Screening Methods of Anti Diarrheals and Laxatives Test On Animal Model

Screening of Anti-diarrheals and Laxatives Diarrhea- Frequent passage of loose or watery motions. 

Acute diarrhea

•       Sudden onset in a previously healthy person
•       Lasts from 3 days to 2 weeks
•       Self-limiting.

Chronic diarrhea

• Lasts for more than 3 weeks. 
• Associated with recurring passage of diarrheal stools, fever, loss of appetite, nausea, vomiting, weight loss, and chronic weakness.

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Causes of Diarrhea

Anti-diarrheal : Mechanism of Action

Adsorbents:

•     Coat the walls of the GI tract.
•     Bind to the causative bacteria or toxin, which is then eliminated through the stool.

Examples: Bismuth subsalicylate (Pepto-Bismol), kaolin-pectin, activated charcoal.

Anticholinergics:

•     Decrease intestinal muscle tone and peristalsis of GI tract.

Result : Slowing the movement of fecal matter through the GI tract.

Examples: Belladonna alkaloids (Donnatal), atropine, hyoscyamine.

Intestinal Flora Modifiers:

Bacterial cultures of Lactobacillus organisms work by:

• Supplying missing bacteria to the GI tract.
• Suppressing the growth of diarrhea-causing bacteria.

Example: L. acidophilus (Lactinex). 

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Opiates:

• Decrease bowel motility and relieve rectal spasms
• Decrease transit time of the bowel, allowing more time for water and electrolytes to be absorbed

Examples: Paregoric, opium tincture, codeine, loperamide, diphenoxylate.

Side Effects Of Diarrhea Agents

 Adsorbents:

• Constipation, dark stools
• Confusion, twitching
• Hearing loss, tinnitus, metallic taste, blue gums 

Anticholinergics:

• Urinary retention, hesitancy, impotence.
• Headache, dizziness, confusion, anxiety, drowsiness.
• Dry skin, rash, flushing.
• Blurred vision, photophobia, increased intraocular pressure.
• Tachycardia.

  Opiates:

• Drowsiness, sedation, dizziness, lethargy
• Nausea, vomiting, anorexia, constipation
• Respiratory depression
• Urinary retention
• Flushing, rash, urticaria

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Laxatives

These are the drugs that promote evacuation of bowel.

According to intensity of action, a distinction is made:- 

• 1) Laxative or aperient :    Milder action, elimination of soft but formed stool. 
• 2) Purgative or cathartic : Stronger action resulting in more fluid evacuation.

Constipation

• Abnormally infrequent and difficult passage of feces through the lower GI tract.
• Symptom, not a disease.
• Disorder of movement of bowel through the colon or rectum.
• Can be caused by a variety of diseases or drugs.

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Laxatives: Mechanism of Action

•     Bulk forming
•     Emollient
•     Hyperosmotic
•     Saline
•     Stimulant

Mechanism of action:

• Bulk forming
• High fiber
• Absorbs water to increase bulk in the intestine
• Distends bowel to initiate reflex bowel activity

Examples: Psyllium (Metamucil), Methylcellulose (Citrucel), Emollient.

Stool softeners and lubricants:

• Promote more water and fat in the stool.
• Lubricate the fecal material and intestinal walls.

 Examples: 

• Stool softeners : Docusate salts (Colace, Surfak)
• Lubricants :       Mineral oil

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 Hyperosmotic:

 Increase fecal water content.

Result: bowel distention, increased peristalsis, and evacuation.

Examples: Polyethylene glycol (GOLYTELY), Sorbitol, Glycerin, Lactulose (Chronulac).

Saline:

Increase osmotic pressure within the intestinal tract, causing more water to enter the intestines

Result: Bowel distention, Increased peristalsis, and Evacuation.

Stimulant:

Increases peristalsis via intestinal nerve stimulation.

Examples: castor oil , senna , cascara.

Screening of anti-diarrheal and laxatives

 In vivo models:

1. Prostaglandin-E₂ induced enteropooling
2. Castor oil induced diarrhea
3. Gastrointestinal motility test
4. Evaluation of anti-diarrheal effect in cold-restrained rats

In vitro method and vivo models-

Enteropooling Test:Purpose And Rational

The enteropooling assay in rats has been developed by Robert et al. (1976) to test the diarrheogenic property of prostaglandins for prediction of this clinically relevant side effects of several synthetic prostaglandins.

Procedure Of Enteropooling Test:

Enterpooling Test Procedure 

Evaluation Of Enteropooling Test:

Using various doses, dose-response curves can be established and potency ratios calculated.

Castor Oil Induced DiarrheaPurpose and Rational

1- The induction of diarrhea with castor oil results from the action of ricinoleic acid formed by hydrolysis of the oil.

2- Ricinoleic acid produces changes in the transport of water and electrolytes resulting in a hypersecretory response.

Procedure Of Castor Oil Induced Diarrhea

Castor Oil Induced Diarrhea

Evaluation Of Castor Oil Induced Diarrhea

• With anti-diarrheal agents dose-response curves are obtained for decrease of hypersecretion (stool weight) and for increase of the diarrhea free period are obtained.

• Inhibitors of prostaglandin biosynthesis increase the diarrhea free period.

Gastrointestinal Motility Test

Flow Chart Gastrointestinal Motility Test procedure

Evaluation Of Gastrointestinal Motility Test

The propulsion of charcoal meal through the gastrointestinal tract was measured.

Evaluation Of Anti-Diarrheal Effect in Cold Restrained RatsPurpose and Rational  

Barone et al. (1990) tested  the effects of various anti-diarrheal and other drugs on increased fecal pellet output in cold-restrained rats resembling clinical observations that stressful situations can produce diarrhea in humans.

Procedure Of Evaluation Of Anti-Diarrheal Effect in Cold Restrained Rats

Procedure Of Evaluation Of Anti-Diarrheal Effect in Cold Restrained Rats

Evaluation Of Evaluation Of Anti-Diarrheal Effect in Cold Restrained Rats

The dose in mg/kg that inhibits the cold restrained stress induced increase in fecal pellet output by 50% (ID₅₀) is determined using least-squares fit analysis directly from the regression line.

In Vitro Method

Flow Chart of Vitro Test