GI Pharm Drill — Answer Key

Parietal Cell Targets

3 Stimulatory Inputs to Parietal Cell (NT → Receptor → Cell of Origin)

1.ACh from vagal postganglionic neurons → M₃ receptor.

2.Histamine from ECL cells → H₂ receptor (Gs → ↑cAMP).

3.Gastrin from antral G cells → CCK-B receptor. All converge on H⁺/K⁺-ATPase.

Final Common Pump Blocked by PPIs/P-CABs

H⁺/K⁺-ATPase (proton pump) on the apical/canalicular membrane of the parietal cell.

Why Anticholinergics Are Rarely Used for Acid Suppression

Non-selective M blockade → prohibitive side effects: tachycardia, dry mouth, blurred vision, constipation, urinary retention, sexual dysfunction. Understand the target conceptually; not first-line.

Which Target Has the Most Potent Acid Suppression?

Proton pump (H⁺/K⁺-ATPase) — PPIs suppress 60–80% of acid output; targeting the final common step gives maximal efficacy.

H₂ Receptor Antagonists ("-tidines")

Drug	Unique Feature	Key ADR / Concern
Cimetidine	First-in-class (1979); classic CYP450 inhibitor (1A2, 2C19, 2D6).	Drug interactions (warfarin, phenytoin, benzos, clopidogrel); antiandrogenic → gynecomastia, impotence; mental confusion in elderly.
Ranitidine	Furan ring replaced imidazole → fewer CYP effects than cimetidine.	Pulled from market — NDMA (nitrosamine) carcinogen contamination. Zantac brand now uses famotidine.
Famotidine	More potent + longer-lasting than cimetidine; minimal CYP interactions.	Preferred H₂ blocker; very few drug interactions; no antiandrogenic effect. Still develops tolerance with chronic use.

MOA of H₂ Blockers (Mechanism Class, Reversibility)

1.Competitive, REVERSIBLE antagonists at H₂ receptors on parietal cells.

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2.↓ cAMP → ↓ proton pump activation.

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3.↓ gastric acid secretion.

Key Limitation of Long-Term H₂ Blocker Use

Tolerance (tachyphylaxis) develops via H₂ receptor upregulation → efficacy wanes over weeks. PPIs preferred for chronic acid suppression (no tolerance).

🚩 TRAP — CIMETIDINE DRUG INTERACTIONS

Cimetidine inhibits CYP1A2, 2C19, and 2D6 → ↑ plasma levels of warfarin (bleeding), phenytoin (toxicity), benzodiazepines (sedation), theophylline. Also ↓ clopidogrel activation (prodrug requiring CYP2C19) → ↓antiplatelet effect. Famotidine does NOT have these interactions — switch if cimetidine interactions are a concern.

Proton Pump Inhibitors ("-prazoles")

MOA (Complete Chain — Prodrug → Activation → Binding Type)

1.Enteric-coated prodrug absorbed in small bowel.

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2.Accumulates in acidic parietal cell canaliculi; protonated to active sulfenamide.

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3.Covalently binds cysteine sulfhydryl groups on H⁺/K⁺-ATPase (IRREVERSIBLE).

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4.Permanent pump inactivation — new pumps (~48 hrs) required to restore acid secretion.

When Must PPIs Be Taken (Meal Timing)? Why?

When:30–60 minutes BEFORE a meal.

Why:The meal activates proton pumps; only active pumps generate the acidic microenvironment needed to activate the PPI prodrug.

Why No Tolerance Develops (vs H₂ Blockers)

Irreversible covalent binding inactivates each pump permanently. Acid suppression depends on synthesis of NEW pumps, not receptor signaling — there's no feedback receptor upregulation.

PPI with LEAST CYP450 Interactions

Pantoprazole — cleanest interaction profile; preferred when patient takes multiple CYP-sensitive drugs (e.g., clopidogrel).

PPI	CYP Effects / Notes
Omeprazole / Esomeprazole	Inhibit CYP2C19 + 3A4 → ↑ warfarin/oxycodone levels; ↓ clopidogrel activation (major interaction). Esomeprazole = S-enantiomer of omeprazole.
Pantoprazole	LOWEST CYP450 interactions of all PPIs — preferred when clopidogrel or warfarin also prescribed.
Lansoprazole	~80% bioavailable; intermediate CYP profile; shorter duration than omeprazole.

