Comprehensive Overview of Autocoids: Histamine and Serotonin Mechanisms

Comprehensive Overview of Autocoids: Histamine and Serotonin Mechanisms

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  Mr. SATENDRA PRADHAN AssistantProfessor Department of Pharmacology COP, SVITS, Bilaspur Dr. Sreeja PA Professor and Head Department of Pharmacy Practice Dr. MGR University, Chennai
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  INTRODUCTION Autocoids (Greek: autos= self, akos = remedy) are endogenous, biologically active substances locally acting chemical mediators that are synthesized, released and act near their site of formation — hence also called “local hormones.” 01 Produced On Demand Unlike classical hormones, Autocoids are usually not pre- formed in large stores — synthesized rapidly when needed (exceptions: histamine, serotonin). 02 Act Locally (Paracrine/Autocrine) They diffuse only short distances and act on nearby cells or the cell of origin, unlike endocrine hormones that travel via blood. 03 Short Biological Half-Life Rapidly inactivated by local enzymes near the site of release — action is brief and self-limiting. 04 Diverse Chemical Nature Includes amines (histamine, serotonin), peptides (kinins, angiotensin), lipid derivatives (eicosanoids) and a gas (nitric oxide).
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  BASICS Every Autocoid —whatever its chemistry — follows the same three-stage pattern. This framework (source → site → fate) is used throughout this deck for each Autocoid. RELEASED FROM ✦Synthesized in / stored within specific cells (e.g., mast cells, platelets, endothelium) ✦Released by a physiological or pathological trigger (injury, antigen, shear stress) ACTS ON ✦Diffuses a short distance to nearby target cells ✦Binds specific membrane receptors → triggers a signal transduction cascade INACTIVATED BY ✦Rapidly degraded by local enzymes, reuptake, or spontaneous decay ✦Confines the action in both space and time WHY THIS MATTERS ✦Knowing the 3 stages for each Autocoid predicts drug strategy: block synthesis, block the receptor or block/mimic breakdown (e.g., antihistamines = receptor block; ACE inhibitors = block kinin/angiotensin breakdown balance).
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  AUTOCOIDS Biogenic Amines Histamine, Serotonin(5-HT) Peptide Autocoids Bradykinin, Kallidin, Angiotensin II, Substance P, Endothelin Eicosanoids (Lipid derivatives) Prostaglandins, Thromboxane A₂, Leukotrienes, PAF Gaseous Autocoid Nitric Oxide (NO) Biogenic amines are autacoids synthesized from amino acids by enzymatic reactions. They are stored in specialized cells or nerve endings and released when required to regulate allergic responses, neurotransmission, gastric secretion, and vascular functions. Peptide autacoids are small biologically active peptides produced enzymatically from plasma or tissue proteins. They regulate inflammation, vascular permeability, blood pressure, and smooth muscle activity. Lipid-derived autacoids (eicosanoids) are biologically active substances produced from arachidonic acid, a 20- carbon polyunsaturated fatty acid present in cell membranes. They are synthesized during tissue injury or inflammation and regulate pain, fever, inflammation, thrombosis, and vascular tone. Gaseous autacoids are endogenous gaseous signaling molecules that diffuse rapidly across cell membranes and regulate vascular tone, neurotransmission, and inflammatory responses.
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  AUTOCOID 1 Histamine isa biogenic amine derived from the amino acid histidine by the enzyme histidine decarboxylase. A biogenic amine, pre-formed and stored — unlike most Autocoids SYNTHESIS ✦Formed from the amino acid L-histidine ✦Enzyme: L-histidine decarboxylase (HDC) ✦One-step reaction — rapid synthesis when needed ✦Occurs mainly in mast cells, basophils & ECL cells STORAGE SITES ✦Mast cells — skin, lungs, GI mucosa, connective tissue (bound to heparin in granules) ✦Basophils — circulating blood ✦Enterochromaffin-like (ECL) cells — gastric mucosa (regulate acid secretion) ✦Histaminergic neurons — tuberomammillary nucleus of hypothalamus (CNS)
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  AUTOCOID 1 Histamine —Release, Site & Fate RELEASED FROM ✦Pre-formed, stored in mast cell/basophil secretory granules bound to heparin ✦Released by IgE-antigen cross- linking, trauma, cold, drugs (morphine, tubocurarine), C3a/C5a anaphylatoxins ACTS ON ✦Diffuses to H1, H2, H3 & H4 receptors on smooth muscle, vascular endothelium, gastric parietal cells & nerve endings INACTIVATED BY ✦Diamine oxidase (histaminase) — oxidative deamination ✦Histamine-N-methyltransferase (HNMT) — methylation ✦Plasma half-life ~1 minute TRIGGER HIGHLIGHT ✦Type I hypersensitivity: allergen cross-links IgE on mast cell surface → receptor aggregation → degranulation → explosive histamine release within minutes ✦Non-immunologic release (“histamine liberators”): opioids, radiocontrast media, certain antibiotics, physical trauma
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  Autocoid 1 ·MECHANISM Histamine — Mechanism of Action (H1 Pathway) Histamine binds the H1 receptor (Gq-protein coupled) on target cell membrane Activates phospholipase C (PLC) PLC cleaves PIP₂ into IP₃ and DAG IP₃ releases Ca²⁺ from the endoplasmic/sarcoplasmic reticulum ↑ Intracellular Ca²⁺ → smooth muscle contraction (bronchi, gut) & endothelial gap formation Endothelium also releases NO → adjacent vascular smooth muscle relaxes → Vasodilation & Flare QUICK NOTES ✦H1 activation on endothelium and H1 activation on smooth muscle produce opposite mechanical effects — vasodilation vs bronchoconstriction — both via Gq/Ca²⁺ ✦H2 receptors instead couple to Gs → ↑ cAMP → gastric acid secretion & mild cardiac stimulation ✦This combination (↑ permeability + vasodilation + smooth muscle spasm) produces the classic “triple response of Lewis”: flush, flare, wheal
