Pharmacology · GI & Allergy

⚛️ Histamine & Receptors

Endogenous autacoid stored in secretory granules of mast cells and basophils
Tissue distribution: highest concentrations in lung, skin, and gastrointestinal mucosa
Release triggers:
- Type I hypersensitivity (IgE-mediated) — allergens cross-link IgE on mast cells
- Drugs — morphine, vancomycin (non-immunologic histamine release)
- Venoms, trauma, physical stimuli (heat, cold)
Receptor family: seven-transmembrane G-protein-coupled receptors (GPCRs)

                        ⏺ High-yield
                        H₁ and H₂ are the primary clinically relevant histamine receptors
H₁ mediates allergic and inflammatory responses; H₂ drives gastric acid secretion

                    

H₁ receptor — downstream effects:
- Vascular: endothelial nitric oxide (NO) release → vasodilation → ↓ peripheral resistance, ↓ BP
- Capillary permeability ↑ → fluid extravasation → edema
- Smooth muscle: bronchoconstriction (IP₃/DAG pathway) — particularly in asthmatic airways
- Sensory: activates nociceptive afferents → pruritus, pain
- Cardiac: slows AV nodal conduction (negative dromotropic effect)
H₂ receptor — downstream effects:
- Gastric parietal cells: ↑ acid secretion via cAMP → contributes to peptic ulcer formation
- Cardiac: ↑ SA node firing rate, positive inotropy, increased automaticity

Histamine release → H₁ → Vasodilation + edema + bronchoconstriction + pruritus | H₂ → Gastric acid ↑ + cardiac stimulation

💊 H₁ Antihistamines

Mechanism: competitive antagonists at the H₁ receptor — efficacy ↓ at high histamine concentrations
Pharmacokinetic commonalities:
- All undergo hepatic metabolism (CYP450-mediated)
- Most cross the placenta — use in pregnancy requires caution

Drug	M-block	Sedation	Antimotion	Key features
Diphenhydramine	+++	+++	++	OTC; sleep aid; acute EPS treatment
Promethazine	++	+++	++	α-block; local anesthetic properties
Chlorpheniramine	+	++	+	Mild CNS stimulation possible
Meclizine	+	++	+++	Highly effective for motion sickness
Cetirizine	±	±	0	Minimal sedation; active metabolite
Loratadine	±	0	0	No CNS entry; non-sedating
Fexofenadine	±	0	0	No CNS entry; non-sedating

First-generation (sedating): diphenhydramine, promethazine, chlorpheniramine, meclizine
- Lipophilic → cross blood-brain barrier → CNS depression
- Significant antimuscarinic (M-block) effects: dry mouth, urinary retention, blurred vision
- Additive sedation with alcohol, benzodiazepines, opioids
Second-generation (non-sedating): cetirizine, loratadine, fexofenadine
- Hydrophilic / P-glycoprotein substrates → limited CNS penetration
- Minimal anticholinergic burden
- Cetirizine: mild sedation in some individuals (active metabolite of hydroxyzine)

⚠️ Exam trap

First-generation antihistamines are contraindicated in elderly patients with dementia risk due to anticholinergic effects
All H₁ antagonists require dose adjustment in hepatic impairment

Therapeutic uses:
- Allergic rhinitis, hay fever, urticaria (hives)
- Motion sickness and vertigo — meclizine, diphenhydramine, promethazine
- Nausea and vomiting of pregnancy — doxylamine (with pyridoxine)
- Preoperative sedation — promethazine
- Over-the-counter sleep aids — diphenhydramine, doxylamine
- Acute dystonic reactions (EPS) — diphenhydramine (anticholinergic + sedative)
Adverse effects: extensions of M-block and sedation; additive with other CNS depressants

🧪 H₂ Receptor Antagonists

Prototype drugs: cimetidine, ranitidine, famotidine
Mechanism:
- Competitively block H₂ receptors on gastric parietal cells
- Suppress both basal (nocturnal) and food-stimulated acid secretion
- Indirectly reduce proton pump (H⁺/K⁺-ATPase) activity
- Partial antagonism of vagal and gastrin-mediated acid release (via ECL-cell histamine)
No effect on gastric emptying time

Therapeutic uses:
- Peptic ulcer disease — less effective than PPIs for healing
- Gastroesophageal reflux disease (GERD)
- Zollinger–Ellison syndrome — control of gastric acid hypersecretion

⚠️ Cimetidine specific

Potent inhibitor of CYP450 isoforms (CYP1A2, CYP2C9, CYP3A4) → ↑ levels of warfarin, phenytoin, theophylline
Antiandrogenic effects: gynecomastia, ↓ libido, impotence (binds to androgen receptors)
Ranitidine and famotidine have fewer drug interactions and no antiandrogenic effects

