Gastrointestinal system

Laxatives are used to treat constipation (defined as passing hard stools less frequently than normal for the patient). The aetiology of constipation is varied and can be a symptom of organic disease, or can be a side effect of certain drug treatments (e.g. opioid-induced constipation, OIC). Laxatives are of clinical value in the treatment of irritable bowel syndrome (IBS), OIC, as part of anthelmintic treatment or to clear the alimentary tract before surgery and radiological procedures. Abuse of laxatives may lead to hypokalaemia.

The mechanism of action of laxatives is varied, being physical or biochemical in nature:

Bulk-forming laxatives improve stool formation by adding bulk to the diet. This group includes wheat bran-based dietary supplements, methylcellulose, ispaghula husk and stercullia. Bulk-forming laxatives are useful in the management of IBS, chronic diarrhoea associated with diverticular disease, and in patients with colostomy, ileostomy, haemorrhoids and anal fissure. Can also be used as an adjunct in the treatment of ulcerative colitis.

Stimulant laxatives for example, bisacodyl, sodium picosulphate, anthroquinines such as senna, and parasympathomimetics such as bethanechol chloride (a muscarinic cholinergic receptor agonist), neostigmine and pyridostigmine bromide (both acetylcholinesterase inhibitors) increase intestinal motility. Over use can cause diarrohea and hypokalaemia.

Faecal softeners ease the passage of stool in the gut. Bulk-forming laxatives, non-ionic surfactant agents, glycerol and arachis oil all have softening properties. Non-ionic stool surfactants (e.g., docusate) lower the surface tension of the stool and so allow water to enter the stool more easily. Glycerol and arachis oil act as both stool softeners and stool lubricants.

Osmotic laxatives commonly contain polyethylene glycol (PEG), nonabsorbable synthetic disaccharides (e.g., lactulose and sorbitol), or salts (e.g., sodium sulphate, potassium sulphate, and magnesium sulphate or magnesium citrate) as the active ingredient. These agents increase water in the large intestine to soften the stool and promote bowel movement. Balanced electrolyte solutions containing PEG or high-dose saline preparations are often used as bowel clearing agents prior to colonoscopy, colonic surgery or radiological examination. Hyperosmotic salt preparations should be avoided or used with caution in patients with renal insufficiency, heart failure, end-stage liver disease, electrolyte imbalance, or taking drugs that alter renal blood flow or electrolyte excretion.    

Other laxative drugs include linactolide (an oral guanylate cyclase C receptor agonist, see Busby et al. (2010)), lubiprostone (a chloride channel activator) and prucalopride (a serotonin 5HT₄ receptor agonist).

In the gastrointestinal system, anti-secretory drugs are used to decrease acid secretion in the stomach.

Drug families include:

Histamine H₂ receptor antagonists are used to treat functional dyspepsia and to promote healing of NSAID-associated ulcers e.g. cimetidine and famotidine.

Proton pump inhibitors (PPIs) are used to treat gastric and duodenal ulcers, dyspepsia, gastro-oesophageal reflux disease (GERD) and NSAID-associated ulcers. Combined with antibacterials, PPIs are used to eradicate Helicobacter pylori infection. Can also be used to reduce the degradation of pancreatic enzyme supplements in cystic fibrosis patients, and to control excessive gastric acid production in Zollinger–Ellison syndrome. Examples are omeprazole and its single active enantiomer esomeprazole, lansoprazole, rabeprazole and pantoprazole. Infrequently, patients taking PPIs have been reported to be suffering from drug-induced subacute cutaneous lupus erythematosus (SCLE), so prescribers should be aware of this rare side-effect and consider discontinuing PPI treatment if feasible.

The Prostaglandin analogue misoprostol is approved for treatment of gastric and duodenal ulceration and NSAID-associated ulceration and prophylaxis of NSAID-induced gastric and duodenal ulcers.

Antimuscarinic drugs such as the muscarinic M₁ receptor antagonist pirenzepine were used to treat peptic ulcer, but are no longer widely used.

Mucosal protectants such as sucralfate may be used to manage benign gastric and duodenal ulceration and chronic gastritis, and as a prophylactic for stress-induced ulcers. Sucralfate aids healing by forming a viscous, protective layer on the ulcer's surface, but does not prevent new ulcer formation.

Antidiarrhoeal drugs are classified according to their mechanism of action:

Oral rehydration agents are used to re-balance fluid and electrolytes lost during a diarrhoeal episode. These contain defined quantities of salts and sugars to be taken with clean water.

Antibacterial agents can be used to treat diarrhea with a confirmed bacterial cause.

Antimotility agents, or antipropulsives, are used to slow intestinal transit. For example, the opioid analogue loperamide (sold as Imodium^®) slows peristalsis and reduces overall stool mass (often combined with the anti-foaming agent simeticone in the brand Imodium Plus^®). Diphenoxylate is another opioid analgesic used with atropine (Lomotil^®) as an antimotility agent.

