Pharmacology Learning Outcomes

By
 After the end of this lecture YOU will be able to
Dr. Muneeb  Describe constipation
 Differentiate between laxatives and purgatives
 Identify drugs to treat constipation
 Describe mechanisms of action of laxatives and purgatives

Drugs acting on GIT  Recognize Side Effects (SE) of laxatives and purgatives

Laxatives &
Purgatives
Dr. Syed Muneeb Anjum (Ph.D.)
IPS, UVAS University of Veterinary and
Animal Sciences 1 2

Constipation Constipation
 Constipation  General Management
 Unsatisfactory defecation  Balanced diet with whole grains, fruits and vegetables
 Infrequent stools, difficult stool passage, or seemingly incomplete  Increased dietary fibre content, adequate fluid intake and exercise
defaecation  Fibre intake should be increased gradually (to minimise flatulence and bloating)
 Can occur at any age  The effects of a high-fibre diet may be seen in a few days although it can take as long as 4 weeks
 Commonly seen in women, the elderly, and during pregnancy  Adequate fluid intake is important (particularly with a high-fibre diet or fibre supplements), but can be difficult for some
 It happens most often due to changes in diet or routine, or due to people (for example, the frail or elderly).
inadequate intake of fiber  Fruits high in fibre and sorbitol, and fruit juices high in sorbitol, can help prevent and treat constipation.
 Bowel habit  Misconceptions
 Bowel habits may lead to excessive laxative use
 Bowel habit can vary considerably in frequency without doing harm
 Laxative abuse may lead to hypokalaemia
 Not having a bowel movement daily is NOT constipation
 Before prescribing laxatives it is important to be sure that the patient is constipated and that the constipation is not
 Constipation and risk of malignancy or other serious bowel secondary to an underlying undiagnosed complaint
disorder
 New onset constipation at age over 50
 Accompanying symptoms such as anaemia, abdominal pain, weight loss,
or overt or occult blood in the stool
 Needs detailed investigations 3 4
 Laxatives and Purgatives Laxatives and Purgatives
 Drugs that promote evacuation of bowels. Classified based on the intensity of action.
 Laxative or aperient
 Milder action, elimination of soft but formed stools
 Purgative or cathartic
 Stronger action resulting in more fluid evacuation
 Many drugs in low doses act as laxative and in larger doses as purgative
 Classification  Classification
 Bulk forming laxatives  Stool softeners
 Dietary fibre: Bran, Psyllium  Docusates (DOSS), Liquid paraffin, Glycerol
(Plantago),Ispaghula, Methylcellulose suppositories
 Stimulant laxatives/purgatives  Osmotic laxatives/purgatives
 Diphenylmethanes  Magnesium sulphate, Magnesium hydroxide
 Phenolphthalein, Bisacodyl, Sodium picosulfate  Sodium sulphate, Sodium phosphate
 Anthraquinones (Emodins)  Sodium potassium Tartrate
 Senna, Cascara sagrada, co-danthramer  Lactulose
 5-HT4 agonist
 Others
 Tegaserod
 Linaclotide, Prucalopride 5 6

Mechanism of action Laxatives and Purgatives

 All purgatives increase the water content of faeces by:  Bulk forming laxatives Indications Contra-indications Adverse Effects

 A hydrophilic or osmotic action  Include hydrophilic colloids ! Bulk forming laxatives