                        ⏺ High-yield
                        H₂ blockers are less potent than PPIs for acid suppression; they are often used for maintenance therapy or mild GERD
Famotidine is preferred over cimetidine to avoid CYP450 interactions

                    

🔥 Proton Pump Inhibitors

Prototype drugs: omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole
Mechanism:
- Irreversible covalent inhibition of the gastric H⁺/K⁺-ATPase (proton pump)
- Block the final common step of acid secretion — regardless of stimulus (histamine, gastrin, vagal)
- Requires acidic activation in the secretory canaliculus to form the active sulfenamide
More potent and longer-lasting acid suppression than H₂ blockers

Therapeutic uses:
- Peptic ulcer disease — first-line for healing and prevention
- GERD — superior to H₂ blockers for erosive esophagitis
- Zollinger–Ellison syndrome — high-dose PPIs are the mainstay
- H. pylori eradication — component of triple/quadruple therapy (with antibiotics)
- NSAID-induced ulcer prophylaxis — in high-risk patients

⚠️ Long-term concerns

Chronic PPI use → ↓ absorption of vitamin B₁₂ (due to achlorhydria)
↑ risk of Clostridioides difficile infection
↑ risk of osteoporosis-related fractures (calcium malabsorption)
Hypergastrinemia with prolonged use → possible rebound hypersecretion upon withdrawal

Any acid stimulus → Parietal cell → H⁺/K⁺-ATPase → PPI blocks → ↓ gastric acid

🛡️ Other PUD & Mucosal Protectants

Misoprostol — PGE₁ analogue
- Mechanism: cytoprotective — ↑ mucus and bicarbonate secretion; ↓ acid secretion
- Use: prevention of NSAID-induced gastric ulcers — largely replaced by PPIs
- Contraindication: pregnancy (induces uterine contractions)

Sucralfate — basic aluminum salt of sulfated sucrose
- Mechanism: polymerizes at pH < 4 to form a viscous gel that adheres to ulcer craters
- Protects mucosa from acid, pepsin, and bile salts
- Requires acidic environment — antacids may reduce efficacy (take 1 hour apart)
- Uses: ulcer healing, recurrence prevention

Bismuth subsalicylate
- Mechanism: forms a protective coating over ulcers; mild antimicrobial activity
- Component of BMT regimen: bismuth + metronidazole + tetracycline for H. pylori eradication
- Also used in traveler's diarrhea

Antacids — Al(OH)₃, Mg(OH)₂, CaCO₃
- Mechanism: simple acid neutralization in the gastric lumen
- Onset: rapid; duration: short (≈30–60 min)
- Side effects:
  - Aluminum-based: constipation (Al³⁺)
  - Magnesium-based: diarrhea (Mg²⁺)
  - Calcium carbonate: rebound hyperacidity (calcium stimulates gastrin)

                        ⏺ Drug interactions — antacids
                        ↓ absorption of weak bases (e.g., quinidine, amphetamines) — increased urinary excretion
↓ absorption of weak acids (e.g., warfarin, aspirin) — decreased urinary excretion
↓ absorption of tetracyclines (chelation with divalent cations)
↓ absorption of fluoroquinolones, iron, and levothyroxine

                    

🤢 Antiemetics — Receptor Targets

Vomiting center integrates inputs from:
- Chemoreceptor trigger zone (CTZ) — area postrema, outside blood–brain barrier
- Vestibular system (motion sickness)
- Gastrointestinal tract (vagal afferents)
- Cerebral cortex (sensory, emotional)
Key receptor types in emetic pathways: 5-HT₃, D₂, H₁, M₁ (muscarinic), NK₁, cannabinoid CB₁

Drug class	Prototype	Receptor target	Primary use
5-HT₃ antagonist	Ondansetron, granisetron	5-HT₃	Chemotherapy-induced nausea (CINV)
D₂ antagonist	Prochlorperazine, metoclopramide	D₂	Post-op nausea, CINV, GERD (prokinetic)
H₁ antagonist	Diphenhydramine, meclizine, promethazine	H₁	Motion sickness, vertigo
M₁ antagonist	Scopolamine	Muscarinic	Motion sickness (transdermal patch)
Cannabinoid	Dronabinol	CB₁	Chemotherapy-induced nausea (refractory)
NK₁ antagonist	Aprepitant	NK₁ (substance P)	CINV (delayed phase)

5-HT₃ antagonists — ondansetron, granisetron, palonosetron
- First-line for moderate-to-high emetogenic chemotherapy
- Common side effect: constipation; headache
- QT prolongation — use caution with other QT-prolonging drugs
D₂ antagonists — prochlorperazine, metoclopramide
- Metoclopramide also has 5-HT₄ agonist activity → prokinetic (↑ GI motility)
- EPS risk (acute dystonia, parkinsonism, tardive dyskinesia) — especially in young women
NK₁ antagonist — aprepitant (fosaprepitant IV)
- Blocks substance P at the NK₁ receptor in CTZ and vomiting center
- Used in combination with 5-HT₃ antagonist + dexamethasone for highly emetogenic chemotherapy
- Induces CYP3A4 — monitor drug interactions

