---

GASTROINTESTINAL PHARMACOLOGY

Comprehensive Notes (Goodman & Gilman / Katzung - KD Tripathi Style)

---

SECTION 1: PHYSIOLOGY OF GASTRIC SECRETION (Quick Review)

Gastric Acid Secretion - Key Points

• Parietal cells secrete HCl (pH ~0.8) via the H+/K+-ATPase (proton pump)
• Three stimulants of acid secretion:
  1. Histamine (via H2 receptors) - most important paracrine mediator
  2. Acetylcholine (via M1/M3 receptors from vagus nerve)
  3. Gastrin (via CCK-B receptors from G cells of antrum)
• All three converge on the parietal cell and activate H+/K+-ATPase
• Chief cells secrete pepsinogen (activated to pepsin at pH <2)
• Mucus cells secrete bicarbonate-rich mucus - the "mucosal barrier"

Mucosal Defense Mechanisms

• Mucus-bicarbonate layer (traps HCO3-)
• Prostaglandins (E2, I2) - stimulate mucus/HCO3- secretion, promote blood flow
• Nitric oxide (NO) - vasodilatory, cytoprotective
• When defenses fail → peptic ulcer disease (PUD)

---

SECTION 2: DRUGS FOR ACID-PEPTIC DISORDERS

A. PROTON PUMP INHIBITORS (PPIs) - Most Important Class

• Are prodrugs - inactive at neutral pH
• Absorbed from small intestine, transported to parietal cell canaliculus
• Concentrated in acidic canaliculus (pH ~1) → converted to sulfenamide (active form)
• Sulfenamide irreversibly binds cysteine residues of H+/K+-ATPase → irreversible blockade
• Block the final common pathway of acid secretion - most potent antisecretory agents
• New parietal cells must be synthesized for acid secretion to resume (~18 h)

• Acid-labile - given as enteric-coated capsules/tablets
• Take 30-60 minutes before meals (parietal cell pumps must be active for drug to work)
• Short plasma t1/2 (~1 h), but prolonged effect (18-24 h per dose, longer with repeat dosing)
• Hepatic metabolism via CYP2C19 (Omeprazole > Rabeprazole)
• Esomeprazole = S-isomer of omeprazole (less CYP2C19 dependent, more consistent)

1. Peptic ulcer disease (PUD) - drug of choice for healing (4-8 weeks)
2. GERD - first-line treatment; healing esophagitis
3. H. pylori eradication - part of triple/quadruple therapy
4. NSAID-related ulcers - prevention and treatment
5. Zollinger-Ellison syndrome - high-dose PPI (1st line)
6. Stress ulcer prophylaxis in ICU patients
7. Upper GI bleed (IV PPI bolus + infusion)

• Generally well tolerated
• Long-term: Hypomagnesemia, vitamin B12 deficiency, osteoporosis/fracture risk
• C. difficile infection (↑ risk)
• Rebound acid hypersecretion on withdrawal (gastrin-driven)
• Interstitial nephritis (rare)
• CYP2C19 interaction - may reduce clopidogrel effectiveness (Omeprazole > others)

---

B. H2 RECEPTOR ANTAGONISTS (H2RAs)

• Oral bioavailability ~50-80%
• Short t1/2 (~2 h); famotidine slightly longer
• Renal elimination (dose reduction in renal failure)

1. PUD (now largely replaced by PPIs)
2. GERD (mild-moderate)
3. Nocturnal acid suppression
4. OTC use for heartburn

• Cimetidine (most side effects):
  • Inhibits CYP1A2, CYP2C9, CYP2D6, CYP3A4 → multiple drug interactions (warfarin, theophylline, phenytoin, lidocaine)
  • Anti-androgenic effects (gynaecomastia, impotence) - blocks androgen receptors
  • Crosses BBB → confusion, hallucinations (especially elderly)
  • Increases serum creatinine (blocks tubular secretion, no true nephrotoxicity)
• Ranitidine, Famotidine: Far fewer CYP interactions; no anti-androgenic effects
• Tolerance develops with continued use (within days)

