DRUGS FOR DIARRHOEA

COMPOSITION OF NEW FORMULA WHO-ORS  High sodium content ORS is use for adult diarrhea  For children and infants, low sodium glucose-based formulation is preferred because losses of sodium are less  Can be used in cholera  May cause hyponatremia in adults with cholera  The composition of new 245mmol/L formula:

Contents Concentrations Sodium chloride – 2.6 g Na+ – 75 mM Potassium chloride – 1.5 g K+ – 20 Mm Sodium citrate – 2.9 g Cl- – 65 mM Glucose – 13.5 g Citrate – 10 Mm Water – 1.0 L Glucose – 75 mM

Total osmolarity = 245 mmol/L

IMPORTANCE OF EACH INGREDIENT IN ORS 1) Potassium: Important constituent; to replace substantial loss of K+ during acute diarrhoea 2) Base (citrate, lactate, bicarbonate): To correct acidosis which developed due to loss of alkali in stools. May independently promote sodium and water absorption 3) Glucose: To capitalize on the intactness of glucose coupled Na+ absorption 4) Na+: Increase Na+ level will facilitate water retention to counter dehydration

NON-DIARRHOEAL USES OF ORAL REHYDRATION THERAPY  Post-surgical, post-burn and post-trauma maintenance of dehydration and nutrition (in place of I.V. infusion)  Heat stroke  During changeover from intravenous to enteral alimentation

SUPER ORS  ORS replaces the fluid or electrolytes what the body has lost due to diarrhoea  Glucose-based ORS can easily be made at home as per WHO standard formula:

Higher sodium preparation Low sodium preparation

Sodium chloride 3.5 g Sodium chloride 2.6 g Potassium chloride 1.5 g Potassium chloride 1.5 g Sodium citrate 2.9 g Sodium citrate 2.9 g Glucose 20.0 g Glucose 13.5 g Water 1.0 L Water 1.0 L Total osmolarity : 311 mmol/L Total osmolarity : 245 mmol/L

Preparation available: Preparation available: 1. RELYTE: one sachet dissolve in 1. ELECTRAL MULTIDOSE, 200 ml water PUNARJAL, ELECTROKIND: one 2. PEDITRAL & GENLYTE: one sachet dissolve in 1.0 L water sachet dissolve in 100 ml water

 Cereal-based ORS (Super ORS)  Has advantage of controlling diarrhoea much more effectively than the glucose-based ORS  Undigested starch is fermented in the colon to short chain fatty acid  stimulate sodium & water absorption back from the colon  Rice powder also has protein which on hydrolysis, yields amino acid-stimulate colonic salt & water absorption  Commonly used cereal-based ORS formula:

Super ORS

Pre-cooked rice flour 10.15 g Sodium chloride 0.94 g Sodium citrate 0.20 g Potassium citrate 0.44 g Water 200 ml Total osmolarity : 311 mmol/L

Preparation available: 1. CERELYTE, RICETRAL: one sachet dissolve in 200 ml water

NON-SPECIFIC ANTI-DIARRHOEAL AGENTS Anti-motility & anti secretory agents:

1) Opiod agonists: Acts by stimulating peripheral µ and δ receptors on small intestine and large intestine. µ receptors decrease motility, while δ receptors decrease intestinal secretions  Loperamide  Diphenoxylate  Difenoxin  Racecadotril

2) Anti-cholinergic: Decrease bowel motility  Hyosyamine  Dicyclomine

3) α₂-adrenergic receptor agonists: Facilitates absorption, inhibits secretions of fluids and electrolytes & increase intestinal transit time  Clonidine

4) Octreotide: Action is similar to somatostatins. Inhibit the release of 5-HT3, gastrin, secretin, CCK, motilin, pancreatic polypeptide. Reduce GIT motility, intestinal fluids & electrolytes secretions, pancreatic secretion, gall bladder contraction

