ANTIDIARRHOEAL DRUGS Dr RAGHU PRASADA M S MBBS

ANTIDIARRHOEAL DRUGS Dr. RAGHU PRASADA M S MBBS, MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1

Diarrhea: Too rapid evacuation of too fluid stools Most patients with sudden onset of diarrhea have a benign self-limited illness requiring no treatment or evaluation. Oral rehydration solution is the cornerstone for patients with acute illnesses resulting in significant diarrhea

Acute diarrhea Rehydration. WHO ORS: 1. Sodium chloride: 3. 5 g 2. Sodium bicarbonate: 2. 5 g Or Trisodium citrate: 2. 9 g 3. Potassium chloride 1. 5 g 4. Glucose: 20 g 5. Potable water: 1 liter Rice based physiological solutions. Rationale of ORS

Home solution: ½ tsp salt (3. 5 g) 1 tsp baking soda (2. 5 g Na. HCO 3) 8 tsp sugar (40 g) 8 oz orange juice (1. 5 g 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.

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-- receptors 2. Intestinal secretion-- receptors 3. 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: 4 mg initially followed by 2 mg after each subsequent stool, up to 16 mg/day. If clinical improvement 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 diphenoxylate Both combined with 25 mcg of atropine to prevent abuse. Excess dose: CNS effects, anticholinergic effects, constipation, toxic megacolon Other opioids: 1. Paregoric: 2 mg morphine/5 m. L. 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 30 m. L 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. 200 mgtid x 3 days Ciprofloxacin 500 mg Ofloxacin 400 mg X 5 to 7 days Norfloxacin 400 mg bd Levofloxacin 500 mg od Cortrimoxazole DS bd Doxycycline 100 mg 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: 4 mg 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. 6 mg twice daily oral Patch: 0. 1 -0. 2 mg/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 -250 mcg subcutaneously three times daily.

Octreotide analogs Lanreotide Vapreotide. Octreotide very useful for treating bleeding esophageal varices.

Cholestyramine: Bile salt binding resin Used in: • Bile salt induced diarrhea • Intestinal resection • Ileal disease Dose: 4 g 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 syndrome Mechanism 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.