2024 Laxatives and Diarrhea PDF

# Antidiarrheal & Laxatives ## UAG School of Medicine The image shows the logo of the **Universidad Autónoma de Guadalajara School of Medicine**. The logo includes the text "UAG", "Universidad Autónoma de Guadalajara", "School of Medicine" and "We Make Doctors". The logo is superimposed over a pic...

# Antidiarrheal & Laxatives ## UAG School of Medicine The image shows the logo of the **Universidad Autónoma de Guadalajara School of Medicine**. The logo includes the text "UAG", "Universidad Autónoma de Guadalajara", "School of Medicine" and "We Make Doctors". The logo is superimposed over a picture of a medical team working in an operation room. ## Presentation of the lecture: - **Title**: Antidiarrheal & Laxatives. - **Speaker**: Simón Quetzalcoatl Rodríguez Lara MD, PhD. - **Institution**: UAG School of Medicine. ## Diarrhea: ### Definition: - **Acute Diarrhea**: Defined as the passage of a great number of stools of decreased form from the normal or an individual that presents with abrupt onset 3 or more loose or liquid stools above baseline in 24-h period to meet the criteria of acute diarrhea lasting 13 days. - **Persistent Diarrhea**: Typically defined as diarrhea lasting between 14 and 30 days. - **Chronic Diarrhea**: Generally considered as diarrheal symptoms lasting for greater than a month (>30 days). ### Etiology: Acute diarrhea of infectious etiology is generally associated with: symptoms of nausea, vomiting, abdominal pain and cramps, bloating, flatulence, fever, passage of bloody stools, tenesmus, and fecal urgency. ### Epidemiology: - **Leading Cause of Outpatient Visits, Hospitalizations and Loss of Quality of Life**: In USA 47.8 millions cases occurring annually with a cost upwards of US$ 150millions to health care economy. - **Acute Gastroenteritis (AGE)**: A major cause of child mortality and morbidity globally, with 760,000 deaths per year in infants and children under 5 years of age, especially in low-income countries. - **Major Cause of Medical Visits and Hospitalization**: Leads to approximately 240,000 emergency department (ED) visits annually, and the hospitalization of 1 in every 10-25 children. ### Treatment: - **Oral Rehydration**: The usage of balanced electrolyte rehydration over other oral rehydration options in the elderly with severe diarrhea or any traveler with cholera-like watery diarrhea is recommended. Most individuals with acute diarrhea or gastroenteritis can keep up with fluids and salt by consumption of water, juices, sports drinks, soups, and saltine crackers. (Strong recommendation; moderate level of evidence) - **Probiotics and Prebiotics**: The use of probiotics or prebiotics for treatment of acute diarrhea in adults is not recommended, except in cases of postantibiotic-associated illness. (Strong recommendation; moderate level of evidence) - **Non-antibiotic Therapies**: - Bismuth subsalicylates (BSSs) can be administered to control rates of passage of stool and may help travelers function better during bouts of mild to moderate illness. (Strong recommendation; high level of evidence) - In patients receiving antibiotics for TD, adjunctive loperamide therapy can be administered to decrease duration of diarrhea and increase chance for a cure. (Strong recommendation; moderate level of evidence) - **Antibiotic Therapy**: - The evidence does not support empiric anti-microbial therapy for routine acute diarrheal infection, except in cases of TD where the likelihood of bacterial pathogens is high enough to justify the potential side effects of antibiotics. (Strong recommendation; high level of evidence) - Use of antibiotics for community-acquired diarrhea should be discouraged as epidemiological studies suggest that most community-acquired diarrhea is viral in origin (norovirus, rotavirus, and adenovirus) and is not shortened by the use of antibiotics. (Strong recommendation; very low level of evidence) ### Treatment recommendations based on antibiotic choice: | Antibiotic | Dose | Treatment duration | | ----- | ----- | ----- | | Levofloxacin | 500mg by mouth | Single dose or 3-day course | | Ciprofloxacin | 750 