The Pharmacology of Laxatives and Emetics

Describe features of laxatives (1)

Used to treat proven constipation (excessive water reabsorption and inadequate peristalsis, often in elderly patients with fibre-deficient diets)

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Describe features of laxatives (2)

Laxatives used (if increased fibre/bran is ineffective) to relieve constipation/evacuate bowel before surgical/medical procedures

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Describe features of laxatives (3)

Water-retaining bulk forming agents (e.g. unprocessed wheat bran, methylcellulose) that swell and bulk then stimulates peristalsis but can be slow onset (days)

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Describe features of laxatives (4)

Stimulant laxatives trigger peristalsis (e.g. senna, bisacodyl), acts in 6-12h, but can cause cramps or atony if used chronically. Osmotic laxatives attract water (Mg salts, lactulose). Lubricants/stool softeners, act in 20-60 min, applied locally

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Describe features of laxatives (5)

Secretagogues - new agents (50% of constipated subjects are unresponsive to conventional laxatives) approved for chronic constipation

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What are the classes of laxatives?

Bulk forming agents, osmotic laxatives, stimulant laxatives, lubricant laxatives and secretagogues

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Describe features of bulk forming agents (1)

Non-starch polysaccharides (NSPs). Ispaghula husk (indigestible vegetable material, attracts water, swells in colon, increasing peristalsis, promoting soft stool, takes several days to start working)

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Describe features of bulk forming agents (2)

Methylcellulose bran, high fibre diets (similar principle, for regular management of constipation caused by poor diet, take plenty of water with all of these, can cause flatulence and abdominal swelling). Sterculia (swells like ispaghula husk)

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Describe features of osmotic laxatives (1)

Poorly absorbed ions/carbs/hypertonic products that cause fluid movement into intestinal lumen by osmosis. Lactulose (synthetic non-absorbable disaccharide, fermented by bacteria to SCFAs, H, CO2, acts in 24-48h, suitable for chronic constipation)

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Describe features of osmotic laxatives (2)

Macrogols (inert polymers of ethylene glycol e.g. PEG, for chronic constipation, superior to lactulose, stool frequency, abdominal pain). Mg salts (Epsom salts, rapid/complete evacuation in 2-4h attracts water, used in bowel cleansing solutions)

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Describe features of osmotic laxatives (3)

S/E - abdominal distension, pain, nausea, usually less effective in more severe forms of constipation. Sodium citrate or phosphate enemas - rectal use for proven constipation and bowel clearance prior to endoscopy/surgery

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Describe features of stimulant laxatives (1)

If osmotic laxatives fail to provide relief. Induces propagated colonic contractions (suited for single dose use)

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Describe features of stimulant laxatives (2)

Bisacodyl (synthetic drug, based on active principle of senna, acts in ~8h, take night before, stimulates enteric nerves to cause peristalsis, suppository acts quicker, abuse of drug can lead to cramps, not suitable for repeatable use)

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Describe features of stimulant laxatives (3)

Senna fruit products or sodium picosulfate (prodrug like bisacodyl, all have similar laxative properties). Bisacodyl or senna are the main OTC therapies, can have limiting S/E e.g. abdominal cramps, diarrhoea, dehydration

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Describe features of stimulant laxatives (4)

Glycerol suppositories act as rectal stimulant (mild irritant). Dantron - for constipation only in terminally ill of all ages (carcinogenic in rodent models)

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Describe features of lubricant laxatives (1)

Stool softeners/emollients. Given PO with care (pneumonia as S/E), useful in management of haemorrhoids and anal fissure. Docusate sodium (detergent often used as a stool softener)

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Describe features of lubricant laxatives (2)

Arachis (peanut/ground nut) oil - warmed enema of 130 mL used to soften impacted faeces, promote bowel movement. Liquid paraffin - not recommended now as it interferes with fat (Vit D) absorption and may cause aspiration lipoid pneumonia

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Describe features of lubricant laxatives (3)

Glycerol - as a suppository for infants

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Describe features of secretagogues (1)

5HT-4 agonist (prucalopride) - for chronic constipation in men/women and elderly who are unresponsive to conventional laxatives of different classes

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Describe features of secretagogues (2)

Increases colonic transit by stimulating 5HT4 in colonic mucosa and enteric nerves involved in colonic peristalsis. Lubiprostone - is PGE1 like, a chloride channel (CFTR) activator, enhances mucosal Cl and fluid secretion, increases colonic motility

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Describe the modulation of colonic electrolyte secretion and motility (1)

Prucalopride - 5HT4 agonist on epithelial cell and sensory neurone (GPCR, excitatory action), promotes peristalsis. 5HT4 receptors widely expressed on epithelial cells and sensory nerves. Myenteric plexi and submucosal plexi modulation

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Describe the modulation of colonic electrolyte secretion and motility (2)