DRUGS USED IN INFLAMMATORY BOWEL DISEASE

Ulcerative Colitis Crohn’s Disease

1. Aminosalicylates: 1. Anti-TNFα Drugs :  Sulfasalazine  Infliximab  Olsalazine  Adalimumab  Balsalazine  Certolizumab 2. Immunosupressant: 2. Methotrexate  Glucocorticoids: Prednisone 3. Antibiotics: & Prednisolone  Metronidazole  Cyclosporine  Ciprofloxacin  Azathioprine & 6- 4. Anti-Integrin Monoclonal antibody : Mercaptopurine  Natalizumab

Role Of Sulfalazine In Inflammatory Bowel Disease  Is a prodrug  An aminosalicylate  Commonly used in ulcerative colitis  Composed of sulfapyridine & 5-aminosalicylic acid (5-ASA)

On oral administration, sulfasalazine reach colon

Broken down by colonic bacteria (azoreductase enzyme) to sulfapyridine & 5-ASA

5-ASA acts locally by inhibiting the production of inflammatory mediators:  Inhibits the synthesis of prostaglandins (by inhibiting cyclo-oxygenase  Inhibit the production of cytokinins  Inhibit the activity of nuclear factor-kB  Suppress the generation of superoxide free radicals

While sulfapyridine get absorbed and causes side effects: nausea, vomiting, headache

Advantages Of Mesalazine Over Sulfalazine  Also 5-ASA  Well absorbed in the upper GIT, therefore has to be given as special formulations (delayed release capsule or pH-dependent tablets)  Have a lower incidence of side effects and more efficacious compared to sulfasalazine

Rational For Combining Diphenoxylate With Atropine In The Treatment Of Diarrhoea  Most popular formulation – LOMOTIL contains diphenoxylate (2.5 mg) with small doses of atropine (0.025 mg) to discourage abuse potential  Atropine, besides providing antispasmodic effects, prevents the possible abuse of diphenoxylate  Undesirable effects of atropine would appear prior to the pleasurable effects of the opioid, if the dose is increased for abuse

MECHANISM OF ACTION OF ANTI-MOTILITY & ANTI-SECRETORY DRUGS 1) Opiod agonists  Drugs: Loperamide, Diphenoxylate, Difenoxine (an active metabolite of diphenoxylate), Racecadotril  Mechanism of action: Stimulate peripheral µ as well as δ receptors present on small and large intestine  Effects: Activation of µ receptor decreases motility, while activation of δ receptor decreases intestinal secretion  Racecadotril (enkephalinase inhibitor) increases local concentration of enkephalins in intestinal mucosa which then stimulate µ and δ receptors 2) Anticholinergics  Drugs: Hyoscyamine, Dicyclomine  Effects: decrease bowel motility which results in an increase of fluid absorption, back from the intestinal tract, and a decrease in abdominal cramps 3) α2 adrenergic receptor agonists  Drug: Clonidine  Effects: facilitate absorption, inhibits secretion of fluids and electrolytes as well as increases the intestinal transit time 4) Octreotide  Actions are similar to somatostatin  Mechanism of action: Inhibition of the release of 5-HT, gastrin, secretin, CCK, motilin and pancreatic polypeptide  Effects: It reduces GIT motility, intestinal fluid and electrolyte secretion, pancreatic secretion and gall bladder contractions  Lactase digests lactose and prevents drawing of water into the GIT

Advantage Of Loperamide Over Codeine As An Anti-Diarrhoeal Agent  CNS effects and dependence liability of codeine limit its usefulness  Loperamide does not cross BBB and has neither analgesic effects nor any addiction liability

ADVERSE EFFECTS AND CONTRAINDICATIONS 1) Opiod agonists  Adverse effects: abdominal discomfort and dry mouth  Contraindications: patients with colitis, acute bacterial diarrhoea associated with high fever or blood in stool, and also for children below 2 years of age 2) Anti-cholinergics  Adverse effects: usual anti-cholinergic effects 3) α2 adrenergic receptor agonists  Adverse effects: blood pressure lowering effect 4) Octreotide  Short term adverse effects: nausea, abdominal discomfort, pain at the site of injection  Long term adverse effects: gall stone formation, hypothyroidism