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  Autocoid 1 Histamine ReceptorSubtypes and Roles H1 Gq → ↑ IP₃/DAG/Ca²⁺ Smooth muscle contraction, ↑ vascular permeability, itching/pain, allergic symptoms, wakefulness Blocked by: Cetirizine, Chlorpheniramine H2 Gs → ↑ cAMP Gastric acid secretion (parietal cells), mild positive chronotropy/inotropy Blocked by: Ranitidine, Famotidine H3 Gi → ↓ cAMP Presynaptic autoreceptor — inhibits release of histamine & other neurotransmitters (CNS) Investigational target for cognition/sleep disorders H4 Gi → ↓ cAMP Expressed on eosinophils, mast cells, dendritic cells — mediates chemotaxis & immune cell activation Investigational target for asthma/pruritus
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  Autocoid 1 Histamine —Physiological & Pathological Roles PHYSIOLOGICAL ROLES ✦Regulates gastric acid secretion (H2, basal & stimulated) ✦Neurotransmitter in CNS — wakefulness, appetite, arousal (H1/H3) ✦Local vasodilator — contributes to regulation of microcirculation ✦Mediator of the immediate (Type I) inflammatory response ✦Modulates immune cell chemotaxis (H4) PATHOLOGICAL ROLES ✦Anaphylaxis — massive systemic release → hypotension, bronchospasm, edema ✦Allergic rhinitis, urticaria, angioedema, atopic dermatitis ✦Bronchial asthma — contributes to bronchoconstriction ✦Peptic ulcer disease — excess H2-mediated acid secretion ✦Motion sickness & vertigo (CNS H1 pathway)
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  Autocoid 2 Serotonin isa biogenic amine synthesized from the amino acid tryptophan. It acts as both a neurotransmitter and an autacoid, regulating mood, gastrointestinal motility, platelet aggregation and vascular tone. ~90% of body serotonin resides in the gut, not the brain SYNTHESIS ✦Formed from the amino acid L-tryptophan ✦Step 1: Tryptophan hydroxylase → 5-hydroxytryptophan (5-HTP) ✦Step 2: Aromatic L-amino acid decarboxylase → 5-HT (serotonin) ✦Synthesized locally in enterochromaffin cells and CNS neurons STORAGE SITES ✦Enterochromaffin cells of the GI mucosa — largest store (~90%) ✦Platelets — take up circulating 5-HT via active transport (do NOT synthesize it) and store it in dense granules ✦CNS neurons — raphe nuclei of the brainstem, project widely ✦Small amounts in mast cells of some species
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  Autocoid 2 Serotonin —Release, Site & Fate RELEASED FROM ✦Released from enterochromaffin cells by mechanical/chemical mucosal stimulation ✦Released from platelet dense granules during platelet activation & aggregation ✦Released by neuronal firing in CNS raphe pathways ACTS ON ✦Acts on 7 receptor families (5-HT1– 5-HT7) in gut smooth muscle, vasculature, platelets, CNS neurons & the vomiting centre INACTIVATED BY ✦Reuptake via SERT (serotonin transporter) into neurons & platelets ✦Metabolized by monoamine oxidase (MAO) → 5-HIAA, excreted in urine CLINICAL MARKER ✦Urinary 5-HIAA (5-hydroxyindoleacetic acid) is measured as a diagnostic marker for carcinoid tumors, which secrete excess serotonin ✦SSRIs (fluoxetine, sertraline) act by blocking SERT reuptake, prolonging serotonin's CNS synaptic action
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  Autocoid 2 ·MECHANISM Serotonin — Mechanism of Action 5-HT released locally can act via two distinct receptor mechanisms Fast pathway: binds 5-HT₃ — a ligand-gated Na⁺/K⁺ ion channel → direct, rapid membrane depolarization Slow pathway: binds 5-HT₁/5-HT₂ GPCRs on smooth muscle & platelets 5-HT₂ (Gq) → PLC → IP₃/DAG → ↑ Ca²⁺ → smooth muscle contraction & platelet aggregation 5-HT₁ (Gi) → ↓ cAMP → cranial vasoconstriction & presynaptic inhibition Net effect depends on receptor mix in that tissue: motility, vasoconstriction/dilation, platelet plug formation, or the vomiting reflex QUICK NOTES ✦5-HT₃ is the only ionotropic (ligand-gated channel) serotonin receptor — all others are GPCRs ✦5-HT₃ receptors on vagal afferents in the gut & chemoreceptor trigger zone mediate nausea/vomiting — blocked by ondansetron (antiemetic) ✦5-HT₁B/1D on cranial vessels mediate the vasoconstrictor action exploited by triptans in migraine treatment
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  Autocoid 2 Serotonin ReceptorSubtypes 5-HT₁ Gi → ↓ cAMP Cranial vasoconstriction, presynaptic autoreceptor, CNS mood regulation Triptans (migraine) act at 5-HT1B/1D 5-HT₂ Gq → ↑ IP₃/Ca²⁺ Smooth muscle contraction, platelet aggregation, CNS behaviour/mood Blocked by atypical antipsychotics 5-HT₃ Ligand-gated ion channel Vagal afferents & CTZ — mediates nausea/vomiting reflex; fast neuronal depolarization Blocked by Ondansetron (antiemetic) 5-HT₄ Gs → ↑ cAMP Enteric neurons — promotes GI motility & secretion Target of prokinetic drugs (e.g., prucalopride) 5-HT₅ Gi → ↓ cAMP Regulates circadian rhythm, learning, memory, and CNS functions (not fully understood) No selective drugs in routine clinical use 5-HT₆ Gs → ↑ cAMP Cognitive function, memory, learning, neurotransmitter release Investigational target for Alzheimer's disease and cognitive disorders. 5-HT₇ Gs → ↑ cAMP Circadian rhythm, thermoregulation, smooth muscle relaxation, mood regulation Potential target for depression, migraine, and sleep disorders
