Note: In Katzung's 16th edition, the GIT pharmacology chapter is Chapter 62 ("Drugs Used in the Treatment of Gastrointestinal Diseases"). It was Chapter 59 in the 13th/14th editions - same content. All notes below are directly from the textbook.

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KATZUNG - GIT PHARMACOLOGY (Ch 59/62)

Concise Notes

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SECTION 1: DRUGS USED IN ACID-PEPTIC DISEASES

Pathophysiology Overview

• Acid-peptic diseases: GERD, peptic ulcer disease (PUD), stress ulcers
• Aggressive factors: acid, pepsin, NSAIDs, H. pylori, bile
• Defensive factors: mucus, bicarbonate, prostaglandins, blood flow

• 90% of peptic ulcers caused by H. pylori OR NSAIDs

Physiology of Acid Secretion

• Parietal cell has 3 receptors: Gastrin (CCK-B), Histamine (H2), Acetylcholine (M3)
• Gastrin and ACh → increase cytosolic Ca2+ → activate protein kinases → stimulate proton pump (H+/K+-ATPase)
• Histamine → activates adenylyl cyclase → increases cAMP → PKA activation → stimulates proton pump
• Proton pump is on the canalicular surface of parietal cells

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A. PROTON PUMP INHIBITORS (PPIs)

• Prodrugs - activated in acid environment to sulfenamide form
• Irreversibly bind to and inhibit H+/K+-ATPase (proton pump)
• Require acidic environment for activation → take 30-60 min before meals
• Inhibit BOTH fasting and meal-stimulated acid secretion (unlike H2 blockers)
• Inhibit 90-98% of 24-hour acid secretion

• Absorbed in small intestine (enteric coated to protect from acid)
• Short serum half-life (~1-2 hours) but long duration (18-24 hours) due to irreversible binding
• Hepatic metabolism (CYP2C19 and CYP3A4); negligible renal clearance
• No dose reduction needed for renal insufficiency or mild-moderate liver disease
• Full effect takes 2-5 days to develop (as existing pumps are replaced)

1. GERD - most effective agent; 85-90% symptom relief with once-daily dosing; >80% relapse within 6 months of stopping
2. PUD - heals 80-90% of duodenal ulcers in 4 weeks; gastric ulcers in 6-8 weeks
3. H. pylori eradication - part of triple/quadruple therapy
4. NSAID-induced ulcers - prevention and treatment
5. Zollinger-Ellison syndrome - high doses needed; treat indefinitely
6. Upper GI bleeding - IV formulation (esomeprazole, pantoprazole)

• Generally safe; most common: headache, diarrhea, nausea, abdominal pain
• Long-term use concerns:
  • C. difficile infection (increased risk)
  • Hypomagnesemia (with >1 year use)
  • Vitamin B12 deficiency (impaired absorption)
  • Bone fractures (hip, spine, wrist) - especially >50 years, >1 year use
  • Community-acquired pneumonia
  • Drug interactions: reduce absorption of drugs needing acidic pH (ketoconazole, iron, ampicillin, clopidogrel - reduced antiplatelet effect via CYP2C19)

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B. H2-RECEPTOR ANTAGONISTS

• Competitively block H2 receptors on parietal cells
• Reduce acid secretion by 60-70%
• Primarily inhibit fasting/nocturnal secretion (not as effective against meal-stimulated acid)

• Oral bioavailability 50% (cimetidine, famotidine) to 90% (nizatidine)
• Half-life 1.1-4 hours
• Renal excretion - dose reduction needed in renal failure

• GERD (mild-moderate), PUD, stress ulcer prophylaxis

• Cimetidine: gynecomastia, decreased libido/impotence (antiandrogenic effects); inhibits CYP450 (major drug interactions - warfarin, phenytoin, theophylline, lidocaine); crosses BBB → confusion in elderly
• Tolerance develops with continuous use (tachyphylaxis)

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C. ANTACIDS

• Neutralize gastric acid; provide rapid symptomatic relief
• Aluminum antacids can cause phosphate depletion (with long-term use)
• Magnesium antacids: contraindicated in renal failure (Mg accumulation)
• High sodium antacids (NaHCO3): avoid in hypertension/cardiac failure

