Pharmacology of laxatives

Question 1

What is the mechanism of action of bulk-forming laxatives?

Answer 1

• The bulk-forming laxatives have a plant origin e.g. cellulose and so are composed of polysaccharides
• When broken down in the gut, the polysaccharides increase the osmolality
• This leads to water retention of water in the GIT causing the stool to expand and soften
• Bulker stool distends the colon (increased pressure)
• This stimulates the colonic mucosal receptors and the stretch receptors to promote peristalsis by increasing the release of the neurotransmitter - acetylcholine
• This increases the parasympathetic drive ‘rest’ by binding to muscarinic acetylcholine receptors (especially M2 + M3 sub-types) which increases peristalsis further.
• Additionally, it has a second moa by increasing the mucus layer of the intestinal lining which facilitates defecation.

Question 2

What is the mechanism of action of osmotic laxatives?

Answer 2

• Osmotic laxatives are poorly absorbed in the gut so act as osmotic agents by increasing water retention in the gut lumen.
• They are hyperosmolar agents so are absorbed into the stool via osmosis. This makes the stools softer and therefore easier to pass.
• Additionally, most osmotic laxatives contain magnesium ions (Mg2+) which stimulate the release of cholecystokinin (CKK) (a peptide hormone in the GIT).
• CCK stimulates an increase in intestinal secretions and also colonic mobility and peristalsis
• This decreases the transit time through the gut making the stools able to pass quicker

increasing the amount of fluid in the large bowel, by retaining fluid in the bowel and by drawing fluid from the body into the bowel. Fluid accumulation in the lower bowel produces distension, leading to stimulation of peristalsis

Question 3

What is the mechanism of action of stimulant laxatives?

Answer 3

• These laxatives stimulate local reflexes in the gut of the myenteric nerve plexus
• this irritates nerve endings in the wall of the intestine, causing the intestine to become irritated and contract therefore having its laxative effect.
• Also has a motor effect on the gut wall which increases propulsion
• This increases the secretion of water into the bowel causing increased gut mobility and decreased transit time

The myenteric plexus lies in between the outer longitudinal and inner circular smooth muscle layers of the intestines. By stimulating these muscles, it controls motility along the gastrointestinal tract

Question 4

What is the mechanism of action of senna?

Answer 4

Senna is an anthraquinone laxative
- It binds with sugars known as glycosides (these are sugars attached to a functional group via a glycosidic bond)
- Glycosidic bonds are hydrolysed by colonic bacteria causing the release of the irritant anthracene glycoside derivatives- Sennosides A + B
- These derivatives are absorbed in the GIT and have an action on the myenteric nerve plexus, increasing smooth muscle activity and therefore gut motility
- Additionally, senna increases the secretion of Prostaglandin E2 (PGE2) which increases the motility of the gut
- Also, decreases colonic water absorption

Question 5

What is the mechanism of action of stool softeners?

Answer 5

• Work as surface wetting agents (surfactants) which decreases the surface tension of the stool.
• This makes it easier for fat and water to penetrate into the stool, making it softer and easier to pass.

Question 6

What is the mechanism of action of prucalopride?

Answer 6

Prucalopride is a 5HT4 receptor agonist
- 5HT4 receptors are found in the GI tract e.g. myenteric nerve plexuses
- When 5ht4 is activated, there is an increased release of acetylcholine
- This causes an increase in rest and digest- PNS drive
- This leads to increased peristalsis and propulsion

Question 7

How do you chose a laxative (according to NHS website + BNF)?

Answer 7

• start with a bulk-forming laxative (take 2-3 days to work) e.g Isphagula husk, methylcellulose
• if your poo remains hard, try using an osmotic laxative in addition to, or instead of, a bulk-forming laxative e.g. lactulose or macrogols (laxido, movicol, cosmocol)
  if your poo is soft but is still difficult to pass, try taking a stimulant laxative in addition to a bulk-forming laxative e.g. senna or bisacodyl