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  Autocoid 2 Serotonin —Physiological & Pathological Roles PHYSIOLOGICAL ROLES ✦Regulates GI motility & secretion ✦Essential for primary hemostasis — promotes platelet aggregation & local vasoconstriction at injury sites ✦Modulates vascular tone (constrictor or dilator depending on receptor/vessel) ✦CNS neurotransmitter — mood, sleep-wake cycle, appetite, temperature regulation ✦Mediates the vomiting reflex via CTZ & vagal afferents PATHOLOGICAL ROLES ✦Carcinoid syndrome — tumor overproduction causes flushing, diarrhea, bronchospasm ✦Migraine pathophysiology — cranial vessel tone changes ✦Depression & anxiety disorders — CNS serotonergic dysfunction (target of SSRIs) ✦Serotonin syndrome — toxic excess from drug interactions (hyperthermia, rigidity, autonomic instability) ✦Chemotherapy-induced nausea/vomiting — 5-HT₃- mediated
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  Autocoid 3 All eicosanoids(prostaglandins, thromboxane, leukotrienes) originate from one precursor via two branching enzymatic pathways. Cell injury/stimulus activates phospholipase A2 on membrane phospholipids Arachidonic acid is liberated from the cell membrane Cyclooxygenase (COX-1/COX-2) pathway converts it to PGG2/PGH2 → Prostaglandins, Prostacyclin, Thromboxane A2 5-Lipoxygenase (5-LOX) pathway converts it to 5-HPETE → Leukotrienes (LTB4, LTC4, LTD4, LTE4) These eicosanoids act locally on smooth muscle, platelets, and immune cells Net result: Inflammation, Pain, Fever, Bronchoconstriction and Platelet Aggregation WHY THIS WORKS This single cascade produces two families of mediators through parallel enzymatic branches. The COX branch and the LOX branch are independent drug targets: NSAIDs block the COX branch (prostaglandins/thromboxane), while leukotriene modifiers block the LOX branch or its receptors - explaining why the two drug classes have complementary, non- overlapping effects, especially in asthma. Drugs: Target of NSAIDs (COX) and leukotriene modifiers (5-LOX)
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  Autocoid 3A Prostaglandins arelocally acting lipid mediators synthesized by the cyclooxygenase pathway from arachidonic acid. They regulate inflammation, pain, fever, gastric protection, uterine contraction, and renal blood flow. Never stored — synthesized fresh, on demand, everywhere SYNTHESIZING ENZYMES ✦COX-1 — constitutive, “housekeeping”: gastric mucosa, platelets, kidney, vascular endothelium ✦COX-2 — inducible by inflammation, cytokines, growth factors (also constitutive in kidney & brain) ✦Tissue-specific terminal synthases determine which prostaglandin (PGE synthase, PGF synthase, PGI synthase) a cell makes KEY FEATURES ✦Virtually every nucleated cell can synthesize some prostaglandin — unlike histamine/serotonin's restricted cell types ✦No storage granules — synthesis begins within seconds of the triggering stimulus ✦Aspirin irreversibly acetylates COX; other NSAIDs reversibly inhibit it — basis of anti-inflammatory therapy
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  Autocoid 3A Prostaglandins —Release, Site & Fate RELEASED FROM ✦No storage — synthesized on demand from membrane arachidonic acid via COX-1 (constitutive) / COX-2 (inducible) ACTS ON ✦Acts locally on EP1–4 (PGE₂), FP (PGF₂α), DP (PGD₂) and IP (PGI₂) receptors on smooth muscle, platelets, vasculature & gastric mucosa INACTIVATED BY ✦Rapidly metabolized, largely during a single pass through the pulmonary circulation, by 15-hydroxy- prostaglandin dehydrogenase ✦Biological half-life: seconds to a few minutes BALANCE CONCEPT ✦PGI₂ (prostacyclin, from endothelium) opposes TXA₂ (from platelets) — vasodilation & anti-aggregation vs. vasoconstriction & aggregation — this balance maintains normal hemostasis
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  Autocoid 3A ·MECHANISM Prostaglandin E₂ — Mechanism of Action PGE₂, synthesized locally, diffuses to nearby cells expressing EP receptors Binds EP2/EP4 receptors (Gs-protein coupled) on target cell membrane Activates adenylate cyclase → ↑ intracellular cAMP Protein Kinase A (PKA) is activated → phosphorylates target proteins In vascular/bronchial smooth muscle: relaxation → vasodilation / bronchodilation In gastric mucosa: ↑ mucus & bicarbonate secretion, ↓ acid secretion — mucosal protection QUICK NOTES ✦Different prostaglandins use different receptors and can produce opposite effects: PGF₂α via FP (Gq) contracts smooth muscle, while PGE₂ via EP2/4 (Gs) relaxes it ✦This receptor diversity explains why “prostaglandins” as a group can both raise and lower blood pressure, and both stimulate and inhibit uterine contraction depending on subtype ✦NSAIDs blunt ALL of these effects at once by inhibiting the shared COX enzyme upstream
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  Autocoid 3A Prostaglandins —Physiological Actions by Type Prostaglandin Receptor Physiological Actions PGE₂ EP1-4 Gastric mucosal protection, fever & pain in inflammation, uterine contraction, keeps ductus arteriosus patent in the fetus PGF₂α FP Uterine/bronchial smooth muscle contraction, luteolysis (used to induce labor/abortion) PGI₂ (Prostacyclin) IP Vasodilation, inhibits platelet aggregation, maintains renal blood flow PGD₂ DP Mast cell mediator — bronchoconstriction, vasodilation, CNS sleep regulation
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  Autocoid 3B RELEASED ✦Synthesized inactivated platelets from PGH₂ via COX-1 + thromboxane synthase ACTS ON ✦Binds TP receptors (Gq) on platelets & vascular smooth muscle INACTIVATED BY ✦Chemically unstable — spontaneously hydrolyzes to inactive TXB₂ within ~30 seconds PHYSIOLOGY ✦Promotes platelet aggregation — essential for primary hemostasis ✦Causes vasoconstriction ✦Opposes prostacyclin (PGI₂) — the two maintain vascular/platelet balance CLINICAL CORRELATION ✦Low-dose aspirin irreversibly inhibits platelet COX-1 → ↓ TXA₂ for the platelet's lifespan → antiplatelet effect ✦Excess TXA₂ activity contributes to arterial thrombosis Thromboxane A₂ is a COX-derived eicosanoid synthesized by platelets that promotes platelet aggregation and vasoconstriction.
