🧬 Serotonin (5‑HT) & Receptor Families

  • Overview
    • Endogenous autacoid — synthesized in enterochromaffin cells, CNS neurons, and platelets
    • Metabolism: oxidative deamination via MAO‑A → 5‑hydroxyindoleacetic acid (5‑HIAA)
    • 5‑HIAA serves as a urinary biomarker for carcinoid syndrome
    • Seven receptor families (5‑HT₁ through 5‑HT₇) — all GPCRs except 5‑HT₃ (ligand‑gated ion channel)
  • 5‑HT₁ (a–h)
    • Location: CNS (predominantly inhibitory) and vascular smooth muscle
    • Buspirone — partial agonist at 5‑HT₁A → anxiolytic in generalized anxiety disorder
    • Triptans (sumatriptan, rizatriptan, etc.) — agonists at 5‑HT₁D on cerebral vessels → vasoconstriction and migraine relief
    • Triptan side effects: asthenia, chest/throat pressure or pain (usually transient)
  • 5‑HT₂ (a–c)
    • Location: CNS (excitatory); periphery → vasodilation, GI/bronchial/uterine smooth muscle contraction, platelet aggregation
    • Olanzapine (atypical antipsychotic) — antagonist at 5‑HT₂A → reduces psychotic symptoms
    • Cyproheptadine — 5‑HT₂ antagonist; also potent H₁ blocker
      • Indications: carcinoid syndrome, GI tumors, postgastrectomy dumping, anorexia nervosa, serotonin syndrome
      • Antihistamine properties → useful in seasonal allergies
  • 5‑HT₃
    • Location: area postrema (chemoreceptor trigger zone), peripheral sensory and enteric nerves
    • Ion channel directly coupled — no second messenger involvement
    • Ondansetron and other ‑setrons — competitive antagonists → antiemetic in chemotherapy, radiation, and postoperative settings
📌 Clinical Pearl
  • 5‑HT₃ antagonists are highly effective for emesis — they block the vagal afferent pathway and the chemoreceptor trigger zone without sedative or extrapyramidal effects

⛰️ Migraine Headache — Acute & Prophylactic Agents

  • Acute migraine — first‑line: Triptans
    • Selective 5‑HT₁D receptor agonists → cranial vasoconstriction and inhibition of trigeminal pain transmission
    • Examples: sumatriptan, zolmitriptan, rizatriptan, eletriptan, almotriptan, naratriptan, frovatriptan
    • Administration: oral, nasal spray, subcutaneous injection, or transdermal patch
  • CGRP antagonists (small molecule)
    • Ubrogepant and rimegepant — oral agents for acute migraine
    • Mechanism: competitive antagonism at calcitonin gene‑related peptide receptors
  • CGRP monoclonal antibodies — prophylaxis
    • Erenumab — fully human mAb targeting the CGRP receptor
    • Others: galcanezumab, fremanezumab (target CGRP ligand)
    • Administered subcutaneously monthly
  • Ergot alkaloids — acute (second‑line)
    • Ergotamine — partial agonist at α‑adrenergic and 5‑HT₂ receptors
    • Vasoconstrictive actions reduce pulsation in cerebral vessels
    • Side effects: GI distress, prolonged vasoconstriction → ischemia, gangrene; uterine contraction (abortifacient near term)
    • Contraindicated in coronary artery disease, hypertension, and pregnancy
  • Other acute agents
    • Analgesics: ASA ± caffeine, NSAIDs, acetaminophen ± caffeine
    • Opioids: oral or injectable; butorphanol nasal spray (reserve for refractory cases)
  • Prophylactic medications
    • Propranolol (β‑blocker) — reduces migraine frequency
    • Topiramate (anticonvulsant) — multiple mechanisms; weight loss side effect
    • Valproic acid (anticonvulsant) — broad mechanism; teratogenic
    • Amitriptyline and other TCAs also used
⚠️ Exam Trap
  • Ergotamine is not a first‑line agent — reserved for triptan‑resistant or intolerant patients due to its narrow therapeutic index and vasospastic risk
  • Triptans are contraindicated in patients with a history of ischemic heart disease or uncontrolled hypertension

⚡ Eicosanoid Synthesis & General Principles

  • Definition
    • Cell‑regulating polyunsaturated fatty acids derived primarily from arachidonic acid (20:4, ω‑6)
    • Released from membrane phospholipids by phospholipase A₂ (PLA₂)
  • General properties
    • Low basal concentrations — synthesized "on demand" in response to stimuli
    • Stimuli: IgE‑mediated reactions, inflammatory mediators, trauma, heat, toxins
    • Act via specific GPCRs coupled to second‑messenger systems (cAMP, Ca²⁺, etc.)
    • Short half‑life — act locally as autocrine or paracrine mediators
  • Two major synthetic pathways
    • Cyclooxygenase (COX) pathway → prostaglandins (PGs) and thromboxanes (TXAs)
    • Lipoxygenase (LOX) pathway → leukotrienes (LTs) and lipoxins
PLA₂ → Arachidonic acid → COX → PGs · TXAs | LOX → LTs
  • Physiologic roles
    • Inflammation, fever, pain sensitization
    • Platelet aggregation (TXA₂) and stabilization (PGI₂)
    • Gastric cytoprotection (PGE₂)
    • Renal blood flow regulation (PGE₂, PGI₂)
    • Uterine contraction (PGE₂, PGF₂α)
    • Ductus arteriosus patency (PGE₂)