5 Long-Term PPI Adverse Effects

1.↑ C. difficile infection (gastric acid is a protective barrier).

2.Vitamin B12 deficiency (acid needed to release B12 from food proteins).

3.Bone fractures (impaired Ca²⁺ absorption — hip, spine, wrist).

4.Hypomagnesemia (can cause tetany, seizures, arrhythmias).

5.Community-acquired pneumonia + acute interstitial nephritis + rebound acid hypersecretion.

Mechanism — Why PPIs Cause B12 Deficiency

1.PPI suppresses gastric acid → achlorhydria.

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2.Acid + pepsin normally cleave B12 from dietary proteins — this step fails.

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3.↓ free B12 available for intrinsic-factor binding → ↓ ileal absorption → B12 deficiency.

🚩 TRAP — PPI + CLOPIDOGREL

Omeprazole and esomeprazole are potent CYP2C19 inhibitors. Clopidogrel is a prodrug activated by CYP2C19 → ↓ active metabolite → ↓ antiplatelet effect → ↑ stent thrombosis / MI risk. Preferred alternative: pantoprazole (minimal 2C19 inhibition) or an H₂ blocker (famotidine).

P-CABs (Potassium-Competitive Acid Blockers)

Feature	PPIs	P-CABs (e.g., Vonoprazan)
Binding	Irreversible (covalent via sulfenamide).	Reversible, ionic/competitive at the K⁺-binding site.
Requires Acid Activation?	YES — prodrug, needs acidic canaliculi.	NO — acid-stable; works without activation.
Onset	Slower (days for full effect).	Fast (hours); immediate full effect.
Meal-Timing Required?	Yes — must take 30–60 min before meals.	No — can be taken with or without food.

Antacids

Antacid	Key Side Effect	Unique Fact
Aluminum Hydroxide	Constipation ("Al = All Locked Up").	Binds phosphate in gut → hypophosphatemia with chronic use.
Magnesium Hydroxide	Diarrhea ("Mg = Must Go") — osmotic effect of MgCl₂.	Avoid in renal failure (Mg accumulation → hypermagnesemia).
Calcium Carbonate	Belching/gas (CO₂), constipation; rebound acid hypersecretion.	Risk of milk-alkali syndrome with high-dose chronic use (Tums).
Sodium Bicarbonate	Bloating (CO₂); metabolic alkalosis; Na⁺ load (worsens HF/HTN).	Rapid onset but short-lived; not for chronic use.

Mnemonic: Mg vs Al GI Effect

MMust (Mg = ...)

GGo → diarrhea. (Mg = Must Go.)

AAll (Al = ...)

LLocked up → constipation. (Al = All Locked.) Combine (Maalox/Mylanta) for balanced GI effect.

Milk-Alkali Syndrome — Triad + Causative Antacid

Triad 1:Hypercalcemia.

Triad 2:Metabolic alkalosis.

Triad 3:Acute kidney injury.

Antacid:High-dose calcium carbonate (Tums) chronic use — especially with thiazides or vitamin D.

🚩 TRAP — ANTACID DRUG INTERACTIONS

Antacids raise gastric pH → ↓ absorption of drugs requiring acid: tetracyclines, fluoroquinolones, iron, ketoconazole/itraconazole, atazanavir. Also chelate divalent cations. Rule: separate dosing by ≥2 hours.

H. pylori — Virulence & Diagnosis

Key Virulence Enzyme + Mechanism of Acid Survival

Enzyme:UREASE.

Mechanism:Converts urea → NH₃ + CO₂; NH₃ locally buffers gastric acid → allows bacterial survival in mucosal layer. Urease is also the target of the urea breath test.

Long-Term Complications of Untreated H. pylori (2)

1.Gastric adenocarcinoma (intestinal type — strong causal link).

2.MALT lymphoma (marginal zone B-cell lymphoma — often regresses with H. pylori eradication alone). Also causes chronic gastritis and PUD.

Gold-Standard Non-Invasive Dx Test + How It Works

Test:Urea breath test.