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  Autocoid 3C RELEASED FROM ✦Synthesizedvia the 5-lipoxygenase (5-LOX) pathway in mast cells, eosinophils, basophils & macrophages ACTS ON ✦LTB₄ → BLT receptors (neutrophil chemotaxis/adhesion) ✦LTC₄/D₄/E₄ (cysteinyl-LTs) → CysLT1 receptors on bronchial smooth muscle INACTIVATED BY ✦Metabolized by omega-oxidation and peptidase cleavage — action limited to minutes PHYSIOLOGY ✦Cysteinyl leukotrienes are potent bronchoconstrictors, ↑ vascular permeability & mucus secretion ✦Historically called “Slow Reacting Substance of Anaphylaxis (SRS-A)” ✦LTB₄ is a powerful neutrophil chemoattractant — drives inflammatory cell recruitment CLINICAL CORRELATION ✦Central mediators of bronchial asthma pathophysiology ✦Montelukast/Zafirlukast — CysLT1 receptor antagonists ✦Zileuton — 5-LOX inhibitor, blocks synthesis upstream Leukotrienes are LOX-derived inflammatory mediators synthesized from arachidonic acid, mainly by leukocytes. They play an important role in asthma, allergy and inflammation.
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  Autocoid 3 Whatever thepathway, eicosanoids share one defining trait: they act within seconds to minutes of formation and are destroyed almost as quickly — true “hit-and-run” local mediators. PGE₂ / PGF₂α Seconds–minutes Degraded chiefly by 15-hydroxy-PG dehydrogenase during first pass through the lungs PGI₂ (Prostacyclin) ~2–3 minutes Spontaneously hydrolyzes to inactive 6-keto-PGF₁α TXA₂ ~30 seconds Chemically unstable — spontaneously hydrolyzes to inactive TXB₂ Leukotrienes Minutes Inactivated by omega-oxidation and peptidase cleavage
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  Autocoid 4 Tissue injury/inflammationactivates Factor XII (Hageman factor) → converts prekallikrein to kallikrein Plasma kallikrein acts on high-molecular-weight kininogen (HMWK) → releases Bradykinin Tissue kallikrein acts on low-molecular-weight kininogen (LMWK) → releases Kallidin (Lys-bradykinin) Aminopeptidase converts kallidin to bradykinin Bradykinin diffuses locally to act on B1/B2 receptors on nearby cells Rapidly degraded within seconds by kininases (kininase I & II) QUICK NOTES ✦Kininase II is identical to Angiotensin- Converting Enzyme (ACE) — the same enzyme that forms Angiotensin II also destroys bradykinin ✦This dual role explains why ACE inhibitors both lower blood pressure (via less Ang II) and potentiate bradykinin (cough, angioedema) ✦Unlike histamine/serotonin, kinins are peptides formed by proteolytic cleavage, not stored pre- formed
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  Autocoid 4 Bradykinin —Release, Site & Fate RELEASED FROM ✦Formed from plasma/tissue kininogen by kallikrein enzymes, activated during tissue injury, inflammation or Factor XII activation ACTS ON ✦B2 receptors — constitutive, most tissues (vascular endothelium, smooth muscle, sensory nerves) ✦B1 receptors — induced/upregulated by tissue injury & inflammation INACTIVATED BY ✦Degraded within seconds by kininase I and kininase II (= ACE) ✦Among the shortest half-lives of all Autocoids (~15 seconds) POTENCY NOTE ✦Bradykinin is one of the most potent endogenous vasodilators known — roughly 10x more potent than histamine on a molar basis for increasing vascular permeability Bradykinin is a vasodilator peptide produced from kininogen by kallikrein. It is one of the most potent mediators of pain and inflammation.
