Laxatives Domina Petric MD Introduction Intermittent constipation is

Laxatives Domina Petric, MD

Introduction Intermittent constipation is best prevented with a high-fiber diet, adequate fluid intake, regular exercise and the heeding of nature´s call. Patients not responding to dietary changes or fiber supplements should undergo medical evaluation before initiating long-term laxative treatment.

Bulk-forming laxatives • Indigestible, hydrophilic colloids that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. • Natural plant products: psyllium, methylcellulose. • Synthetic fibers: polycarbophil. • Bacterial digestion of plant fibers within the colon may lead to increased bloating and flatus.

Stool surfactant agents (softeners) • These agents soften stool material, permitting water and lipids to penetrate. • They may be administered orally or rectally. • Examples: docusate (oral, enema), glycerin suppository. • Docusate is used in hospitalized patients to prevent constipation and minimize straining. • Mineral oil is a clear, viscous oil that lubricates fecal material, retarding water absorption from the stool. • It is used to prevent and treat fecal impaction in young children and debilitated adults. • Long-term use can impair absorption of fat-soluble vitamins (K, A, D, E).

Osmotic laxatives • The colon can neither concentrate nor dilute fecal fluid. • Fecal water is isotonic throughout the colon. • Osmotic laxatives are soluble, but nonabsorbable compounds that result in increased stool liquidity due to an obligate increase in fecal fluid. Osmotic laxatives are: • NONABSORBABLE SUGARS OR SALTS • BALANCED POLYETHYLENE GLYCOL

Nonabsorbable sugars or salts • These agents may be used for the treatment of acute constipation or the prevention of chronic constipation. • Magnesium hydroxide (milk of magnesia) is a commonly used osmotic laxative. • It should not be used for prolonged periods in pateints with renal insufficiency due to the risk of hypermagnesemia. • Sorbitol and lactulose are nonabsorbable sugars that can be used to prevent or treat chronic constipation. • These sugars are metabolized by colonic bacteria, producing severe flatus and cramps.

Nonabsorbable sugars or salts • High doses of osmotically active agents produce prompt bowel evacuation (purgation) within 1 -3 hours. • The rapid movement of water into the distal small bowel and colon leads to a high volume of liquid stool followed by rapid relief of constipation. • Magnesium cistrate, sodium phosphate: it is very important that patients maintain adequate hydration by taking increased oral liquids to compensate for fecal fluid loss. • Sodium phosphate frequently causes hyperphosphatemia, hypocalcemia, hypernatremia and hypokalemia, which can lead to cardiac arrhythmias or acute renal failure.

Nonabsorbable sugars or salts • Acute renal failure may happen due to tubular deposition of calcium phosphate (nephrocalcinosis). Sodium phosphate preparations should not be used in patients who: • are frail or elderly • have renal insufficiency • have significant cardiac disease • are unable to maintain adequate hydration during bowel preparation

Balanced polyethylene glycol (PEG) • Large solutions containing PEG are used for complete colonic cleansing before gastrointestinal endoscopic procedures. • These balanced, isotonic solutions contain an inert, nonabsorbable, osmotically active sugar (PEG) with sodium sulfate, sodium chloride, sodium bicarbonate and potassium chloride. • PEG is safe: no significant intravascular fluid or electrolyte shifts occur and does not produce significant cramps or flatus. • Bowel cleansing: 2 -4 L over 2 -4 hours. • Treatment or prevention of chronic constipation: 17 g/8 oz (powder mixed with water or juices, daily use).

Stimulant laxatives • Also called cathartics. • Induce bowel movements through a direct stimulation of the enteric nervous system and colonic electrolyte and fluid secretion. Cathartics are: • ANTHRAQUINONE DERIVATIVES • DIPHENYLMETHANE DERIVATIVES

Anthraquinone derivatives • Aloe, senna and cascara: poorly absorbed, after hydrolysis in the colon, produce a bowel movement in 6 -12 hours when given orally and within 2 hours when given rectally. • Chronic use leads to a characteristic brown pigmentation of the colon: MELANOSIS COLI. Laendo. ne t

Diphenylmethane derivatives • Bisacodyl is available in tablet and suppository formulations for the treatment of acute and chronic constipation. • It is also used in conjunction with PEG solutions for colonic cleansing prior to colonoscopy. • It induces a bowel movement within 6 -10 hours when given orally and 30 -60 minutes when taken rectally. • It has minimal systemic absorption and it is safe for acute and long-term use.

Chloride channel activator • Lubiprostone is a prostanoic acid derivative labeled for use in chronic constipation and irritable bowel syndrome (IBS) with predominant constipation. • It acts by stimulating the type 2 chloride channel (Cl. C -2) in the small intestine. • This increases chloride-rich fluid secretion into the intestine, which stimulates intestinal motility and shortens intestinal transit time. • Lubiprostone has minimal systemic absorption, but it is not recommended for pregnant women (category C). • It may cause nausea (30%) due to delayed gastric emptying.

Opioid receptor antagonists • Acute and chronic opioids therapy may cause constipation by decreasing intestinal motility, which results in prolonged transit time and increased absorption of fecal water. • Use of opioids after surgery (pain treatment) and endogenous opioids released after surgery may prolong the duration of postoperative ileus: intestinal μ-opioid receptors. • Selective antagonists of the μ-opioid receptors are: METHYLNALTREXONE and ALVIMOPAN. • These agents do not readily cross the blood-brain barrier and inhibit peripheral μ-opioid receptors without impacting analgesic effects within the CNS.

Opioid receptor antagonists • Methylnaltrexone is approved for the treatment of opioid-induced constipation in patients receiving palliative care for advanced illness who have had inadequate response to other agents. • It is administered as a subcutaneous injection 0, 15 mg/kg every 2 days. • Alvimopan is approved for short-term use to shorten the period of postoperative ileus in hospitalized patients who have undergone small or large bowel resection. • It is administered orally 12 mg capsule 5 hours before surgery and twice daily after surgery (no more than 7 days).

Serotonin 5 -HT 4 receptor agonists • Stimulation of 5 -HT 4 receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves enhances the release of neurotransmitters, including calcitonin generelated peptide (CGRP). • CGRP stimulates second-order enteric neurons to promote the peristaltic reflex. • These enteric neurons stimulate proximal bowel contraction (acetylcholine, substance P) and distal bowel relaxation (nitric oxide, vasoactive intestinal peptide). • Agents are tegaserod, cisapride and prucalopride.

Serotonin 5 -HT 4 receptor agonists Tegaserod is serotonin 5 -HT 4 partial agonist that has high affinity for 5 -HT 4 receptors, but no appreciable binding to 5 -HT 3 or dopamine receptors. It was approved for the patients with chronic constipation and IBS with predominant constipation. Both tegaserod (removed from general market) and cisapride can cause serious cardiovascular events.

Serotonin 5 -HT 4 receptor agonists Prucalopride is high-affinity 5 -HT 4 agonist available for the treatment of chronic constipation in women. It does not have significant affinities for h. ERG channels and 5 -HT 1 B receptors (in constrast to tegaserod and cisaprid).

Guanylate cyclase C agonists Linaclotide is a poorly absorbed 14 amino-acid peptide that binds to the guanylate cyclase C receptor on the luminal surface of intestinal enterocytes. It activates the cystic fibrosis transmembrane conductance channels and stimulates intestinal fluid secretion.

Literature • Katzung, Masters, Trevor. Basic and clinical pharmacology. • Laendo. net