Dr Anuj 1

DRUGS USED FOR TREATMENT OF

CONSTIPATION AND DIARRHOEA

Dr Anuj Kumar PathakSR, Dept of PharmacologyIGIMS, Patna

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Laxatives are used 1) To treat constipation2) To avoid undue straining at defecation3) Before or after any anorectal surgery4) In bedridden patients

Laxatives have mild activity and are usually stool softeners.

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Purgatives are used for complete colonic cleansing prior to GI endoscopic procedures, pre-post MI bed ridden patients , also to prepare bowel before surgery or abdominal X-ray, may be needed for neurologically impaired patients.

Purgative either provide semisolid stool or lead to watery evacuation

In low doses these can be used as laxative also

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CLASSIFICATION

1. Bulk forming:- Dietary fibre : Bran Psyllium, Ispaghula2. Stool softener :- Docusates (DOSS), Liquid paraffin3. Stimulant purgativea) Diphenylmethanes:- Phenolphthalein, Bisacodylb) Anthraquinones(Emodins) :- Senna, Cascara sargadac) 5HT4 agonist:- Prucaloprided) Fixed oil :- Castor oil5. Osmotic purgatives :-

Magnesium salts : sulfate , hydroxide Sodium salts: sulfate phaophate Sod. Pot. Tartrate Lactulose

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Bulk formingLuminally active, hydrophilic indigestible

vegetable fibresStimulates peristalsis and defecation reflexes by

increasing faecal bulk

Adequate water must be taken with all Bulk forming agents

Effect appears within 1-3 days

S/E Bloating and flatus causing abdominal discomfort

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Stool softener : Docussates(Dioctyl sodium

sulfosuccinate)

Also known as surfactant laxativesLuminally active agents , an anionic surfactant ,

softens stool by decreasing surface tension of fluids in the bowel.

100-400 mg oral per day in divided dosesIndicated when straining at defecation is avoidedLatency period 1-3 day

Bitter in taste can cause nauseaCramps and abdominal pain may occurHepatotoxicity may occur after prolonged use

Increases absorption of liquid paraffin , hence should not be given together

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Stimulant purgativeStimulate peristalsis by irritant action on intestinal mucosaAlso stimulate colonic electrolyte and fluid secretion by

altering absorptive and secretory activity of mucosal cells.Inhibit Na+ K+ ATPase at the bosolateral membrane of villous

cellsSecretion is enhanced by activation of cAMP in crypt cells as

well as by increasing PG synthesis

Laxative action of bisacodyl and cascara is dependent upon NO synthesis/action in colon

Larger dose of stimulant purgative can lead to purgation resulting in fluid and electrolyte imbalance, hypokalemia.

Regular and long term use – colonic atonyCan reflexly stimulate gravid uterus- C/I in PregnancyOter C/I- Subacute or Chronic intestinal obstruction

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Bisacodyl: (DULCOLAX 5 mg)

Partly absorbed and reexcreted in bile.Activated in intestine by deacetylation.Primary site of action is colon- Irritate

mucosa, produce inflammation & increase secretion

Effect appears within 6-8 hrs.

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Anthraquinones: Senna, Cascara sargada

Senna : Leaves and pods of Cassia spp.Cascara sargada: bark of buck thorne tree

Degraded by colonic bacteria to liberate anthrol form which either acts locally or absorbed into circulation and excreted in bile to act on small intestine

Takes 6-8 hrs to produce action

Active principle of these drugs act on myenteric plexus to increase peristalsis and decrease segmentation

Senna has been found to stimulate PGE2 secretion in rats

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Prucalopride :- selective 5HT4 receptor agonist for tt of chronic constipation in

womenTegaserod :- 5HT4 receptor partial agonist ,\Used for tt of constipation predominant IBS

Withdrawn from market due to cardiovascular risk

Lubiprostone: PG analogue, activates Chloride channel in small intestine to promote intestinal secretions and motility

used for tt of constipation predominant IBS

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Osmotic purgativesThese are soluble inprganic salts , that increases

the faecal bulk by retaining water osmotically and distend the bowel increasing peristalsis indirectly.

Act on small as well as large intestineMagnesium salts release Cholecystokinin which

further helps in increasing intestinal secretions and peristalsis.

Milk of Magnesia is most commonly used , other salts have an unpleasant taste

30 ml of its 8% w/w suspension is given in morning, effects comes within 2-3 hrs.

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Usually preferred for bowel preparation before surgery, colonoscopy, in food/drug poisoning and as after purge in tt of tapeworm infestation

Should not be used for prolonged period in pt with renal insufficiency due to risk of hypermagnesaemia.

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Lactulose(DUPHALAC 10gm/15ml syp)Semisynthetic disaccharide of fructose and lactose,

neither digested nor absorbed in small intestine-retains water

Broken down in the colon by bacteria to osmotically more active product

Produces soft, formed stool in 1-3 days.