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  Autocoid 4 ·MECHANISM Bradykinin — Mechanism of Action Bradykinin binds the B2 receptor (Gq-coupled, constitutive) on vascular endothelial cells Activates PLC → IP₃/DAG → ↑ intracellular Ca²⁺ Stimulates endothelial NO synthase (eNOS) and phospholipase A₂ (→ prostacyclin) NO & PGI₂ diffuse to adjacent vascular smooth muscle → activate guanylate/adenylate cyclase Smooth muscle relaxation → pronounced vasodilation & increased capillary permeability Also directly stimulates sensory nerve endings → Pain ROLES ✦Mediator of inflammatory edema and pain ✦Contributes to hypotension in septic shock ✦Regulates local blood flow in exocrine glands (e.g., salivary, sweat glands) during active secretion ✦ACE inhibitor side effects (dry cough, angioedema) result directly from reduced bradykinin breakdown
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  Autocoid 5 Nitric oxideis a gaseous autacoid synthesized from L-arginine by nitric oxide synthase (NOS) that acts as a potent vasodilator. The only gaseous Autocoid — needs no receptor to enter cells SYNTHESIS ✦Formed from L-arginine + O₂ → NO + L-citrulline ✦Catalyzed by nitric oxide synthase (NOS) enzymes ✦Requires NADPH, FAD, FMN & tetrahydrobiopterin as cofactors THREE NOS ISOFORMS ✦eNOS — endothelium, constitutive, Ca²⁺/calmodulin- dependent, activated by shear stress/ACh/bradykinin ✦nNOS — neurons, constitutive, Ca²⁺/calmodulin-dependent, neurotransmission ✦iNOS — macrophages & inflammatory cells, inducible by cytokines/LPS, Ca²⁺-independent, produces large sustained amounts (host defense)
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  Autocoid 5 ·MECHANISM Nitric Oxide —Mechanism of Action Shear stress, acetylcholine or bradykinin stimulate eNOS in endothelial cells → NO synthesized from L-arginine NO freely diffuses across the cell membrane (a gas — no transporter or receptor needed) into adjacent smooth muscle Activates soluble guanylate cyclase (sGC) → converts GTP to cGMP ↑ cGMP activates Protein Kinase G (PKG) PKG lowers intracellular Ca²⁺ in smooth muscle → relaxation → vasodilation NO itself has a half-life of only seconds — rapidly oxidized to nitrite/nitrate or bound by hemoglobin QUICK NOTES ✦NO is unique among Autocoids: it diffuses freely through membranes rather than binding a surface receptor to signal ✦The same NO → cGMP pathway underlies nitrate drugs (nitroglycerin, exogenous NO donors) and PDE5 inhibitors (sildenafil, which prevents cGMP breakdown) ✦Also inhibits platelet aggregation and leukocyte adhesion to endothelium Nitric Oxide 27
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  Autocoid 5 Nitric Oxide— Physiological & Clinical Roles PHYSIOLOGICAL ROLES ✦Maintains basal vascular tone — continuous low-level eNOS-derived NO keeps vessels dilated ✦Mediates penile/clitoral erection (parasympathetic → NO → corpus cavernosum relaxation) ✦Neurotransmitter role (nNOS) in CNS & enteric nervous system — gut peristalsis ✦Inhibits platelet aggregation & leukocyte-endothelial adhesion ✦iNOS in macrophages provides bactericidal/tumoricidal activity CLINICAL CORRELATIONS ✦Nitroglycerin/organic nitrates — exogenous NO donors, relieve angina via venodilation ✦Sildenafil (PDE5 inhibitor) — prolongs cGMP action, treats erectile dysfunction ✦Excess iNOS-derived NO contributes to septic shock hypotension ✦Endothelial dysfunction (↓ NO bioavailability) is central to atherosclerosis & hypertension
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  Autocoid 6 RELEASED FROM ✦Synthesizedby platelets, neutrophils, macrophages & endothelium via the remodeling pathway (PLA₂ → lyso- PAF → acetylation) ACTS ON (SITE) ✦Binds a specific PAF receptor (Gq- coupled GPCR) on platelets, neutrophils & smooth muscle INACTIVATED BY (TILL) ✦Inactivated by PAF-acetylhydrolase, which removes the acetyl group PHYSIOLOGY ✦Extremely potent — active at nanomolar concentrations, roughly 1000-10,000x more potent than histamine by weight ✦Causes platelet aggregation, neutrophil activation, potent bronchoconstriction & ↑ vascular permeability CLINICAL CORRELATION ✦Implicated in the pathophysiology of bronchial asthma, anaphylaxis & sepsis ✦Contributes to thrombosis via its platelet-activating effect Platelet-Activating Factor (PAF) is a potent phospholipid-derived autocoid produced by various inflammatory and immune cells. It acts through PAF receptors (PAFR), which are G-protein-coupled receptors (GPCRs) to mediate inflammation, platelet aggregation, bronchoconstriction, and increased vascular permeability.
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  SYNTHESIS Autocoid Source Receptor(s)Inactivation Histamine Mast cells, basophils, ECL cells (pre- formed) H1–H4 Diamine oxidase, HNMT (~1 min) Serotonin Enterochromaffin cells, platelets, CNS neurons 5-HT1–7 MAO → 5-HIAA; SERT reuptake Prostaglandins Any cell, on demand (COX-1/2) EP, FP, DP, IP 15-OH-PG dehydrogenase (sec–min) Thromboxane A₂ Activated platelets TP Spontaneous hydrolysis (~30 sec) Leukotrienes Mast cells, eosinophils, macrophages (5-LOX) BLT, CysLT1 Omega-oxidation, peptidases Bradykinin Kininogen, cleaved by kallikrein B1, B2 Kininase I & II / ACE (~15 sec) Nitric Oxide Endothelium/neurons/macrophages (NOS) sGC (no membrane receptor) Oxidation to nitrite/nitrate (sec)
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  SYNTHESIS Antihistamines Block H1 (allergy)or H2 (peptic ulcer) receptors NSAIDs / Aspirin Inhibit COX → ↓ prostaglandins & thromboxane Leukotriene modifiers Montelukast (CysLT1 blocker), Zileuton (5-LOX inhibitor) — asthma Triptans 5-HT1B/1D agonists — cranial vasoconstriction in migraine Ondansetron 5-HT3 antagonist — antiemetic (chemotherapy, post-op nausea) ACE Inhibitors ↓ Angiotensin II & ↓ bradykinin breakdown (cough/angioedema side effect) Organic Nitrates Exogenous NO donors — venodilation, relieve angina PDE5 Inhibitors Sildenafil — prolongs NO/cGMP signal for erectile dysfunction SSRIs Block SERT — prolong serotonin action in CNS synapses
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  INTRODUCTION Drugs related toautocoids are pharmacological agents that mimic, block, enhance or inhibit the synthesis, release, metabolism or receptor actions of endogenous autocoids. 01 Modify Autocoid Activity These drugs either stimulate (agonists) or block (antagonists) autocoid receptors, or alter the synthesis, release and degradation of endogenous mediators to regulate physiological responses. 02 Target Specific Receptors & Enzymes Most drugs act on histamine (H₁–H₄), serotonin (5-HT₁–5-HT₇), prostaglandin, leukotriene, bradykinin, endothelin, nitric oxide and PAF receptors, or inhibit enzymes such as cyclooxygenase (COX) and lipoxygenase (LOX). 03 Wide Therapeutic Applications Autocoid drugs are extensively used in the management of allergic disorders, bronchial asthma, peptic ulcer disease, pain, inflammation, migraine, glaucoma, pulmonary hypertension, chemotherapy-induced nausea and cardiovascular disorders.