• Tolerance to H2RAs occurs rapidly due to upregulation of H2 receptors and hypergastrinemia
• PPIs do not show this tachyphylaxis

---

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

• Reversibly block the K+-binding site of H+/K+-ATPase (competitive with K+)
• Unlike PPIs - do NOT require acid activation; work at any pH
• Faster onset, more consistent acid suppression; effective even without a meal
• Useful in patients with CYP2C19 poor/rapid metabolizer phenotypes

---

D. ANTACIDS

• Antacids impair absorption of: tetracyclines, fluoroquinolones, digoxin, iron (chelation/adsorption)
• Take other drugs at least 2 hours before or after antacids

---

E. MUCOSAL PROTECTIVE AGENTS (Cytoprotectants)

1. Misoprostol

• Synthetic PGE1 analogue
• Acts on EP2/EP3 receptors on parietal cells → ↓ acid secretion
• Also stimulates mucus and bicarbonate secretion, enhances mucosal blood flow
• Primary use: Prevention of NSAID-induced ulcers (taken with the NSAID)
• Other uses: Labor induction, medical abortion (with mifepristone), cervical ripening
• Adverse effects: Diarrhea (most common, dose-dependent), abdominal cramps
• Contraindicated in pregnancy (uterotonic) except for obstetric uses
• Dose: 200 mcg four times daily with food (for NSAID ulcer prophylaxis)

2. Sucralfate

• Aluminum sucrose octasulfate (Al(OH)3 + sucrose octasulfate)
• Activated in acid (pH <4) → forms viscous sticky polymer
• Adheres to ulcer craters for up to 6 hours - acts as a physical barrier
• Inhibits pepsin activity (adsorbs pepsin), binds bile salts
• Stimulates PG and EGF production locally (cytoprotective)
• Uses:
  • GERD in pregnancy (not absorbed → safe)
  • Mucositis from radiation/chemotherapy
  • Stress ulcer prophylaxis (may have advantage over PPIs - less nosocomial pneumonia risk)
  • Bile reflux gastropathy
• Adverse effects: Constipation (~2%), bezoar formation, aluminum toxicity (in renal failure)
• Take on empty stomach, 1 h before meals; avoid antacids within 30 min
• Drug interactions: Reduces absorption of phenytoin, digoxin, fluoroquinolones, ketoconazole

3. Bismuth Compounds (Bismuth Subsalicylate / Colloidal Bismuth Subcitrate)

• Coat ulcer base, inhibit pepsin, stimulate mucus/PG secretion
• Antibacterial against H. pylori
• Used in: H. pylori eradication regimens (quadruple therapy), traveler's diarrhea
• Side effects: Black stools and tongue (not harmful), constipation; long-term: neurotoxicity

---

F. H. pylori ERADICATION REGIMENS

Triple Therapy (14 days - preferred):

• PPI + Clarithromycin + Amoxicillin (Clarithromycin-based)
• Or: PPI + Clarithromycin + Metronidazole (penicillin allergy)

Quadruple Therapy (bismuth-based, 14 days - for resistant cases):

• PPI + Bismuth + Metronidazole + Tetracycline

Sequential Therapy:

• PPI + Amoxicillin (5 days) → then PPI + Clarithromycin + Nitroimidazole (5 days)

Concomitant Therapy:

• PPI + Amoxicillin + Clarithromycin + Metronidazole simultaneously

Test-of-cure: Urea breath test or stool antigen test (≥4 weeks after completing therapy)

---

SECTION 3: PROKINETIC DRUGS

A. Metoclopramide

• Mechanism: D2 receptor antagonist (primary); also 5-HT4 agonist and 5-HT3 antagonist
• Actions:
  • ↑ esophageal sphincter tone
  • ↑ gastric emptying (antrum coordination)
  • Coordinates duodenal peristalsis
  • Antiemetic (blocks dopamine in CTZ)
• Uses: Gastroparesis, GERD, post-op/chemo nausea, facilitating small bowel intubation
• Adverse effects:
  • Extrapyramidal reactions (acute dystonia, akathisia, tardive dyskinesia with long-term use) - dopamine blockade in basal ganglia
  • Hyperprolactinemia → galactorrhea, amenorrhea, gynaecomastia
  • Drowsiness, restlessness
  • Crosses BBB readily

