Constipation is one of the most common, as well as one of the more frustrating, symptoms that patients encounter. Here, we'll take you through the pharmacology of constipation - going through the principal drug classes involved in its treatment.
Constipation, also referred to as costiveness or dyschezia, refers to the inability to pass stools; or the passage of hard, small stools which are infrequently passed. Studies show that approximately 10 percent of the population is affected by some form of constipation. Bowel habits differ between patients, but those who pass stools between three times a day and once every three days is considered regular. A disruption of this frequency is often dietary related, as patients who do not consume the recommended daily allowance of dietary fibre are more likely to suffer from constipation.
Pharmacology of Laxatives
There are four main classes of laxative - each of which is listed below. These classes differ in their mechanism, but they are all united behind a single function - which is to ease the passage of stools.
- Bulking Agents
- Osmotic Laxatives
- Irritant and Stimulant Laxatives
- Faecal Softeners
Examples: Bran, Ispaghula Husk, Methylcellulose, Sterculia
These pharmaceutical agents are mostly from plant origin, including natural polysaccharides – substances that are poorly broken down by the digestive process. The mechanism of action of the various bulking agents depends on the drug in question:
- Hydrophilic activity through the retention of water in the intestinal tract, thereby expanding and softening the faeces.
- Promotion of peristalsis via stimulation of colonic mucosal receptors.
- Growth and proliferation of colonic bacteria, increasing faecal bulk.
- Sterculia itself contains polysaccharides which are, in turn, degraded to osmotic products in the gut, thereby promoting water retention.
Clinical pharmacology has revealed that bulking agents take at least 24 hours to work. Furthermore, patients are advised to increase their consumption of liquids, which serves to lubricate the intestinal tract while reducing the colonic obstruction risk. The following table lists the circumstances where bulking agents are both recommended and to be avoided:
|Chronic Constipation||When the Colon is Atonic|
|Diverticular Disease||Cases of Faecal Impaction|
|Inflammatory Bowel Syndrome|
Unwanted effects of bulking agents include flatulence, abdominal pain and bloating sensations.
Examples: Lactulose, Magnesium Salts, Macrogols, Sodium Acid Phosphate, Sodium Citrate
Central to any study of the pharmacology of constipation are osmotic laxatives. Magnesium compounds, such as the sulphated Epsom salts (and hydroxide equivalents), are some of the most frequently deployed compounds in the treatment of constipation. These salts are poorly absorbed from the gut, as they act as osmotic agents which retain water in the intestinal lumen. Furthermore, these salts also trigger the release of cholecystokinin from the small intestine, a substance which enhances the rates of intestinal secretions and colonic motility.
This results in the rapid transit of faecal matter through the intestines. However, approximately 20 percent of magnesium salts are retained by the body, which can result in cardiovascular, central nervous system, and neuromuscular blocking effects. This is particularly true for patients with renal failure, as it increases the circulation of these compounds. Magnesium hydroxide treatment is quite mild compared to the sulphate counterpart, which is infamously known to cause considerable abdominal discomfort.
Another commonly employed osmotic laxative, lactulose, is a disaccharide of fructose and galactose. As the disaccharide passes through the colon, bacteria cleave it into its constituent components of fructose and galactose, which are then fermented into lactic and acetic acids (and an accompaniment of gas). These fermentation products, lactic and acetic acid, lower the intestinal pH which, in turn, favour the growth of colonic flora while inhibiting the proliferation of ammonia-producing bacteria. Indeed, this inhibition of ammonia-producing bacteria renders Lactulose useful in treating hepatic encephalopathy. Thus, lactulose increases faecal bulk while acting to retain water through its osmotically active fermentation products. Unwanted effects of lactulose include abdominal cramps and flatulence. It often takes longer than 24 hours for its effects to manifest.
Another class of drugs in the pharmacology of constipation which cannot be overlooked are the macrogols (polyethylene glycols). These are large inert molecules which aren’t themselves absorbed from the gut, but they still exert an osmotic effect. Usually these molecules contain sodium salts and, as a result, prove problematic for patients with impaired cardiac function. Other osmotic laxatives include sodium acid phosphate and sodium citrate. These drugs are usually administered as an enema or suppository. They are typically used to prepare patients for bowel surgery or other local procedures.