mg by mouth or 500mg by mouth | Single dose or 3-day course | | Ofloxacin | 400 mg by mouth | Single dose or 3-day course | | Azithromycin | 1,000 mg by mouth or 500mg by mouth | Single dose or 3-day course | | Rifaximin | 200mg by mouth three times daily | 3-days | * **ETEC**: Enterotoxigenic Escherichia coli. * **Antibiotic regimens may be combined with loperamide**: 4 mg first dose, and then 2 mg dose after each loose stool, not to exceed 16mg in a 24-h period. * **If symptoms are not resolved after 24h**: complete a 3-day course of antibiotics. * **Use empirically as first line in Southeast Asia and India**: to cover fluoroquinolone-resistant Campylobacter or in other geographical areas if Campylobacter or resistant ETEC are suspected. * **Preferred regimen for dysentery or febrile diarrhea**. * **Do not use if clinical suspicion for Campylobacter, Salmonella, Shigella, or other causes of invasive diarrhea.** ## Acute Diarrhea in Children - **Relation Between Severe or Persistent Diarrhea and Etiology**: Rotavirus is the most severe enteric pathogen of childhood Diarrhea. In children with persistent diarrhea the main pathogens detected are as follows: - Rotavirus, norovirus, astrovirus, enteroaggregative Escherichia coli, and atypical E coli. - Giardia - Cryptosporidium and Entamoeba histolytica ### Clinical Condition and Risk of Severe: - **Loss of appetite, fever, vomiting, and mucus in stools are frequently associated with persistent diarrhea**. - **Fever, severe dehydration, and lethargy, which are more common in rotavirus infection, indicate systematic involvement and are associated with severe diarrhea.** ### Indications for a Medical Visit: - **A telephone triage can be appropriate in the management of uncomplicated AGE or to evaluate the need for a medical visit.** - Age <2 months - High-output diarrhea with elevated stool volumes (>8 episodes/day) - Severe underlying disease - Family-reported signs of severe dehydration - Persistent vomiting ### Assessment Of Dehydration in Children: - **Most guidelines identified loss of body weight as the most reliable parameter to assess the presence and severity of dehydration.** - **Several clinical signs and symptoms have been used to indirectly estimate the degree of dehydration.** The most recommended parameters reported by the 15 CPGs, which are Clinical Practice Guidelines, were skin turgor and sunken eyes (11/15, 73.3%), general appearance (11/15, 66.6%), capillary refill time, and mucous membranes (9/15, 60%). ### Severity of Dehydration: | Clinical sign | Mild | Moderate | Severe | | ----- | ----- | ----- | ----- | | Bodyweight | 5% loss | 10% loss | 15% loss | | Skin turgidity | Decrease | Smooth | Smooth | | Mucous | Dry | Very dry | Desquamation | | Skin colour | Pale | Gray | Marmoreal | | Urinary spend | Decrease + | Decrease ++ | Hyperazoemia | | Arterial pressure | Normal | Normal or decrease | Very decrease | | Cardiac rate | Normal or increased | Increased | Very increased | | Fontanelle (Ped) | Flat | Soft | depressed | | CNS | Comfortable | Irritable | Letargic/comatose | *Bodyweight refers to weight loses in relation to baseline bodyweight.* ### Clinical Dehydration Scale: | Characteristics | 0 | 1 | 2 | | ----- | ----- | ----- | ----- | | General appearance | Normal | Thirsty, restless or lethargic but irritable when touched | Drowsy, limp, cold or sweaty ± comatose | | Eyes | Normal | Slightly sunken | Extremely sunken | | Mucous membranes (tongue) | Moist | Sticky | Dry | | Tears | Tears | Decreased tears | Absent tears | *A score of 0 represents no dehydration; a score of 1 to 4, some dehydration; and a score of 5 to 8 moderate/severe dehydration. CDS = clinical dehydration scale* ### Modified Vesikari score: | Points | 0 | 1 | 2 | 3 | | ----- | ----- | ----- | ----- | ----- | | Diarrhea duration, h | 0 | 1-96 | 97-120 | ≥121 | | Maximum number of diarrheal stools per 24-h period (in the course of the disease) | 0 | 1-3 | 4-5 | ≥6 | | Vomiting duration, h | 0 | 1-24 | 25-48 | >49 | | Maximum number of episodes per 24-h period (in the course of the disease) | 0 | 1 | 2-4 | ≥5 | | Maximum recorded fever, °C | <37.0 | 37.1-38.4 | 38.5-38.9 | ≥39.0 | | Future health care visit | 0 | — | — | — | | Treatment | None | IV rehydration | Primary care Hospitalization | Emergency department | *Adapted from (94). IV = intravenous. There are 7 variables to differentiate whose scores range between: 0-8 mild illness, 9-10 moderate illness, >11 severe illness* ### Rehydration in Children: - **Oral rehydration solution (ORS) is universally recognized as first-line treatment is recommended by all CPGs.