Antispasmodic agents are used to reduce the pain and cramping that can accompany diarrhea. For example mebeverine, sold as Colofac^® in the UK.

Intestinal adsorbents such as purified naturally occurring clays (e.g., diosmectite and kaolin) and pectin, an indigestible carbohydrate derived from apples, can be used acutely to treat diarrhoea. They adsorb bacteria, bacterial toxins and fluid, decreasing stool liquidity and number. Intestinal adsorbents can impair the absorption of other drugs and so should not be taken within at least two hours of other orally administered drugs. 

Colloidal bismuth compounds act as intestinal adsorbents of bacterial toxins but additionally have antibacterial and mucosal protective actions. Bismuth subsalicylate also rapidly dissociates, allowing the absorption of salicylate. Salicylic acid acts as a nonselective non-steroidal anti-inflammatory drug (NSAID), inhibiting cyclooxygenase-1 (COX-1). The resulting reduction in prostaglandin production lowers intestinal chloride secretion, reducing osmotic fluid retention in the lumen of the intestine. The antidiarrhoeal actions of bismuth occur in the lumen of the intestine, and bismuth is poorly absorbed. However, elimination is very slow once absorbed. So bismuth compounds should not be used frequently and should be avoided in patients with renal impairment to prevent accumulation in the body.

Lyophilisate of heat-killed Lactobacillus acidophilus can be used to treat mild bacterial diarrhoea. Lactobacillus acidophilus is found in the normal intestinal flora of people who eat fermented dairy products. Freeze-dried fragments of heat-inactivated Lactobacillus acidophilus adhere to the intestinal walls and, when administered in excess, can competitively exclude other microorganisms, preventing over-colonisation by bacteria causing diarrhoea. While it remains controversial whether live probiotic formulations can reliably achieve sufficient colonisation to competitively exclude pathogenic bacteria, lyophilisate of heat-killed Lactobacillus acidophilus can be administered at sufficiently high concentrations to have an antidiarrhoeal effect against bacterial diarrhoea.

Bile salt-binding resins, such as colestyramine, are used to treat colonic secretory diarrhoea caused by excess faecal bile salts. Bile salts are normally reabsorbed in the ileum. Disease (e.g., Crohn's disease) or surgical resection of the ileum can result in malabsorption of bile salts, causing diarrhoea due to an osmotic laxative-like effect of excess bile salts reaching the colon. Bile salt-binding resins prevent this effect. Bile salt-binding resins can impair the absorption of other drugs and so should not be given within at least two hours of other orally administered drugs.

Other antidiarrhoeal drugs include octreotide (a somatostatin mimetic) used for the treatment of diarrhoea associated with acute graft-versus-host disease, refractory diarrhoea associated with chemotherapy, and secretory diarrhoea associated with gastroenteropancreatic neuroendocrine tumours (e.g., gastrin-secreting or vasoactive intestinal peptide-secreting tumours).  

Antispasmodic drugs are used to reduce the pain and cramping that can accompany conditions such as irritable bowel syndrome (IBS) and diverticular disease. For example mebeverine, sold as Colofac^® in the UK, and scopolamine butylbromide (a.k.a. hyoscine butylbromide or butylscopolamine) sold under the trade name Buscopan.

Antacids are used to relieve symptoms in dyspepsia and in gastro-oesophageal reflux disease and usually contain aluminium or magnesium compounds. They should be given when symptoms occur or are expected, usually between meals and at bedtime. They may have to be given several times each day. Although they may help with ulcer-healing, their impact is much less than for antisecretory drugs. Liquid preparations are usually more effective than tablet preparations.

Aluminium- and magnesium-containing antacids (e.g. aluminium hydroxide, and magnesium carbonate, hydroxide and trisilicate), being relatively insoluble in water, are long-acting if retained in the stomach. They are suitable for most antacid purposes. Magnesium-containing antacids tend to be laxative whereas aluminium-containing antacids may be constipating; antacids containing both magnesium and aluminium may reduce these colonic side-effects. Aluminium accumulation does not appear to be a risk if renal function is normal.

Sodium bicarbonate should no longer be prescribed alone for the relief of dyspepsia but it is present as an ingredient in many indigestion remedies. It is still used to treat urinary-tract disorders and acidosis. Sodium bicarbonate contains a significant salt load and should be avoided in patients who may retain this.  

Bismuth-containing antacids are not recommended because absorbed bismuth can be neurotoxic and lead to encephalopathy.

Calcium-containing antacids can induce rebound acid secretion: with modest doses the clinical significance is doubtful, but prolonged high doses also cause hypercalcaemia and alkalosis, and can precipitate the milk-alkali syndrome.

Simeticone (activated dimeticone) is added to an antacid as an antifoaming agent to relieve flatulence. These preparations may be useful for the relief of hiccup in palliative care. 

Alginates, added as protectants, may be useful in gastro-oesophageal reflux disease. The amount of additional ingredient or antacid in individual preparations varies widely, as does their sodium content, so that preparations may not be freely interchangeable.