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D. MUCOSAL PROTECTIVE AGENTS

• Polymerized sucrose-aluminum salt; activated in acid (pH <4)
• Forms a viscous paste that coats and protects ulcer base
• Stimulates prostaglandin and bicarbonate secretion
• Does NOT reduce acid secretion
• Requires acidic pH - avoid concurrent PPIs/antacids (or give 2 hours apart)
• Constipation (most common side effect); can bind and reduce absorption of other drugs
• Used: PUD treatment, stress ulcer prophylaxis

• Coat ulcer base
• Have direct antimicrobial activity against H. pylori
• Used in H. pylori eradication regimens (quadruple therapy)
• May cause black stool, black tongue; neurotoxicity with long-term high-dose use

• Synthetic PGE1 analog
• Stimulates mucus and bicarbonate secretion; inhibits acid secretion; increases mucosal blood flow
• Used for NSAID-induced ulcer prevention
• Contraindicated in pregnancy (uterotonic - causes abortion; used therapeutically for medical abortion)
• Adverse effects: diarrhea, abdominal cramping (dose-limiting)

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E. H. PYLORI ERADICATION REGIMENS

• PPI + Clarithromycin + Amoxicillin (or Metronidazole if penicillin allergy)

• PPI + Bismuth + Metronidazole + Tetracycline

• PPI + Amoxicillin (5 days) → PPI + Clarithromycin + Metronidazole (5 days)

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SECTION 2: GI MOTILITY DRUGS

Enteric Nervous System (ENS)

• Submucosal plexus (Meissner's) and myenteric plexus (Auerbach's)
• Serotonin (5-HT) from EC cells is key mediator:
  • 5-HT3 receptors on extrinsic afferents → nausea, vomiting, pain
  • 5-HT4 receptors → enhance ACh release → promote motility
• Dopamine: inhibitory neurotransmitter in GIT

A. PROKINETICS

• D2 receptor antagonist; also 5-HT3 antagonist and 5-HT4 agonist
• Increases esophageal sphincter pressure; accelerates gastric emptying
• Also has central antiemetic action (blocks CTZ)
• Uses: GERD, diabetic gastroparesis, chemotherapy nausea
• Adverse effects: tardive dyskinesia (with long-term use - irreversible), extrapyramidal effects (acute dystonia), drowsiness, restlessness; hyperprolactinemia → galactorrhea, gynecomastia

• D2 antagonist; does NOT cross BBB (fewer CNS side effects)
• But: prolongs QT interval; risk of cardiac arrhythmias
• Not approved in USA

• Motilin receptor agonist
• Potent gastric prokinetic; useful for gastroparesis
• Tachyphylaxis develops with continued use

• Selective 5-HT4 agonist; approved for chronic constipation
• Fewer cardiovascular effects than older 5-HT4 agonists (cisapride - withdrawn due to QT prolongation)

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SECTION 3: LAXATIVES

• PEG (polyethylene glycol): osmotic; used for whole bowel irrigation pre-colonoscopy and chronic constipation
• Lactulose: metabolized by colonic bacteria → lactic acid → osmotic effect; also used in hepatic encephalopathy (traps NH3 as NH4+)
• Chronic stimulant laxative use → cathartic colon, melanosis coli (with anthraquinone laxatives like senna)

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SECTION 4: ANTIDIARRHEALS

• Opioid receptor agonist (μ); does NOT cross BBB at normal doses
• Decreases intestinal motility and increases anal sphincter tone
• Increases electrolyte and water absorption
• No CNS/analgesic effects
• Drug of choice for traveler's diarrhea; IBS-D

• Opioid agonist; atropine added to discourage abuse
• Crosses BBB slightly; some CNS effects

• Antimicrobial; antisecretory (salicylate component)
• Used for traveler's diarrhea prevention

• Somatostatin analog; inhibits secretion of gut hormones and acid
• Uses: secretory diarrhea (VIPoma, carcinoid), dumping syndrome, short bowel syndrome, GI bleeding
• Low doses (50 mcg SC) → stimulate motility; high doses (>100 mcg) → inhibit motility
• Adverse effects: steatorrhea, nausea, gallstones (>50% with long-term use), hyperglycemia, hypothyroidism, bradycardia