Mechanism:Patient ingests ¹³C- or ¹⁴C-labeled urea → bacterial urease splits it → labeled CO₂ detected in exhaled breath. Highly sensitive + specific; confirms active infection.

Why Serology (IgG) Is NOT Used to Confirm Eradication

IgG antibodies persist for months–years after bacteria cleared — cannot distinguish active from past infection. Use urea breath test or stool antigen for eradication confirmation.

Treatment Regimens

Regimen	Drugs (all 4 / all 3)	Duration / When Used
Quadruple Therapy (preferred, 1st-line)	PPI + Bismuth subsalicylate + Metronidazole + Tetracycline.	10–14 days. First-line due to rising clarithromycin resistance; preferred in most populations.
Triple Therapy (older, falling out of favor)	PPI + Amoxicillin + Clarithromycin.	10–14 days. Use only if local clarithromycin resistance <15% and no prior macrolide exposure.

Why Is Triple Therapy Falling Out of Favor?

Rising clarithromycin resistance (>15% in many regions) → treatment failure rates climbing. Quadruple therapy covers resistance and is now preferred empirically.

PPI's Dual Role in H. pylori Therapy

1.Suppresses acid → promotes ulcer healing and symptom relief.

2.Raises gastric pH → improves efficacy of acid-labile antibiotics (amoxicillin, clarithromycin) at the mucosal surface.

Post-Treatment Retesting: When? Which Test(s)?

When:4 weeks AFTER completing antibiotics; stop PPI ≥2 weeks before testing to avoid false negatives.

Test(s):Urea breath test or stool antigen — NOT serology.

Bismuth in Quadruple Therapy — Why Added? (2 roles)

1.Intrinsic antimicrobial activity against H. pylori (disrupts bacterial wall + inhibits urease).

2.Forms protective coating over ulcer base and reduces inflammation. (Side effect: harmless black stools and black tongue.)

Cytoprotective Agents

Drug	MOA	Key Use / Unique Fact	Contraindication / ADR
Sucralfate	Polymerizes in acidic environment → sticky viscous gel adheres to ulcer base; barrier against acid/pepsin.	Ulcer healing; minimal systemic absorption — safe in pregnancy. Give on empty stomach.	Needs ACID to work → do NOT co-administer with PPI/H₂ blocker. Constipation.
Misoprostol	PGE₁ analog → ↑ mucus + bicarbonate secretion; ↓ acid secretion; maintains mucosal blood flow.	Prevention of NSAID-induced peptic ulcers (esp. high-risk: elderly, prior ulcer, on steroids).	CONTRAINDICATED in pregnancy (Category X — uterotonic, induces abortion/labor). Diarrhea, cramping.
Bismuth subsalicylate	Coats ulcer base; antimicrobial vs H. pylori; anti-inflammatory.	Component of quadruple therapy; traveler's diarrhea; functional dyspepsia.	Harmless black stools + black tongue; salicylate toxicity with excess dosing; avoid in children (Reye syndrome risk).

🛑 HARD TRAP — MISOPROSTOL IN PREGNANCY

Misoprostol is a PGE₁ analog and potent uterotonic — induces uterine contractions and cervical ripening. Category X for ulcer indications. Used therapeutically in obstetrics ONLY for: labor induction (term), medical abortion (with mifepristone), postpartum hemorrhage prevention/treatment. NEVER prescribe for NSAID ulcer prophylaxis in pregnant women — use a PPI instead.

GERD Pathophysiology

Primary Mechanical Defect in GERD

Reduced lower esophageal sphincter (LES) tone → retrograde movement of gastric contents into the esophagus → mucosal inflammation.

Normal LES Resting Pressure (mmHg)

~20 mmHg (range 10–30 mmHg) — high enough to prevent reflux at rest.

3 Normal Esophageal Defense Mechanisms

1.LES tone (mechanical barrier).

2.Esophageal peristalsis (clears refluxed material).

3.Salivary bicarbonate (neutralizes residual acid).

Progression: Chronic GERD → ??? → ??? (name both)

1.Barrett's esophagus (intestinal metaplasia — columnar epithelium with goblet cells).

2.Esophageal adenocarcinoma.

