Drugs used in GI disorders

Dr. Khairun Nain

Learning outcomes

Common causes of constipation & diarrhoea Drugs that increase GI motility Drugs that decrease GI motility Drugs that relieve nausea & vomiting Mechanisms of action and common adverse effects

CONSTIPATION AND DIARRHOEA

Drugs affecting motility

GI MOTILITY

Myogenic

Intrinsic rhythmicity

Hormonal

Endocrine & paracrine Hormones released due to nervous stimulation, distention, chemical stimulation
Extrinsic sympathetic and parasympathetic Intrinsic

Neuronal

Recap of gut motility

CONSTIPATION

Constipation

Infrequent BO/hard stools/difficulty passing General causes:

Specific causes:

Inadequate fibre/ high in red meat Dehydration Lack of activity

Drugs opioids, tricyclics, anticonvulsants, CCBs, excessive laxatives Hormones hypothyroidism, pregnancy etc Pathology Ca colon, Hirschsprungs, DM, IBS/IBD

Drugs for Constipation

Purgatives/Laxatives

Bulk & osmotic laxatives Faecal softeners Stimulant laxatives

Drugs than increase motility/Prokinetics

Bulk Laxatives

Methycellulose, sterculia, agar, bran, ispaghula husk, psylium, polycarbophil Plant fibres Undigestible, absorbs water Stretches and promotes peristalsis

Osmotic laxatives

Soluble but unabsorbable increased stool liquidity Lactulose, sorbitol nonabsorbable sugars Magnesium oxide, MgOH should be avoided in poor renal function and children => hypermagnesaemia Purgatives/bowel prep Mg citrate, sodium phosphate, PEG

Faecal softeners

Soften stool by acting as a detergent mixing of lipid and water Docusate Glycerin supp Arachis/mineral oil Liquid paraffin

Stimulant laxatives

Mech

Increase electrolyte and water secretion Direct stimulation of enteric nerves & peristalsis Cramping & dependency

Bisacodyl PO/supp Glycerol supp Aloe, senna, cascara, castor oil and dantron plant based stimulants

Prokinetics

Domperidone

Increases gastric emptying and duodenal peristalsis

Metoclopramide 5-HT4 agonists

Cisapride fatal arrhythmias Tegaserod

stimulate enteric neurons peristalsis Increase gastric emptying Increase chloride secretion at colon

Diarrhoea

1.5 million child deaths due to diarrhoea Rehydrate.org

Diarrhoea

Frequent passage of liquid faeces Physiology

Common Causes

Increased motility Increased secretion Decreased absorption

Infection and toxins Underlying disease IBD/IBS Drugs/radiation Psychological

Infective diarrhoea

Vibrio cholera E. coli, campylobacter sp, salmonella, shigella Giardia, cryptosporidium Erythromycin & ciprofloxacin

Antidiarrhoeals

Antimotility and spasmolytics

Opioid agonists Colloidal bismuth compounds Octreotide inhibition of endocrine tumours Kaolin & Pectin Bile salt-binding resins

Adsorbents

Opioids

Well-known constipator Complex mechanism CNS penetration & dependency

Diphenoxylate Loperamide

Antispasmodics

Muscarinic receptor antagonists

Atropine Hyoscine Propanthelin Dicycloverine Mebeverine

Adsorbents

Kaolin

Hydrated magnesium aluminium silicate Indigestible carbohydrate

Pectin

Binds bacteria, toxins and possibly coating intestinal mucosa Chalk, charcoal, etc

NAUSEA & VOMITING

ANTI-EMETICS

Nausea & Vomiting

Forced evacuation of gastric contents through the mouth Nausea feeling of impending vomiting Retching repetitive contraction of abdo muscles with or without discharge

Anti-emetics

Serotonin 5-HT3 antagonists H1-receptor antagonists Muscarinic antagonists D2-receptor antagonists Cannabinoids Corticosteroids Neurokinin-1 antagonists

Serotonin 5-HT3 antagonists

Blocks serotonin receptors at CTZ and vomiting centre Blocks extrinsic vagal and afferent nerves Effective for emesis due to vagal stimulation

Ondansetron, granisetron, dolasetron, palonosetron Can be given PO/IV

post-operative post-chemotherapy post-radiation

Serotonin 5-HT3 antagonists

Half life 4-9 hours, palonosetron 40 hrs Well-tolerated, mild QT-prolongation

H1-receptor antagonists

Weak anti-emetic but useful in motion sickness Diphenhydramine,dimenhydrinate, meclizine AEs: dizziness, sedation, confusion, dry mouth, cycloplegia, urinary retention

Muscarinic antagonists

Hyoscine (scopolamine) is the prototype Widely used for motion sickness Anticholinergic effects: dry mouth, blurred vision Drowsiness PO or transdermal patch

D2-receptor antagonists

Metoclopramide (maxolon)

Central action on CTZ Peripheral action increases motility AEs

movement disorders (blocks D-receptors) gynaecomastia, galactorrhoea, menstrual disorder (stimulates PRL release)

D2-receptor antagonists

Domperidone similar drug Less penetration of BBB Both given PO (Metoclopramide also IV) T1/2 4-5 hours

Cannabinoids

Nabilone ,Dronabinol Tetrahydrocannabinoids Mech unknown Appetite stimulant AEs: euphoria,dysphoria sedation,hallucinations dry mouth Autonomic tachycardia,conjunctival injection,orthostatic hypotension

Corticosteroids

Dexamethasone PO or IV Unknown mechanism

Neurokinin-1 antagonists

Aprepitant Blockade at CNS area postrema Used in combination with serotonin 5HT3 antagonists and corticosteroids in chemotherapy Metabolised via CYP3A4 pathway AEs: fatigue, dizziness, diarrhea Given PO, bioavailability ~ 65%

Other anti-emetics

Antipsychotics

Phenothiazines: prochlorperazine, promethazine, thiethylperazine Droperidol (fatal QT-prolongation) Lorazepam/diazepam

Benzodiazepines

CONCLUSION

Commonly used drugs but are important eg. chemotherapy, pregnancy, IBS/IBD etc.