

Antidiarrheal drugs: treat only symptoms!

– Diarrhea is usually caused by infection (Salmonella, shigella, campylobacter,clostridium, E. coli), toxins, anxiety, drugs…

– In healthy adults mostly discomfort and inconvenience

– In children (particularly mal-nourished) a principal cause of death is due to excessive loss of water and minerals.

Drug therapy

• Specific antimicrobial agentsNo valueOnly on severity basisOn regular basis• Probiotics• Drugs of IBD• Non-specific agents

Antimotility agents:

– Muscarinic receptor antagonists (not useful due to side effects) and opiates:• Diphenoxylate •Difenoxin•Loperamide

– All have CNS effects – to be use carefully in treatment of diarrhea! 

Antimotility agents & anti-secretory agents:

Opiods continue to be used widely

Mechanism of action: 1. Intestinal motility-- receptors2. Intestinal secretion-- receptors3. Intestinal absorption--- & receptors

All the commonly used opioids act principally via peripheral receptors and are preferred over opioids that penetrate central nervous system

Loperamide:

•40-50 times more potent than morphine as an anti- diarrheal agent

•Increases small intestinal and mouth to cecum transit time.

•Increases anal sphincter tone

•Anti-secretory activity against cholera toxin and some forms of E.coli toxin

Loperamide:

Half- life 11 hours

Dose: 4mg initially followed by 2mg after each subsequent stool, up to 16mg/day.

If clinical improvement does does not occur in acute diarrhea within 48 hours, DISCONTINUE loperamide

Not recommended in children <2 years.

Loperamide:

•Effective in travellers diarrhea

•Used alone or in combination with antimicrobial agents (trimethorim with or without sulfamethoxazole)

•Adjunctive treatment in almost all forms of chronic diarrheal diseases.

•Lacks significant abuse potential

•Overdose: CNS depression, paralytic ileus, toxic megacolon.

Difenoxin-

Active metabolite of diphenoxylateBoth combined with 25 mcg of atropine to prevent abuse.Excess dose: CNS effects, anticholinergic effects,

constipation, toxic megacolon

Other opioids:

1. Paregoric: 2mg morphine/5mL.2. Deodorized tincture of opium.

DO not use loperamide in:

1. Patients with bloody diarrhea

2. High fever

3. Systemic toxicity

4. Worsening diarrhea despite treatment

Racecadotril:

•A dipeptide•Reinforces effects of endogenous enkephalins on the opioid receptor•Leads to anti-diarrheal effect

Bismuth subsalicylate:

Trivalent bismuth suspended in a mixture of magnesium aluminium silicate clay.

In stomach: Combines with HCl Bismuth oxychloride + Salicylic acid

Bismuth subsalicylate

2 tab or 30mL up to 8 times daily

•Anti-inflammatory

•Anti-bacterial

•Anti- secretoty

•Also decreases vomiting

Diphenoxylate and atropine contraindicated in acute diarrhea because of rare precipitation of toxic megacolon.

GIVE APPROPRIATE ANTIBIOTICS, IF CAUSATIVE ORGANISM IS KNOWN

Rifaximin: Non absorbed oral antibiotic . 200mgtid x 3 daysCiprofloxacin 500mgOfloxacin 400mg X 5 to 7 daysNorfloxacin 400mg bdLevofloxacin 500mg odCortrimoxazole DS bdDoxycycline 100mg bd

Liquid paraffin - No longer recommended - more ADR

Malabsorption of fat soluble vitamins

It foreign body reactions in small bowel (paraffinoma

fecal leak at anal canal & pruritus ani

Treatment of Chronic diarrhea

A number of antidiarrheal agents may be used in certain patients with chronic diarrheal conditions.

Opioids are safe in most patients with chronic, stable symptoms.

Loperamide: 4mg initially ,then 2 mg after each loose stool ( maximum: 16 mg/d).

Diphenoxylate with atropine: One tablet three or four times daily as needed.

Treatment of Chronic diarrhea

Codeine and tincture of opium: Chronic, intractable diarrhea. Codeine 15-60 mg every 4 hours

Tincture of opium: 10-25 drops every 6 hours

Clonidine:Inhibits intestinal electrolyte secretion

Used in:•Secretory diarrhea•Diabetic diarrhea•Cryptosporiodiosis

Dose: 0.1-0.6mg twice daily oral

Patch: 0.1-0.2mg/day

Octreotide: Somatostatin analog

•Stimulates intestinal fluid and electrolyte absorption•Inhibits intestinal fluid secretion•Inhibits release of gastrointestinal peptides.

Given for: secretory diarrheas due to tumors--- VIPomas, Carcinoid, AIDS related diarrhea

Dose: 50-250mcg subcutaneously three times daily.

Octreotide analogsLanreotideVapreotide.

Octreotide very useful for treating bleeding esophageal varices.

Cholestyramine:

Bile salt binding resin

Used in: •Bile salt induced diarrhea•Intestinal resection•Ileal disease

Dose: 4g once to three times daily

Bulk forming and hydroscopic agents:

Carboxymethylcellulose & Calcium polycarbophil– absorb water and stool bulk.Useful in mild chronic diarrhea in patients with irritable bowel syndromeMechanism of action: Works as a gel to modify stool texture & viscosity to produce perception of decreased stool fluidity.

Others:Clays such as kaolin and other silicates like attapulgite ( magnesium aluminium disilicate) bind water avidly.

Kaolin and pectin: useful in mild diarrhea.

Calcium channel blockers like verapamil and nifedipine: decrease gut motility, promote intestinal water absorption.

Berberine:

Plant alkaloid. It has:•Antimicrobial activity•Inhibits smooth muscle contraction•Delays intestinal transit by antagonizing effects of acetylcholine.

Chloride channel blockers:Antisecretory agents.Calmodulin inhibitors including chlorpromazine and ZALDARINE MALEATE

Drugs for IBD

• Steroids • Immunosuppressants• TNF alpha inhibitors• 5-ASA compoundsSulfasalazineMesalazineOlsalazineBalsalazide