Gi Drug-i & Ii

‫بسم ال الرحمن الرحيم‬ ‫‪GI drugs - I & II‬‬

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Laxatives • Introduction • Drugs that help easy evacuation of the bowel contents during defecation • Usually self-prescribed for the relief of constipation • Constipation is best prevented with high fiber diet, adequate fluid intake & regular exercise • Besides constipation there are some other valid uses of laxatives & mentioned with each group • Various groups of laxatives: • Bulk forming, faecal softeners, stimulants, osmotic & Balanced polyethylene glycol 2

I. Bulk forming laxatives •

Methyl-cellulose, bran, ispagula husk

•

Absorb water, increase the bulk of stool and stimulate peristalsis Uses: Constipation, diverticular disease, colostomy, hemorrhoids & fissure, irritable bowl syndrome Adv. Effects: May cause intestinal obstruction, take sufficient water to prevent obstruction Bacterial digestion of fiber may cause flatus

• • • • •

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II. Faecal softners • Liquid paraffin • • • • • • •

Lower surface tension & make stool soft Uses: Constipation (can be used in pregnant ladies) To avoid straining at stool in myocardial infarction Adv. Effects: May cause aspiration pneumonia or leakage Long term use causes deficiency of Vit. A, D, E & K

• Glycerin suppository Glycerin suppository is inserted via anal canal if oral route not suitable 4

III. Stimulant laxatives • Bisacodyl • Stimulate intestinal motility, & decrease Na & water absorption from bowl (onset of action 6-8hours) • Repeated effect due to entero-hepatic re-circulation • Uses: (oral or suppository) • Constipation & preparation for radiology • Adv. Effects: • May cause diarrhoea, fluid and electrolyte loss • Avoid in intestinal obstruction & pregnancy • Other stimulant laxatives: Senna 5

IV. Osmotic laxatives • Mg hydroxide, Mg sulphate, Na sulphate, Na citrate • Hold water due to osmotic pressure, cause distension & prompt evacuation (1-3 hours) • Uses: • Constipation, preparation for radiology • Expulsion of worms • Adverse effects: • May cause diarrhoea and fluid and electrolyte loss • Avoid in pregnancy • Avoid Na-salts in CVS, liver & renal disease 6

IV. Osmotic laxatives (Cont.) • Lactulose • Non-absorbable sugar, cause osmotic effect • Reduces pH of GI • Converts NH3 to NH4 , ↓ absorption of ammonia • • • • •

Uses: Constipation Control of encephaopathy in liver cirrhosis Adverse effects: Bacterial metabolism in GI causes flatus & cramps 7

V. Balanced polyethylene glycol • Contains: • Polyethylene glycol, sodium sulfate, sodium chloride, sodium bicarbonate, potassium chloride & water • Isotonic to intestinal contents • Water & electrolytes are retained in the lumen of GI & take faecal matter out along with it • Uses: • Bowl cleaning to prepare for surgery, colonic endoscopy & radiology

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Anti-emetics Motion Labyrinth Cerebellum

Anti--dopamine Anti-histamine Anti- 5-HT3 Ant-muscarinic

Toxins Drugs Circulation

CTZ

Pain, emotion Smell, sight Cerebrum

D2, H1 , 5-HT3 & M3 receptors

Vomiting Center

GI-tract 9

Anti-emetics (Cont.) • • • • • • • • •

Dopamine D2 receptor antagonists Metoclopramide, domperidone & droperidol Inhibit D2 receptors in CTZ & control vomiting Metoclpramide & domperidone also have prokinetic effect Adverse effects: Metoclopramide causes extrapyramidal reaction, diarrrhoea Domperidone does not cross BBB, so no CNS effects Droperidol causes sedation & extrapyramidal reaction May ↑ QT-interval & cause ventricular tachycardia

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Anti-emetics (Cont.) • • • •

Anti-histamines (H1 receptor antagonists) Cyclizine, meclozine, diphenhydramine Inhibit H1 & M3 receptors in CTZ & vomiting center Can cause sedation & anti-muscarinic side effects: dryness of mouth, tachycardia, constipation, etc.

