Drugs used in treating and IBS

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Faris Alwarhi, Faris Al-Mutairi, Mohammed Abunayan, Monirah Alsalouli, Khalid Aburas, Atheer Alnashwan

Revision: Lina Al Bawardi, Qusay Ajlan, Atheer Alnashwan Mind Map

Decreased motility in colon

causes Difficulty in constipation evacuation

Drug-induced Drugs for constipation ()

Bulk forming laxatives

Osmotic laxatives

Stool Stimulant softeners or irritant (lubricants) laxatives To Understand Better

What is constipation?

Infrequent defecation, often with straining and the passage of hard, uncomfortable stools. - May be accompanied by: Abdominal discomfort and rectal pain, Flatulence, Loss of appetite, Lethargy & Depression.

Causes of constipations

Decreased motility in colon: - Decrease in water and fiber contents of diet. Difficulty in evacuation: - Local painful conditions: anal fissures, piles. - Lack of muscular exercise. Drug-induced: - Anticholinergic agents, , Iron, Antipsychotics.

Treatment by general measures

- Adequate fluid intake. - Avoid drugs causing - High fiber contents in diet. constipation. - Regular exercise - Use drugs (laxatives or - Regulation of bowel habit. purgatives).

Medications used in constipations

Drugs that hasten the transit of food through the gastrointestinal tract Or we say the) )محركات( or purgatives )ملينات( are called laxatives drugs that increase GI motility). Classification of Laxatives or Purgatives

Bulk forming laxatives

Increase volume of non-absorbable solid residue.

Osmotic laxatives

Increase water content in .

Stimulant or irritant laxatives

Act by direct stimulation of nerve endings in colonic mucosa.

Stool softeners (lubricants)

Alter the consistency of feces  easier to pass

Drug Bulk (fiber) Laxatives

نفس اللي يصير مع الجلي، أسا ًسا هو بودرة بس لما أضيفه مع الموية :Hydrophilic colloids بيصير قوامه مثل الجيالتينين :Dietary fibers - Indigestible parts of vegetables &fruits. - seed (powder)

 Powder + water - (مسحوق النخالة) .Bran powder - Include (Carboxymethyl Cellulose (CMC - (مثل الخميرة لما نحطها مع العجينة تنف ّش وتكبر) (تنفش)  increase the volume

Dietary fibers and hydrophilic colloids are non-absorbable substances  Increase the bulk of intestinal contents by water retention   mechanical pressure on the

MOA walls of intestine  stimulation of stretch receptors   peristalsis  evacuation of soft stool.

ما أستخدمه للحاالت المستعجلة Delayed onset of action (1-3 days)  -

ألنه بودرة، فيحتاج موية عشان يسوي األكشن حقه ويزيد حجمه. (Intestinal obstruction (should be taken with enough water -

- Bloating, flatulence, distension. ADRs - Interfere with other drug absorption e.g. iron (anti-anaemic drugs), cardiac glycosides. (تمسك األشياء معها وما تخليها تُمتص)  Decrease their absorption, especially w\ colloids, bc they have adsorption action Osmotic Laxatives

أكيد ماراح يصير لها امتصاص كبير ألن األكشن حقها يصير داخل األمعاء! .o They are Water soluble compounds, poorly absorbed o They remain in the bowl attract water by osmosis increase the volume of feces increase peristalsis & evacuation

Sugars

- sulphate or Salts hydroxide. (saline laxatives) - Sodium or potasium phosphate.

Polyethylene glycol PEG & electrolytes Osmotic Laxatives Osmotic (PEG)

Osmotic Laxatives

Drug Lactulose o Semi synthetic disaccharide of fructose & galactose. o Non absorbable.

o In the colon metabolized by bacteria to fructose & galactose. P.K o These sugars are fermented into lactic acid & acetic acid that function as osmotic laxatives (they cause acidification of the colon)

o Prevention of chronic constipation o Hemorrhoids o Hepatic encephalopathy (Hyperammonemia) o Liver cirrhosis  Why lactulose is used in Liver cirrhosis & Hyperammonemia?  Acidification of the colon (increases the H+ concentration) by lactic acid & + acetic acid causes increase of H concentration, this will cause NH3 (ammonia-lipid soluble  absorbed easily) trapping by the formation of NON- Indications + absorbable NH4 (ammonium-polar “water soluble”  poorly absorbed) and thus reducing absorption.  Simply: Lactulose  Lactic acid + Acetic acid  Acidification of the colon  + ↓ ammonia absorption (NH4 ). o Delayed on set action (2-3 Days) o Abdominal cramps & flatulence.