Activation of 5HT4 receptor causes an increase in cAMP, cause epithelium to secrete/reduce constipation and promote motility. Lubiprostone - PGE-1 like, Cl channel activator (opens CFTR and activates EP receptors)

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What is constipation? (1)

Less frequent bowel emptying than the patient's own normal pattern, faeces hard, dry, pain in passing. Common in elderly with fibre-deficient diet (reduced peristalsis). Can also be caused by drugs (e.g. opioids, Ca antagonists, anti-depressants)

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What is constipation? (2)

In patients receiving palliative care peripherally acting opioid antagonist, methylnaltrexone is a laxative that blocks opioid induced constipation. May be associated with other diseases/pregnancy/after surgery

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What is constipation? (3)

Laxatives may be needed prior to surgery or medical diagnostic procedures

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Describe features of diarrhoea (1)

Increases with frequency (>3 days), fluidity and volume of stools. General causes - too rapid transit through colon, hyper-motility, failure of colonic water reabsorption. Often transient (protective), no need for drugs

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Describe features of diarrhoea (2)

Serious/chronic diarrhoea needs active intervention especially fluid replacement

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Describe features of diarrhoea (3)

World-wide, diarrhoeal diseases (cholera or rotaviral infections) are still a major cause of infant mortality, notably in the tropics where infective diarrhoeal epidemics occur, especially after natural disasters

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Describe features of diarrhoea (4)

Treatment depends upon cause (e.g. eliminate infection)

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What are the different causes of diarrhoea? (1)

Viral gastro-enteritis (usually self-limiting, rarely needs treatment). Bacterial (food poisoning, bacillary dysentery and versions of 'travellers' tummy'). Larger parasites including amoebic dysentery and worm infestations. Irritant drugs/poisons

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What are the different causes of diarrhoea? (2)

Allergic reactions such as food intolerance. Chronic malabsorption syndromes, need specialised dietary management. Chronic relapsing inflammatory bowel diseases (CD and UC). IBS

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What is IBS?

Abnormal bowel activity, alternating episodes of diarrhoea and constipation associated with colic and pain. Patients often anxious (role of emotional stress). More common in women than men

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Describe the treatment for IBS (1)

Treatment can be symptomatic and reassurance - anxiolytics, anti-spasmodics, dietary improvement. Direct acting anti-spasmodics - peppermint oil capsules, mebeverine (relax smooth muscle, reduce pain), these are preferred to anti-cholinergics

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Describe the treatment for IBS (2)

(e.g. dicyclomine/muscarinic antagonist/ACh is excitatory/reduce ACh release/reduce peristalsis, S/E - blurred vision, dry mouth etc.). Anti-motility drugs e.g. loperamide, reduce diarrhoea (better than codeine - CNS actions)

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Describe the treatment for IBS (3)

Lubiprostone - stimulates colonic fluid secretion (as for laxative mechanism). Used to treat chronic idiopathic constipation in adults

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Describe practical hints on diarrhoea (1)

Best treatment of mild diarrhoea in healthy people is to abstain from food and drink plenty of clear fluids. In infants, children and elderly, check that fluid intake is adequate. Increasing amount of dietary fibre may help in longer term

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Describe practical hints on diarrhoea (2)

Traditional remedies such as charcoal, kaolin (china clay) are helpful for mild infective diarrhoea (but will also help toxins if not a mild infection). Do not employ bulk-forming agents with anti-spasmodics, could lead to intestinal obstruction

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Describe features of oral rehydration therapy (1)

Life saver. PO, can be given IV. Aims to replace electrolytes and water to prevent dehydration and electrolyte imbalance. Vital to include glucose or other simple carbohydrate (glucose enhances intestinal absorption of salts and water)

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Describe features of oral rehydration therapy (2)

Also contain NaHCO3 or Na citrate as alkalinising agent to counter acidosis. Formulations - simple, effective, palatable, widely available. Rice water with electrolytes is an effective alternative

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Which drugs are used to treat diarrhoea? (1)

Narcotic, anti-diarrhoeal drugs used to reduce intestinal hypermotility (loperamide, co-phenotrope/diphenoxylate with atropine), codeine phosphate (not available OTC anymore). Reduces ACh release from enteric nerves. Kaolin (not in acute diarrhoea)

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Which drugs are used to treat diarrhoea? (2)

In charcoal to absorb toxins. Anti-muscarinic drugs not the best option (reduce peristalsis). Racecadotril (prodrug of thiophan) - enkephalinase inhibitor, inhibits degradation of endogenous enkephalins that are pro-absorptive

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Which drugs are used to treat diarrhoea? (3)

Used to treat acute diarrhoea as adjunct to ORT. Ciprofloxacin - antibiotic used occasionally, prophylactic against traveller's diarrhoea

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What are the benefits of dietary fibre? (1)

Indigestible vegetable fibre (cellulose of plant cell walls - roughage). Gives bulk, enhances mechanical efficiency of intestine, speeds up transit (reduces exposure to toxins), absorbs water (keeps stools but bulky), promotes regular bowel habit.

