Diarrhoea lecture

Anti-diarrheal drugs

Word meaning

• Greek and Latin: dia, through, and rheein, to flow or run

• Diarrhea is not a disease, but a symptom of some other problem characterized by

“either more frequent bowel movement and/or the texture of the stool is thin and sometimes watery .”

• WHO defined as “ 3 or more than 3 loose or watery stools in 24 hour period.”

• Diarrhea is abnormal: increase in frequency liquidity of stool.

• Main factor in causation of diarrhea.

• Increase GI motility and

• Decrease intestinal ability to absorb water from stool

• Increase in GI secretion

Causes of diarrhea

Diet ( eating something that is difficult to digest )

Genetic Disorder ( lactase deficiency )Infection ( bacterial, viral, parasitic )Drug-inducedStress (IBS)Anxiety

Diarrhea may be classified into:- Acute ( sudden onset )

Food induced ( traveler’s )

- Chronic ( 2 weeks or longer ) IBD, Stress or Irritable bowel syndrome

Classification of diarrhea

Causes of acute infectious diarrhea

• Noninflammatory Diarrhea1. Viral - Norwalk virus, Norwalk-like virus, Rotavirus2. Protozoal - Giardia lamblia, Cryptosporidium3. Bacterial - Preformed enterotoxin production Staphylococcus aureus, Bacillus cereus, Clostridium perfringens Enterotoxin production; Enterotoxigenic

E coli (ETEC), Vibrio cholerae

Causes of chronic diarrhea

• Osmotic diarrhea CLUES: Stool volume decreases with fasting;

increased stool osmotic gap1). Disaccharidase deficiency: lactose

intolerance• Secretory diarrhea• Drug induced diarrhea

Osmotic diarrhea

• Under normal circumstances, the major osmoles are Na+, K+, Cl–, and HCO3–. The stool osmolality may be estimated by multiplying the stool (Na+ + K+) × 2 (multiplied by 2 to account for the anions)

• The osmotic gap is the difference between the measured osmolality of the stool (or serum) and the estimated stool osmolality and is normally less than 50 mosm/kg

Secretory diarrhea

• Large volume ( >1 L/d); little change with fasting; normal stool osmotic gap

1. Hormonally mediated: VIPoma, carcinoid, medullary carcinoma of thyroid (calcitonin), Zollinger-Ellison syndrome (gastrin)

2. Factitious diarrhea (laxative abuse): phenolphthalein, cascara, senna

3. Villous adenoma4. Bile salt malabsorption (ileal resection; Crohn's

ileitis; postcholecystectomy)

Drugs causing diarrhea

• Magnesium antacids• Antibiotics :erythomycin• GI prokinetic drugs: cisapride• Quinidine• Prostaglandin analoguage

Patho-physiologyWater and electrolyte are absorbed as well as secreted in intestine.Jejunum is freely permeable to salt and water which are passively absorbed secondary to

nutrient( glucose, amino acid, ect,) In jejunum most water absorption occurs passively in response to the osmotic pressure generated by absorption of soluble products of digestion.

An excess of unabsorbed material in gut cause increase water in stool thus it may cause diarrhea.

In Ileum and colon active Na k ATPase mediated salt absorption.Inhibition of Na k ATPase cause structural damage to mucosal cell lead to diarrhea by

reduced absorption.

Intracellular cyclic nucleotide are important regulators of absorptive and secretary processes.

Increase in cAMP and cGMP cause net loss of salt and water both by inhibition of NaCl absorption in villous cell and by promoting secretion in crypt cell.

Principles of management

a) Treatment of fluid depletion

b) Maintenance of nutrition.

c) Drug therapy

ASSESSMENT OF DEHYDRATION

DehydrationMild Moderate Severe

Appearance irritable,thirsty

irritable,verythirsty

lethargy,coma, orunconscious

AnteriorFontanelle

normal depressed markedlydepressed

Eyes normal sunken sunken

DehydrationMild Moderate Severe

Tongue normal dry very dry,furred

Skin normal slowretraction

very slowretraction

Breathing normal rapid very rapid

DehydrationMild Moderate Severe

Pulse normal rapid andlowvolume

feeble orimperceptible

Urine normal dark scanty

Weightloss

< 5% 6 - 9% 10% or more

a) Rehydration therapy

A) Oral rehydration : If fluid loss is mild < 5 % body weight moderate 6-9 % body weight

B) Intra venous rehydration: More than 10%body weight

ORS-History

• First developed in the early 1950’s and was formulated to minor ions lost in stool.

• In the early 1960’s the mechanism by which ORT works, the coupled transport of sodium and glucose, was discovered.

• In 1971, the efficacy of ORT demonstrated during an epidemic of cholera in a refugee camp in Bangladesh.

• World Health Organization estimates that 90% of diarrheal deaths worldwide could be prevented with appropriate treatment with ORS

Oral rehydration

Principles of oral rehydration salt/solution: a) Isotonic or hypotonic(total osmolarity 200-

300)b)Molar ratio of glucose should be higher or

equal than sodium.c)Enough potassium and bicarbonate/citrate

should be provided to make up losses in stool.

New formula WHO-ORS• CONTENT CONCENTRATION

• NaCL :2.6 gm Na 75 mM• KCL :1.5 gm K 20 mM• Trisod. Citrate:2.9 gm Cl 65 mM• Glucose:13.5 gm Citrate 10 mM • Water:1 L Glucose 75 mM

Total osmolarity 245 mOsm/L

Questions related to ORS

How should I prepare ORS?How do I feed the solution?What if the child vomits?How do I store the ORS solution?How do I measure the Salt and Sugar?