ADRs o Electrolyte disturbance. seen with high doses. dose o 15 ml for constipation & 30 ml for Liver crirrhosis. (not imp in our level) Osmotic Laxatives (cont.) Polyethylene Drug Saline Laxatives glycol (PEG) o Magnesium sulphate (epson salt) o (milk of magnesia)  Antacids, Mg(OH) causes Drugs 2 diarrhea. o Sodium phosphate o Isotonic solution of o potassium phosphate & o Poorly absorbed (90% NOT electrolytes (NaCl, KCl, absorbed) Na bicarbonate) o Rapid effect (1-3 h) acute o Is a colonic lavage situations (emergency) solution. o Isotonic or hypotonic solution o It is a salt with some P.K modifications. should be used. If you used hypertonic solution it will cause dehydration by ↑ vomiting. o It increases evacuation of watery stool. o Limited fluid & electrolyte imbalance. Advantages o Less flatulence & cramps. o Used for whole bowel irrigation (removal of feces) prior to or Indications o Treatment of Acute Constipation. surgery. It should be ingested rapidly (4L over 2-4h)  this is the only use for it!

o Disturbance of fluid & electrolyte ADRs o May have systemic effect (especially Na salts)

o Sodium salts in: • Congestive heart failure. o Magnesium salt in: • Renal failure (little % excreted by the C.I kidney) • Heart blockers. • CNS depression. • Neuromuscular blockers (e.g. Aminoglycosides) Stimulant Laxatives

Bisacodyl  Are the most powerful groups among & should be used with care.  They act via direct Anthraquinone stimulation of ENS increase peristalsis & purgation.

(Senna) Stimulant laxatives Stimulant ENS: enteric nervous system Stimulant Laxatives Anthraquinone glycoside Castor oil زيت الخروع (Drug (Senna, cascara, aloes

o Delayed onset action (8-12h) o Bowel movements in 12h o Onset of action (2-6h) (orally) or 2h (rectally as o Given orally, 5-20 ml suppository) on empty stomach in o Given orally, o Given at night. the morning Onset of o Hydrolyzed by bacterial colon o Act in small intestine action (6-12h) into sugar + emodin (The o Vegetable oil degraded P.K Per absorbed emodin has direct by lipase gives (1h). stimulant action) ricinoleic acid + o Act on colon o Act on colon glycerin. o Emodin may pass into milk*. o Ricinoleic acid is very o Senna is useful in treating irritating to mucosa. induced constipation.

ألنها تزود حركة األمعاءo Abdominal cramps  o Dependence & destruction of myenteric plexus leading to Atonic Colon in

ADRs prolonged use (the patient can’t go to the bathroom without these drugs!!)

In pregnancy (causes Senna is contraindicated in reflex contraction of uterus C.I breast feeding* (lactation) this will lead to abortion) Fecal softeners

o Non-absorbed drugs o Act by either decreasing surface tension or by softening the feces thus promote defecation.

o Treat constipation in patient with hard stool or specfice condotion and for general info. general people who should avoid straining.

Docusate Paraffin oil Glycerin

Drug (sodium dioctyl sulfactants)

o Surfactant act by o Meniral oil, Acts as decresing surface lubricant thus tension of feces >

of action of softening the feces o Lubricant. increase water snd promote penetration into it thus Mech. defecation softening of feces.

o Given orally (1-3 days) o Given orally (not o given rectally

(تحميلة P.K or (5-20 min) palatable) (suppository

o often used as prophylaxis rather than acute treatment, - o good for radiology especially in hospitalized o Good for children. patients-because of preparation.