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What are the benefits of dietary fibre? (2)

Primitive diets of cereals, lower incidence of colon cancer, IBS and other disorders of LI (e.g. IBD)

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Describe features of IBS (UC and CD)

Acute or chronic relapsing diseases, abdominal pain, bloody diarrhoea with mucus, weight loss, can be life threatening. Mechanism - inhibit phospholipase A2 activity and AA-PG cytokine cascades

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What are the treatment aims for IBD? (1)

Restore electrolyte balance in seriously ill patients (IV nutrition). Use anti-inflammatory corticosteroids e.g. prednisolone, hydrocortisone (for severe IBD), orally, IV or locally, budesonide (oral CS for CD affecting ileum and ascending colon)

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What are the treatment aims for IBD? (2)

Aminosalicylates e.g. sulfasalazine for less severe acute moderate disease affecting rectum or recto-sigmoid colon. Anti-TNF alpha monoclonal antibodies e.g. infliximab or adalimumab (severe IBS not CS-treatable)

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What are the treatment aims for IBD? (3)

Some drugs can be used to prevent relapse of UC (maintain remission)

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Describe features of nausea and vomiting (emesis) - 1

Common non-specific features of disease or drug toxicity. Vomiting associated with cancer chemotherapy or migraine or vertigo. Vomiting - activation of chemoreceptor trigger zone (CTZ) in brain stem, via vagus (from the stomach)

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Describe features of nausea and vomiting (emesis) - 2

With influence from vestibular apparatus (VA e.g. motion sickness)

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Describe the mechanisms of anti-emetics (1)

Vomiting centre - receives vagal input, irritants (ipecacuanha) can activate fibres. 5HT containing enterochromaffin cells sense toxins to cause 5HT release. D2/5HT3 receptors in CTZ. Muscarinic, H1, NK-1 in vomiting centre (anti-emetic ligands).

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Describe the mechanisms of anti-emetics (2)

5HT3 and NK-1 receptors on vagal sensory fibres. D2 antagonist block D2 receptors in CTZ. 5HT3 antagonists block CTZ and block receptors in the periphery

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Give examples of D2 antagonists

Trifluperazine, prochlorperzine, droperidol, domperidone

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Give examples of 5HT3 antagonists

Ondansetron, granisetron

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Give examples of drugs which block the vomiting centre

Hyoscine (muscarinic antagonist). Promethazine (H1 antagonist). Aprepitant (NK-1 antagonist)

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Describe features of emesis and anti-emetics (1)

Emesis - <4 hr post-poisoning with e.g. pesticides, ipecacuanha (syrup, local irritant, CTZ) take plus water (not to be used if strong acids/alkali or petrol based liquid has been ingested). Vomiting reflex - CNS/peripheral mechanisms

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Describe features of emesis and anti-emetics (2)

Vestibular apparatus (VA) and CTZ stimulate (D2, 5HT3, NK-1 receptor involved)

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Give examples of emetic treatment (1)

Anti-cholinergic drug (M antagonist) e.g. hyoscine. Sedating anti-histamines (H1 antagonists) e.g. promethazine, cinnarizine (useful against motion sickness). Phenothiazines (D2 antagonists) e.g. prochlorperazine

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Give examples of emetic treatment (2)

Other D2 antagonists e.g. droperidol, domperidone. 5HT3 antagonists e.g. granisetron, ondansetron. NK-1 antagonists e.g. aprepitant, fosaprepitant. Dexamethasone (anti-emetic effect) useful against vomiting associated with chemotherapy (unclear)

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Emetic treatments are used for which conditions? (1)

Motion sickness (VA, hyoscine). Pregnancy-associated sickness, promethazine (sedating H1 antagonist). Vertigo and other vestibular disorders - cinnarizine or cyclizine (H1 antagonists, less sedating than promethazine)

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Emetic treatments are used for which conditions? (2)

Post-operative nausea and vomiting - effective drugs are 5HT3 and H1 antagonists and dexamethasone, some phenothiazines

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Describe features of radiation and cytotoxic drug emesis (1)

Ondansetron, granisetron, dolasetron (5HT3 antagonists) effective against severe nausea/vomiting, especially after anticancer chemotherapy (IV plus oral dexamethasone). Aprepitant (NK-1 antagonists)

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Describe features of radiation and cytotoxic drug emesis (2)

Nabilone (synthetic cannabinoid given if patient is refractory to above drugs or significant S/E). Dexamethasone - anti-emetic corticosteroid. Domperidone , short term only (D2 antagonist, less sedating)

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Describe features of radiation and cytotoxic drug emesis (3)

Combination therapy - where risk of emesis is high e.g. 5HT3 antagonist + dexamethasone + NK-1 antagonist, improves control of cisplatin-related nausea

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The Pharmacology of Laxatives and Emetics

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