Important note: KD Tripathi's Essentials of Medical Pharmacology is not available in this library's collection. These notes are compiled from Goodman & Gilman's Pharmacological Basis of Therapeutics and Katzung's Basic & Clinical Pharmacology (16th Ed.) - organized in the same systematic, topic-by-topic format that KD Tripathi uses. The content is equivalent and exam-ready.

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GASTROINTESTINAL PHARMACOLOGY - COMPREHENSIVE NOTES

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SECTION 1: PHYSIOLOGY OF GASTRIC SECRETION (Revision)

• Parietal cells secrete HCl via the H+/K+-ATPase (proton pump)
• Three stimulants of acid secretion:
  1. Histamine (via H2 receptors) - the dominant paracrine mediator
  2. Acetylcholine (via M1/M3 receptors, vagal)
  3. Gastrin (via CCK-B receptors, from antral G cells)
• All three converge on the parietal cell and activate the proton pump
• Chief cells secrete pepsinogen (activated to pepsin at pH <2)
• Mucosal defense: Mucus-bicarbonate layer, prostaglandins (PGE2, PGI2), nitric oxide, mucosal blood flow

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SECTION 2: DRUGS FOR ACID-PEPTIC DISORDERS

A. PROTON PUMP INHIBITORS (PPIs)

• Prodrugs - inactive at neutral pH
• Absorbed from small intestine, concentrated in the acidic parietal cell canaliculus (pH ~1)
• Converted to the active sulfenamide form
• Irreversibly binds cysteine residues of H+/K+-ATPase - blockade of the final step of acid secretion
• Most potent antisecretory agents; block all stimuli (histamine, ACh, gastrin)

• Acid-labile - dispensed as enteric-coated preparations
• Take 30-60 min before first meal (pumps must be active/stimulated for drug to bind)
• Short plasma t1/2 (~1 h), but prolonged effect (18-24 h) due to irreversible binding
• Hepatic metabolism via CYP2C19 (Omeprazole has highest, Rabeprazole least dependence)
• Esomeprazole = S-isomer of omeprazole (more consistent levels, less CYP2C19 variability)

1. PUD - drug of choice (4-8 weeks for healing)
2. GERD / Reflux esophagitis
3. H. pylori eradication (as part of combination regimens)
4. NSAID-induced ulcer prevention and treatment
5. Zollinger-Ellison syndrome (high dose)
6. ICU stress ulcer prophylaxis
7. Upper GI bleeding (IV bolus + infusion)

• Generally well tolerated short term
• Long-term use: Hypomagnesemia, vitamin B12 deficiency, iron malabsorption, osteoporosis/fracture risk
• Increased risk of C. difficile infection
• Rebound acid hypersecretion on stopping (gastrin-mediated)
• Interstitial nephritis (rare)
• Drug interaction: Omeprazole (CYP2C19 inhibitor) reduces clopidogrel activation - prefer pantoprazole

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B. H2 RECEPTOR ANTAGONISTS (H2RAs)

• Tolerance: Develops rapidly with H2RAs; PPIs do not show tachyphylaxis

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C. POTASSIUM-COMPETITIVE ACID BLOCKERS (P-CABs)

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D. ANTACIDS

• Antacids reduce absorption of: fluoroquinolones, tetracyclines, digoxin, iron, ketoconazole (take other drugs 2 h apart)

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E. MUCOSAL PROTECTIVE AGENTS

1. Misoprostol

• Synthetic PGE1 analogue
• ↓ Acid secretion + ↑ mucus/bicarbonate + ↑ mucosal blood flow
• Primary use: Prevention of NSAID-induced ulcers
• Also used: Medical abortion (+ mifepristone), cervical ripening, labor induction
• SE: Diarrhea and cramps (common, dose-dependent); uterine contractions
• Contraindicated in pregnancy (for ulcer therapy)