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  AUTOCOIDS H1 Antihistamines Diphenhydramine, Cetirizine,Loratadine, Fexofenadine → block allergic/inflammatory histamine actions H2 Antihistamines Famotidine, Cimetidine, Ranitidine → reduce gastric acid secretion 5-HT3 Antagonists Ondansetron, Granisetron, Palonosetron → potent antiemetics NSAIDs (COX Inhibitors) Aspirin, Ibuprofen, Diclofenac, Celecoxib → block prostaglandin synthesis Leukotriene Modifiers Montelukast, Zafirlukast, Zileuton → block the 5-LOX pathway or its receptors PAF Antagonists Rupatadine and investigational agents → block platelet-activating factor receptors
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  CLASS 1 ·H1 BLOCKERS H₁ antihistamines are drugs that competitively block (or act as inverse agonists at) H₁ histamine receptors, thereby preventing the actions of histamine released during allergic reactions. Drug competitively binds and blocks the H1 receptor (Gq-coupled) on target tissues Prevents histamine from activating the PLC → IP3/DAG signaling cascade Blocks histamine-induced smooth-muscle contraction, vasodilation, and capillary permeability Suppresses the wheal-and-flare response and sensory-nerve-mediated itching First-generation agents cross the blood-brain barrier → central H1 blockade → sedation; second-generation agents are poor BBB penetrants (P-glycoprotein substrates) and are largely non-sedating Net Result: relief of Allergic Symptoms - Sneezing, Rhinorrhea, Itching and Urticaria WHY THIS WORKS H1 receptors mediate the immediate hypersensitivity (Type I) reaction through the Gq/PLC/IP3 pathway. Because these drugs are competitive receptor antagonists rather than mediator-release blockers, they work best when given prophylactically or early, before extensive receptor occupation by released histamine - explaining their limited benefit once severe symptoms are established. Drugs: Cetirizine, Loratadine
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  CLASS 1 ·H1 BLOCKERS H1 Antihistamines - Uses & Adverse Effects Examples:- 1st gen: Diphenhydramine, Chlorpheniramine 2nd gen: Cetirizine, Loratadine, Fexofenadine Therapeutic Uses ✦ Allergic rhinitis, allergic conjunctivitis, urticaria ✦ Pruritus (insect bites, atopic dermatitis) ✦ Motion sickness and vertigo (1st generation agents) ✦ Adjunct in anaphylaxis (with epinephrine) and mild sedation/sleep aid (1st generation) Adverse Effects ✦ Sedation and psychomotor impairment (1st generation) ✦ Anticholinergic effects - dry mouth, blurred vision, urinary retention (1st generation) ✦ Second-generation agents - less sedation; rare QT prolongation with older non-selective agents (e.g., terfenadine, withdrawn) ✦ Paradoxical CNS stimulation in children (1st generation)
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  CLASS 2 ·H2 BLOCKERS H2 Antihistamines - Mechanism of Action H₂ antihistamines (H₂ receptor antagonists or H₂ blockers) are drugs that competitively block histamine H₂ receptors on gastric parietal cells, thereby reducing gastric acid (HCl) secretion Drug competitively blocks the H2 receptor (Gs-coupled) on gastric parietal cells Prevents histamine-stimulated activation of adenylyl cyclase Intracellular cAMP levels fall, reducing protein kinase A activity Reduced PKA activity decreases activation/insertion of the H+/K+-ATPase (proton pump) at the canalicular membrane Basal and stimulated gastric acid secretion is reduced - histamine normally amplifies gastrin- and acetylcholine-driven acid secretion, so blocking it blunts all three pathways Net Result: Reduced Gastric Acidity, Allowing Mucosal Healing WHY THIS WORKS Histamine acts as the final common amplifier of parietal cell acid secretion: gastrin and vagal (ACh) stimulation both partly act through local histamine release from ECL cells. Blocking H2 receptors therefore blunts acid output triggered by all three secretagogues, which is why a single- receptor blockade achieves broad antisecretory efficacy. Drugs: Famotidine, Cimetidine
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  CLASS 2 ·H2 BLOCKERS H2 Antihistamines - Uses & Adverse Effects Examples:- Famotidine, Cimetidine, Nizatidine (Ranitidine largely withdrawn) Therapeutic Uses ✦ Peptic ulcer disease (gastric and duodenal) ✦ Gastroesophageal reflux disease (GERD) ✦ Zollinger-Ellison syndrome (adjunct) ✦ Stress ulcer prophylaxis in critically ill patients Adverse Effects ✦ Cimetidine - antiandrogenic effects (gynecomastia, reduced libido) ✦ Cimetidine - potent CYP450 inhibitor, many drug interactions ✦ Headache, dizziness, diarrhea ✦ Confusion in elderly/renally impaired patients (especially with IV use)
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  CLASS 3 ·ANTIEMETICS 5-HT3 Receptor Antagonists - Mechanism of Action 5-HT₃ receptor antagonists are drugs that selectively block serotonin (5-hydroxytryptamine) type-3 (5-HT₃) receptors located in the chemoreceptor trigger zone (CTZ), nucleus tractus solitarius (NTS), vagal afferent nerves and gastrointestinal tract. WHY THIS WORKS 5-HT3 receptors are ligand-gated cation channels present both peripherally (vagal afferents in the gut) and centrally (area postrema). Chemotherapy-induced release of serotonin from enterochromaffin cells is the dominant trigger of acute emesis, so dual peripheral-plus-central 5-HT3 blockade gives near-complete control of the acute emetic reflex arc. Drugs: Ondansetron, Granisetron Chemotherapy, radiation or surgery triggers serotonin release from enterochromaffin cells in the gut mucosa Drug competitively blocks 5-HT3 receptors on vagal afferent nerve terminals in the gut wall Blocks 5-HT3 receptors in the chemoreceptor trigger zone (area postrema) of the brainstem as well Peripheral vagal afferent signaling to the vomiting center is interrupted Central relay of the emetic signal from the CTZ to the vomiting center is also blocked Net Result: Marked Suppression of Nausea and Vomiting