** - **Several ORS formulations are available worldwide: the majority of CPGs recommend hypo-osmolar (Na+ concentration 45-60 mmol/L, 11/15, 66.6%) or low-osmolality (Na+ concentration 75 mmol/L, 9/15, 60%) ORS.** - **Only a minority of CPGs considers the standard WHO solution containing 90 mmol/L of sodium (4/15, 26.6%).** - **No significant difference was observed between the formulations used in HIC and LIC according to the Na+ concentration (P = 0.56).** - **It should be, however, noted that 3 CPGs recommend the use of a specific ORS for malnourished children ReSoMal (Rehydration Solution for Malnutrition) containing 45 mmol/L Na+ and 40 mmol/L K+.** *Such variability may reflect local variations in etiologic agents causing enteritis.* ### Oral Rehydration Solutions: | Description | Previous standard ORS (1975) | Current standard ORS (2002) | ReSoMal | | ----- | ----- | ----- | ----- | | Glucose (mmol/L) | 111 | 75 | 125 | | Sodium (mEq/L) | 90 | 75 | 45 | | Potassium (mEq/L) | 20 | 20 | 40 | | Chloride (mEq/L) | 80 | 65 | 76 | | Citrate (mmol/L) | 10 | 10 | 7 | | Osmolarity (mOsm/L) | 311 | 245 | 300 | **ORS**: oral rehydration solution **ReSoMal**: rehydration solution for malnutrition ### Mechanism of action of oral rehydration solutions: - Unlike the nutrient independent sodium absorption of intestinal epithelial cells which is compromised in diarrheal disease, the sodium-glucose transporter type 1 (SGLT1) is retained and mediates transport of glucose against its concentration gradient by coupling it to sodium transport. - The resultant electropositive gradient achieves electrochemical equilibrium by transport of negative chloride ions. - The subsequent NaCl is electroneutral but creates an osmotic gradient leading to water absorption to achieve osmotic neutrality. ### Rehydration Options: - **In children who fail on oral rehydration**, other rehydration options need to be attempted such as administering fluids either by nasogastric tube (NGT) or intravenously (IV). - **NGT is preferred to IV rehydration as second-line rehydration treatment by 5 of 15 CPGs (33.3%), whereas 10 of 15 (66.6%) recommend IV rehydration rather than NGT.** - **NGT is more commonly recommended in guidelines arising from HIC and IV rehydration in LIC.** - **Enteral rehydration is associated with significantly fewer major adverse events and a shorter hospital stay than IV rehydration and is successful in most children.** - **The rapid (40-50 mL/kg within 3-6 hours) and standard (24 hours) rehydration regimens are equally effective and may be recommended.** ### Intravenous Rehydration: - **IV fluids for uncomplicated hospitalized children**: Rapid rehydration with 20 mL kg1 h1 for 2 to 4 hours followed by oral rehydration or continuous infusion of dextrose solution is adequate for initial rehydration of most patients requiring hospital assistance; use of loperamide or other antidiarrheals are contraindicated. - **IV fluids for children presenting with shock**: Rapid IV infusion of isotonic crystalloid solution (0.9% saline or lactated Ringer’s solution) with a 20-mL/kg bolus. If the blood pressure has not improved after the first bolus, a second (or even a third) bolus of 20 mL/kg should be administered >10 to 15 minutes and other possible causes of shock should be considered. - **IV fluids for children with severe dehydration without shock**: Children with severe dehydration requiring IV fluids may receive rapid rehydration with 20 mL * kg * h of 0.9% saline solution for 2 to 4 hours. - **IV fluids for maintenance**: In IV-rehydrated children, a dextrose-containing solution may be used for maintenance. After the child starts to urinate and if serum electrolyte values are known, add 20 mEq/L of K+ chloride. ### Treatment and Prevention: - **Patient level counseling on prevention of acute enteric infection is not routinely recommended but may be considered in the individual or close-contacts of the individual who is at high risk for complications. (Conditional; very low level of evidence).