Therapies for Constipation Lecture

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Questions and Answers

Which of the following salts is commonly used in rectal preparations?

MgSO4

Mg(OH)2

Na3PO4 (correct)

All of the above

What is the typical time frame for achieving a laxative effect with a lower dose of oral MgSO4?

12-16 hours

3 hours

1 hour

6-8 hours (correct)

Which of the following is a contraindication for the use of Na+ salts as laxatives?

Hypertension

Renal insufficiency

Congestive heart failure (correct)

Gastrointestinal bleeding

Which of the following adverse effects is associated with phosphate salts?

Hyperphosphatemia Signup and view all the answers

Which of the following groups should avoid using saline laxatives?

Patients with renal disease Signup and view all the answers

Which of the following best describes the effect of pectins on stool?

They increase stool bulk and have less effect on transit time. Signup and view all the answers

What is the primary mechanism by which unfermented fiber increases stool bulk?

Attracting water into the stool. Signup and view all the answers

Which of the following is a characteristic of psyllium husk preparations?

They form a gelatinous mass with water. Signup and view all the answers

Which compound is least likely to undergo significant fermentation in the colon?

Methylcellulose Signup and view all the answers

What is the typical onset of action for bulk-forming laxatives?

12-72 hours Signup and view all the answers

How do bacterial digestive metabolites of dietary fiber contribute to laxative effects?

By producing some osmotic activity Signup and view all the answers

Which of the following is NOT a typical use for bulk-forming laxatives?

Treatment of bacterial infections of the gut Signup and view all the answers

How do readily fermentable fibers like pectins most significantly affect stool?

They increase stool bulk but do not significantly affect colonic transit time. Signup and view all the answers

Which of the following best describes the primary difference between laxatives and cathartics?

Laxatives evacuate soft, formed fecal matter, while cathartics evacuate unformed, watery fecal matter. Signup and view all the answers

Which of the following is NOT a common cause of constipation as mentioned in the text?

Excessive intake of dietary fiber Signup and view all the answers

How do laxatives generally affect the intestine?

They decrease the net absorption of fluid and electrolytes. Signup and view all the answers

According to the lecture notes, what is a characteristic of dietary fiber?

It resists digestion by GIT secretions and enzymes. Signup and view all the answers

Which of the following statements about the effects of laxatives on the colon is most accurate?

Laxatives convert the intestine from an absorptive to a secretory organ. Signup and view all the answers

What is the typical daily recommendation for wheat bran to promote regular bowel movements?

6-10 g/day Signup and view all the answers

Terms such as laxatives, evacuants, and cathartics...

are often used interchangeably Signup and view all the answers

What is the relationship between fiber content and the softness and hydration of fecal matter?

Higher fiber content generally leads to softer, more hydrated feces. Signup and view all the answers

Which of the following is NOT considered a bulk-forming laxative as listed in the text?

Magnesium hydroxide Signup and view all the answers

Colonic motility is important for:

promoting water absorption and propulsion. Signup and view all the answers

Which drug is classified as a 5-HT4 receptor agonist with prokinetic effects?

Prucalopride Signup and view all the answers

Which of the following is not a bulk-forming laxative?

Lactulose Signup and view all the answers

Which of the following drugs is indicated for chronic constipation and works by activating chloride channels in the intestine?

Lubiprostone Signup and view all the answers

What is the primary therapeutic indication for Linaclotide?

Irritable Bowel Syndrome with constipation Signup and view all the answers

Which of the following drugs is primarily used for its action in reducing abdominal pain from IBS?

Tegaserod Signup and view all the answers

Which of the following non-absorbable sugars is primarily used for chronic liver disease?

Lactulose Signup and view all the answers

What is the primary mechanism of action for stool-wetting agents like docusate?

Coating stool for easier passage Signup and view all the answers

Which stimulant laxative is derived from beans of the castor plant?

Castor oil Signup and view all the answers

Which of the following statements regarding anthraquinones is true?

They require hydrolysis by colonic bacteria. Signup and view all the answers

Which laxative has a mechanism that involves increasing intestinal peristaltic activity through hydrolysis to ricinoleic acid?

Castor oil Signup and view all the answers

How do prokinetic agents primarily function in the gastrointestinal tract?

By increasing contractions while preserving motility patterns Signup and view all the answers

What is the typical time frame for the laxative effect of bisacodyl to occur when taken at bedtime?

Next morning Signup and view all the answers

Which statement correctly describes the absorption characteristics of polyethylene glycol?