💨 Leukotrienes — Synthesis, Actions & Pharmacologic Targets

  • Synthesis
    • Derived from arachidonic acid via lipoxygenase (5‑LOX) pathway
    • Initial product: LTA₄ → converted to LTB₄ or LTC₄ (via conjugation with glutathione)
    • LTC₄ → LTD₄ → LTE₄ (cysteinyl leukotrienes)
  • Key leukotrienes & actions
    • LTB₄ — potent neutrophil chemoattractant; activates PMNs; promotes free‑radical formation → tissue damage
    • LTC₄ · LTD₄ · LTE₄ — "slow‑reacting substances of anaphylaxis"
      • Bronchoconstriction (potent, prolonged)
      • Vascular permeability → edema
      • Mucus hypersecretion
      • Central role in asthma pathogenesis
  • Pharmacologic intervention points
    • Glucocorticoids — inhibit PLA₂ (via lipocortin induction) → reduced arachidonic acid release → ↓ all eicosanoids
    • Zileuton — 5‑LOX inhibitor → ↓ leukotriene synthesis; used in asthma
    • Zafirlukast · Montelukast — cysteinyl LT₁ receptor antagonists; used in asthma and allergic rhinitis
📌 Clinical Pearl
  • Montelukast is often used as adjunctive therapy in asthma, particularly in patients with exercise‑induced bronchoconstriction or aspirin‑exacerbated respiratory disease

🩸 Prostaglandins, Prostacyclin & Thromboxane A₂

  • COX‑1 vs COX‑2
    • COX‑1 — constitutive; expressed in most tissues
      • Platelets → TXA₂ synthesis
      • Stomach → cytoprotective PGs (PGE₂, PGI₂)
      • Kidney → renal PGs (maintains blood flow)
    • COX‑2 — inducible (by inflammatory stimuli, cytokines, LPS)
      • Expressed at sites of inflammation
      • Brain (fever, pain perception) and kidney
      • Also constitutive in kidney and certain tissues
  • Prostaglandin E₂ (PGE₂)
    • Misoprostol — PGE₁ analog; used for NSAID‑induced ulcer prevention (cytoprotective)
    • Alprostadil — PGE₁ analog; maintains ductus arteriosus patency; vasodilator in erectile dysfunction
    • Dinoprostone — PGE₂; uterine contraction; cervical ripening and abortion
    • Contraindicated in pregnancy (except for termination/cervical ripening under strict supervision)
  • Prostaglandin F₂α (PGF₂α)
    • Uterine and bronchiolar smooth muscle contraction
    • Carboprost — abortifacient (used in second‑trimester termination)
    • Latanoprost — PGF₂α analog; reduces intraocular pressure in glaucoma (increases uveoscleral outflow)
  • Prostacyclin (PGI₂)
    • Platelet stabilizer (inhibits aggregation) and potent vasodilator
    • Epoprostenol — used in pulmonary arterial hypertension
  • Thromboxane A₂ (TXA₂)
    • Potent platelet aggregator and vasoconstrictor
    • Inhibition of TXA₂ synthesis is the basis for aspirin's cardioprotective effect
EicosanoidKey ActionsRepresentative DrugUse
PGE₂Uterine contraction, cervical ripeningDinoprostoneAbortion, cervical ripening
PGF₂αUterine/bronchiolar contractionCarboprost · LatanoprostAbortion, glaucoma
PGI₂Platelet stabilization, vasodilationEpoprostenolPulmonary hypertension
TXA₂Platelet aggregation, vasoconstriction(target of ASA)Antiplatelet prophylaxis
PGE₁Ductus patency, vasodilationAlprostadil · MisoprostolDuctus‑dependent CHD, ulcers
⚠️ High‑Yield
  • Indomethacin (a COX inhibitor) is used to close a patent ductus arteriosus — opposite of alprostadil (which maintains patency)
  • NSAIDs that inhibit COX‑1 can cause gastric ulcers by reducing cytoprotective PGE₂