2. Sucralfate

• Aluminum sucrose octasulfate - at acid pH (<4) forms viscous sticky polymer
• Adheres to ulcer/erosion for up to 6 h; physical barrier
• Also: Inhibits pepsin, adsorbs bile salts, stimulates local PG + EGF
• Uses: GERD in pregnancy (not absorbed - safe), radiation mucositis, stress ulcer prophylaxis
• SE: Constipation, bezoar formation, Al toxicity in renal failure
• Take on empty stomach, 1 h before meals; avoid antacids within 30 min
• Reduces absorption of: phenytoin, digoxin, fluoroquinolones, ketoconazole

3. Bismuth Compounds

• Coat ulcer base, inhibit pepsin, stimulate mucus/PG
• Antibacterial against H. pylori
• Used in quadruple therapy for H. pylori; traveler's diarrhea
• SE: Black stools/tongue (benign), constipation; neurotoxicity with prolonged use

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F. H. PYLORI ERADICATION REGIMENS

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SECTION 3: PROKINETIC DRUGS

Metoclopramide

• D2 antagonist + 5-HT4 agonist + 5-HT3 antagonist
• ↑ LES tone, ↑ gastric emptying, coordinates duodenojejunal peristalsis; antiemetic (CTZ)
• Uses: Gastroparesis, GERD, chemo/post-op nausea
• SE: Extrapyramidal reactions (dystonia, tardive dyskinesia), hyperprolactinemia (galactorrhea, amenorrhea, gynecomastia), drowsiness

Domperidone

• D2 antagonist, does NOT cross BBB well → fewer extrapyramidal SE
• Hyperprolactinemia still occurs (pituitary D2, outside BBB)
• Cardiac risk: QT prolongation
• Uses: Gastroparesis, nausea, GERD

Itopride

• D2 antagonist + AChE inhibitor (dual mechanism) → enhances ACh at ENS
• Fewer cardiac SE than domperidone; used for functional dyspepsia

Erythromycin

• Motilin receptor agonist → strong phase III MMC-like contractions
• Used for diabetic gastroparesis, gastric ileus
• Rapid tolerance with prolonged use

Prucalopride

• Selective 5-HT4 agonist (high affinity), no hERG inhibition → cardiac safe
• ↑ High-amplitude propagating contractions in colon
• Used for chronic constipation (women especially)

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SECTION 4: ANTIEMETICS

Vomiting Pathway:

• Chemoreceptor Trigger Zone (CTZ) - area postrema (outside BBB); detects blood-borne emetics; receptors: D2, 5-HT3, NK1, H1, M
• Vomiting Center (VC) - nucleus tractus solitarius; receives signals from CTZ, vestibular apparatus, GI vagal afferents, cortex

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Drug Classes:

1. Dopamine (D2) Antagonists

• Metoclopramide, Domperidone, Prochlorperazine, Chlorpromazine, Haloperidol
• Block D2 in CTZ → antiemetic
• Uses: Post-op, chemo, drug-induced, gastroparesis
• SE: EPS, hyperprolactinemia, sedation

2. 5-HT3 Antagonists (Setrons) - KEY CLASS for CINV

• Block 5-HT3 in CTZ, vagal afferents (gut), NTS
• Uses: CINV (acute phase), post-op N/V, radiotherapy-induced
• SE: Headache, constipation, QT prolongation (less with palonosetron)

3. NK1 Receptor Antagonists - KEY for DELAYED CINV

• Block Substance P at NK1 in brain (NTS, VC)
• Especially effective for delayed CINV (24-120 h post-chemo)

4. H1 Antihistamines - KEY for Motion Sickness

• Dimenhydrinate (Dramamine), Promethazine, Cyclizine, Meclizine (less sedating), Cinnarizine
• Block H1 in vestibular nucleus; some also block M receptors

5. Anticholinergics

• Hyoscine (Scopolamine) - transdermal patch, best for motion sickness
• Blocks M receptors in vestibular apparatus and VC