B. Domperidone

• Mechanism: D2 antagonist (like metoclopramide) but does NOT cross BBB well
• Fewer CNS/extrapyramidal side effects
• Still causes hyperprolactinemia (pituitary D2 blockade - outside BBB)
• Cardiac risk: QT prolongation (caution)
• Uses: Gastroparesis, nausea/vomiting, GERD

C. Itopride

• D2 antagonist + acetylcholinesterase inhibitor
• Fewer cardiac side effects than domperidone
• Used for functional dyspepsia

D. Cisapride (historical)

• 5-HT4 agonist → ACh release → ↑ motility throughout GI tract
• Withdrawn due to fatal cardiac arrhythmias (QT prolongation, CYP3A4 interaction)

E. Erythromycin (Motilin receptor agonist)

• Binds motilin receptors → strong phase III MMC-like contractions
• Used for gastroparesis (especially diabetic), gastric ileus
• Low doses more effective (100-250 mg) than antibiotic doses
• Tolerance develops with prolonged use

F. Prucalopride

• Selective, high-affinity 5-HT4 agonist
• Increases high-amplitude propagating contractions in colon
• Used for chronic constipation (especially in women)
• Unlike cisapride - does NOT inhibit hERG channels, safer cardiac profile

---

SECTION 4: ANTIEMETICS

Vomiting Reflex:

• Vomiting Center (VC) - in lateral reticular formation of medulla
• Chemoreceptor Trigger Zone (CTZ) - area postrema, floor of 4th ventricle (outside BBB)
• CTZ receptors: D2 (dopamine), 5-HT3 (serotonin), NK1 (substance P), M (muscarinic), H1 (histamine)

---

Classification of Antiemetics:

1. D2 Receptor Antagonists (Dopamine antagonists)

2. 5-HT3 Receptor Antagonists (Setrons) - Most Important for Chemotherapy

• Block 5-HT3 in CTZ, vagal afferents in GI tract, and NTS
• Uses: Chemo-induced (CINV), post-op, radiation-induced nausea
• SE: Headache, constipation, QT prolongation

3. NK1 Receptor Antagonists (Neurokinin antagonists)

• Block Substance P at NK1 receptors in CNS (NTS, VC)
• Particularly effective for delayed phase CINV (24-120 h post-chemo)
• Aprepitant is a CYP3A4 inhibitor - increases levels of dexamethasone, some chemo agents

4. Corticosteroids

• Dexamethasone - used in combination regimens for CINV (mechanism not fully known)
• Enhances efficacy of setrons and aprepitant

5. H1 Antihistamines (Useful for Motion Sickness)

6. Anticholinergic (Muscarinic Antagonists)

• Hyoscine (Scopolamine) - transdermal patch for motion sickness
• Blocks M receptors in vestibular apparatus and VC
• SE: Dry mouth, blurring of vision, urinary retention

7. Cannabinoids

• Dronabinol (THC), Nabilone
• CB1 receptor agonists
• Reserve use for refractory CINV
• SE: Dysphoria, sedation, ataxia, hallucinations

8. Benzodiazepines

• Lorazepam: Adjunct in CINV; especially for anticipatory nausea
• Anxiolytic + amnestic properties

---

Standard CINV Prophylaxis:

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

---

SECTION 5: LAXATIVES

Classification:

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

• Drugs: Psyllium (Ispaghula husk), Bran, Methylcellulose, Calcium polycarbophil
• Mechanism: Absorb water → ↑ stool bulk → stimulate peristalsis
• Mimic dietary fiber; soften stool
• Safest laxatives - suitable for long-term use, IBS, pregnancy, hemorrhoids
• Take with plenty of water (risk of intestinal obstruction if inadequate fluid)

