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Xenobiotics that promote intestinal evacuation are referred to as laxatives, cathartics, purgatives, promotility agents, and evacuants. Depending upon dose, the same xenobiotic may accomplish some or all of these tasks, with differing side effect profiles. Laxatives promote a soft-formed or semifluid stool within 6 hours to 3 days. Cathartics promote a rapid, watery evacuation within 1 to 3 hours.119 The term purgatives relates the force associated with bowel evacuation. Evacuants are commonly used for pre-procedural bowel cleansing, with an onset of action of as little as 30 to 60 minutes, but typically require 4 hours for a more complete effect. Promotility agents stimulate GI motor function via the enteric nervous system via acetylcholine, serotonin, motilin, or intestinal chloride channels.
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Laxatives are further classified into categories of bulk forming, softener or emollient, lubricant, stimulant or irritant, saline, hyperosmotic, and evacuant. Bulk-forming agents include high-fiber products such as methylcellulose, polycarbophil, and psyllium; softeners or emollients include docusate calcium. Mineral oil is the sole lubricant. None of these cathartics is used therapeutically in medical toxicology because their onset of action is delayed. Stimulant or irritant laxatives include anthraquinones (sennosides, aloe, and casanthranol), diphenylmethane (bisacodyl), and castor oil. Saline (meaning salt) cathartics, which include magnesium citrate, magnesium hydroxide, magnesium sulfate, sodium phosphate, and sodium sulfate, are used infrequently. Hyperosmotic agents, generally nonabsorbable sugars and alcohols including sorbitol and lactulose, are occasionally considered in poisoned patients. The most common process of evacuating the intestinal tract in poisoned patients is WBI.
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Chemistry and Preparation
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Magnesium citrate (C6H6MgO7) and magnesium sulfate (MgSO4, “Epsom salt”) are water-soluble salts of magnesium; magnesium hydroxide (Mg{OH}2, “milk of magnesia”) is insoluble.56 Sodium sulfate can be prepared through purification of naturally occurring brine deposits or other manufacturing processes. Sodium phosphate is supplied as a combination of the monobasic monohydrate (NaH2PO4·H2O) and dibasic anhydrous (Na2HPO4) forms. d-Sorbitol (C6H14O6), an isomer of mannitol, is a hexitol naturally occurring in many fruits and is produced commercially by the reduction of glucose. Lactulose is a water-soluble, synthetic disaccharide, 4-O-β-d-galactopyranosyl-d-fructofuranose.
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The addition reaction of ethylene oxide (C2H4O) to an ethylene glycol equivalent creates ethylene oxide polymerization into polyethylene glycol (PEG). The “n” in the molecular structure of PEG, H-(OCH2CH2)n-OH refers to the average number of repeating oxyethylene groups.60 The number after PEG represents its average molecular weight (MW). PEG, also known as macrogol, has numerous medicinal applications. It can be conjugated to pharmaceuticals to delay vascular clearance (“PEGylation”), serve as a solvent in oral liquids and soft capsules, function as a nonalcohol solubilizer and diluent for liquid oral-dose medications, provide a base for medical ointment and cosmetics, and act as a base liquid for producing vapor in electronic cigarettes.103 Low-molecular-weight PEG (eg, 300 or 400 Da), because of its advantageous solvent properties, is used to decontaminate phenol burns, although animal studies demonstrated the equal efficacy of copious (deluge) quantities of water.51 Higher-molecular-weight variants are used to promote laxation. Although PEG’s physical properties (eg, water solubility, hygroscopicity, vapor pressure, melting or freezing range, and viscosity) vary with MW and blending because of chain-length effects, the chemical properties are similar.131 PEG 3350 used in pharmaceutical, personal care, and food applications is water soluble. It has a MW range of 3015 to 3685 Da, an average number of 75.7 repeating oxyethylene units, a pH of a 5% aqueous solution of 4.5 to 7.5 at 25°C, a density of 1.09 g/cm3 at 60°C, a melting or freezing range between 53° and 57°C, a water solubility of 67% by weight at 20°C, and a viscosity of 90.8 centistokes at 100°C.130,132 PEG 3350 without electrolytes is sold for nonprescription use for short-term constipation treatment. WBI used in poison management is typically accomplished using PEG 3350 added to a balanced electrolyte lavage solution (PEG-ELS), which contains an isotonic mixture of sodium sulfate, sodium bicarbonate, sodium chloride, and potassium chloride.119
