Laxatives

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.

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

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

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

Laxatives: • Stimulate peristalsis • Soften bowel content

Fiber laxatives Bran powder Psyllium Methycellulose Calcium polycarbophil Guargum Stool surfactants Docusate sodium Mineral oil Osmotic laxatives Mg (OH)2 Lactulose or 70 % sorbitol PEG 3350 Stimulant laxatives Bisacodyl Cascara Senna Lubiprostone

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

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.

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

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

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).

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

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

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

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)

– 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)

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.

Lactulose,sorbitol, mannitol: Used in treatment of: Constipation caused by opioids & vincristine Idiopathic chronic constipation Constipation in elderly 15-60mL at night. Takes 24-48 hours for effect to occur. Lactulose also used in hepatic encephalopathy

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.

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.

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

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

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)

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

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

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

Refractoty constipation: Colchicine 0.6mg Misoprostol 200-40mcg twice/thrice daily 5-HT4 agonist Tegaserod

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