6. Cannabinoids

• Dronabinol (delta-9-THC), Nabilone - for refractory CINV
• CB1 agonists; SE: dysphoria, hallucinations

7. Corticosteroids

• Dexamethasone - adjunct in CINV combination regimens; mechanism uncertain (may involve PG inhibition)

8. Benzodiazepines

• Lorazepam - for anticipatory nausea; amnestic + anxiolytic

Standard CINV Regimens:

• High emetogenic (Cisplatin): NK1 antagonist + 5-HT3 antagonist + Dexamethasone ± Olanzapine
• Moderate emetogenic: 5-HT3 antagonist + Dexamethasone
• Low emetogenic: Dexamethasone or metoclopramide alone

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SECTION 5: LAXATIVES

Classification and Key Drugs:

1. Bulk-Forming (onset 1-3 days) - SAFEST

• Psyllium, Bran, Methylcellulose, Calcium polycarbophil
• Absorb water → ↑ stool bulk → reflex peristalsis
• First choice for chronic constipation, IBS, pregnancy, hemorrhoids
• Must be taken with adequate water

2. Osmotic Laxatives (onset variable)

• Magnesium sulfate, Magnesium hydroxide, Sodium sulfate
• Draw water by osmosis; also stimulate CCK release
• Avoid in renal failure (Mg accumulation)

• Lactulose - galactose + fructose disaccharide; fermented by colon bacteria → lactic/acetic acid → osmotic effect + colonic acidification
  • Also used for hepatic encephalopathy (NH3 → NH4+, trapped and excreted)
  • SE: Flatulence, bloating
• Sorbitol - cheaper alternative

• Non-absorbed polymer; holds water; minimal electrolyte disturbance
• Safe for long-term use; also used for bowel prep (isotonic with electrolytes = GoLYTELY)

3. Stimulant/Irritant Laxatives (onset 6-12 h oral, 15-60 min rectal)

• Bisacodyl (tablets/suppositories) - colonic bacteria hydrolysis → active compound → stimulates myenteric plexus → ↑ peristalsis + fluid secretion
• Sodium picosulfate - similar; used in bowel prep

• Senna, Cascara - glycosides hydrolyzed by colonic bacteria → active anthrones → stimulate myenteric plexus
• Chronic abuse → melanosis coli (reversible pigmentation), cathartic colon (atonic), hypokalemia

• → Ricinoleic acid (active) in small intestine; strong irritant; rapid action (2-6 h)

4. Stool Softeners/Emollients (onset 1-3 days)

• Docusate (sodium/calcium): Anionic surfactant → ↓ stool surface tension → water penetrates
• Liquid paraffin (Mineral oil): Lubricates; caution - aspiration pneumonitis, fat-soluble vitamin malabsorption, anal seepage

5. Prosecretory Agents (newer)

• Lubiprostone: CIC-2 Cl- channel activator → ↑ Cl- and water secretion; for IBS-C, chronic constipation, opioid-induced constipation
• Linaclotide, Plecanatide: GC-C agonists → ↑ cGMP → ↑ Cl-/HCO3- secretion; also reduce visceral pain; for IBS-C
• Tenapanor: NHE3 inhibitor → blocks Na+ absorption → ↑ luminal water; for IBS-C

6. For Opioid-Induced Constipation (OIC) - PAMORAs

• Methylnaltrexone (subcutaneous), Naloxegol, Naldemedine: Peripheral mu-opioid antagonists - relieve constipation without crossing BBB (no reversal of analgesia)
• Alvimopan: For postoperative ileus (peripherally restricted)

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SECTION 6: ANTIDIARRHEALS

1. Opioid Agonists (most effective)

2. Adsorbents

• Kaolin-pectin, Attapulgite - adsorb toxins and water; limited evidence

3. Bismuth Subsalicylate

• Antisecretory (salicylate) + antimicrobial; traveler's diarrhea, H. pylori

4. Enkephalinase Inhibitors

• Racecadotril (Acetorphan): Inhibits enkephalinase → ↑ endogenous enkephalins → ↓ intestinal secretion via delta opioid receptors
• Antisecretory without antimotility effect; used in children with secretory diarrhea