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The effects of saline cathartics are largely attributed to their relatively nonabsorbable ions that establish an osmotic gradient and draw water into the gut.104 The increased water leads to increased intestinal pressure and a subsequent increase in intestinal motility. Magnesium ions also lead to the release of cholecystokinin from the duodenal mucosa, which stimulates intestinal motor activity and alters fluid movement, contributing to catharsis.14,119,126 A lack of endogenous hydrolytic enzymes allows sorbitol and lactulose to reach the colon unchanged. Colonic bacteria metabolize sorbitol into acetic and other short chain fatty acids and lactulose into lactic acid and small amounts of formic and acetic acids. This results in a slight acidification of colonic contents, an increase in osmotic pressure that draws water into the lumen, and stimulation of colonic propulsive motility.119
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Long-chain PEGs (eg, MW ~3350 Da) are nonabsorbable, isoosmotic, indigestible molecules that remain in the colon together with the water diluent, resulting in WBI primarily by the mechanical effect of large-volume lavage. The added balanced electrolyte solution practically eliminates electrolyte abnormalities and helps preclude fluid shifts across the GI mucosa. Sodium sulfate in many preparations reduces sodium absorption in the small intestine because of the absence of chloride, the accompanying anion necessary for active absorption against the electrochemical gradient.83
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Promotility agents such as metoclopramide and erythromycin stimulate gut motor function. Metoclopramide mediates GI 5-HT4 receptor agonist and D2 receptor antagonist activity, which both result in increased acetylcholine release and GI motility. Erythromycin also stimulates gut motor function but via direct stimulation of GI motilin receptors.139 Lubiprostone is a promotility drug that stimulates chloride secretion and enhances the contraction of gastric and colonic musculature.61 Although lubiprostone has been used with WBI for the treatment of constipation, their combined use has not yet been reported in poisoned patients.
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Absorption of magnesium, phosphate, and other electrolytes contained in hypertonic products is well described and may risk morbidity.27,98,104 In one prospective, nonrandomized study, nine of 14 patients developed elevated magnesium concentrations (2.2–5.0 mEq/L) after multiple doses of magnesium-containing cathartics for suspected drug overdose despite normal blood urea nitrogen and creatinine values.123 During the 24 hours after administration of oral sodium phosphate solution in seven healthy volunteers, serum phosphorus reached a mean peak of 7.6 mg/dL (range, 3.6–12.4 mg/dL), and ionized calcium reached a mean nadir 4.6 mg/dL (range,4.4–5.2 mg/dL).27
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By virtue of its high osmotic nature long-chain PEG is poorly absorbed, is retained in the lumen, and does not distribute. PEG is therefore eliminated unmetabolized in rectal effluent.
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Patients ingesting 45 mL of an aqueous sodium phosphate preparation taken the evening before and the morning of a procedure initiated bowel activity within 1.7 hours of the first dose and within 0.7 hours of the second dose, with a mean duration of activity of 4.6 and 2.9 hours, respectively, and an end of bowel activity within 4 to 5 hours.74 In six volunteers, saline cathartics decreased activated charcoal (AC) mean GI transit time from 29.3±1.2 hours to 24.4±1.2 hours, 15.4±3.0 hours, 17.3±1.9 hours, and 17.5±2.3 hours with sodium chloride, sodium sulfate, magnesium sulfate, and a proprietary cathartic “salt” (36.7% anhydrous citric acid, 17.65% magnesium sulfate, and 45.6% sodium bicarbonate), respectively.105 When different cathartics were compared with respect to time to first stool and number of stools,54,68,96,97,127 sorbitol produced 10 to 15 watery stools and the most abdominal cramping before catharsis. Sorbitol produced stools in the shortest amount of time, which also was associated with the highest incidence of nausea, vomiting, generated gas, and flatus.62,64,99 In one systematic review, mean transit times after administration of sorbitol, magnesium citrate, magnesium sulfate, and sodium sulfate were 0.9 to 8.5 hours, 3 to 14 hours, 9.3 hours, and 4.2 to 15.4 hours, respectively.5 In comparison, the first bowel movement typically occurs relatively quickly after the initiation of WBI with PEG-ELS. Patients ingesting GoLYTELY (1.2–1.8 L/h until the rectal effluent was clear) completed their colonic preparation within 1.5 to 3 hours after averaging a total of 5.5 L per patient (range, 3–8 L).39