2. Osmotic Laxatives (onset 1-3 h for saline; 24-48 h for non-saline)

• Magnesium sulfate (Epsom salt), Magnesium hydroxide (Milk of Magnesia), Sodium sulfate
• Draw water into lumen osmotically → rapid, watery evacuation
• Also stimulate CCK release → ↑ motility and secretion
• Caution in renal failure (Mg2+ accumulation)

• Lactulose (synthetic disaccharide - galactose + fructose) - not digested, fermented by colonic bacteria → lactic/acetic acid → osmotic effect + acidification
  • Also used for hepatic encephalopathy (acidic pH converts NH3 to NH4+ which is not absorbed)
  • SE: Flatulence, cramps, abdominal distension
• Sorbitol - similar to lactulose, cheaper

• Large non-absorbed polymer; holds water in colon
• Minimal electrolyte disturbance; safe for long-term use
• Used for chronic constipation, bowel prep (GoLYTELY - isotonic solution)

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

• Bisacodyl (tablets/suppositories): Converted to active compound by colonic bacteria; stimulates myenteric plexus → ↑ peristalsis + ↑ fluid secretion
• Sodium picosulfate: Similar mechanism; used for bowel prep

• Senna, Cascara: Prodrugs; glycosides hydrolyzed by colonic bacteria → active anthrones → stimulate myenteric plexus
• Used widely; chronic use → melanosis coli (brownish pigmentation of colonic mucosa - harmless)
• Long-term abuse → "cathartic colon" (atonic colon), hypokalemia

• Hydrolyzed to ricinoleic acid (active) in small intestine
• Strong intestinal irritant; rapid action (2-6 h)
• Historically used for bowel prep; largely replaced by safer agents

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

• Docusate sodium/calcium: Anionic surfactant - reduces surface tension of stool → water penetrates stool → softening
• Not a stimulant; minimal effect alone; used post-surgery, hemorrhoids, MI
• Mineral oil (liquid paraffin): Lubricates stool; caution - aspiration pneumonia, fat-soluble vitamin malabsorption

5. Prosecretory Agents (newer)

• Lubiprostone: CIC-2 chloride channel activator → ↑ Cl- secretion into lumen → water follows → ↑ fluid content
  • Uses: Chronic idiopathic constipation, IBS-C, opioid-induced constipation
  • SE: Nausea
• Linaclotide, Plecanatide: Guanylate cyclase C (GC-C) agonists → ↑ cGMP → ↑ Cl-/HCO3- secretion, ↑ motility; also reduce visceral pain (via cGMP acting on afferent neurons)
  • Uses: IBS-C, chronic idiopathic constipation
• Tenapanor: NHE3 inhibitor → reduces Na+ absorption → ↑ luminal water; used for IBS-C

6. Drugs for Opioid-Induced Constipation (OIC)

• Methylnaltrexone (Relistor): Peripherally acting μ-opioid receptor antagonist (PAMORA); does not cross BBB → relieves constipation without reversing analgesia
• Naloxegol, Naldemedine: Oral PAMORAs for OIC
• Alvimopan: For postoperative ileus

---

SECTION 6: ANTIDIARRHEAL DRUGS

Classification:

1. Opioid Receptor Agonists

• Mechanism: ↑ segmental contractions (propulsive motility ↓), ↑ sphincter tone, ↓ secretion
• Loperamide is 1st line for mild-moderate diarrhea; avoided in invasive bacterial diarrhea (prolongs illness)

2. Absorbents/Adsorbents

• Kaolin + Pectin (Kaopectate): Adsorb bacterial toxins and fluid; mechanically reduce diarrhea
• Attapulgite: Similar

3. Bismuth Subsalicylate

• Anti-secretory (salicylate component), mild antimicrobial
• Used for traveler's diarrhea, H. pylori

4. Antisecretory Agents

• Racecadotril (Acetorphan): Enkephalinase inhibitor → ↑ endogenous enkephalins → ↓ intestinal secretion via delta-opioid receptors; used in children with secretory diarrhea
• Crofelemer: Chloride channel blocker; used for HIV-associated diarrhea