⚠️ Clinical nuance

Opioids have dual effects: ↓ emesis via pain reduction (analgesia) but ↑ emesis via CTZ stimulation — balance is dose-dependent
Antihistamines and anticholinergics are preferred for motion sickness, NOT for chemotherapy-induced nausea

🫀 Inflammatory Bowel Disease — Therapies

Crohn's disease (CD)
- Site: any part of GI tract — terminal ileum most common
- Pattern: transmural inflammation; discontinuous (skip lesions)
- Complications: strictures, fistulae, abscesses
Ulcerative colitis (UC)
- Site: confined to rectum and colon — contiguous, continuous involvement
- Pattern: mucosal and submucosal inflammation only

Drug	Composition	Mechanism	Use
Mesalamine (5-ASA)	5-aminosalicylic acid	Topical anti-inflammatory (PPAR-γ, antioxidant)	Mild–moderate CD & UC
Sulfasalazine	5-ASA + sulfapyridine	Colonic bacteria cleave → active 5-ASA released locally	Mild–moderate UC (colonic)
Corticosteroids	Prednisone, budesonide	Broad immunosuppression; ↓ cytokine production	Moderate–severe flares (short-term)
Cyclosporine	Calcineurin inhibitor	↓ T-cell activation (IL-2)	Severe UC (steroid-refractory)
Anti-TNF-α	Infliximab, adalimumab, certolizumab	Neutralizes TNF-α; ↓ granulomatous inflammation	Moderate–severe CD & UC; fistulising CD

5-ASA agents — key points
- Mesalamine: delayed-release or rectal formulations for topical delivery
- Sulfasalazine: active in the colon; sulfapyridine carrier causes side effects (headache, nausea, oligospermia)
- Both: anti-inflammatory via local inhibition of prostaglandins and leukotrienes
Immunosuppressants — advanced therapy
- Reserved for moderate-to-severe disease not responding to 5-ASA
- Anti-TNF-α: risk of reactivation of latent TB; rule out with PPD/IGRA before starting
- Cyclosporine: nephrotoxicity, hypertension, need monitoring

                        ⏺ Treatment algorithm (simplified)
                        Mild–moderate UC: 5-ASA (oral + rectal) → if refractory, corticosteroids → immunomodulators (azathioprine) → anti-TNF or vedolizumab
Mild–moderate CD: 5-ASA (limited efficacy) → corticosteroids → immunomodulators → anti-TNF
Perianal/fistulising CD: anti-TNF (infliximab) is first-line biologic

                    

💎 Clinical Pearls & Exam Essentials

Histamine antagonist selection:
- Allergic rhinitis / urticaria → second-generation non-sedating (loratadine, fexofenadine) preferred for daytime use
- Motion sickness → first-generation anticholinergic/antihistamine (meclizine, scopolamine)
- Acute insomnia → diphenhydramine (short-term)
Acid suppression ladder:
- Antacids → rapid, short-lived relief
- H₂ blockers → moderate, longer suppression (maintenance)
- PPIs → profound, sustained suppression (healing, severe GERD)
Antiemetic selection by cause:
- Motion sickness: H₁ or M₁ antagonists
- Chemotherapy: 5-HT₃ antagonist + dexamethasone ± NK₁ antagonist
- Post-operative: D₂ antagonist or 5-HT₃ antagonist
- Pregnancy: doxylamine + pyridoxine (H₁ antagonist + vitamin B₆)
IBD drug monitoring:
- Sulfasalazine: CBC (leukopenia), LFTs (hepatotoxicity)
- Anti-TNF: TB screening, hepatitis B testing, fungal infections
- Cyclosporine: serum creatinine, blood pressure, potassium, magnesium

⚠️ Common USMLE traps

Cetirizine is a second-generation antihistamine but can cause mild sedation — unlike loratadine and fexofenadine
Cimetidine inhibits CYP450 — other H₂ blockers (famotidine, ranitidine) do not
PPIs are irreversible inhibitors — acid suppression lasts beyond the drug's plasma half-life
Sucralfate requires acidic pH — do not co-administer with antacids or PPIs

                        ⏺ Fast facts
                        H₁ receptor: Gq → PLC → IP₃/DAG → Ca²⁺ release (smooth muscle contraction, NO-mediated vasodilation)
H₂ receptor: Gs → AC → cAMP → acid secretion (parietal cell)
Ondansetron: 5-HT₃ antagonist; single most effective agent for CINV
Mesalamine: works topically in the gut; sulfasalazine is a prodrug activated by colonic bacteria

                    