It retains water in the colon but is poorly absorbed. Signup and view all the answers

What effect do stimulant laxatives have on mucosal Na+-K+ ATPase?

Inhibits Na+ absorption Signup and view all the answers

Which type of agents primarily work by emulsifying feces, water, and fats to ease stool passage?

Stool-wetting agents Signup and view all the answers

What is the primary mechanism of action of metoclopramide in enhancing gastrointestinal motility?

Antagonism of dopamine D2 receptors Signup and view all the answers

Which of the following is a prokinetic agent that acts as a 5-HT4 receptor agonist?

Prucalopride Signup and view all the answers

What is a common adverse effect associated with metoclopramide?

CNS depression Signup and view all the answers

How is metoclopramide primarily metabolized in the body?

Metabolized by the liver Signup and view all the answers

What role does prucalopride play in managing gastrointestinal conditions?

Act as a prokinetic agent Signup and view all the answers

What is the estimated bioavailability of metoclopramide when taken orally?

75% Signup and view all the answers

Which potential side effect of prucalopride is minimized due to its low affinity for hERG-K+ channels?

Arrhythmogenicity Signup and view all the answers

What is the duration of action (T1/2) for metoclopramide?

4-6 hours Signup and view all the answers

Study Notes

Therapies for Constipation: Laxatives, Cathartics, and Prokinetic Agents

This lecture discusses therapies for constipation, including laxatives, cathartics, and prokinetic agents.
The presenter is Nissar A. Darmani, Professor of Pharmacology and Associate Dean of Research at Western University.
The lecture was recorded on January 9, 2025.

Objectives

The lecture covers various therapies for constipation. Other topics related to IBS (Irritable Bowel Syndrome) will be covered in seperate lectures.
Students will learn about laxative and cathartic agents and their classifications.
Pharmacology of bulk-forming, saline, and stool-wetting agents, and laxatives will be discussed alongside their clinical uses.
Different types of prokinetic drugs and their clinical uses.

Laxatives & Cathartics I

Laxatives promote defecation and reduce constipation.
Laxative effects are dose-related.
Many laxatives are available over-the-counter as well as by prescription.
Common terms used, such as laxatives, evacuants, and cathartics, are often used interchangeably.
Colonic motility is important for mixing luminal contents, promoting water absorption, and propulsion.
Often constipation is resolved by increasing fiber and water content in the diet.

Laxatives & Cathartics II

Classification of laxatives:
- Laxatives evacuate soft, formed stool from the rectum.
- Cathartics evacuate unformed, watery stool from the entire colon.
Laxatives convert the intestine from an absorptive to a secretory organ.
Constipation relief and bowel evacuation occurs via:
- Retention of intraluminal fluid via osmotic or hydrophilic mechanisms
- Net absorption of fluid and electrolytes from the GI tract.
- Propulsive or non-propulsive (segmenting) contractions.
Laxatives are classified according to their mechanism of action or the type of effects they produce.

Classification of Laxatives and Cathartics

Luminally active agents: Hydrophilic colloids (bulk-forming agents), osmotic agents (non-absorbable salts/sugars), stool-wetting agents/emollients.
Nonspecific stimulants or irritants: Diphenylmethanes (bisacodyl), anthraquinones (senna, cascara), castor oil.
Prokinetic agents: 5-HT4 receptor agonists, dopamine receptor antagonists, motilides (erythromycin).

Bulk-forming Laxatives I

Dietary fiber, semi-synthetic polysaccharides, cellulose, calcium polycarbophil.
Dietary fiber (e.g., wheat bran) supports healthy gut function.
Softness and stool bulk depend on fiber content.
Colonic bacteria ferment fiber to create short-chain fatty acids, which benefit the colon.

Bulk-forming Laxatives II

Psyllium preparations (e.g., Konsyl, Metamucil): Derived from Plantago seeds.
Methylcellulose (Cologel) & carboxymethylcellulose (Citrucel): Poorly fermentable, increase stool bulk through water absorption.
Calcium polycarbophil: Polymer of acrylic acid and resin, minimal fermentation, increases fecal bulk.

Bulk-forming Laxatives III

Mechanisms of action: Onset of action 12-72 hours, binding water and ions, softening stools, increasing stool bulk, decreasing colon transit time, and supporting beneficial bacteria growth.
Uses: Prevention of constipation especially in patients with diverticulitis or IBS, treating acute diarrhea.