• Used for bile acid-induced diarrhea (after ileal resection)

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SECTION 5: ANTIEMETICS

Mechanism-based Classification

• 5-HT3 antagonist; peripheral (gut) + central (CTZ)
• No D2 blockade → no EPS
• Side effect: headache, constipation, QT prolongation
• Drug of choice for CINV

• NK1 receptor antagonist (blocks substance P in CNS)
• Used for prevention of acute AND delayed CINV
• Prodrug fosaprepitant given IV

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SECTION 6: DRUGS FOR INFLAMMATORY BOWEL DISEASE (IBD)

Types: Ulcerative Colitis (UC) vs Crohn Disease (CD)

A. AMINOSALICYLATES (5-ASA Drugs)

• Act topically on diseased mucosa
• Inhibit prostaglandin synthesis, decrease cytokines

• Sulfapyridine (carrier, absorbed) + 5-ASA (active part, stays in colon)
• Sulfapyridine causes most side effects: nausea, headache, hemolytic anemia, male infertility (reversible), rare agranulocytosis

• Various formulations to deliver 5-ASA to different GI sites
• Oral (Asacol, Pentasa, Lialda), rectal suppositories/enemas
• Side effects: nephrotoxicity (rare), pancreatitis (rare)

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B. CORTICOSTEROIDS

• Prednisone, methylprednisolone (systemic)
• Budesonide (oral controlled ileal release - minimal systemic absorption; fewer side effects)
• Used for moderate-severe flares; not for maintenance (side effects)
• Budesonide: first-line for mild-moderate CD of terminal ileum/proximal colon

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C. IMMUNOMODULATORS

• Purine analogs - inhibit lymphocyte proliferation
• Slow onset: 3-6 months to full effect
• Uses: maintenance of remission in IBD, steroid-sparing
• Metabolized by TPMT (thiopurine methyltransferase) - check TPMT status before use
• Adverse effects: bone marrow suppression, hepatotoxicity, pancreatitis, increased risk of lymphoma and non-melanoma skin cancer

• Inhibits dihydrofolate reductase → decreased folate → inhibits purine/pyrimidine synthesis
• Used in CD (not as effective in UC)
• Given weekly IM; oral less effective
• Adverse effects: hepatic fibrosis, pulmonary toxicity, teratogenic (Category X)

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D. BIOLOGIC AGENTS

• Reactivation of latent TB (screen with TST/IGRA before starting)
• Serious infections (bacterial, viral, fungal)
• Hepatitis B reactivation
• Hepatic reactions
• Demyelinating disorders
• Worsening CHF
• Psoriatic skin rashes
• Lymphoma risk (increased vs. background)
• Hepatosplenic T-cell lymphoma (rare; young patients on combo immunosuppression)
• Non-melanoma skin cancers

• Risk of PML (progressive multifocal leukoencephalopathy) due to JC virus reactivation
• Rarely used now

• Blocks leukocyte trafficking to gut only
• No CNS JC virus risk (brain-sparing)
• IV infusion: 300 mg at 0, 2, 6 weeks → then every 8 weeks
• Second-line for moderate-severe UC or CD

• Blocks TH1 and TH17 responses
• IV induction, then SC maintenance every 8 weeks
• Used for moderate-severe CD (biologic-naive or failed other biologics)

• Risks: serious infections, PE/DVT, cardiovascular events, malignancy

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SECTION 7: DRUGS FOR IBS

• IBS: abdominal pain + altered bowel habits (no structural disease)

• Loperamide (antidiarrheal)
• Alosetron (5-HT3 antagonist) - women with severe IBS-D only; risk of ischemic colitis
• Rifaximin (non-absorbable antibiotic) - reduces gut bacterial overgrowth
• Eluxadoline (μ/κ opioid agonist + δ opioid antagonist) - reduces pain and diarrhea

• Fiber, osmotic laxatives (PEG, MgOH)
• Linaclotide and Plecanatide (guanylate cyclase-C agonists) - increase fluid secretion into lumen
• Lubiprostone (ClC-2 chloride channel activator) - increases intestinal fluid secretion

