Laxatives

Constipation, pathophysiology:Disorder of delayed colonic transit because of:Underlying defect in colonic motilityIsolated 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 laxativesBran powder PsylliumMethycellulose Calcium polycarbophilGuargum

Stool surfactantsDocusate sodium Mineral oil

Osmotic laxativesMg (OH)2 Lactulose or 70 % sorbitolPEG 3350

Stimulant laxativesBisacodyl CascaraSenna Lubiprostone

EnemasTap water Na(PO4)2 enemaSoapsuds 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

Poor

0

15

Non cellulose polysaccharides:

Hemicellulose

Mucilages & gums

Pectins

Good

Good

Good

56-87

85-95

90-95

Classification:

• 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:

a. Hydrophilic colloids, bulk forming agents (bran, psyllium)

b. Osmotic agents (nonabsorbable inorganic salts or sugars

c. Stool wetting agents (surfactants) & emollients (docusate, mineral oil).

Alternate Classification: contd…

Nonspecific stimulants/irritants:• Diphenylmethanes (bisacodyl)• Anthraquinones (senna, cascara)• Castor oil

Prokinetic agents:a. 5HT4 agonistsb. Opioid antagonists

Softening of feces (1-3 days) Soft/semi-solid stools (6-8hrs)

Watery evacuation (1-3hrs)

Bulk forming laxatives:

1. Bran

2. Psyllium preparations

3. Methylcellulose

4. Calcium polycarbophil

Surfactant laxatives:

1. Docusates

2. Poloxamers

3. Lactulose

Stimulant laxatives:

1. Diphenylmethane derivatives

2. Bisacodyl

Anthraquinone

derivatives:

1. Senna

2. Cascara sagrada

Osomotic laxatives:

1. Sodium phosphates

2. MgSO4

3. Milk of magnesia

4. Mg citrate

5. Castor oil

Laxative effect and latency in usual clinical dosage

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)

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:

1. Constipation caused by opioids & vincristine

2. Idiopathic chronic constipation

3. 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 ~100g)

Large bowel irritantsAnthraquinones:

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 irritantsDiphenolmethanes– 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:

1. Colchicine 0.6mg

2. Misoprostol 200-40mcg twice/thrice daily

3. 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 saltscauses release of aldosterone stimulates reabsorption in intestine, but increases renalexcretion of K+ double loss of K+ causes hypokalemia, which in turn reduces peristalsis.

This is then often misinterpreted asconstipation repeated use