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  CLASS 3 ·ANTIEMETICS 5-HT3 Receptor Antagonists - Uses & Adverse Effects Examples:- Ondansetron, Granisetron, Palonosetron Therapeutic Uses ✦ Chemotherapy-induced nausea and vomiting (CINV) ✦ Postoperative nausea and vomiting (PONV) ✦ Radiotherapy-induced emesis ✦ Severe hyperemesis gravidarum (selected cases, off- label) Adverse Effects ✦ Headache ✦ Constipation ✦ QT interval prolongation (dose-dependent, monitor in cardiac risk patients) ✦ Dizziness; transient elevation of liver transaminases
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  CLASS 4 ·COX INHIBITORS NSAIDs (Prostaglandin Synthesis Inhibitors) - MOA Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are a group of drugs that inhibit the cyclooxygenase (COX-1 and/or COX-2) enzymes, thereby reducing the synthesis of prostaglandins, prostacyclin (PGI₂), and thromboxane A₂ (TXA₂) from Arachidonic acid. WHY THIS WORKS COX is the rate-limiting, shared enzyme of the entire prostaglandin/thromboxane branch of the arachidonic acid cascade. Because prostaglandins mediate the cardinal features of inflammation and fever, blocking their synthesis - rather than a single receptor - gives NSAIDs broad antipyretic, analgesic, and anti-inflammatory activity, while also explaining their characteristic GI and renal toxicity from loss of protective COX-1- derived prostaglandins. Drugs: Ibuprofen, Aspirin, Celecoxib Tissue injury/stimulus activates phospholipase A2, releasing arachidonic acid from membrane phospholipids NSAID inhibits cyclooxygenase (COX-1 and/or COX-2), the enzyme converting arachidonic acid to PGG2/PGH2 Downstream synthesis of prostaglandins (PGE2), prostacyclin (PGI2), and thromboxane A2 is reduced Reduced PGE2 at the hypothalamus lowers the febrile set-point - antipyretic effect Reduced PGE2/PGI2 sensitization of peripheral nociceptors - analgesic effect; reduced PG-mediated vasodilation/permeability - anti-inflammatory effect COX-1 inhibition also reduces protective gastric Mucosal Prostaglandins and Platelet Thromboxane A2
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  CLASS 4 ·COX INHIBITORS NSAIDs - Uses & Adverse Effects Examples:- Aspirin, Ibuprofen, Diclofenac, Naproxen (non-selective); Celecoxib (COX-2 selective) Therapeutic Uses ✦ Mild-to-moderate pain and dysmenorrhea ✦ Fever reduction ✦ Inflammatory conditions - osteoarthritis, rheumatoid arthritis ✦ Low-dose aspirin for antiplatelet/cardioprotective effect Adverse Effects ✦ GI ulceration and bleeding (COX-1-related) ✦ Nephrotoxicity - reduced renal prostaglandin-mediated perfusion ✦ Increased cardiovascular thrombotic risk (especially COX-2 selective agents) ✦ Bronchospasm in aspirin-sensitive asthmatics; platelet dysfunction with non-selective agents
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  CLASS 5 ·LOX PATHWAY Leukotriene Modifiers - Mechanism of Action Leukotriene modifiers are drugs that inhibit the synthesis or block the actions of leukotrienes, thereby reducing bronchoconstriction, airway inflammation, mucus secretion and eosinophil recruitment. WHY THIS WORKS Cysteinyl leukotrienes are markedly more potent bronchoconstrictors than histamine and are the principal mediators of the late- phase asthmatic response. Because this pathway runs parallel to, and independent of, the COX/prostaglandin branch, leukotriene modifiers provide benefit that complements (rather than duplicates) inhaled corticosteroids and beta-agonists, especially in allergen- or exercise-triggered asthma. Drugs: Montelukast, Zileuton Arachidonic acid is metabolized via the alternate 5-lipoxygenase (5-LOX) pathway to form LTA4, then cysteinyl leukotrienes (LTC4, LTD4, LTE4) 5-LOX inhibitors (e.g., zileuton) block the enzyme directly, halting leukotriene synthesis at the source Leukotriene receptor antagonists (e.g., montelukast, zafirlukast) instead block the CysLT1 receptor on airway smooth muscle and immune cells Either strategy prevents leukotriene-driven bronchoconstriction, mucus hypersecretion, and airway wall edema Eosinophil recruitment and airway inflammation are reduced Net Result: Bronchodilation and Reduced Airway Inflammation, particularly in Allergic and Exercise-induced Asthma
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  CLASS 5 ·LOX PATHWAY Leukotriene Modifiers - Uses & Adverse Effects Examples:- Montelukast, Zafirlukast (receptor antagonists); Zileuton (5-LOX synthesis inhibitor) Therapeutic Uses ✦ Chronic asthma - add-on/prophylactic therapy ✦ Exercise-induced bronchospasm ✦ Allergic rhinitis (montelukast) ✦ Aspirin-exacerbated respiratory disease (adjunct) Adverse Effects ✦ Headache, GI upset ✦ Neuropsychiatric effects - mood changes, sleep disturbance, vivid dreams (montelukast; boxed warning) ✦ Hepatotoxicity - especially zileuton; requires LFT monitoring ✦ Churg-Strauss syndrome (rare, reported with steroid tapering)