** - **Individuals should undergo pretravel counseling regarding high risk food/beverage avoidance to prevent TD. (Conditional; very low level of evidence).** - **Frequent and effective hand washing and alcohol-based hand sanitizers are of limited value in preventing most forms of traveler’s diarrhea but may be useful where low-dose pathogens are responsible for the illness as for an example during a cruise ship outbreak of norovirus infection, institutional outbreak, or in endemic diarrhea prevention. (Conditional recommendation; low level of evidence).** - **Bismuth subsalicylates have moderate effectiveness and may be considered for travelers who do not have any contraindications to use and can adhere to the frequent dosing requirements. (Strong recommendation; high level of evidence).** - **Probiotics, prebiotics, and synbiotics for prevention of traveler's diarrhea are not recommended. (Conditional recommendation; low level of evidence).** - **Antibiotic chemoprophylaxis has moderate to good effectiveness and may be considered in high-risk groups for short-term use. (Strong recommendation; high level of evidence).** ### Prebiotics and Probiotics: - **Prebiotics affect intestinal bacteria by increasing the numbers of beneficial anaerobic bacteria and decreasing the population of potentially pathogenic microorganisms.** These mechanisms can lead to antagonism of potential pathogens, an improved intestinal environment, bolstering the intestinal barrier, down-regulation of inflammation, and up-regulation of the immune response to antigenic challenges. - **Probiotics affect the intestinal ecosystem by impacting mucosal immune mechanisms, by interacting with commensal or potential pathogenic microbes, by generating metabolic end products such as short-chain fatty acids, and by communicating with host cells through chemical signaling.** ## Constipation: ### Definition: - Is characterized by difficult or infrequent bowel movements, often accompanied by excessive exertion during defecation or a feeling of incomplete evacuation. - Chronic idiopathic constipation is the presence during the last 3 months of 2 or more of the follows: - Lumpy or hard stools - Straining during defecation - Sensation of anorectal obstruction/blockage - Sensation of incomplete evacuation - Manual manoeuvres to facilitate defecations - Fewer than three defecations per week - Loose stools are rarely present without the use of laxatives ### Epidemiology: - In the world has a prevalence 14-16%. - Is more prevalent in women. - 68% of the patients has been constipated by 10 year prior diagnosis. - Prevalence increase after 60 years of age. ### Diseases associated with chronic constipation: - **Digestive Problems (structural and gastrointestinal)** - Neoplasia - Intestinal stenosis: ischaemic colitis, inflammatory bowel disease, post-surgical changes (flanges, adhesions) - Idiopathic rectal ulcer - Rectal intussusception - Rectal prolapse - Enterocele - Rectocele - Anal stenosis - Pelvic floor weakness - **Endocrine/Metabolic** - Diabetes mellitus - Hypothyroidism - Chronic renal failure - Hypercalcaemia - Hypermagnesaemia - Hyperparathyroidism - Hypokalaemia - Hypomagnesaemia - Multiple endocrine neoplasia I - Dehydration - Heavy metal poisoning - Panhypopituitarism - Addison’s Disease - Pheochromocytoma - Porphyria - **Neurological** - Cerebrovascular disease - Neoplasia - Autonomic neuropathy - Spinal disease - Spinal cord injuries - Parkinson’s Disease - Multiple sclerosis - **Psychiatric/Psychological** - Depression - Eating disorders - Denial of defecation - **Myopathic disorders, collagenosis and vasculitis** - Polymyositis - Dermatomyositis - Scleroderma - Systemic sclerosis - Myotonic dystrophy - Systemic lupus erythematosus - Family visceral myopathy - Amyloidosis *Adapted from Lindberg et al. 22.