Indications delayed onset when given orally.

o Impairs absorption of fat soluble vitamins

A,D,E,K. ADRs طعمه غير محبذ o Not palatable Quick summary of purgatives Purgatives Site of action Onset time 12-72 h (days) Bulk purgatives Small & large intestine (Delayed) 1-3 h Saline purgatives Small & large intestine (Rapid) 12-72 h (days) Lactulose Colon (Delayed) Colon 6-8 h Enema  5-20 min Small & large intestine Orally  12-72 h Stimulants - Cascara . - Senna . - Aloe vera 8-12 h - Their Type: Anthraquinone. Colon Bisacodyl - Type: 6-8 h Diphenylmethane Castor Oil Small intestine 2-6 h Type: ricinoleic acid Irritable bowel syndrome (IBS)

Chronic bowel disorder charachterized by: 1- Abdominal discomfort (bloating, pain, distension, cramps) 2- Alteration in bowel habits (diarrhea or constipation or both) Symptomatic treatment

- Low dose of tricyclic antidepressant e.g. amitriptyline or SSRIs TCAs acts via: - ↓ GI motility because of anticholinergic action. - ↓ visceral afferent sensation.

- Antispasmatic e.g. Mebeverine )↓ GI motility  smooth muscle relaxant) - Alosetron (IBS-D)

Anti-diarrheal in IBS-D  - Luxative in IBS-cons. (IBS-C) (diphenoxylate – loperamide) Treatment of IBS (cont.) Alosetron

o Selective 5HT3 antagonist

o Block 5-HT3 receptors of the enteric nervous system of the GIT results into: • Inhibition of colon motility  means there is time for the water to be

MOA absorbed  thus hardening of stool. • Inhibition of unpleasant visceral afferent pain sensation (nausea, pain, bloating).

o Used in severe IBS with diarrhea in women (not approved for men) who have

not had success with any other treatment. Uses o Used as a late stage when other medications not worked.

o Sever Constipation and ischemic colitis (blood flow to GIT is restricted) may occur.

ADRs o  People taking alosetron must sign a consent form before starting to take the medicine.

Tegaserod

o 5HT4 agonist.

MOA o Stimulation of 5HT4 of enteric nervous system of GIT → increases peristalsis

o Short term treatment of IBS with constipation in women <55 years old with no

history of heart problems. Uses o May still be used in limited emergency situations.

o CVS side effects ADRs MOA of 5-HT agonist \ antagonist

Extra explanation

 For Tegaserod:

Stimulation of 5-HT4 receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves enhances the release of their neurotransmitters, including calcitonin gene-related peptide, which stimulate second-order enteric neurons to promote the peristaltic reflex. These enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide).

 For Alosetron: 5-HT3 receptors in the gastrointestinal tract activate visceral affer- ent pain sensation via extrinsic sensory neurons from the gut to the spinal cord and central nervous system. Inhibition of afferent gastrointestinal 5-HT3 receptors may reduce unpleasant visceral afferent sensation, including nausea, bloating, and pain. Blockade of central 5-HT3 receptors also reduces the central response to visceral afferent stimulation. In addition, 5-HT3-receptor blockade on the terminals of enteric cholinergic neurons inhibits colonic motility, especially in the left colon, increasing total colonic transit time. Summary-1

Treatment of constipation

1- Adequate fluid intake. 4- Regulation of bowel habit.

2- High fiber contents in diet. 5- Avoid drugs causing constipation.

3-Regular exercise. 6- Use drugs (laxatives or purgatives).

Laxatives drugs g

Dru Bulk forming laxatives Osmotic laxatives

Increase volume of non-absorbable Increase water content in large intestine.

solid residue. MOA

• Hydrophilic colloids - Psyllium seed - Methyl cellulose. - Carboxymethyl cellulose (CMC) Sugars: e.g. Salts Polyethylene • Dietary fibers: lactulose (saline) glycol includes - Indigestible parts of vegetables & fruits - Bran powder.

are water soluble compounds

P.K Poorly absorbable compounds (salts or sugars)

- Prevention of Is a colonic lavage chronic constipation solution Used for whole - Hepatic Treatment of acute & chronic constipation acute bowel irrigation encephalopathy constipation. prior to

Indications (Hyperammonemia) colonoscopy or - Hemorrhoids surgery

- Delayed onset of action (1-3 Disturbance of Advantages: Delayed onset of fluid and Limited fluid or days). action (2-3 days) electrolyte electrolyte - Intestinal obstruction (should Abdominal cramps balance imbalance

ADRs and flatulence. be taken with enough water). May have Electrolyte less flatulence - Bloating, flatulence, systemic disturbances. and cramps distension effects.

