Pharmacology of Laxatives 2024 PDF

Pharmacology of Laxatives and Therapies for Constipation February 9th 2024 Mary S. Erclik PhD PHM101  Overview Outline - Physiology of GI Water and Salt Transport - Laxative Pharmacology Bulk-forming agents Osmotic agents Surfactants and Emo...

Pharmacology of Laxatives and Therapies for Constipation February 9th 2024 Mary S. Erclik PhD PHM101  Overview Outline - Physiology of GI Water and Salt Transport - Laxative Pharmacology Bulk-forming agents Osmotic agents Surfactants and Emollients Stimulants (irritants) - Pro-kinetic Agents - Prosecretory Agents - Opioid Antagonists 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 Laxatives: Colonal prokinetic agents 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 such that laxatives are not necessary  Mechanism of Action of Laxatives Laxatives: MOA Retain luminal Decrease absorption Alter motility by inhibiting fluid by osmotic of fluid by targeting non-propulsive or bulk transport processes contractions or by mechanisms stimulating propulsive contractions Bulk and Osmotic Laxatives- Mechanism of Action Bulk Laxatives Osmotic Laxatives Laxatives Bulk Forming Laxatives (Hydrophilic Colloids) - Polysaccharide or cellulose derivatives (eg. Agar, bran, psyllium, methylcellulose, sodium carboxymethylcellulose) - Swell in water to form viscous solution/emollient gel - The fiber present in bran and psyllium ferments in the colon to produce short chain fatty acids that increase fecal mass - Increase the fecal mass and distend the colon - Must be taken with fluids to prevent obstruction formation Bulk Forming Laxatives (Hydrophilic Colloids)  Osmotic Laxatives These drugs favor water retention which stimulates peristalsis  Osmotic Laxatives Magnesium Salts - Slowly absorbed, therefore stay in the lumen and increase the amount of water in the lumen - Distends colon and stimulates catharsis Phosphate Salts - Eg. Fleet Phospho-Soda - More absorption than magnesium salts therefore require higher concentrations - High concentrations may pose risk of electrolyte imbalances - Contraindicated in the elderly, renal disease and individuals on ACE inhibitors, ARBs, NSAIDS and diuretics  Osmotic Laxatives Lactulose - Disaccharide that is resistant to hydrolysis in intestine - Increased water retention leads to increased volume of fluid in colon - In colon, lactulose is metabolized into lactic acid and fatty acids that are non-absorbable; these have an osmotic effect Polyethylene Glycol (PEG) - long-chains that are poorly absorbed and retain water due to their high osmotic pressure PEG  Stool Softeners Mineral oil: - Indigestible - May be given as enema (eg. Fleet enema) - Lubricates fecal mass, coats the gut wall to prevent water reabsorption and prevents dehydration of fecal mass - Interferes with absorption of fat-soluble vitamins - Leakage may occur  Stool Softeners/Irritant Glycerin Suppository Hygroscopic agent that draws water into fecal matter and increases peristalsis Also acts as a lubricant May cause local discomfort and sensation of burning  Stool Wetting-Agents Docusate - Surfactant that decreases surface tension of stool; allows for mixing of water and fatty substances - Softens stool - May also stimulates intestinal fluid secretion  Stimulant (Irritant) Laxatives Eg. Bisacodyl, cascara, senna Produce a low-grade inflammation in intestines that promotes water and salt accumulation; stimulates peristalsis Molecular mechanisms probably involve prostaglandins, NO, PAF and Na/K ATPase  Stimulant (Irritant) Laxatives Diphenylmethanes Bisacodyl: - Require hydrolysis by esterases for activity therefore delayed onset of >6hrs (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 - Sodium Picosulfate is another diphenylmethane Anthraquinones: Stimulants/Irritants - Eg. Senna, Cascara - Requires actions by bacteria in large intestine- causes 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; increases peristalsis - Very unpleasant taste  Laxatives- Adverse Effects Adverse effects: - Diarrhea - Abdominal pain - Cramping - Dilated colon - Mucosal inflammation  Laxatives- Adverse Effects Adverse effects, cont: - Hypokalemia: - increases the loss of sodium and decreases plasma sodium levels - activates the renin-aldosterone system - kidneys increase sodium reabsorption and increase potassium excretion  Prokinetic Agents 5-HT has and essential role in GI motility and secretion 5-HT-4 is the receptor subtype most involved in controlling motility Prucalopride is a highly selective 5HT-4 agonist used in the treatment of chronic constipation Mainly renal elimination so minimal potential for drug-drug interaction Mechanism of Prucalopride in Intestine https://doi.org/10.1016/j.apsb.2015.05.006  Pro-Secretory Agents Pro-secretory agents can stimulate electrolyte secretion into the gut lumen and thereby increase the bulk of intestinal contents Linaclotide Agonist of guanylate cyclase C receptor (GC-C) Activation results in guanylate cyclase activity and subsequently activation of CFTR- secretion of chloride and bicarbonate into lumen Very low bioavailability- may be considered to act topically; adverse effects are GI related, eg. Diarrhea, abdominal pain, flatulence 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 Very low bioavailability- topical action; adverse effects nausea, headache, vomiting, dyspepsia, dizziness and hypotension Mechanism of Prosecretory Agents in Intestine https://doi.org/10.1016/j.apsb.2015.05.006  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 - Requires subcutaneous administration Naloxegol - Orally available - Heavily metabolized and inactivated by CYP3A4, therefore potential for interaction with other foods and drugs should be considered Mechanism of Drugs used to Treat Opioid-Induced Constipation http://dx.doi.org/10.1016/S0140-6736(09)60139-2  SUMMARY - Drugs/diet that distends the intestinal wall can stimulate peristalsis and are effective treatments of constipation - Bulk laxatives including bran and psyllium increase fecal bulk and their fermentation also contributes to their laxative effect - Osmotic laxatives are usually either simple unabsorbable sugars (e.g. lactulose) or ions - Irritant laxatives (e.g. bisacodyl, senna, etc..) cause low grade inflammation in the lumen of the gut to stimulate secretions and therefore a laxative effect - Prokinetic agents such as prucalopride target specific receptors in the gut such as 5HT4 and stimulate motor activity - Prosecretory agents such as linaclotide and lubiprostone favor ion and then water secretion into the gut lumen