Saline (Osmotic) Laxatives I

These are soluble but not easily absorbed inorganic salts.
Preparations are available orally or rectally (e.g., MgSO4, Mg(OH)2, Na3PO4).
They induce nausea and have a bitter taste. Oral administration may cause laxative effect in 6-8 hours.

Saline (Osmotic) Laxatives II

Adverse effects: Flatulence, some absorption may cause Mg toxicity in renal insufficiency. Sodium salts are contraindicated in patients with congestive heart failure or renal failure.
Phosphate salts can induce hyperphosphatemia that reduces calcium levels in the blood. These should be avoided in conditions like renal disease and elderly patients on ACE inhibitors or receptor blockers.

Saline (Osmotic) Laxatives III

Non-digestible sugars and alcohols: Lactulose, sorbitol, mannitol. Lactulose resists hydrolysis by human enzymes.
These are broken down by colonic bacteria into short-chain fatty acids and increase colonic motility. Used for chronic liver disease.
Glycerin (rectal route only), Polyethylene glycol, and cathartic solutions are also used.

Stool-wetting agents and Emollients I

Act as dispersing or wetting agents.
Hydrate and soften stool by emulsifying feces, water, and fats.
Stimulate adenylate cyclase, increasing fluid/electrolyte secretion into the intestinal lumen. (Na docusate, Ca docusate, K docusate.)

Stool-wetting agents and Emollients II

Mineral oil: An indigestible complex mixture of saturated hydrocarbons, the only lubricant laxative agent available.
Mechanism of action: Coats stool and makes it easier to pass, inhibits colonic water absorption, increases stool weight, and reduces stool transit time.

Stimulant (Contact) Laxatives I

Direct effects on enterocytes, enteric neurons, and GI smooth muscle; induce limited low-grade inflammation.
Induce peristalsis and inhibit (Na+ - K+) ATPase, inducing water retention in the gut lumen.
Increase PGE2 synthesis, activating adenylate cyclase, inducing chloride secretion and fluid accumulation in the gut lumen.

Stimulant (Contact) Laxatives II

Diphenylmethanes (e.g., bisacodyl): taken at bedtime, and has a laxative effect the next morning. Can be given as a tablet, coated tablet, or suppository.
Mechanism of action: Converted by intestinal bacteria into an active metabolite.

Stimulant (Contact) Laxatives III

Anthraquinones (e.g., senna, cascara sagrada).
Prodrug hydrolyzed by colonic bacteria to produce free anthraquinones.
Effective in preventing constipation after surgery because straining can be avoided

Stimulant (Contact) Laxatives IV

Castor oil: Derived from castor oil beans.
Taken orally, acts as a triglyceride that is hydrolyzed into ricinoleic acid in the small intestine.
Increases intestinal peristalsis, NO and PAF production, water secretion, and strong purgation.

Prokinetic Agents I

Prokinetic drugs increase gastrointestinal (GI) motility/contractions, but they don't disrupt rhythm of contractions.
Cholinergic agents: e.g., bethanechol and acetylcholine esterase.
Uses: Abdominal discomfort, bloating, constipation, GERD, nausea, vomiting, or gastroparesis.

Prokinetic Agents II

Metoclopramide versus bethanechol in relieving gastric retention.
Relief mechanism by increasing the frequency and strength of contractions in the GI tract.

Prokinetic Agents III

Mechanism of action of Metoclopramide, including inhibiting dopamine D2 receptors, antagonizing serotonin 5-HT3 receptors, agonism against serotonin 5-HT4 receptors, and their effects on acetylcholine release.

Prokinetic Agents IV (Metoclopramide)

Pharmacokinetics of metoclopramide, including oral administration, rapid absorption, significant hepatic first-pass effect, but high bioavailability.
Metoclopramide has relatively short half-life, mostly metabolized by the liver, and partially excreted unchanged through kidneys.

Prokinetic Agents V (5-HT4 receptor agonists)

Prucalopride (Resolor): Highly selective 5-HT4 receptor agonist with reduced risk of arrhythmogenicity compared to earlier prokinetic agents.

Other Drugs used in Constipation

Lubiprostone, Linaclotide, Tenapanor, Placanatide, and Tegaserod - these are all further information sources for IBS related constipation.

Practice Questions

Questions and answers related to identification of bulk-forming laxative, 5-HT4 receptor agonists with prokinetic effects.

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Description

This lecture explores various therapies for constipation, focusing on laxatives, cathartics, and prokinetic agents. Presented by Nissar A. Darmani, the session includes classifications, pharmacology, and clinical uses of these treatments. Students will gain insights into both over-the-counter and prescription options.