Factors That Reduce LES Pressure (Drug/Food)

Category	Examples
Dietary (≥4)	Fatty foods, caffeine, chocolate, alcohol, citrus, peppermint.
Drugs (≥5 classes)	Calcium channel blockers, anticholinergics, nitrates, β-agonists, α-antagonists, opioids (morphine), benzodiazepines, barbiturates, progesterone.
Systemic disease	Scleroderma (impairs esophageal motility and acid clearance).
Physiologic	Pregnancy (progesterone ↓ LES tone + gravid uterus ↑ abdominal pressure); obesity.

Stepwise Treatment

Step 1 (Lifestyle)

Weight loss, elevate head of bed, avoid late meals (≥3 hrs before supine), avoid trigger foods, smoking cessation, smaller meals.

Step 2 (On-Demand Drug Class)

Antacids (or alginate) — rapid, symptomatic relief of infrequent/mild heartburn.

Step 3 (Mild/Intermittent Symptoms)

H₂ blocker (famotidine) — daily or BID for more persistent symptoms.

Step 4 (Frequent/Severe or Erosive)

PPI once daily — standard for erosive esophagitis and frequent symptoms.

Step 5 (Refractory / Failed BID PPI)

P-CAB (vonoprazan) — for severe erosive esophagitis or PPI-refractory GERD.

Surgical Option for Refractory GERD

Nissen fundoplication (wrapping gastric fundus around distal esophagus to recreate a competent LES).

🚩 TRAP — DRUG-INDUCED GERD

Common offenders: (1) Calcium channel blockers; (2) Anticholinergics (antihistamines, TCAs); (3) Nitrates; (4) Opioids (morphine); (5) Benzodiazepines. Recognize drug-induced GERD before adding yet another acid suppressant — deprescribe the offender when possible.

Vomiting Reflex — 4 Centers & Receptor Profiles

Center	Location / Feature	Key Receptors	Stimulus
Emetic Center	Lateral reticular formation of medulla; final coordinator of vomiting.	Muscarinic (M₁), H₁.	Integrates all afferent inputs.
CTZ (Area Postrema)	Floor of 4th ventricle; OUTSIDE blood-brain barrier → senses circulating toxins.	D₂, 5-HT₃, NK₁, μ-opioid.	Chemotherapy, opioids, uremia, pregnancy hormones, toxins.
NTS (Nucleus Tractus Solitarius)	Medulla — receives vagal afferents from gut.	5-HT₃, NK₁, D₂.	Gut distension, mucosal irritation, chemo-induced enterochromaffin 5-HT release.
Vestibular System	Inner ear → cerebellum → emetic center; responds to motion.	H₁, M₁ (muscarinic).	Motion sickness, vertigo (Meniere's, BPPV).

Why Is the CTZ Uniquely Accessible to Blood-Borne Toxins?

The area postrema is a circumventricular organ — it lacks a blood-brain barrier, so circulating drugs, toxins, and metabolites directly stimulate its chemoreceptors. This is why chemo, opioids, and uremia cause N/V via the CTZ.

Which 2 Receptors Dominate Motion Sickness (Vestibular)?

1.H₁ (histamine) — blocked by meclizine/dimenhydrinate.

2.M₁ (muscarinic) — blocked by scopolamine.

Antiemetic Classes

Class	Prototype Drug(s)	Best Use	Key ADR
5-HT₃ Antagonists	Ondansetron, granisetron, palonosetron.	Chemotherapy-induced N/V, post-op N/V (PONV), hyperemesis gravidarum.	QTc prolongation, headache, constipation, serotonin syndrome with SSRIs.
NK₁ Antagonists	Aprepitant, fosaprepitant, rolapitant.	Delayed chemo N/V (given with 5-HT₃ + dexamethasone).	Fatigue, diarrhea; CYP3A4 interactions.
D₂ Antagonists	Metoclopramide (also prokinetic), prochlorperazine, promethazine, haloperidol.	Gastroparesis, chemo N/V, postop, migraine-associated N/V.	Extrapyramidal symptoms, tardive dyskinesia (black box), hyperprolactinemia, QTc prolongation.
H₁ Antagonists	Meclizine, dimenhydrinate, diphenhydramine.	Motion sickness, vertigo, mild pregnancy N/V.	Sedation, anticholinergic effects (dry mouth, urinary retention, confusion in elderly).
M₁ Antagonists	Scopolamine (transdermal patch).	Motion sickness prophylaxis (apply behind ear 4 hrs before travel).	Anticholinergic: dry mouth, blurred vision, urinary retention, confusion.
Cannabinoids	Dronabinol, nabilone.	Refractory chemo N/V; AIDS-related anorexia.	Euphoria, dysphoria, tachycardia, hypotension, dependence.
Corticosteroids	Dexamethasone.	Adjunct in chemo N/V (acute + delayed); synergistic with 5-HT₃ and NK₁.	Hyperglycemia, mood changes, insomnia (usually tolerable with short courses).