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Anti-emetics (Cont.) • Phenothiazines: Promethazine • Inhibit D2 H1 & M3 receptors in CTZ & vomiting center • Can cause sedation & anti-muscarinic side effects • Anti-muscarinic drugs: Hyoscine • Inhibit M3 receptors & used in motion sickness • Can cause dry mouth, tachycardia, constipation, etc.

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Anti-emetics (Cont.) • 5-HT3 receptor antagonists: Ondansetron • Inhibit 5-HT3 receptors in CTZ & vomiting center • • • •

Used in sever vomiting, e.g. in cancer chemotherapy Marijuana derivatives: Dronabinol & Nabilone Inhibit cannabinoid receptors Used in sever vomiting, e.g. in cancer chemotherapy

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Prokinetic drugs Control of GI-motility & action of prokinetic drugs Dopamine antagonists

Dopaminergic neuron

De

Cholinergic neuron

Neuron of myenteric plexus

Macrolides

Motilin R Mot

D2

-

M

+

Ach

5-HT4R 5-HT4 agonists

Ach M

Cholinergic drugs

Smooth muscle of GI 14

Prokinetic drugs (Cont.) • Dopamine D2 (R) antagonists & 5-HT4 (R) agonists: • Metoclopramide, domperidone • Mechanism: • Both block D2 receptors in GI & ↑ cholinergic activity in upper GI (pro-kinetic) • Both block D2 receptors in CTZ & control vomiting (anti-emetic) • Metoclopramide also activates 5-HT4 receptors • Adverse effects: • Metoclopramide: • Extrapyramidal reaction (tremors, dyskinesia) • Gynecomastia & menstrual irregularities (↑ prolactin secretion) • Diarrhoea • Domperidone: • Do not cross BBB, no central effects, can cause diarrhoea 15

Prokinetic drugs (Cont.) • Uses: (Metoclopramide & domperidone) • Gastro-esophageal reflux disease • Diabetic gastroparesis • To prevent aspiration of gastric contents during surgery & delivery • Post vagatomy upper GI atonia

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Site of action of anti-diarrhoeals & drugs that decrease GI motility 5-HT3R

Neuron of myenteric plexus

+

Non-adrenergic 5-HT3 antagonists non-cholinergic neuron Opioid drugs

Opioid R

Ach Mu

M

Anti-cholinergic drugs

Smooth muscle of GI

Adsorbents 17

Anti-diarrhoeals (Cont.) I. Opioids • • • • • •

Diphenoxylate, Loperamide Agonists of opioid receptors (e.g. μ receptors) Have more effect on GI Decrease peristalsis & constrict sphincters Cause minimal sedation & dependence Usually combined with atropine

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Anti-diarrhoeals (Cont.) • II. Anti-muscarinics • Dicyclomine, Hyoscine-N-butyl bromide • Competitively block muscarinic M3 receptors in GI • Decrease peristalsis & constrict sphincters • Adverse effects: • Dry mouth, constipation, tachycardia, palpitation, raised IOP & urine retention • Caution: elderly patients (glaucoma) & male patients (prostatic hypertrophy) 19

Anti-diarrhoeals (Cont.) • III. 5-HT3 antagonists • Alosetron • Competitively block 5-HT3 receptors & ↓ GI motility • Well absorbed from GI, short half life but long acting • Use: • Control of sever diarrhoea & colic in irritable bowl syndrome (diarrhoea predominant IBS) in women • Adverse effects: • Constipation, ischemic colitis 20

Anti-diarrhoeals (Cont.)