* ### Drugs associated with Chronic Constipation: - **Central Nervous System** - Antiepileptics (carbamazepine, phenytoin, clonazepam, amantadine, etc.) - Antiparkinson drugs (bromocriptine, levodopa, biperiden, etc.) - Anxiolytics and hypnotics (benzodiazepines, etc.) - Antidepressants (tricyclics, selective serotonin reuptake inhibitors, etc.) - Antipsychotics and neuroleptics (butyrophenones, phenothiazines, barbiturates, etc.) - **Digestive system** - Antacids (containing aluminium, calcium) - Proton-pump inhibitors - Anticholinergic antispasmodics (natural alkaloids and synthetic and semisynthetic derivatives with a tertiary and quaternary amine structure such as atropine, scopolamine, butylscopolamine, methylscopolamine, trimebutine, pinaverium, etc.) or musculotropic drugs (mebeverine, papaverine, etc.) - Antiemetics (chlorpromazine, etc.) - Supplements (salts of calcium, bismuth, iron, etc.) - Antidiarrhoeal agents - **Circulatory system** - Antihypertensives (beta-blockers, calcium-antagonists, clonidine, hydralazine, ganglion blockers, monoamine oxidase inhibitors, methyldopa, etc.) - Antiarrhythmics (quinidine and derivatives) - Diuretics (furosemide) - Hypolipidemics (cholestyramine, colestipol, statins, etc.) - **Other** - Analgesics (non-steroidal anti-inflammatory drugs, opiates and derivatives, etc.) - Antihistamines against H1 receptors - Antitussives (codeine, dextromethorphan, etc.) - Metallic ions (aluminium, barium sulphate, bismuth, calcium, iron, etc.) - Cytostatic agents *Adapted from Lindberg et al. 22.* ### Treatment of Constipation: - **Non-pharmacological measures** - High fiber intake - Water intake - Physical exercise - **Pharmacological Measures** - Bulk-forming laxatives - Osmotic laxatives - Emollient and lubricant laxatives - Prokinetic laxatives - Secretory laxatives - **Other Treatments** - Biofeedback (pelvic floor rehabilitation) - Surgery (Colectomy) ### Non-pharmacological Measures in Detail: - **High-fibre diet**: Consuming foods high in soluble fibre is recommended (fruits, vegetables, greens, legumes, nuts, rye bread) (moderate evidence, strong recommendation in favour). It is advised that fibre-rich foods be introduced gradually so that the gastrointestinal tract can adapt. - **Water intake**: Adequate fluid intake is recommended to complement the effects of fibre supplements (low evidence, weak recommendation in favour). - **Physical exercise**: Performing regular physical exercise adapted to the patient's condition is recommended (low evidence, weak recommendation in favour). ### Pharmacological Measures in Detail: - **Bulk-forming laxatives**: - Psyllium (plantago ovata) is suggested as a treatment option in people with chronic functional constipation (low evidence, weak recommendation in favour). The use of methylcellulose is recommended as an alternative to psyllium (low evidence, strong recommendation in favour). - **Mechanism of action**: Psyllium seeds are comprised of dietary fibre which, when mixed with water forms a gel-like mass that works as a mild laxative. - **Pharmacological effect**: Gel-like mass moves down a patient's digestive system and makes stools softer by increasing their water contents, lubricates the intestine, which improves the transit of stools, as the presence of the gel-like mass increases the stool bulk it also increases the tension and/or the stretch stimulus in the bowel wall which serves to trigger bowel movements. - **Osmotic laxatives**: - Polyethylene glycol is recommended as a treatment option in people with chronic constipation (moderate evidence, strong recommendation in favour). Lactulose is recommended as a treatment option in people with chronic constipation (low evidence, strong recommendation in favour). The use of polyethylene glycol is preferred over lactulose (moderate evidence, weak recommendation in favour). - **Mechanism of action**: Osmotic agent, causing excess water to be retained in the stool, stimulating a bowel movement. - **Pharmacological effect**: Is its inverse relation between molecular mass and intestinal absorbability, with practically