Colonic atony • Abdominal distension
 Retaining water and electrolytes in the intestinal lumen—increase volume of colonic content and make it easily propelled.  Indigestible parts of fruits and vegetable Faecal impaction • Bronchospasm
 Decrease in net absorption of water and electrolyte  Form gels in the large intestine, causing water retention and intestinal distension, thus Intestinal obstruction • Conjunctivitis
increasing peristaltic activity Reduced gut motility • GI disorders
 Acting on intestinal mucosa, decrease net absorption of water and electrolyte; intestinal transit is enhanced indirectly by the • Hypersensitivity
fluid bulk.  Examples: • Rhinitis
 Bran, Methylcellulose, psyllium seeds (plantago or Ispaghula) • Skin reactions
 Increasing propulsive activity as primary action
 Allowing less time for absorption of salt and water as a secondary effect  Bran
 A by-product of flour industry  consists of 40% dietary fibre
 Increased water content of stools as the primary action or it is a consequence of increased motility
 Absorbs water in the intestines, swells, increases water content of faeces and facilitates its
 Laxatives modify the fluid dynamics of the mucosal cell and may cause fluid accumulation in gut lumen by one or colonic transit, 20-40 g/day for 3- 4 days
more of following mechanisms:  Methylcellulose
 Inhibiting Na+/K+ATPase of villous cells— impairing electrolyte and water absorption.  A semi-synthetic, colloidal hydrophilic derivative of cellulose; 4-6 g / day is satisfactory
 Stimulating adenylyl cyclase in crypt cells— increasing water and electrolyte secretion. in most individuals
 Enhancing PG synthesis in mucosa which increases secretion.  Psyllium seed (ispaghula husk)
 Structural injury to the absorbing intestinal mucosal cells  Contains natural colloidal mucilage that absorbs water and makes a gelatinous mass
 3-12 g of refined husk freshly mixed with water or milk, taken daily-acts in 1-3 days
 Generous amounts of water must be taken, with all bulk forming agents
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 Laxatives and Purgatives Laxatives and Purgatives
 Stimulant Laxatives/purgatives  Diphenylmethanes
 Some of them primarily increase motility by acting on myenteric plexuses  Phenolphthalein
 More important mechanism of action is accumulation of water and electrolytes in the lumen by altering  An indicator and in use as purgative from the beginning of the 20th century. It turns urine pink if alkaline
absorptive and secretory activity of the mucosal cells  Dose: 60-130 mg, to be taken at bedtime
 They inhibit Na/K-ATPase at the basolateral membrane of villous cells   Bisacodyl (DULCOLAX)
 Transport of Na+ and accompanying water into the interstitium is reduced  Bisacodyl is activated in the intestine by deacetylation. Primary site of action is in the colon: irritate the mucosa, produce
 Activation of c-AMP in crypt cells mild inflammation and secretion. One or two semi-formed motions occur after 6-8 hours. Optimum doses vary considerably
 Secretion is enhanced by activation of c-AMP in crypt cells and by increased PG synthesis among individuals.
  Dose: 5-15 mg, q 24h
 Sadium picosulfate (LAXOBERON, SKILAX)
 Hydrolysed by colonic bacteria to the active form  acts locally to irritate the mucosa and activate myenteric neurones.
Bowel movement generally occurs after 6-72 hours of oral dose.
 Together with Mag. Citrate solution  Colon evacuation for colonoscopy or surgery
 Dose Adults: 5-15 mg , Child dose: 0.25mg/kg , q 24h

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Laxatives and Purgatives Laxatives and Purgatives

 Anthraquinones (Emodins)  Osmotic Purgatives Indications Adverse Effects

 Senna (‫)سنامیک‬  Magnesium Salts ! Lectulose

• Galactosaemia • Abdominal pain
 Obtained from leaves of cassia sp., Cascara sagrada is the powdered bark of the buck-thorn tree  Non-absorbable salts  hold water in the intestine by osmosis  bowl distension 
• Gl obstruction. • Diarrhoea
 Contain anthraquinone glycosides, also called emodins  Inc. intestinal activity  defecation • Gl perforation. • Flatulence
 The active principle acts on the myenteric plexus to increase peristalsis and decrease segmentation. • Risk of GI • Nausea
 Magnesium ions release cholecystokinin which may aid purgative action of Magnesium salts perforation • Vomiting
 They also promote secretion and inhibit salt and water absorption in the colon.  Mag. Hydroxide (8%, Milk of magnesia)
 Senna anthraquinone has been found to stimulate PGE2 production in rat intestine  Infrequent use for constipation
Indications
 5HT4 Agonists  Used in case of colonic surgery, colonoscopy, food drug poisoning, after purge in treatment of tape worm infestations
! Prucalupride
 Prucalupride  Poly-ethylene glycol (PEG)
• Chronic Constipation
 It is a new selective 5HT4 receptor agonist with no action on other receptors • Constipation – predominant IBS  Used as colonic lavage solutions to prepare the gut for radiologic or endoscopic procedures
 Activates pre-junctional 5-HT4 receptors on intrinsic enteric afferent nerves   Causes less cramping and gas than other laxatives
 Enhances release of excitatory transmitter Ach and calcitonin gene related peptide (CGRP)  Lactulose
 Both promote peristaltic reflex and colonic secretion (by enhancing cAMP mediated CI- efflux)  Semisynthetic disaccharide of fructose and lactose (both are non digestible and nor absorbable in small intestine)
 Propulsive activity is increased in the stomach, ileum and most prominently in colon  Cannot be hydrolysed by GI enzymes, Broken down in the colon by bacteria to osmotically more active and weakly acidic
 Enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) products
and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide)  Lactic, formic, and acetic acids
 Tegaserod (withdrawn now)  Dose (Child): 2.5 – 10 ml twice daily
 5HT4 receptor partial agonist  Dose (adult): 15ml initially  then adjusted according to response
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 Laxatives and Purgatives
 Stool Softners
 Docusates (Dioctyl sodium sulfosuccinate)
 An anionic detergent, softens stools by net water accumulation in the lumen by an action on the intestinal mucosa.
 Emulsifies the colonic contents and increases penetration of water into the faeces.
 By a detergent action, it can disrupt the mucosal barrier and enhance absorption of many non-absorbable drugs, e.g.
 liquid paraffin  should no t be combined with it
 It is a mild laxative: especially indicated when straining at stools must be avoided.
 Liquid paraffin (CREMAFFIN)
 A viscous liquid and mixture of petroleum hydrocarbons, introduced as a laxative at the turn of 19th century
 Pharmacologically inert. Taken for 2-3 days.
 Softens stools, retards water absorption and is said to lubricate hard scybali (stool balls) by coating them.
 Dose: 15- 30 ml/day oil as such or in emulsified form

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