Best Regimen for Chemo-Induced N/V (Acute, Triple Therapy)

1.5-HT₃ antagonist (ondansetron or palonosetron).

2.NK₁ antagonist (aprepitant).

3.Dexamethasone. (Covers both acute [first 24 hr] and delayed [day 2–5] phases.)

Ondansetron Key ADR to Monitor on ECG

QTc prolongation → risk of torsades. Check ECG if combined with other QT-prolonging drugs (methadone, haloperidol, fluoroquinolones) or in hypokalemia/hypomagnesemia.

Prokinetics

Drug	MOA (Dual)	Clinical Use	Key ADR / Black Box
Metoclopramide	D₂ antagonist (central + peripheral) + 5-HT₄ agonist → ↑ ACh release at myenteric plexus → ↑ gastric emptying + LES tone.	Diabetic gastroparesis, refractory GERD, chemo N/V, post-op ileus.	BLACK BOX — tardive dyskinesia (irreversible); EPS; hyperprolactinemia; limit to ≤12 weeks. Contraindicated in Parkinson's and bowel obstruction.
Erythromycin	Motilin receptor agonist → ↑ gastric emptying (independent of antibiotic effect).	Short-term gastroparesis (inpatient); pre-endoscopy gastric clearance in UGI bleed.	Tachyphylaxis (efficacy fades with chronic use); QTc prolongation; CYP3A4 interactions; nausea at prokinetic doses.

🛑 HARD TRAP — METOCLOPRAMIDE IN PARKINSON'S

Metoclopramide crosses the blood-brain barrier and blocks central D₂ receptors in the nigrostriatal pathway — this directly worsens parkinsonian motor symptoms and can precipitate a parkinsonian crisis. CONTRAINDICATED in Parkinson's disease. Also avoid in mechanical bowel obstruction (prokinetic effect may cause perforation). Safer alternative for gastroparesis: trimethobenzamide or dietary measures.

Antidiarrheal Agents

Drug	MOA	Key Use / Unique Fact
Loperamide	Peripheral μ-opioid agonist → ↓ gut motility; P-glycoprotein substrate → excluded from CNS at therapeutic doses.	OTC first-line for acute non-infectious diarrhea; AVOID in inflammatory/bloody diarrhea.
Diphenoxylate/Atropine	μ-opioid agonist (diphenoxylate) + anticholinergic (atropine).	Atropine added at subtherapeutic dose to DETER abuse (unpleasant anticholinergic effects at supratherapeutic doses). Schedule V.
Bismuth subsalicylate	Coats mucosa; antibacterial; anti-inflammatory; binds enterotoxins.	Traveler's diarrhea prophylaxis + treatment; harmless black tongue/stools; avoid in children (Reye syndrome — salicylate).
Octreotide	Somatostatin analog → ↓ secretion of GI hormones (gastrin, VIP, serotonin, glucagon); ↓ splanchnic blood flow.	VIPoma, carcinoid syndrome, acromegaly, variceal bleeding, refractory secretory diarrhea.
Rifaximin	Non-absorbable (gut-selective) antibiotic — inhibits bacterial RNA polymerase.	Traveler's diarrhea (non-invasive E. coli), hepatic encephalopathy (↓ ammonia-producing gut flora), IBS-D.

🛑 HARD TRAP — LOPERAMIDE IN C. DIFFICILE / EHEC

Slowing gut motility in toxin-mediated or invasive infectious diarrhea prolongs mucosal toxin exposure → ↑ risk of toxic megacolon, hemolytic uremic syndrome (EHEC O157:H7), and sepsis. Contraindicated in C. difficile, EHEC, Shigella, and any bloody/febrile diarrhea. Rehydration + targeted antibiotics instead.