💊 NSAIDs — General Properties & Mechanism

  • Definition & mechanism
    • Nonselective COX‑1/COX‑2 inhibitors (most agents)
    • Decrease synthesis of prostaglandins and thromboxanes
    • Acetylsalicylic acid (ASA) is the prototypical NSAID
  • Core pharmacologic effects
    • Analgesic — reduce pain via ↓ PGE₂ sensitization of nociceptors
    • Antipyretic — ↓ PGE₂ in hypothalamus → resetting of thermoregulatory set point
    • Anti‑inflammatory — ↓ vasodilation and edema via ↓ PGs at inflammatory sites
    • Antiplatelet — ↓ TXA₂ (particularly aspirin via irreversible COX‑1 inhibition)
  • Clinical indications
    • Mild‑to‑moderate pain (arthritis, dysmenorrhea, musculoskeletal)
    • Fever reduction
    • Inflammatory conditions (RA, OA, gout)
    • Cardiovascular prophylaxis (low‑dose aspirin)
  • Key side effects (class‑based)
    • GI: gastritis, ulcers, bleeding (COX‑1 inhibition reduces cytoprotective PGs)
    • Renal: fluid retention, reduced GFR in susceptible patients (COX‑1/COX‑2 inhibition of renal PGs)
    • Cardiovascular: increased risk of thrombosis with selective COX‑2 inhibitors (due to unopposed TXA₂)
    • Hypersensitivity: bronchospasm in aspirin‑exacerbated respiratory disease (AERD)
🔹 COX‑1 inhibition
  • GI cytoprotection ↓ → ulcers
  • Platelet TXA₂ ↓ → bleeding risk
  • Renal PGs ↓ → fluid retention
🔸 COX‑2 inhibition
  • Inflammation ↓ (therapeutic)
  • Fever ↓ (hypothalamic PGE₂)
  • Pain ↓ (peripheral nociceptors)
  • Increased thrombotic risk (unopposed TXA₂)

⚠️ Aspirin — Mechanism, Dose‑Dependent Effects & Overdose

  • Mechanism of action
    • Irreversible acetylation of a serine residue in the COX‑1 (and COX‑2) active site
    • Covalent modification → permanently inactivates the enzyme
    • Platelet COX‑1 is affected for the life of the platelet (7–10 days)
  • Dose‑dependent effects
    • Low dose (75–100 mg/d) — antiplatelet (↓ TXA₂); post‑MI prophylaxis, TIA prevention
    • Moderate dose (300–600 mg) — analgesia and antipyresis
    • High dose (≥ 2–4 g/d) — anti‑inflammatory (RA, rheumatic fever)
  • Uric acid effects
    • Low–moderate doses: ↓ tubular secretion of uric acid → hyperuricemia
    • High doses: ↓ tubular reabsorption → uricosuria
  • Acid‑base & electrolyte effects
    • Therapeutic doses — mild uncoupling of oxidative phosphorylation
      • ↑ respiration → ↓ pCO₂ → respiratory alkalosis
      • Renal compensation → ↑ HCO₃⁻ excretion → compensated respiratory alkalosis (normal pH, ↓ HCO₃⁻, ↓ pCO₂)
      • Children are more susceptible to toxicity at therapeutic doses
    • Toxic doses
      • Inhibition of respiratory center → ↓ respiration → ↑ pCO₂ → respiratory acidosis
      • Severe uncoupling of oxidative phosphorylation + Krebs cycle inhibition → ↓ ATP → metabolic acidosis, hyperthermia, hypokalemia
      • Mixed acid‑base disturbance with eventual metabolic acidosis and respiratory acidosis
      • Zero‑order elimination kinetics at toxic doses (rate‑limited by hepatic metabolism)
  • Adverse effects
    • GI: gastritis, erosions, bleeding — risk ↑ with alcohol and warfarin
    • Salicylism: tinnitus, vertigo, hearing loss (early signs of toxicity)
    • Bronchoconstriction: exacerbates asthma (especially in AERD triad: asthma, nasal polyps, rhinitis)
    • Reye syndrome: encephalopathy and hepatic failure in children with viral infections (avoid ASA in children < 16 years with febrile illness)
    • Bleeding: ↑ bleeding time due to irreversible antiplatelet effect
    • Renal dysfunction: chronic use may cause analgesic nephropathy
    • Drug interactions: ethanol (↑ GI bleeding), warfarin (↑ anticoagulation), uricosurics (↓ effect)
  • Overdose management
    • No specific antidote
    • Supportive care: gastric lavage ± activated charcoal (if early)
    • Ventilatory support for respiratory depression
    • Correction of acid‑base and electrolyte disturbances
    • Management of hyperthermia and dehydration
    • Urinary alkalinization — ↑ urine pH (sodium bicarbonate) enhances salicylate excretion by trapping ionized salicylate in renal tubules
    • Enhanced elimination: hemodialysis in severe cases (with metabolic acidosis, renal failure, or very high levels)
⚠️ USMLE High‑Yield
  • Salicylate toxicity produces a mixed respiratory alkalosis and metabolic acidosis — early: respiratory alkalosis; late: metabolic acidosis with respiratory compensation failure
  • Zero‑order kinetics at toxic doses means doubling the dose more than doubles the toxicity — half‑life may increase from 2–4 h to > 20 h
  • Use of activated charcoal is most effective within 1–2 hours of ingestion