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  CLASS 6 ·PAF BLOCKERS Platelet-Activating Factor (PAF) Antagonists - MOA Platelet-Activating Factor (PAF) antagonists are drugs that block the action of platelet-activating factor (PAF) by antagonizing PAF receptors (PAFR) or inhibiting PAF-mediated signaling. WHY THIS WORKS PAF is one of the most potent lipid mediators known, active at sub-nanomolar concentrations, and functions as an amplification signal that recruits and activates platelets and leukocytes across multiple inflammatory pathways. Because PAF is synthesized on demand by several cell types rather than stored, receptor blockade (rather than synthesis inhibition) is the practical pharmacological strategy. Drugs: Rupatadine Allergic or inflammatory stimulus triggers PAF synthesis and release from mast cells, basophils, platelets, and endothelium PAF binds its Gq-coupled receptor on platelets, leukocytes, and airway smooth muscle PAF receptor antagonist competitively blocks this receptor, preventing PAF from binding PAF-induced platelet aggregation and degranulation are prevented PAF-driven bronchoconstriction and increased vascular permeability are blocked Net Result: attenuation of the amplifying loop that PAF normally adds to allergic/inflammatory cascades
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  CLASS 6 ·PAF BLOCKERS PAF Antagonists - Uses & Adverse Effects Examples:- Rupatadine (dual PAF/H1 antagonist, clinically used); Modipafant, Apafant (investigational) Therapeutic Uses ✦ Allergic rhinitis and chronic urticaria (rupatadine, via combined PAF/H1 blockade) ✦ Investigational role in severe asthma ✦ Investigational role in sepsis and ischemia-reperfusion injury Adverse Effects ✦ Somnolence (mild, via residual H1 activity) ✦ Headache ✦ Fatigue ✦ Dry mouth (uncommon)
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  SYNTHESIS Comparing the SixDrug Classes Class Primary Target Main Effect Chief Clinical Use H1 Antihistamines H1 receptor ↓ Allergic symptoms Allergic rhinitis, urticaria H2 Antihistamines H2 receptor ↓ Gastric acid secretion Peptic ulcer, GERD 5-HT3 Antagonists 5-HT3 receptor ↓ Nausea/vomiting CINV, PONV NSAIDs COX-1 / COX-2 ↓ Prostaglandins/TXA2 Pain, fever, inflammation Leukotriene Modifiers 5-LOX / CysLT1 ↓ Leukotrienes Chronic asthma PAFAntagonists PAF receptor ↓ Platelet/leukocyte activation Allergic rhinitis, urticaria All six classes act on distinct autocoid pathways but converge on the shared goal of limiting inflammatory, allergic or secretory amplification.
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  CLINICAL APPLICATION Choosing theRight Drug Allergic Rhinitis / Urticaria Second-generation H1 antihistamine first-line; add leukotriene modifier or rupatadine if refractory. Peptic Ulcer / GERD H2 antagonist for mild disease; proton pump inhibitors are preferred for severe/erosive disease. Chemotherapy-Induced Vomiting 5-HT3 antagonist ± NK1 antagonist and dexamethasone for highly emetogenic regimens. Pain, Fever, Inflammation Non-selective NSAID for short-term use; COX-2 selective agent if high GI bleeding risk. Chronic / Allergic Asthma Inhaled corticosteroid remains first-line; add leukotriene modifier for allergen- or exercise-triggered symptoms. Severe Allergic/Anaphylactic Reaction Epinephrine is first-line; H1 (± H2) antihistamines are adjuncts, not substitutes.
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  SAFETY Monitoring & Precautions ✦First-generation H1 antihistamines: caution with driving/operating machinery due to sedation; avoid in elderly (anticholinergic burden) ✦ Cimetidine: review concurrent medications for CYP450-mediated interactions (e.g., warfarin, phenytoin) ✦ 5-HT3 antagonists: obtain baseline ECG in patients with cardiac risk factors before high-dose IV use (QT prolongation) ✦ NSAIDs: use lowest effective dose for shortest duration; co-prescribe a proton pump inhibitor in high GI-risk patients; monitor renal function ✦ Zileuton: monitor liver function tests periodically; montelukast - counsel patients/families on mood and behavior changes ✦ Avoid NSAIDs in aspirin-sensitive asthma (risk of bronchospasm) and in the third trimester of pregnancy ✦ All patients: review for drug-allergy history before initiating any autocoid-related therapy
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  SUMMARY Summary of KeyPoints ✦ Autocoids are locally-acting, rapidly-degraded endogenous mediators - histamine, serotonin, eicosanoids, kinins, and PAF - central to allergy, inflammation, pain, and secretory physiology ✦ Six major drug classes act on distinct autocoid pathways: H1 and H2 antihistamines block histamine receptors; 5-HT3 antagonists block serotonin receptors; NSAIDs block the COX branch and leukotriene modifiers block the 5-LOX branch of the arachidonic acid cascade; PAF antagonists block a separate potent phospholipid mediator ✦ Understanding each mediator's receptor and signaling pathway explains both the therapeutic benefit and the characteristic adverse- effect profile of each drug class ✦ NSAIDs and leukotriene modifiers are complementary, not redundant, because they target parallel branches of the same arachidonic acid cascade ✦ Drug selection should always be guided by the specific clinical indication, the patient's risk profile, and appropriate monitoring
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  Thank You