Renal failure Heart block Interfere with other drug CNS

C.I absorption e.g. iron, cardiac depression glycosides. Neuromuscular block. Summary-2 Laxatives drugs (cont.) Stool softeners Stimulant or irritant laxatives

Drug (lubricants) Alter the consistency of feces  Act by direct stimulation of nerve endings in easier to pass colonic mucosa. Act by either decreasing surface

MOA tension or by softening the feces thus promoting defecation.

Anthraquinone glycosides e.g. Bisacodyl Castor Oil Docusate Paraffin oil Glycerin senna, cascara, includs aloe vera

Sodium dioctyl Is a mineral oil, is given sulfosucci orally nate Given orally acts as One type Lubricant 5-20 ml on lubricant of Is given empty thus Given orally, acts Act in colon surfactants softening stomach in rectally

P.K on colon the feces the morning. (supposit Act by and ory) acts in small promoting intestine decreasing defecation. surface Good for tension of radiology feces preparation

Treat constipation in patients with hard stool or specific conditions and for people who should avoid straining. prevention of straining after rectal

Indications surgery and in acute perianal disease

impairs Abdominal cramps may occur. absorption Prolonged use  dependence & destruction of of fat

ADRs myenteric plexus leading to atonic colon. soluble vitamins.

Senna is contraindicated in breast feeding. Castor oil  in pregnancy  reflex contraction of C.I uterus  abortion. Summary-3

Alosetron Tegaserod Drug

Selective 5HT3 antagonist 5HT4 agonist. 5-HT3 receptors antagonism of the Stimulation of 5HT4 of enteric nervous enteric nervous system of the system gastrointestinal tract results into: o inhibition of colon motility. of GIT  increases peristalsis.

MOA o inhibition of unpleasant visceral afferent pain sensation (nausea, pain, bloating).

Used in IBS with severe diarrhea in Short term treatment of IBS-associated women with constipation in women <55 years old who have not had success with any with no history of heart problems. other

treatment. Indications

Constipation and ischemic colitis may CVS side effects

occur ADRs

Cardiac problems C.I

Extra summary MCQs

1- A patient is undergoing 7- A patient presented with abdominal colonoscopy, which of the following pain and frequent unsatisfactory bowel drugs should the doctor give him the movement. For the last one year he has night before? been using a purgative twice weekly to A- PEG open his bowel. On colonoscopy the B- Senna colon was found to be atonic with C- Castor oil bluish pigmentation of the mucosa. D- Lactulose Which is the most likely purgative that the patient has been using: 2- Which of these drugs act on small A- intestine? B- Ispaghula A- Senna C- Senna B- Bisacodyl D- Lactulose C- Castor oil 8- The following laxative lowers blood D- Saline laxatives ammonia level in hepatic 3- Which of the following is used to treat encephalopathy liver cirrhosis? A- Bisacodyl A- Saline laxatives B- Lactulose B- Lactulose C- Liquid paraffin D- C- Senna D- Sodium salts 9- Used as a laxative, liquid paraffin has 4- Which of the following drugs used for the following drawbacks except: treatment of constipation by increasing A- It causes gripping the bulk of intestinal content: B- It is unpleasant to swallow C- It interferes with absorption of fat A- Castor oil soluble vitamins B- Saline laxative D- It may produce foreignbody C- Methyl cellulose granulomas D- Glycerin

5- Which of the following drugs may 10- Select the purgative that should not cause iron deficiency? be taken at bed time: A- Ispaghula A- Bulk forming laxatives B- Bisacodyl B- Osmotic laxatives C- Senna C- Stimulant laxatives D- Magnesium sulfate D- Stool softeners

6- Which of the following drugs acts as 11- The most suitable laxative for a a lubractant: patient of irritable bowel syndrome with spastic constipation is: A- Paraffin oil A- Dietary fibre B- Docusate B- Bisacodyl C- Tegaserod C- Liquid paraffin D- Amitriptyline D- Senna

Answers: 1-A 2-C 3-B 4-C 5-A 6-A 7-C 8-B 9-A 10-D 11-A Thank you for checking our team!

Sources: 1. 435’s slides. 2. Pharmacology (Lippincotts Illustrated Reviews Series), chapter 28, 5th edition. 3. Basic & Clinical Pharmacology by Katzung, chapter 62,12th edition. 4. Rang & Dale’s pharmacology, chapter 29, 7th edition. 5. Wikipedia.