• II. Adsorbents • • • •

Kaolin (Al & Mg silicate) Pectin (indigestible carbohydrate from apple) Colloidal bismuth Adsorb microorganisms & toxins; absorb water

• • • •

Adverse effects: Can cause constipation Decrease absorption of many drugs Colloidal bismuth also gives black color to tongue & stool 21

Anti-diarrhoeals (Cont.) • Management of dehydration (complication of diarrhoea) • For mild to moderate dehydration: • ORS (oral rehydrate salt) Lumen Epithelium • NaCl, KCl, Na HCO3, • • • •

glucose & water Glucose CoFor sever dehydration: trans Na IV fluids Water 5% dextrose & normal saline KCl &/or Na HCO3, when hypokalemia &/or acidosis 22

Drugs for inflammatory bowel disease Two forms of disease: Ulcerative colitis & Chron’s disease Two types of drugs used: I. Amino-salicylates (5-amino-salicylates, 5-ASA) II. Immuno-suppresive drugs a. Glucocorticoids b. Cytotoxic agents c. Cytokine inhibitors

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Amino-salicylates (5-amino-salicylates, 5-ASA) • 1. Sulfasalazine: 5-ASA & sulfapyridine by azo-bond • 2. Olsalazine: 2 molecules of 5-ASA by azo-bond • 3. Balsalazide: 5-ASA & amino-benzoyl alanine by azo-bond • Azo-bond broken in GI (colon) by bacterial enzyme (azo-reductase) • 5-ASA released has local anti-inflammatory action • 4. Mesalamine (enteric coated form of 5-ASA) • Time released preparations of mesalamine for small intestine & colon. Also enema & suppository 24

Amino-salicylates (cont.) • Mechanism of action: • 5-ASA inhibits cyclo-oxygenase & lipo-oxygenase & ↓ synthesis of PGs & leukotrienes • Primarily has anti-inflammatory action • Clinical use: • Both azo-compounds & mesalamine are first line drugs for treatment of mild to moderate ulcerative colitis & Chron’s disease in colon or rectum • Mesalamine also useful for treatment mild to moderate Chron’s disease or ulcerative colitis in small intestine 25

Amino-salicylates (cont.) • Adverse effects: • Sulfasalazine: due to sulfapyridine released in GI & absorbed has more adverse effects & can cause: • GI: Nausea, vomiting • Hematological: Bone marrow suppression & megaloblastic anemia • Renal: Crystal urea & renal stones • Hypersensitivity: Skin rash • General: Headache, malaise, arthralgia & myalgia • Olsalazine: diarrhoea in 10 % cases • Mesalamine: renal damage (like NSAIDs) 26

Glucocorticoids • • • ∀ ∀ • • • • •

Prednisolone & budesonide (oral) Hydrocortisone (IV) Mechanism: Anti-inflammatory, immune suppressant ↓ phospholipae A & C, ↓ synth of PGs & leukotrienes ↓ synth of cytokines (TNF- α , IL-1), chemokine (IL-8) Destroy lymphoid cells & some T-cells Clinical use: For acute & sever ulcerative colitis & Chron’s disease Adverse effect: Hypertension, hyperglycemia, peptic ulcer, infections and adrenal suppression • Terminate treatment with tapering doses (to avoid adrenal suppression) 27

Cytotoxic immune-suppressants • Azathioprine: Purine analog, ↓ DNA synth • Methotraxate: Inhibitor of dihydrofolate reductase, ↓ DNA synth Both damage lymphoid & T- cells • Clinical use: • Refractory ulcerative colitis & chron’s disease, as alternate or additional therapy • Adverse effects: • Nausea, vomiting, bone marrow depression, infections, infertility 28

Cytokine inhibitor-immune suppressants • Infliximab • Anti- TNFα (pro-inflammatory cytokine) ∀ ↓ release of cytokines from inflammatory cells • Clinical use: • Refractory ulcerative colitis & chron’s disease, as alternate or additional therapy • Adverse effects: • Infections • Infusion reaction; fever, chills, urticaria, chest pain & dyspnoea 29