Questions related to ORS

How should I prepare ORS?How do I feed the solution?What if the child vomits?How do I store the ORS solution?How do I measure the Salt and Sugar?

ADMINISTRATION OF ORS

• Drink ORS at ½-1 hourly intervals.• Subsequently it may be left to demand but it

should cover the rate of loss in stool.

• 5-7.5 % BW volume equivalent is given in 2-4 hours. In children (5 ml/kg/hr).

5gm of table salt +

20gm sugar +One liter of boiled and cooled water

Non diarrheal uses of ORS

a) Post surgical, post burn and post trauma patient maintenance of hydration and nutrition.

b) Heat strokec) During change over from intravenous to

enteral alimentation.

Intra venous rehydration

• Use when > 10% BW• Recommended composition of i.v. fluid (Dhaka

fluid): NaCl 85 mM=5 g KCL 13 mM=1 gNaHCO3 48mM=4 g in 1Lof water or 5%

glucose solution.

Intravenous therapy Age First give Then give

child 30 ml/kg in 1 hour 70 ml/kg in 5 hour

adult 30 ml/kg in 30 min. 70 ml/kg in 2 & ½ hour

b) Maintenance of nutrition

• Patients of diarrhea should not be starved.• Fasting decreases brush border

disacchairedase enzyme and reduces absorption of salt water and electrolyte and these may lead to prolonged diarrhea.

c) Drug therapy

1)Nonspecific antidiarreal drug

2)Drugs for inflammatory bowel disease (IBD)

3)Probiotics

4)Specific antimicrobial drug

1) Non specific anti diarrheal drugs.

1) Opioid agonists: Loperamide Diphenoxylate Racecadotril2)Anticholinergics: Dicyclomine Hyoscyamine3)Alpha-2 Adrenergic receptor agonists: Clonidine4)Octereotide

Opioid agonists

• M/A: act on mu and delta receptor• mu activation lead to decrease motility.• Delta activation lead to decrease intestinal

secretion.---------------------------------------------------------------------• Loperamide:4 mg followed by 2 mg after each

loose motion maximunm up to 16 mg/day• Difenoxylate 2.5 mg TDS • Racecadotril:100-300 mg TDS

• A/E:• Abdominal discomfort, dry mouth• constipation

• C/I• Patient suffering from acute bacterial diarrhea• Children < 2 years• Lactating mothers• Patient suffering from colitis.

Anticholinergics:

M/A: • Decrease bowel motility : this lead to increase absorption of fluid back from

intestinal tract• Decrease in abdominal cramps.• Not use as a mono therapyCan be used with combined with Opioid agonists

Alpha-2 Adrenergic receptor agonists

• Facilitates absorption• Inhibit secretion of fluids and electrolyte• Specifically used in diarrhea caused by opiate

withdrawal & diabetic diarrhea.• Clonidine: 0.1 mg BD oral

octereotide

• Synthetic octapeptide • Decrease release of

5HT,gastrin,secretin,motilin.• Reduces GI motility, intestinal fluid and

electrolyte secretion.

A/E:slight nausea ,abdominal discomfort and pain

• Mainly used for secretory diarrhea.• Dose: 100 mcg TDS sub cutaneously.• A/E• Short term therapy:• Slight nausea,abdominal discomfort,pain at a

site of injection• Long term therapy:• Gall stone formation,hypothyroidism.• Impaired pancreatic secretion lead to

steatorrhoea which can lead to fat soluble vitamin deficiency.

2) Drug therapy for inflammatory bowel disease

ULCERATIVE COLITIS

1. Aminosalicylates5-aminosalicylic acidSulfasalazine(5-ASA+sulfapyridine)Olsalazine(5-ASA+5-ASA)Balsalazide (5-ASA+aminobenzoyl alanine)Mesalamine (TR)

• Azo compounds• Least absorbes from stomach.• When they reach terminal ileum and colon,

colonic bacteria split azo compound by an azoreductase enzyme

• Release 5-ASA at site of action.• 5-ASA has topically anti inflammatory action• Inhibit nuclear factor kb.(pro inflammatory

cytokine)

As immunosuppressant

Glucocorticoids1. Prednisone2. Prednisolone3. Hydrocortisone4. BudenosideCyclosporin

Azathioprine and 6-Mercaptopurin

CROHN’S DISEASE1)Anti –TNF alpha• Infliximab• Adalimumab• Certolizumab2)Methotrexate

1)Anti –TNF alpha

• Monoclonal antibody –cross linked with TNF-alpha lead to inhibits T cell and macrophase functions

• Release of other pro inflammatory cytokines is prevented.

• Decrease prostaglandin secretion

Methotrexate

• It is a cytotoxic agent• Useful in relapse case of crohn’s disease.• Act as a immunosuppressive agent and also • Have anti inflammatory property.

3) Probiotics

• These are live non pathogenic bacteria or yeast .

• Probiotics contain variable lactobacillus species and yeast

• Acetic acid and propionic acid produced by these bacilli lower intestinal pH and inhibit growth of certain pathogenic intestinal bacteria.

• Eg: home made curd,butter milk,yogurt etc.

Anti microbial drugs: regularly useful

a)cholera: Tetracyclin: reduce stool volume to nearly half. co-trimoxazole For multidrug resistance cholera : norfloxacin/ciprofloxacinb)Campylobacter jejuni: Norfloxacin and other fluoquinolones c)Clostridium difficile: metronidazole,/vancomycind)Amoebiasis: metronidazolee)Giardiasis: metronidazole/diloxanidefuroate

“Good nutrition and hygiene can prevent most diarrhea”.

Thanks