1. Laxatives

2. Constipation, pathophysiology:
Disorder of delayed colonic transit because of:
Underlying defect in colonic motility
Isolated disorder of defecation or evacuation (outlet disorder) due to dysfunction of neuromuscular apparatus of anorectal region.
Mixing in colon: Short/long duration stationary non-propulsive contractions.
Propulsive contractions- giant migrating contractions- “colonic mass actions”- defecation.
Decreased motility of mass action type or increased motility of nonpropulsive type leads to constipation.

3. • Laxative – production of a soft formed stool over a period of 1 or more days.
• Catharsis – prompt, fluid evacuation of the bowel, more intense

4. Indications for laxative use:
• Pain associated with bowel movements
• To decrease amount of strain under certain conditions
• Evacuate bowel prior to procedures or examinations
• Remove poisons
• To relieve constipation caused by pregnancy or drugs

5. Contraindications: • Inflammatory bowel diseases
• Acute surgical abdomen
• Chronic use and abuse

6. Laxatives:
• Stimulate peristalsis
• Soften bowel content

7. Fiber laxatives
Bran powder Psyllium
Methycellulose Calcium polycarbophil
Guargum
Stool surfactants
Docusate sodium Mineral oil
Osmotic laxatives
Mg (OH) Lactulose or 70 % sorbitol
PEG 3350
Stimulant laxatives
Bisacodyl Cascara
Senna Lubiprostone

8. Enemas
Tap water Na(PO4)2 enema
Soapsuds enema Mineral oil enema
Agents used for acute purgative or to clear bowel prior to medical procedures
PEG Na(PO4)2
Mg citrate
Combination kits: Na(PO4)2 & Bisacodyl

9. Laxatives generally act in one of the following ways:
 Retention of intraluminal fluid by hydrophilic/ osmotic mechanisms.
 Net absorption of fluids by effects on small bowel & large bowel fluid & electrolyte transport.
Altering motility by either inhibiting segmenting (nonpropulsive) contractions or stimulating propulsive contractions.
Most laxatives  activity of NO synthase & biosynthesis of platelet activating factor in the gut. 
Both stimulate colonic secretion & GI motility.

10. Fibre rich diet 20-30gm/day,especially fermented ones.
TYPE OF FIBRE
WATER SOLUBILITY
% FERMENTED
Non polysaccharides:
Lignin
Cellulose
Poor 15
Non cellulose polysaccharides:
Hemicellulose
Mucilages & gums
Pectins
Good
56-87
85-95
90-95

11. Classification: – Non-absorbable carbohydrates
• Bulk laxatives
– Non-absorbable carbohydrates
– Osmotically active laxatives
• Irritant laxatives = purgatives
– Small bowel irritants
– Large bowel irritants
• Lubricant laxatives
– Paraffin
– Glycerol

12. Alternate Classification:
Luminally acting agents:
Hydrophilic colloids, bulk forming agents (bran, psyllium)
Osmotic agents (nonabsorbable inorganic salts or sugars
Stool wetting agents (surfactants) & emollients (docusate, mineral oil).

13. Alternate Classification: contd…
Nonspecific stimulants/irritants:
Diphenylmethanes (bisacodyl)
Anthraquinones (senna, cascara)
Castor oil
Prokinetic agents:
5HT4 agonists
Opioid antagonists

14. Laxative effect and latency in usual clinical dosage
Softening of feces (1-3 days)
Soft/semi-solid stools (6-8hrs)
Watery evacuation (1-3hrs)
Bulk forming laxatives:
Bran
Psyllium preparations
Methylcellulose
Calcium polycarbophil
Surfactant laxatives:
Docusates
Poloxamers
Lactulose
Stimulant laxatives:
Diphenylmethane derivatives
Bisacodyl
Anthraquinone
derivatives:
Senna
Cascara sagrada
Osomotic laxatives:
Sodium phosphates
MgSO4
Milk of magnesia
Mg citrate
Castor oil

15. Bulk laxatives:
Increase in bowel content volume triggers stretch receptors in the intestinal wall 
Causes reflex contraction (peristalsis) that propels the bowel content forward