• Low-dose tricyclic antidepressants (amitriptyline 10-50 mg/d) - alter visceral afferent processing

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SECTION 8: DRUGS FOR GI BLEEDING

• Octreotide IV - decreases splanchnic blood flow; reduces portal pressure
• Beta blockers (propranolol, nadolol) - reduce portal pressure long-term
• Vasopressin (terlipressin) - vasoconstriction of splanchnic vessels; risk of coronary ischemia

• IV PPIs (esomeprazole/pantoprazole continuous infusion) - maintain pH >6, stabilize clot
• Endoscopic hemostasis

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MCQs - KATZUNG GIT PHARMACOLOGY

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• A) H2 receptor
• B) M3 muscarinic receptor
• C) CCK-A receptor
• D) 5-HT4 receptor

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• A) It competitively blocks H2 receptors on parietal cells
• B) It irreversibly binds H+/K+-ATPase after activation in acidic environment
• C) It increases prostaglandin synthesis in gastric mucosa
• D) It requires alkaline pH for activation

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• A) They irritate gastric mucosa if taken on empty stomach
• B) They need a meal to activate their prodrug form
• C) Active proton pumps are needed for drug activation; meals stimulate pump activity
• D) Food increases their intestinal absorption

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• A) Famotidine
• B) Nizatidine
• C) Ranitidine
• D) Cimetidine

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• A) Sucralfate
• B) Misoprostol
• C) Bismuth subsalicylate
• D) Omeprazole

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• A) Alkaline (pH >7)
• B) Neutral (pH 7)
• C) Acidic (pH <4)
• D) pH-independent

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• A) Sucralfate
• B) Omeprazole
• C) Misoprostol
• D) Famotidine

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• A) Ondansetron
• B) Metoclopramide
• C) Aprepitant
• D) Prochlorperazine

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• A) Parkinson disease
• B) Drug-induced tardive dyskinesia
• C) Huntington chorea
• D) Neuroleptic malignant syndrome

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• A) D2 dopamine
• B) H1 histamine
• C) 5-HT3 serotonin
• D) NK1 substance P

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• A) Directly reduces ammonia production by liver
• B) Is converted by gut bacteria to acids that trap NH3 as NH4+ and acidify colon
• C) Directly absorbs ammonia in the colon
• D) Inhibits urease-producing bacteria

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• A) Cisapride
• B) Tegaserod
• C) Prucalopride
• D) Metoclopramide

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• A) Blocks 5-HT3 receptors peripherally
• B) Inhibits hormonal secretion from tumor via somatostatin receptor agonism
• C) Directly destroys carcinoid tumor cells
• D) Stimulates intestinal motility to clear serotonin faster

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• A) Echocardiogram
• B) Renal function tests
• C) Tuberculin skin test (TST) or IGRA for latent TB
• D) Serum ammonia level

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• A) Rapid metabolism and drug inefficacy
• B) Accumulation of toxic thioguanine nucleotides → severe bone marrow suppression
• C) Hypersensitivity reaction only
• D) Increased risk of opportunistic infections unrelated to drug levels

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• A) Blocks α4β1 integrins systemically
• B) Specifically blocks α4β7 integrin, restricting effect to gut and sparing CNS trafficking
• C) Inhibits IL-23 signaling
• D) Is an oral small molecule drug

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• A) Bisacodyl
• B) Lactulose
• C) Linaclotide
• D) Docusate

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• A) Tardive dyskinesia
• B) Ischemic colitis
• C) PML
• D) Hepatosplenic T-cell lymphoma

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• A) Category B
• B) Teratogenic (Category X)
• C) A Category C drug with acceptable risk
• D) Only contraindicated in the third trimester

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• A) An excitatory neurotransmitter increasing esophageal contractions
• B) An inhibitory neurotransmitter decreasing intensity of esophageal and gastric contractions
• C) A stimulant of parietal cell acid secretion
• D) A selective agonist at 5-HT3 receptors

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Source: Katzung's Basic and Clinical Pharmacology, 16th Edition - Chapter 62: Drugs Used in the Treatment of Gastrointestinal Diseases (equivalent to Chapter 59 in earlier editions)