Irritant and Stimulant Laxatives
Examples: Senna, Dantron, Bisacodyl, Sodium Picosulfate
Also known as contact laxatives, stimulant laxatives work by stimulating local reflexes of the myenteric nerve plexus of the gut, thereby enhancing gut motility, water retention, and electrolyte transfer to the gut. Due to their nature, stimulant laxatives are usually reserved for more severe cases of constipation –stimulating defecation within 6-12 hours after oral use. Unwanted effects include abdominal cramps.
- The gentlest purgative action of this group comes from senna. Senna is hydrolysed by colonic bacteria to release the irritant anthracene glycoside derivatives sennosides A and B.
- Dantron is available as co-danthramer, in combination with the surfactant poloxamer ‘188’, and also available as co-danthrusate, in combination with the softening agent docusate. However, Dantron is also carcinogenic. Its use in the UK, therefore, is restricted to the terminally ill or elderly. Dantron is known to discolour urine a red hue.
- Bisacodyl may be administered orally, or for more rapid action (15-30mins), rectally. Bisacodyl undergoes enterohepatic circulation.
- The irritant, sodium picosulfate, is often used in bowel preparation in patients undergoing surgery or colonoscopy. It is a powerful irritant which acts in less than 6 hours.
Stimulant laxatives are the most powerful class of drugs in the pharmacology of constipation. If stimulant laxatives are used for prolonged periods of time, they may damage the haustral folds of the colon, making it even more difficult to pass stools - or - to cause atony of the colon itself.
Examples: Arachis Oil, Docusate Sodium
Docusate sodium works by enhancing the rate of fluid and fat penetration into hard stools. In this way, it can be said to harbour detergent properties. In addition, docusate also possesses some intrinsic stimulant activity, but overall, it’s a relatively ineffective laxative. It can be administered rectally, orally, alone or in combination with dantron (co-danthrusate).
Arachis oil may be administered orally as liquid paraffin, or rectally. Liquid paraffin, however, is not recommended as it impairs absorption of fat-soluble vitamins as well as causing anal seepage and lipoid pneumonia (if inhaled). Liquid paraffin does have an appreciable level of laxative activity, though may be used in combination with magnesium salts.
Management of Constipation
There are two main ways to manage constipation depending on the severity of your condition. Patients with simple constipation should adopt a high-fibre diet, supplemented by use of a bulking agent. Consumption of fluids (typically water) and engaging in exercise also assist the transit of stools. For short-term use, a stimulant laxative, such as senna or bisacodyl, may be taken orally - at night - to trigger bowel movements the next morning. Should these simple effort fail, use of magnesium salts or macrogols may be considered.
- Senna, magnesium salts, and docusate appear to be safe in pregnancy.
- Bisacodyl, co-danthramer and co-danthrusate are suitable for the elderly or terminally ill with opioid-induced constipation.
- The peripheral opioid receptor antagonist, methylnaltrexone, may be added to this regimen should other laxatives prove ineffective.
- Lactulose is useful in patients with constipation associated with hepatic encephalopathy. Otherwise, lactulose is considered a second-line agent.
- Faecal softeners should be used in patients for whom neurological disease is the cause of their constipation.
- High dose stimulant laxatives are useful in refractory idiopathic constipation. For this condition, bulk laxatives are ineffective, while a high-fibre diet may increase abdominal distension and discomfort.
Here are fifteen statements, each of which is either true or false. Below you can find the answers to these statements.
- All laxatives serve to stimulate bowel movements within approximately 3-6 hours.
- Administration of bulk laxatives should be accompanied by drinking plenty of water.
- Cholecystokinin release is inhibited through use of magnesium sulfate.
- Stimulation of enteric nerves is the mechanism of action of lactulose.
- Sterculia exerts its laxative effects within 12 hours.
- The majority of cases of simple constipation can be treated by lifestyle changes.
- Chronic use of senna causes progressive hyperactivity of colonic motility.
- Sodium acid phosphate is an example of an osmotic laxative.
- Magnesium hydroxide is a milder osmotic laxative compared to magnesium sulphate.
- Docusate appears to be safe in pregnancy.
- Bisacodyl and dantron are examples of anthraquinones.
- Bulking agents take at least 24 hours to work after ingestion.
- Lactulose is indicated for the treatment of hepatic encephalitis.
- Liquid paraffin impairs absorption of water-soluble vitamins.
- Bulk laxatives are effective in the treatment of refractory idiopathic constipation.
1. False 2. True 3. False 4. False 5. False 6. True 7. False 8. True 9. True 10. True 11. False 12. True 13. True 14. False 15. False