16. Carbohydrate-based laxatives
– Insoluble and non-absorbable
– Non digestible; take several days for effect
– Expand upon taking up water in the bowel
– Must be taken with lots of water
• Vegetable fibers (e.g. Psyllium, lineseed)
• Bran (husks = milling waste product)

17. – Partially soluble, but not absorbable
Osmotically active laxatives (Saline laxatives)
– Partially soluble, but not absorbable
– Saline-based (mostly sulfates)
– Effect in 1-3 hrs  used to purge intestine (e.g. surgery, poisoning)
• MgSO4 (= Epsom salt)
• Na2SO4 (= Glauber’s salt)

18. Non-digestible sugars & alcohols:
Lactulose,sorbitol, mannitol.
Lactulose- synthetic disaccharide of galactose and fructose resists intestinal disaccharidase activity.
These are hydrolysed in colon to short chain fatty acids stimulate colonic propulsive motility by osmotically drawing water in to the lumen.

19. Lactulose,sorbitol, mannitol:
Used in treatment of:
Constipation caused by opioids & vincristine
Idiopathic chronic constipation
Constipation in elderly
15-60mL at night.
Takes hours for effect to occur.
Lactulose also used in hepatic encephalopathy

20. Poly ethylene glycol (PEG)- electrolyte solutions:
Poorly absorbed, retained in intestinal lumen 
High osmotic nature
Produce effective catharsis
Colonic cleansing for radiological, surgical & endoscopic procedures
Small doses used for treatment of constipation in difficult cases.

21. Stool wetting agents & emollients:
Docusate salts- anionic surfactants. Low surface tension of stool to allow mixing of aqueous & fatty substance ---Easier defecation.
Mineral oils:
Aliphatic hydrocarbons from petrolatum. 
Taken orally for 3-4 days.
Penetrates & softens stools.

22. Mineral oils:
Adverse drug reactions:
Interferes with absorption of fat soluble vitamins.
Elicits foreign body reaction in intestinal mucosa
Leakage of oil past the anal sphincter
Rare complication: Lipid pneumonitis due to aspiration

23. Irritant laxatives: Cause irritation of the enteric mucosa 
more water is secreted than absorbed
softer bowel content and increased peristaltic due to increase volume

24. Small bowel irritants • Ricinoleic acid (Castor oil)
– Active ingredient of Ricinus communis
– The oil (triglyceride) is inactive
– Ricinoleic acid released from oil through lipase activity
Ricin:
– Lectin from the beans of R.communis
– Potent toxin: inhibits protein synthesis
– Potential bioterrorism agent (LD ~100mg)

25. Large bowel irritants Anthraquinones:
Active ingredient of Senna sp. (Folia and fructus sennae),Rhamnus frangulae (cortex frangulae) and Rheum sp. (rhizoma rhei):
contain inactive glycosides  active anthraquinones released in colon
Take 6-10 hours to act

26. Large bowel irritants Diphenolmethanes – Derivatives of phenolphtalein
• Bisacodyl
– Oral administration: effect in 6-8 hrs
– Rectal administration: effect in 1 hr
– Often used to prepare for intestinal surgery
• Sodium picosulfate

27. Stimulant ( irritant)
Diphenylylmethane derivatives :-
Sodium Pico sulfate- hydrolyzed by colonic bacteria to its active form.
Bisacodyl :- Enteric coated – 10 – 15 mg Adults /Child 5 – 10mg
Suppository
Hydrolysis by endogenous esterases in the bowel
Take at bed time – Effect next morning
Suppositories work with in 30 – 60 min
Not for more than 10 days – atonic , nonfunctioning colon

28. Refractoty constipation:
Colchicine 0.6mg
Misoprostol mcg twice/thrice daily
5-HT4 agonist Tegaserod

29. Laxative abuse:
Most common cause of constipation!
– Longer interval needed to refill colon is misinterpreted as constipation  repeated use
– Enteral loss of water and salts
causes release of aldosterone  stimulates reabsorption in intestine, but increases renal
excretion of K+  double loss of K+ causes hypokalemia, which in turn reduces peristalsis.
This is then often misinterpreted as
constipation  repeated use