Flatulence and flatus is common , cramps occur in few,some pt may feel nauseated due to peculiar sweet taste

Also used for tt of hepatic encephalopathy in dose of 20gm TDS orally

Lactulose is degraded to lactic acid and converts NH3 to ionised NH4+ salts which is then excreted.

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QuestionsActive principle of these drug act on

myenteric plexus Anthraquinones (Senna & cascara sargada)Lactulose is used in tt ofHepatic encephalopathyIt turns urine pink if alkalinePhenolphthaleinCholecystokinin is release by Magnesium salts

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Alvimopanperipherally acting μ opioid receptor antagonist for the tt of postoperative ileus and constipation after surgery

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TREATMENT OF DIARRHOEASToo frequent, often too precipitate passage of

poorly formed stoolWHO “ 3 or more loose or watery stools in a

24 hr period”Cause

↓ed electrolyte and water absorption ↑ed secretion by intestinal mucosa ↑ed luminal osmotic load Inflmm of mucosa & exudation into lumen

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1. Treatmrnt of fluid depletion, shock and acidosis

2. Maintainance of Nutrition3. Drug therapy

Oral rehydration if fluid loss is mild 5-7%BW

IV rehydration only when fluid loss is > 10% of BW

Dhaka fluid NaCl -85 mM=5gm KCl- 13mM=1gm, NaHCO3 48mM =4gm in 1 ltr of water

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New formula WHO-ORS NaCl: 2.6g KCl: 1.5g Trisod. Citrate : 2.9 g Glucose : 13.5 g Water : 1 L

Total osmolarity 245 mOsm/L

Zinc in pediatric diarrhea Maintainance of nutrition

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Drug Therapy

1. Special antimicrobial drug2. Probiotics3. Drugs for Inflammatory bowel disease4. Nonspecific antidiarrhoeal drug

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antimicrobial drug are of no value in diarrhoea due to noninfectious causes1. IBS2. Coeliac disease3. Pancreatic enzyme deficiency4. Tropical Sprue5. Thyrotoxicosis

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antimicrobial drug are useful in severe cases of 1. Travellers diarrhoea :- Cotrim, Norflox, Doxy,

Rifaximin2. EPEC :- Cotrim, FQ3. Shigella enteritis :- Cipro norflox4. Nontyphoid salmonella :- FQ Cotrim5. Yersinia :- Cotrim Cipro

Antimicrobial drug are regularly useful in1. Cholera :- Fluid replcement, Tetracyclin, Cotrim, 2. C. jejuni:- Norflox and other FQ3. Clostridium difficile:- Metronidazole, Vancomicin4. Amoebiasis, giardiasis :- Metron , Dilox furoate

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• Drugs for IBD(Inflammatory bowel disease)chronic relapsing inflammatory disease of ileum colon or both a/w

systemic manifestation

Drugs used can be grouped in 5-ASA compounds Corticosteroids Immunosuppressants TNF-α inhibitors

A. Ulcerative colitis:- Aminosalicylates(sulfasalazine),glucocorticoids, cyclosporine,azathioprine , 6-mercaptopurine

B. Crohn’s disease :- AntiTNF-α drugs( Infliximab adalimumab, Certolizumab), Methotrexate, Antibiotics( metron cipro), Anti integrin monoclonal antibody (Natalizumab)

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5-ASA compounds( Sulfasalazine)Azo bond split by colonic bacteria to release 5-ASA &sulfapyridine 5-ASA :- exerts antiinflammatory effectsulfapyridine :- serves to carry 5-ASA to colon without being absorbed proximally.

MesalazineOlsalazineBalsalazide

Corticosteroid :- 40-60 mg/day Immunosoppressant :- Azathioprine (purine

antimetabolite)Methotrexate(DHFRase inhibitor)Cyclosporine

TNF-α inhibitors :- Infliximab

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Nonspecific antidiarrhoeal drugs1. Antisecretory drugs2. Antimotility drugs

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Antisecretory drugs

Racecadotril:- (Thiorphan)Enkephalinase inhibitor↓ intestinal hypersecretion without affecting motility lowers mucosal cAMP due to enhanced ENK actionindicated in short term treatment of acute secretary diarrhoea(REDOTIL 100 mg cap)

Bismuth subsalicylateAnticholinergicsOctreotideOpioids

α2 adrenergic receptor agonist :- clonidine

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Antimotility drugsOpioid drugs which increase small bowel

tone and segmenting activity, ↓ propulsive movements, ↓ intestinal secretions , enhancing absorptions

Diphenoxylate (2.5mg) + atropine(0.025mg):- LOMOTIL Loperamide

opiate analogue with major peripheral μ opioid and weak additional anticholinergic property

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Probiotics in Diarrhoea : (ECONORM, BIFILAC, ENTEROGERMINA)

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Drug used for tt of dirrhoea in diabetic ptClonidineDrug used to treat secretary diarrhoeaOctreotideVariceal blleeding can be controlled byOctreotideAlosetron ,a drug useful in pt of Irritable

bowel syndrome with diarrhea acts through5-HT3 receptor antagonistAn effective antidiarrhoeal agent that inhibits

peristalsis movtDiphenoxylate