Laxatives by Class

Class	Prototype Drug(s)	Onset	MOA / Unique Fact
Bulk-Forming	Psyllium, methylcellulose.	1–3 days.	Absorb water → ↑ stool bulk → mechanical stretch → ↑ peristalsis. Safest for chronic use.
Osmotic	PEG (MiraLAX), lactulose, sorbitol, magnesium citrate/hydroxide.	Hours to days (PEG: 1–3 days; Mg: faster).	Non-absorbed solutes draw water into lumen. Lactulose also traps NH₃ in gut (↓ systemic absorption).
Stimulant	Senna, bisacodyl.	6–12 hours.	Directly stimulate enteric nerves → ↑ motility. Long-term use → melanosis coli (benign).
Stool Softener	Docusate sodium.	1–3 days.	Surfactant — allows water/fat to mix with stool. Minimal efficacy data; often used prophylactically.
Cl⁻ Channel Activator	Lubiprostone.	24 hours.	Activates ClC-2 channels → ↑ Cl⁻/fluid secretion into lumen. For IBS-C, chronic idiopathic constipation, opioid-induced constipation.
Guanylate Cyclase-C Agonist	Linaclotide, plecanatide.	Days.	↑ intracellular cGMP → ↑ Cl⁻/HCO₃⁻ secretion + accelerates transit. For IBS-C and chronic constipation.
PAMORA (peripheral μ-opioid antag.)	Methylnaltrexone, naloxegol, alvimopan.	Hours.	Polar/charged or P-gp substrate → excluded from CNS. For opioid-induced constipation WITHOUT reversing central analgesia.

Lactulose Dual Use — Laxative AND ???

Hepatic encephalopathy treatment: colonic bacteria ferment lactulose → acidification of gut lumen → converts NH₃ → NH₄⁺ (charged, non-absorbable) → trapped and excreted in stool → ↓ serum ammonia.

Why Do PAMORAs NOT Reverse Central Analgesia?

They are highly polar/charged or actively pumped out by P-glycoprotein at the blood-brain barrier → cannot cross into CNS → block only peripheral (enteric) μ-opioid receptors. Relieves constipation without reversing central pain control.

IBD Treatment Pyramid (Bottom = Mild → Top = Severe)

Step 1 (Mildest)

5-ASAs (mesalamine, sulfasalazine) — induction and maintenance, primarily in UC.

Step 2 (Induction only — NOT maintenance; why?)

Corticosteroids (prednisone, budesonide). Used only for induction of remission — chronic use causes Cushingoid toxicity (osteoporosis, DM, infection, cataracts, adrenal suppression). Budesonide has high first-pass metabolism → fewer systemic effects.

Step 3 (Immunomodulators — name 2)

1.Azathioprine / 6-mercaptopurine (purine antimetabolites).

2.Methotrexate (dihydrofolate reductase inhibitor — more effective in Crohn's disease).

Step 4 (Biologics — 3 target categories)

1.Anti-TNF-α (infliximab, adalimumab, certolizumab, golimumab).

2.Anti-integrin (vedolizumab α4β7; natalizumab α4).

3.Anti-IL-12/23 (ustekinumab) or anti-IL-23 alone (risankizumab). Plus: JAK inhibitors (tofacitinib) and S1P modulators (ozanimod).

Step 5 (Last-Line)

Surgery — colectomy (curative for UC), segmental resection or strictureplasty (CD; recurrence common).

5-ASAs (Mesalamine & Related)

MOA (Local Anti-Inflammatory)

1.Topically active in colonic lumen (minimal systemic absorption).

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2.Inhibits COX + lipoxygenase → ↓ prostaglandins + leukotrienes; scavenges ROS; inhibits NF-κB.

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3.Net: local anti-inflammatory effect on colonic mucosa.

More Effective in UC or CD? Why?

UC or CD:Ulcerative colitis.

Why:Disease limited to colon, where 5-ASAs are delivered and act locally. Less effective in Crohn's because CD often affects small bowel (proximal to colonic release).

Sulfasalazine — What Is the 2nd Component? ADR It Causes?

