Therapies for Constipation Lecture

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.

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.