Therapies for Constipation: Laxatives, Cathartics, & Prokinetics PDF

Therapies for constipation: Laxatives Cathartics and Prokinetic Agents Nissar A. Darmani Professor of Pharmacology Associate Dean Research Office Room # 2301 This is a recorded lecture Ask questions via Elentra or e-mail E-mail: n...

Therapies for constipation: Laxatives Cathartics and Prokinetic Agents Nissar A. Darmani Professor of Pharmacology Associate Dean Research Office Room # 2301 This is a recorded lecture Ask questions via Elentra or e-mail E-mail: [email protected] January 9, 2025 1  Objectives 1. Discuss the therapies used for constipation: some are covered in this lectures and others in the IBS lecture 2. What are laxative and cathartic agents? 3. Why are laxatives/cathartics divided into different classes? 4. Discuss the pharmacology of bulk-forming laxatives 5. Explain the pharmacology of saline laxatives 6. Understand the pharmacology of stool-wetting agents and softeners 7. What are stimulant laxatives? Describe their pharmacology and clinical uses 8. Discuss the pharmacology of different classes of prokinetic agents and their clinical uses. 2  Laxatives & Cathartics I Promote defecation & reduce constipation Their effects are dose-related Hundreds of products over the counter, a few available by prescription Terms such as laxatives, evacuants, and cathartics are often used interchangeably Colonic motility is important for mixing luminal contents to promote water absorption and propulsion Loading… Often constipation can be resolved by increasing fiber and water content of diet Exercise and bowel training Constipation can be caused by: Diseases: e.g., diabetes mellitus, hypothyroidism, Irritable Bowel syndrome (IBS), diverticulitis Drugs: e.g., opiates, anticholinergics, tricyclic antidepressants Improper diets that lack fiber 3  Laxatives & Cathartics II Classification Laxatives evacuate soft formed fecal material from rectum Cathartics evacuate unformed, usually watery, fecal material from the entire colon Laxatives: Convert the intestine from an absorptive to a secretory organ They relieve constipation and promote evacuation via: retention of intraluminal fluid by hydrophilic or osmotic mechanisms net absorption of fluid and electrolytes from the GIT nonpropulsive (segmenting) contractions, but propulsive contractions Are classified according to mechanism of action or the type of effects produced 4  In large doses laxatives promote catharsis Classification Mechanism of Action Type of Effect Loading… 5  Bulk-forming Laxatives I Dietary fiber, semi-synthetic polysaccharides, cellulose, Calcium polycarbophil Dietary fiber wheat Bran (6-10 g/day), is rich in lignins and contains more than 40% fiber Dietary fiber is that part of plant cell-wall that resists digestion by GIT secretions and enzymes Softness, degree of hydration and bulk of feces depend upon fiber content. There are different types of dietary fibers Colonic bacteria ferment different dietary fibers to varying degrees Fermentation of dietary fiber such as pectins produce short chain fatty acids* * are tropic for colonic epithelium and bacterial mass Fermentation can decrease stool water Fruits and vegetables contain more pectins & hemicellulose which are readily fermentable and produce less effect on stool transit, but they tend to increase stool bulk 6 Unfermented fiber (e.g., lignins) can attract water and increase both stool bulk and GIT  Bulk-forming Laxatives II Psyllium husk preparations Konsyl & Metamucil derived from plantago seeds Contain a mucilage that forms gelatinous mass with water increased colonic bacterial mass Undergo fermentation in the colon Methylcellulose (Cologel) & Carboxymethylcellulose (Citrucel) Are poorly fermentable compounds, increase fecal bulk via water absorption Calcium polycarbophil Polymer of acrylic acid and resin no significant fermentation increase fecal bulk via water absorption 7  Bulk-forming Laxatives III Mechanisms of action: Onset of action 12 – 72 hours Bind water and ions (e.g. lignins) Soften stools and increase stool bulk Decrease colonic transit time Bacterial digestive metabolites of dietary fiber (e.g. pectins) produce some osmotic activity Dietary fiber (e.g., pectins) support growth of bacteria to increase fecal mass Uses: Prevention of constipation, especially in patients with diverticulitis or irritable bowel syndrome (IBS) Acute diarrhea absorbs water and provides mass Modify effluent in ileostomy and colostomy patients 8  Saline (Osmotic) laxatives I 1. Are soluble but poorly absorbable inorganic Salts: Oral and rectal preparations are available MgSO4 Mg (OH)2 bitter taste, they induce nausea Na3PO4 oral pleasant taste, fleet enema preparation via rectum At full oral cathartic doses (e.g., 15 grams MgSO4) they can produce watery evacuation in 3 hours Lower doses produce laxative effects at 6-8 hours Rectal administration Effects are seen within 1 hour Uses Evacuation of the bowel i.e. diagnostic examination; after acute poisoning; elimination of parasites Short-term constipation at lower doses 9  Saline (Osmotic) laxatives II MgSO4 ; Mg (OH)2 ; Na3PO4 Adverse effects Flatulence Some absorption occurs Can lead to Mg toxicity in renal insufficiency Na+ salts contraindicated in congestive heart failure or renal failure Phosphate salts can induce hyperphosphatemia can reduce plasma [Ca2+] Oral phosphates not recommended in treatment of constipation due to increased risk of phosphate nephropathy Should be avoided in elderly, renal disease, patients on ACE inhibitors and angiotensin 10  Saline (Osmotic) laxatives III 2. Nondigestible sugars & alcohols Lactulose, sorbitol, mannitol are non-absorbable sugars or sugar alcohols Lactulose is a synthetic disaccharide of galactose and fructose and resists hydrolysis by human enzymes Loading… Are hydrolyzed in intestine by colonic