Sulfapyridine (sulfa antibiotic) — cleaved by colonic bacteria to release 5-ASA. Sulfapyridine causes the sulfa-related ADRs: rash/Stevens-Johnson, hemolysis in G6PD deficiency, and REVERSIBLE OLIGOSPERMIA (male infertility).

Key Renal ADR of Mesalamine

Interstitial nephritis (check baseline + periodic creatinine).

Biologics

Class / Drug	Target	Black Box / Key Concern
Anti-TNF-α (infliximab, adalimumab)	TNF-α (soluble + membrane-bound).	Reactivation of latent TB (screen PPD/IGRA first) and hepatitis B; ↑ serious/opportunistic infections; lymphoma (esp. hepatosplenic T-cell lymphoma with thiopurine combo); demyelination; CHF worsening.
Ustekinumab	p40 subunit — shared by IL-12 AND IL-23.	Infection risk (less than anti-TNF); injection-site reactions; rare PRES. No TB reactivation class effect comparable to anti-TNF but still screen.
Risankizumab	p19 subunit — IL-23 ONLY (more selective than ustekinumab).	Infection risk; injection-site reactions; generally favorable safety profile.
Vedolizumab	α4β7 integrin — GUT-SELECTIVE (blocks lymphocyte trafficking to gut endothelium only).	Infection risk (mostly enteric); minimal systemic immunosuppression; NO PML risk (unlike natalizumab).
Natalizumab	α4 integrin — NON-SELECTIVE (blocks both gut α4β7 AND CNS α4β1).	BLACK BOX: progressive multifocal leukoencephalopathy (PML) from JC virus reactivation. Screen JC virus antibody before + during therapy.

🛑 HARD TRAP — NATALIZUMAB & PML

Natalizumab blocks α4 integrin non-selectively → reduces CNS lymphocyte trafficking → allows JC virus to reactivate in brain → progressive multifocal leukoencephalopathy (PML — often fatal demyelinating disease). Screen anti-JC virus antibody BEFORE starting and periodically during therapy; highest risk with JCV-positive patients on prolonged therapy + prior immunosuppression. Vedolizumab (α4β7, gut-selective) does NOT cross into CNS trafficking → no PML risk.

Immunomodulators

Azathioprine / 6-MP — What Enzymes to Check Before Starting? Why?

Enzymes:TPMT (thiopurine methyltransferase) and NUDT15 activity/genotype.

Why:Deficiency → excess active 6-thioguanine nucleotides → severe myelosuppression and potentially fatal pancytopenia.

Azathioprine / 6-MP Key ADRs (3)

1.Myelosuppression (dose-related; monitor CBC).

2.Pancreatitis (idiosyncratic, usually early).

3.Hepatotoxicity. (Plus ↑ lymphoma/skin cancer risk, especially in combination with anti-TNF.)

Methotrexate — Preferred in UC or CD?

Crohn's disease — effective for maintenance of remission. Limited efficacy in UC.

MTX Pre-Screening Before Starting for IBD (Tests)

Baseline CBC, LFTs, creatinine, hepatitis B/C serology, pregnancy test (MTX is teratogenic — contraindicated in pregnancy). Chest X-ray if pulmonary risk. Supplement folic acid to ↓ ADRs.

Anti-TNF Pre-Screening & ADRs

Mandatory Infectious Pre-Screens Before Anti-TNF (2)

1.Latent TB screen — PPD or IGRA (QuantiFERON); treat latent TB before/with therapy.

2.Hepatitis B serology (HBsAg, anti-HBc) — risk of reactivation fulminant hepatitis; treat or monitor with antivirals.

Malignancy Risk Increased with Anti-TNF + Thiopurine Combo

Hepatosplenic T-cell lymphoma (rare but often fatal) — classically in young males on combined anti-TNF + azathioprine/6-MP. Also ↑ non-melanoma skin cancers.

FMT (Fecal Microbiota Transplant)

Gold-Standard Indication for FMT

Recurrent (multiple-episode) C. difficile infection refractory to standard antibiotics — cure rates >85%.

Emerging (Non-Standard) Indication

Ulcerative colitis — some randomized trials show benefit for induction of remission; not yet standard-of-care.

Review anything you missed. For mechanism questions, re-draw the parietal cell signaling diagram and the vomiting reflex receptor map from memory.