5. Somatostatin Analogues

• Octreotide: Used for secretory diarrhea from carcinoid, VIPoma, chemotherapy
• Inhibits hormone (VIP, serotonin) release, ↓ splanchnic blood flow

6. ORS (Oral Rehydration Solution) - The Most Important Treatment

• WHO ORS: Glucose 13.5 g, NaCl 2.6 g, KCl 1.5 g, Sodium citrate 2.9 g per liter (reduced osmolarity)
• Glucose enhances Na+ and water absorption via SGLT1 co-transporter (this cotransporter is preserved even in cholera)

---

SECTION 7: DRUGS FOR IRRITABLE BOWEL SYNDROME (IBS)

Drugs for IBS-D:

Drugs for IBS-C:

For IBS Pain:

• Antispasmodics: Mebeverine, Hyoscine butylbromide, Dicyclomine, Peppermint oil (Ca2+ channel antagonist in smooth muscle)
• Antidepressants: TCAs (amitriptyline) for IBS-D; SSRIs (fluoxetine) for IBS-C
• Peppermint oil capsules - enteric-coated; relax smooth muscle via Ca2+ antagonism

---

SECTION 8: DRUGS FOR INFLAMMATORY BOWEL DISEASE (IBD)

A. Aminosalicylates (5-ASA agents)

• Active moiety: 5-aminosalicylic acid (5-ASA)
• Acts locally in gut mucosa - inhibits NF-kB, COX, lipoxygenase → ↓ PG and LT synthesis → ↓ inflammation
• Sulfasalazine = Sulfapyridine + 5-ASA (joined by azo bond; split by colonic bacteria)
• Sulfapyridine = carrier (absorbed, responsible for systemic SE)
• Mesalazine = pure 5-ASA (formulated with delayed/extended release coatings; less SE)

• Mild-moderate UC (oral + rectal preparations)
• Maintenance of remission in UC
• Crohn's colitis (less effective than in UC)

• Nausea, anorexia, headache (sulfonamide effects - dose related)
• Reversible oligospermia (sulfapyridine)
• Hemolytic anemia (G6PD deficiency)
• Folate deficiency (rare); Stevens-Johnson syndrome (rare)
• Mesalazine: Nephrotoxicity (interstitial nephritis - monitor renal function)

---

B. Corticosteroids

• Prednisolone/Prednisone (systemic) - for moderate-severe flares
• Budesonide - topically acting steroid with high first-pass metabolism (>90%) → minimal systemic SE; used for ileocecal Crohn's disease and microscopic colitis
• Hydrocortisone enemas/suppositories - for distal UC/proctitis

---

C. Immunosuppressants

1. Azathioprine / 6-Mercaptopurine (6-MP)

• Prodrug (azathioprine → 6-MP → 6-thioguanine nucleotides)
• Inhibit purine synthesis → suppress lymphocyte proliferation
• Slow onset (3-6 months) - used for maintenance, not acute flares
• Toxicity: Myelosuppression (check TPMT enzyme activity before starting - TPMT deficiency → severe toxicity), hepatotoxicity, pancreatitis, ↑ risk of lymphoma
• Interaction: Allopurinol inhibits xanthine oxidase → ↑ 6-MP toxicity (reduce dose by 75% or avoid combination)

2. Methotrexate (MTX)

• Folic acid antagonist → ↓ DNA synthesis in lymphocytes
• Used in CD (steroid-sparing); less commonly in UC
• SE: Hepatic fibrosis (cumulative dose-dependent), pneumonitis, myelosuppression, mucositis
• Must take folic acid supplementation to reduce SE
• Teratogenic - contraindicated in pregnancy