bacteria to short chain fatty acids They produce osmotic effects & stimulate colonic motility Lactulose inhibits ammonia formation Used for chronic liver disease Glycerin for rectal route only, can cause local irritation and burning Polyethylene glycol (petroleum derivative in antifreeze) Poor absorption, retains water in colon 11  Stool-wetting agents and Emollients Docusates I Are anionic detergents are employed as emulsifying agents Act as dispersing or wetting agents Hydrate & soften stool by emulsifying feces, water and fats Stimulate adenylate cyclase net secretion of fluid & electrolytes into intestinal lumen Na docusate (Colace) Ca docusate (Surfak) K docusate (Kasof) limited absorption, excreted in bile Uses constipation, when 12  fecal material hard or dry irritation & pain (hemorrhoids) Stool-wetting agents and Emollients II oil Mineral An indigestible complex mixture of saturated hydrocarbons Petroleum derivative The only lubricant laxative available Mechanisms of action Coats stool & allows easier passage Inhibits colonic water absorption Increases stool weight and decrease stool transit time Can be administered orally or rectally Effect seen 2-3 days of use 13  Absorption: 30% after oral intake; Rectal absorption is small Stimulant (Contact) laxatives Mechanisms of action I Direct effects on enterocytes, enteric neurons & GIT smooth muscle Evoke limited lowgrade inflammation of small and large intestine Induce peristalsis via irritation of local reflexes Inhibit mucosal (Na+-K+) ATPase Na+ absorption salt and water retention in gut lumen Increase synthesis of PGE2 activation of adenylate cyclase cAMP Cl- secretion and fluid accumulation in the 14  lumen of colon Stimulant (Contact) laxatives II Diphenylmethanes Taken at bedtime Laxative effect occurs next morning Bisacodyl (Dulcolax) Tablet, also enteric coated tablets, suppository formulations Mechanism of action: Converted by intestinal 15  bacteria to an active metabolite Stimulant (Contact) laxatives III Anthraquinones Are prodrugs (glycoside conjugates) hydrolyzed by colonic bacteria to Anthraquinones colonic bacteria reduce free anthraquinones to active anthral form Effect is limited to the colon, requires 6 hours Absorbed in small intestine and excreted via bile Not effective in treating constipation Effective in prevention of constipation Can be used following surgery so that straining can be avoided Agents Senna obtained from Cassia leaves & seed pods Cascara Sagrada Obtained from buckthorn tree bark It is the mildest anthraquinone 16  Stimulant (Contact) laxatives Castor oil IV Derived from beans of caster plant Used from early Egyptian times Taken orally Is a triglyceride and is hydrolyzed to ricinoleic acid in the small intestine Increases intestinal peristaltic activity Increases NO and PAF production Increases net secretion of electrolytes and water in the intestinal lumen Has strong purgative action After oral administration effect at 2-6 Hours Do not take before going to bed Not for routine constipation treatment 17  Prokinetic Agents I gastrointestinal motility Prokinetic drugs increase Prokinetics increase the frequency/strength of GIT contractions without disrupting the normal pattern of motility and rhythm of contractions Cholinergic agents also enhance GIT contractions and motor function, but they do so in an uncoordinated manner and thus no significant propulsive motor activity occurs e.g. bethanechol or acetylcholine esterase inhibitors (neostigmine) Uses Depending upon the agent, they can be used for the treatment of abdominal discomfort, bloating, constipation, GERD, nausea, vomiting, IBS, or gastroparesis Prokinetic Agents Metoclopramide 18 Prucalopride  Prokinetic Agents II Relief of gastric retention Metoclopramide Versus Bethanechol 19 Mechanisms Prokinetic Agents of Actions III Major role Tegaserod (see IBS lecture) Prucalopride Metoclopramide Are 5-HT4 receptor Agonists Post-ganglionic primary motor Minor neuron in myenteric role plexus M3 20  Prokinetic Agents IVI Metoclopramide Mechanisms of action Dopamine stimulates dopaminergic D2 receptors Inhibits GIT motility and reduces gastro-esophageal sphincter Pressure tone Metoclopramide stimulates GI motility in a coordinated fashion via: Agonist antagonism of dopamine D2 receptors Possibly antagonism of serotonin 5-HT3 receptors (?) Agonism of serotonin 5-HT4 receptors These effects increase release of acetylcholine from post-ganglionic cholinergic nerve terminals in the myenteric plexus to evoke coordinated contractions of the upper GIT GI effects of metoclopramide can be blocked by atropine but not vagotomy 21  Prokinetic Agents MetoclopramideVII Pharmacokinetics Oral administration completely & rapidly absorbed from the GIT Significant hepatic first-pass effect bioavailability 75% No significant plasma protein binding Most metabolized by liver T1/2 4-6 hours 20% excreted unchanged by kidneys Adverse effects 22  CNS depression, drowsiness Prokinetic Agents VII 5-HT4 receptor agonists Prucalopride (Resolor) Highly selective 5-HT4 receptor agonist Low affinity for hERG-K+ channels; Thus, little potential for arrhythmogenicity Stimulates GIT motility 23  Increases gastric emptying Other Drugs used for treatment of chronic constipation and/or IBS constipation include: 1. Lubiprostone 2. Linaclotide 3. Tenapanor 4. Placanatide 5. Tegaserod See IBS Lecture note and power-point 24  Practice Questions 1. Prokinetic agents increase the frequency 2. Which drug is Not a bulk-forming and strength of gastrointestinal laxative? contractions without disrupting their rhythm. Which one of the following drugs is a 5-HT4 receptor agonist with prokinetic a) Psyllium effects: b) Methylcellulose a) Bethanechol b) Palonosetron c) d) - Lactulose* Bran c) Sodium picosulfate e) Carboxymethylcellulose d) Sorbitol e) ② Prucalopride* 25 Any Question? 26