no intestinal absorption at molecular masses exceeding 3000, its lack of intestinal enzymatic degradation or bacterial metabolism, and its water binding capacity, causing excess water in the stool. - **Emollient and lubricant laxatives**: - The use of stimulant laxatives is recommended as a rescue treatment option (moderate evidence, strong recommendation in favour). - The use of stimulant laxatives is suggested as a treatment option in people with chronic constipation who have not responded to bulk-forming and/or osmotic laxatives (moderate evidence, weak recommendation in favour). - **Bisacodyl**: - **Indications**: Indicated for cleansing of the colon as a preparation for colonoscopy in adults. - **Mechanism of action**: Is hydrolyzed by intestinal brush border enzymes and colonic bacteria to form an active metabolite [bis-(p-hydroxyphenyl) pyridyl-2 methane; (BHPM)] that acts directly on the colonic mucosa to produce colonic peristalsis. - **Emollient and lubricant laxatives**: - The use of stimulant laxatives is recommended as a rescue treatment option (moderate evidence, strong recommendation in favour). The use of stimulant laxatives is suggested as a treatment option in people with chronic constipation who have not responded to bulk-forming and/or osmotic laxatives (moderate evidence, weak recommendation in favour). - **Senosides A and B**: - **Indications**: For the over the counter treatment of constipation - **Mechanism of action**: They are metabolized by gut bacteria into the active metabolite rheinanthrone, which, appears to increase cyclooxegenase 2 (COX2) expression in macrophage cells leading to an increase in prostaglandin E2 (PGE2), associated with a decrease in aquaporin 3 expression in mucosal epithelial cells of the large intestine. A decrease in aquaporin 3 expression likely produces the laxative effect by restricting water reabsorption by the large intestine thereby increasing fecal water content. - **Target**: Aquaporin-3 inhibitor - **Prokinetic laxatives**: - Prucalopride is suggested as a treatment option in women with chronic constipation who have not responded to other treatments (moderate evidence, weak recommendation in favour). - **Prucalopride**: - **Mechanism of action**: Selective stimulator of 5-HT4 receptors. Receptors that can be found throughout the gastrointestinal tract primarily in smooth muscle cells, enterochromaffin cells, and myenteric plexus. - **Pharmacological effect**: Its activation produces the release of acetylcholine which is the major excitatory neurotransmitter in the Gl tract and further contraction of the muscle layer of the colon and relaxation of the circular muscle layer leading to the propulsion of luminal content - **Secretory laxatives**: - Lubiprostone is not marketed in Spain. Linaclotide is approved in Spain only for the treatment of irritable bowel syndrome with constipation (IBS-C). - **Lubiprostone**: - **Mechanism of action**: Activates CIC-2 chloride channels that causes an efflux of chloride ions into the lumen, which in turn leads to an efflux of sodium ions through a paracellular pathway to maintain isoelectric neutrality. As a result, water follows sodium into the lumen in order to maintain isotonic equilibrium, thereby increasing intestinal fluid secretion. - **Pharmacological effect**: Increase the intestinal fluid secretion, inducing motility in the intestine, passage of stool and alleviating symptoms. Also stimulate the recovery of muscosal barrier function by restoring tight junction protein complexes in the intestine. ### Bibliography: - Mearin F, Ciriza C, Minguez M, Rey E, Mascort J, Pena E, et al. Irritable bowel syndrome with constipation and functional constipation in adults: Treatment (Part 2 of 2). Semergen. 2017;43(2):123-40. - Mearin F, Ciriza C, Mínguez M, Rey E, Mascort J, Peña E, et al. Guía de práctica clínica: síndrome del intestino irritable con estreñimiento y estreñimiento funcional en adultos: concepto, diagnóstico y continuidad asistencial. (Parte 1 de 2). SEMERGEN-Medicina de Familia. 2017;43(1):43-56. - Merenstein D, Salminen S. 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