PHM101: Pharmacology of Laxatives and Constipation Therapies

Physiology of GI Water and Salt Balance

• Net stool fluid content is a balance of ingested or secreted fluids and salts, and fluids absorbed along the GI tract

Laxatives

• Do not use in the presence of (especially persistent) abdominal pain because there may be an obstruction
• A balanced diet should contain enough fiber and water to ensure regular bowel movements, making laxatives unnecessary

Mechanism of Action of Laxatives

• Retain luminal fluid by osmotic or bulk mechanisms
• Decrease absorption of fluid by targeting transport processes
• Alter motility by inhibiting non-propulsive contractions or by stimulating propulsive contractions

Bulk and Osmotic Laxatives

• Bulk laxatives (hydrophilic colloids) increase fecal mass and distend the colon, stimulating peristalsis
• Examples: Agar, bran, psyllium, methylcellulose, sodium carboxymethylcellulose
• Must be taken with fluids to prevent obstruction formation

Osmotic Laxatives

• Favor water retention, which stimulates peristalsis
• Examples: Magnesium salts, phosphate salts, lactulose, polyethylene glycol (PEG)

Magnesium Salts

• Slowly absorbed, increasing the amount of water in the lumen
• Distend the colon and stimulate catharsis

Phosphate Salts

• Examples: Fleet Phospho-Soda
• More absorption than magnesium salts, requiring higher concentrations
• High concentrations may pose a risk of electrolyte imbalances
• Contraindicated in the elderly, renal disease, and individuals on ACE inhibitors, ARBs, NSAIDs, and diuretics

Lactulose

• Disaccharide that is resistant to hydrolysis in the intestine
• Increased water retention leads to increased volume of fluid in the colon
• Metabolized into lactic acid and fatty acids in the colon, which have an osmotic effect

Polyethylene Glycol (PEG)

• Long-chains that are poorly absorbed and retain water due to their high osmotic pressure

Stool Softeners

• Mineral oil: lubricates the fecal mass, coats the gut wall to prevent water reabsorption, and prevents dehydration of the fecal mass
• Interferes with the absorption of fat-soluble vitamins
• May cause leakage

Stool Softeners/Irritant

• Glycerin suppository: hygroscopic agent that draws water into the fecal matter, increases peristalsis, and acts as a lubricant
• May cause local discomfort and a sensation of burning

Stool Wetting-Agents

• Docusate: surfactant that decreases the surface tension of stool, allowing for mixing of water and fatty substances
• Softens stool and may stimulate intestinal fluid secretion

Stimulant (Irritant) Laxatives

• Examples: Bisacodyl, cascara, senna
• Produce a low-grade inflammation in the intestines, promoting water and salt accumulation and stimulating peristalsis
• Molecular mechanisms may involve prostaglandins, NO, PAF, and Na+/K+ ATPase

Diphenylmethanes

• Bisacodyl: requires hydrolysis by esterases for activity, resulting in a delayed onset of >6 hours (rectal administration can produce effects as soon as 20 minutes)
• Na+/K+ inhibitor
• Can damage the intestinal mucosa; should not be used for more than 10 days

Anthraquinones

• Examples: Senna, cascara
• Requires actions by bacteria in the large intestine, causing a delayed onset of action (6-12 hours)
• Inhibit colonic mucosal Na+/K+ ATPase, resulting in the accumulation of salt and water in the colon lumen
• May directly stimulate colonic contractions

Ricinoleic Acid

• Castor oil: hydrolyzed to form ricinoleic acid, which stimulates water and electrolyte secretion and increases peristalsis
• Has an unpleasant taste

Adverse Effects of Laxatives

• Diarrhea
• Abdominal pain
• Cramping
• Dilated colon
• Mucosal inflammation
• Hypokalemia: increases the loss of sodium and decreases plasma sodium levels, activates the renin-aldosterone system, and leads to kidney increase sodium reabsorption and increase potassium excretion

Prokinetic Agents

• 5-HT has an essential role in GI motility and secretion
• 5-HT-4 is the receptor subtype most involved in controlling motility
• Prucalopride: a highly selective 5HT-4 agonist used in the treatment of chronic constipation
• Mainly renal elimination, with minimal potential for drug-drug interaction

Pro-Secretory Agents

• Stimulate electrolyte secretion into the gut lumen, increasing the bulk of intestinal contents
• Linaclotide: agonist of guanylate cyclase C receptor (GC-C), activating guanylate cyclase and subsequently activating CFTR, leading to secretion of chloride and bicarbonate into the lumen
• Lubiprostone: mechanism may involve activation of ClC-2 channel with resultant increase in chloride flux and likely also involves agonist at prostaglandin E4 receptor, which secondarily activates CFTR to increase chloride conductance

Opioid Antagonists

• Opioids can cause constipation by a mechanism distinct from their analgesic effects in the CNS
• Peripherally acting μ-opioid receptor antagonists are effective at treating drug-induced constipation without affecting the analgesia
• Methylnatrexone: a μ-opioid receptor antagonist requiring subcutaneous administration
• Naloxegol: orally available, heavily metabolized and inactivated by CYP3A4, with potential for interaction with other foods and drugs