Anti Diarrhoeal Drugs

Some Patho-Physiological Aspects Of Diarrhea

Diarrhea means differently to different people.

Definition

Frequent and excessive loss of fluid and electrolytes accompanying:

• more than 200 grams of stool per day
• major portion is water à 70-80%

Fluid content and consistency grades

1.      Grade I

Solid stool

2.      Grade II

Semi solid stool

3.      Grade III

Fluid and decal material mixed but its consistency is so much low that it takes shape of any container.

4.      Grade IV

Water content and solid material separate.

5.      Grade V

Only water content

For clinicians, grade IV and V are very dangerous, especially in children and elderly, because they rapidly develop dehydration and electrolyte imbalance.

When absorptive capacity is exceeded or less time is provided for absorption, it leads to diarrhea

From Mechanistic prospective

It can be due to:

1. Increased osmotic load in lumen
2. Secretion of water and electrolytes in lumen
3. Exudation of proteins and fluids from mucosa
4. Increased intestinal motility

All these 4 mechanisms are readily affected by:

1. Neurohormonal mechanisms
2. Pathogens
3. Drugs

Management

Correction  Of Dehydration And Electrolyte Imbalance

1. Oral rehydration therapy ORT – ORS

ORS basically exploits the nutrient dependent co-transport, which remains intact (Na and Cl transported always with glucose)

In condition where vomiting occurs, oral therapy is not effective:

I/V Rehydration

Normal saline (normotonic solution)

Ringer lactate (hypertonic solution)

So in patients, we start with Ringer’s lactate and then switch to normal saline. Never let the patient to die of hypovolemic shock.

Treat the cause
Symptomatic relief – drugs

Classification Of Anti-Diarrheal Drugs

Opiates

1. Diphenoxylate

2. Diphenoxin

3. Loperamide

Adsorbents

1. Kaolin (attapulgite)

2. Pectin

Miscellaneous

1. Bismuth subsalicylte

2. Bismuth carbonate

3. Octreotide

4. Ispagullah husk and methylcellulose

Diphenoxylate

8-10 times more potent than morphine in decreasing gastrointestinal motility.

Mechanism of Action

Opioids in gut cause decrease in intestinal motility.

So, Diphenoxylate is converted into Diphenoxin/Diphenoxilic acid (active metabolite) producing anti diarrheal effect by three mechanisms:

1. Inhibit presynaptic cholinergic nerve in submucosal and myenteric plexus by binding to peripheral mew receptors, that results in decreasing motility, leading to increased absorption of water.
2. Increased tone of anal sphincter
3. Increased mass colonic movements and gastrocolic reflex.

Side effects

Can cross BBB so adverse effects occur.

1. CNS depression
2. Respiratory depression
3. Addictive potential
   

To counter addictive potential, it is marketed with small doses of atropine

Lomotil contains 2.5 mg diphenoxylate and 0.25 mg atropine.

Subtherapeutic doses do not have anticholinergic effect on this dose.

Motefen contains 1 mg diphenoxin and 0.025 mg atropine

Rationale of using atropine

So if patient will try to use more and more Lomitil, subtherapeutic doses of atropine are converted into therapeutic doses, producing anticholinergic effects leading to:

1. Dryness of mouth
2. Constipation
3. Urinary retention

Loperamide

Mechanism of Action

Same mechanism of action, 40-50 times more potent than morphine in reducing gut motility.

Differences With Diphenoxylate

	Loperamide	Diphenoxylate
Potency	More potent	Less potent
BBB	Does not cross	Crosses BBB
	No CNS depression	CNS depression
	No addictive effect	Will occur, having analgesic effect in high doses
	Does not need atropine	Needs atropine

Contraindications

1. Ulcerative colitis

If given, increases chances of toxic mega colon (abnormal dilatation of colon) leading to increased risk of perforation and toxicity.

Ineffective diarrhea like:

2. Acute bacillary dysentery –irritation of GI leading to diarrhea
3. Amoebic dysentry

Anti motility drugs decrease the motility, leading to increased chances of toxin absorption, producing systemic adverse effects.

So as a rule, not used in children and infants.

Bismuth Subsalicylate

Mechanism of Action

Rapidly dissociates into bismuth and subsalicylate..

Bismuth then reacts with HCl and forms oxichloride which is not absorb at all.

1. Anti-Bacterial Activity

Anti bacterial effect is by adsorbing bacteria. It binds bacteria and excretes them, very effective in H. pylori infections.

2. Anti-Inflammatory Action

The other part of subsalicylate is rapidly absorbed and produces anti inflammatory effects by decreasing prostaglandins synthesis.

3. Anti-secretory activity

Side Effects

Well tolerated drug.

1. Black stools –darkening of stools, false impression of malena
2. Dark coating of tongue

Methyl Cellulose & Ispagullah Husk

These two are not true anti diarrheals.

They absorb water and reduce fecal water content, leading to increased consistency of stools and giving false impression of bettering the diarrhea.

Orally proven uses of these are two:

1. Colostomy
2. Ileostomy

Kaolin And Pectin

Active form of Kaolin is Attapulgite – hydrated Mg Al disilicate

Pectin – indigestible carbohydrate derived from apple

Mechanism of Action

Both act as absorbants of bacterial toxins and fluids and decrease stool fluidity and frequency.

Side Effect And Caution

Well tolerated.

May cause constipation.

Used cautiously when other drugs are used because they will hamper their absorption.

Octreotide

Synthetic somatostatin analogue – peptide released in GIT & pancreatic d cells, enteric nerves and hypothalamus.

Mechanism of Action

1. Inhibition of hormonal secretion

Decrease secretion of many hormones and neurotransmitters like gastrin, VIP and glucagon, insulin and CCK

2. Decreases secretions

Decreases intestinal and pancreatic secretions

3. Decreases motility

Inhibit contractions of gall bladder

4. Decreases portal blood flow

By direct vasoconstrictor action

5.  Decrease secretion of anterior pituitary hormones

Somatostatin half life is 2-3 minutes thus has limited clinical use

Octreotide half life is 1.5-2 hours, having the same actions

Uses

1. Diarrhea due to vagotomy
2. Short bowel syndrome
3. AIDs

Octreotide has multiple effects on GI motility:

1. High dose decreases motility (150-250 mcg/day)
2. Low dose increases motility
3. Carcinoid syndrome
4. Tumors that secrete increased VIP
5. Varices

Side effects

1. GIT

a.      Steatorrhea (absorption of fat soluble vitamins is decreased)
b.      Abdominal pain
c.       Flatulence
d.      Diarrhea

On long term use:

• Acute cholecystitis
• Hyperglycemia or hypoglycemia because it alters balance between insulin, growth hormone and glucagon.
• Hypothyroidism
• Bradycardia