5. Somatostatin Analogues

• Octreotide: For secretory diarrhea (carcinoid, VIPoma), chemo-induced, short bowel syndrome

6. ORS - Most Important Treatment for Diarrhea

• WHO ORS (reduced osmolarity): Glucose 13.5 g, NaCl 2.6 g, KCl 1.5 g, Na citrate 2.9 g per liter
• Glucose-Na co-transport via SGLT1 (intact even in cholera)

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SECTION 7: IRRITABLE BOWEL SYNDROME (IBS)

Drugs for IBS-D:

Drugs for IBS-C:

• Linaclotide, Plecanatide (GC-C agonists), Lubiprostone, Prucalopride, Tegaserod (5-HT4 agonist)

For IBS Pain/Spasm:

• Antispasmodics: Mebeverine, Hyoscine butylbromide, Dicyclomine, Peppermint oil (smooth muscle Ca2+ antagonist)
• TCAs (amitriptyline low dose) for pain modulation + ↓ gut motility (IBS-D)
• SSRIs (fluoxetine) for IBS-C (↑ gut motility)

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SECTION 8: INFLAMMATORY BOWEL DISEASE (IBD)

A. Aminosalicylates (5-ASA)

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B. Corticosteroids

• Prednisolone: Systemic; for moderate-severe UC/CD flares
• Budesonide: High first-pass metabolism (>90%); topical effect with minimal systemic SE; used for ileocecal CD and microscopic colitis
• Hydrocortisone enemas: For distal UC/proctitis

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C. Immunosuppressants

Azathioprine / 6-Mercaptopurine

• Azathioprine → 6-MP → 6-thioguanine nucleotides (active)
• Inhibit purine synthesis → suppress T-cell/B-cell proliferation
• Onset: 3-6 months (not for acute flares; for maintenance)
• TPMT genotyping/activity before starting (TPMT deficiency → severe myelosuppression)
• SE: Myelosuppression, hepatotoxicity, pancreatitis, ↑ lymphoma risk
• Allopurinol interaction: Inhibits xanthine oxidase → ↑ 6-MP levels → toxicity; reduce 6-MP/AZA dose by 75%

Methotrexate

• Folic acid antagonist; ↓ lymphocyte proliferation
• Used in CD (steroid-sparing); less common in UC
• SE: Hepatic fibrosis (cumulative), pneumonitis, myelosuppression, mucositis; teratogenic
• Give folic acid supplementation

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D. Biologics

Anti-TNF-α Agents:

• Screen for latent TB (PPD/IGRA) before starting
• SE: Infusion/injection reactions, infections (TB reactivation, opportunistic), lymphoma, demyelination, drug-induced lupus (infliximab > others)

Anti-IL-12/23:

• Ustekinumab (anti-p40): IV then SC maintenance; for moderate-severe CD and UC

Anti-Integrins (Gut-selective):

• Vedolizumab (anti-α4β7): Prevents lymphocyte gut homing; very selective, minimal systemic immunosuppression; IV every 8 weeks; for UC and CD

JAK Inhibitors (Oral small molecules):

• Tofacitinib (JAK1/3): UC; risk of infections, VTE, MACE
• Upadacitinib, Filgotinib (JAK1-selective): Newer, UC/CD

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SECTION 9: DRUGS FOR HEPATIC ENCEPHALOPATHY

1. Lactulose (1st line) - acidifies colon, converts NH3 → NH4+ (non-absorbable), cathartic
2. Rifaximin 550 mg BD - reduces ammonia-producing gut bacteria; prevents HE recurrence
3. Zinc supplementation (urea cycle enzyme cofactor)
4. BCAA - correct amino acid imbalance; reduce aromatic AA uptake to brain

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KEY EXAM POINTS (High-Yield)

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