---

D. Biologics (Anti-TNF-α agents)

1. Infliximab (IFX)

• Chimeric (25% mouse, 75% human) anti-TNF-α monoclonal antibody (IgG1)
• Binds soluble and membrane-bound TNF-α → ↓ inflammation, induces apoptosis in activated T-cells
• IV infusion every 8 weeks (after loading doses at weeks 0, 2, 6)
• Uses: Moderate-severe UC and CD; steroid-refractory disease; fistulizing CD
• SE: Infusion reactions, infections (TB reactivation - screen before starting), increased lymphoma risk, demyelination, drug-induced lupus

2. Adalimumab

• Fully human anti-TNF-α monoclonal antibody
• Subcutaneous injection (every 2 weeks)
• Advantages: Subcutaneous, less immunogenic than infliximab

3. Certolizumab pegol

• PEGylated Fab fragment of anti-TNF-α
• Cannot cross placenta (unlike full IgG) → relatively safe in pregnancy

4. Golimumab

• Fully human anti-TNF-α; used in UC

Anti-IL-12/23 agents:

• Ustekinumab: Anti-p40 subunit (shared by IL-12 and IL-23) mAb - IV then SC; used in CD and UC

Anti-integrin agents (Gut-selective):

• Vedolizumab: Anti-α4β7 integrin mAb → prevents lymphocyte migration to gut
  • Gut-selective → very low systemic immunosuppression
  • IV every 8 weeks; used in moderate-severe UC and CD

JAK Inhibitors (Small molecules):

• Tofacitinib: JAK1/3 inhibitor; oral; used for moderate-severe UC
• Upadacitinib, Filgotinib: More selective JAK1 inhibitors; newer options for IBD
• SE: Infections, VTE risk, MACE risk (monitor)

---

SECTION 9: DRUGS FOR FUNCTIONAL DYSPEPSIA

• Antacids / H2RAs - symptomatic relief
• PPIs - 4-8 week trial
• Prokinetics (Itopride, Domperidone, Metoclopramide) - for postprandial fullness/early satiety
• Buspirone - 5-HT1A agonist; ↑ fundus relaxation; reduces early satiety
• Low-dose TCAs (amitriptyline) - for pain modulation
• Rifaximin - if small intestinal bacterial overgrowth suspected

---

SECTION 10: DRUGS FOR HEPATIC ENCEPHALOPATHY

1. Lactulose - 1st line; acidifies colon → converts NH3→NH4+ → traps ammonia; also cathartic (eliminates ammonia-producing bacteria)
2. Rifaximin - 550 mg BD; non-absorbable antibiotic; reduces ammonia-producing gut bacteria; used for prevention of recurrence
3. Zinc supplementation - cofactor for urea cycle enzymes
4. BCAA (Branched chain amino acids) - IV or oral; corrects amino acid imbalance

---

SECTION 11: DRUGS FOR NAUSEA/VOMITING IN SPECIFIC SETTINGS

Pregnancy (Morning Sickness):

• 1st line: Vitamin B6 (Pyridoxine) ± Doxylamine
• 2nd line: Ginger, antihistamines (dimenhydrinate, meclizine)
• Severe (Hyperemesis gravidarum): Ondansetron, metoclopramide, corticosteroids

Motion Sickness:

• Hyoscine (Scopolamine) transdermal patch - most effective
• Dimenhydrinate / Promethazine (H1 antihistamines)

Post-op Nausea & Vomiting (PONV):

• Ondansetron 4 mg IV, Dexamethasone 4 mg, Droperidol
• Combination preferred

---

QUICK SUMMARY TABLE

---

---

GASTROINTESTINAL PHARMACOLOGY - COMPREHENSIVE NOTES

---

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

---

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

---

B. H2 RECEPTOR ANTAGONISTS (H2RAs)

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

---

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

---

D. ANTACIDS

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

---

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

---

F. H. PYLORI ERADICATION REGIMENS

---

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)

---

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

---

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

---

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)

---

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)

---

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)

---

SECTION 8: INFLAMMATORY BOWEL DISEASE (IBD)

A. Aminosalicylates (5-ASA)

---

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

---

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

---

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

---

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

---

KEY EXAM POINTS (High-Yield)

---