Introduction to Autocoids & Anti-inflammatory Drugs
Autocoids are ‘local hormones’ — substances produced, acting, and metabolized locally in tissues. This unit covers the major autocoids: Histamine (allergies), Serotonin (mood, GI motility), Prostaglandins (inflammation, pain, fever), Leukotrienes (asthma), and peptide autocoids (Angiotensin, Bradykinin, Substance P). It then covers the drugs targeting inflammation: NSAIDs (the most prescribed drug class worldwide), Anti-gout agents, and Disease-Modifying Antirheumatic Drugs (DMARDs).
Syllabus & Topics
- 1Autocoids – Introduction: ‘Autos’ (self) + ‘Akos’ (remedy/drug). Locally produced signaling molecules with paracrine or autocrine actions. Not classical hormones (not transported via blood to distant targets). Include amines (Histamine, 5-HT), lipids (PGs, TXs, LTs), and peptides (Angiotensin, Bradykinin).
- 2Histamine – Synthesis, Storage, Release: Synthesized from L-Histidine by histidine decarboxylase. Stored in mast cell and basophil granules. Released by: (1) IgE-mediated degranulation (allergy/anaphylaxis). (2) Complement-mediated (C3a, C5a). (3) Physical injury. (4) Drugs (morphine, d-tubocurarine). Actions via H1, H2, H3, H4 receptors.
- 3Histamine – Actions & Antagonists: H1: bronchoconstriction, vasodilation, itching, ↑capillary permeability. H1 blockers: First-gen (Diphenhydramine – sedating) and Second-gen (Cetirizine, Loratadine – non-sedating). H2: gastric acid secretion. H2 blockers: Ranitidine, Famotidine (for peptic ulcer). H3: presynaptic autoreceptor (↓histamine release).
- 4Serotonin (5-HT) – Pharmacology: Synthesized from L-Tryptophan. 90% in gut enterochromaffin cells. 5-HT receptor subtypes: 5-HT₁ (sumatriptan – migraine), 5-HT₂ (vasoconstriction, platelet aggregation), 5-HT₃ (emesis center – Ondansetron blocks → best antiemetic for chemotherapy-induced vomiting), 5-HT₄ (GI motility – Cisapride). Antagonists: Cyproheptadine (non-selective 5-HT₂ + H1 blocker), Ketanserin (selective 5-HT₂).
- 5Prostaglandins (PGs) – Synthesis & Actions: Derived from Arachidonic acid via COX pathway. COX-1 (constitutive – gastric cytoprotection, platelet TXA₂, renal blood flow). COX-2 (inducible – inflammation, pain, fever). PGE₂: vasodilation, ↑pain sensitivity (hyperalgesia), fever (hypothalamic thermostat), gastric cytoprotection, uterine contraction. PGI₂ (prostacyclin): vasodilation + ↓platelet aggregation (opposes TXA₂).
- 6Thromboxanes & Leukotrienes: TXA₂ (produced by platelets via COX-1): vasoconstriction + platelet aggregation. Blocked by low-dose Aspirin. Leukotrienes (from arachidonic acid via 5-LOX pathway): LTC₄, LTD₄, LTE₄ = SRS-A (Slow Reacting Substance of Anaphylaxis) → potent bronchoconstriction, mucus secretion. Blocked by: Montelukast (LT receptor antagonist), Zileuton (5-LOX inhibitor).
- 7Angiotensin: Angiotensinogen (liver) → Angiotensin I (by Renin from kidney) → Angiotensin II (by ACE in lungs). Angiotensin II: most potent endogenous vasoconstrictor, stimulates aldosterone secretion, promotes cardiac remodeling, thirst. Blocked by ACE inhibitors (Enalapril) and ARBs (Losartan).
- 8Bradykinin & Substance P: Bradykinin: potent vasodilator, ↑vascular permeability, pain mediator. Formed from kininogens by kallikrein. Degraded by ACE (kininase II) → ACE inhibitors ↑bradykinin → dry cough. Substance P: neuropeptide in sensory C-fibers, mediates pain transmission and neurogenic inflammation. Capsaicin depletes Substance P → topical analgesic.
- 9NSAIDs – Mechanism: Non-Steroidal Anti-Inflammatory Drugs inhibit COX enzymes → ↓prostaglandin synthesis → anti-inflammatory, analgesic (↓hyperalgesia), antipyretic (↓PGE₂ in hypothalamus). Non-selective (COX-1 + COX-2): Aspirin, Ibuprofen, Naproxen, Diclofenac, Piroxicam. COX-2 selective (Celecoxib) – less GI toxicity.
- 10NSAIDs – Aspirin: Irreversibly acetylates COX (unique among NSAIDs). Low dose (75-150 mg): antiplatelet. Analgesic dose (300-600 mg): headache, myalgia. Anti-inflammatory dose (3-5 g/day): rheumatic fever. ADRs: GI ulceration/bleeding, Reye’s syndrome (children < 12 with viral infection – fatty liver + encephalopathy), Salicylism (tinnitus, dizziness), Aspirin-sensitive asthma.
- 11NSAIDs – Other Important Drugs: Ibuprofen (safest NSAID, OTC), Diclofenac (most commonly prescribed, potent), Piroxicam (long-acting, once daily), Indomethacin (potent but toxic – used to close Patent Ductus Arteriosus in neonates), Ketorolac (most potent analgesic NSAID, IV available). Paracetamol/Acetaminophen (weak COX inhibitor in CNS only – antipyretic + analgesic, no anti-inflammatory action, hepatotoxic in overdose → N-acetylcysteine antidote).
- 12Anti-gout Drugs: Gout = hyperuricemia → monosodium urate crystal deposition in joints. Acute: Colchicine (inhibits microtubule polymerization in neutrophils → ↓phagocytosis of crystals → ↓inflammation), Indomethacin (NSAID of choice). Chronic: Allopurinol (xanthine oxidase inhibitor → ↓uric acid synthesis), Probenecid (uricosuric → ↑renal uric acid excretion), Febuxostat (selective XO inhibitor).
- 13Antirheumatic Drugs – DMARDs: Rheumatoid arthritis = autoimmune chronic joint inflammation. DMARDs modify disease progression (unlike NSAIDs which only relieve symptoms). Methotrexate (folic acid antagonist – first-line DMARD, low-dose weekly), Sulfasalazine, Hydroxychloroquine, Leflunomide. Biologics: TNF-α inhibitors (Infliximab, Etanercept, Adalimumab), IL-6 inhibitor (Tocilizumab), B-cell depleting (Rituximab).
Learning Objectives
Frequently Asked Questions (FAQs)
Q1. Why Do NSAIDs Cause Gastric Ulcers?
Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase-1 (COX-1), which normally produces protective prostaglandins such as PGE₂ and PGI₂ in the gastric mucosa. These prostaglandins stimulate mucus and bicarbonate secretion, maintain mucosal blood flow, and reduce gastric acid secretion. When COX-1 is inhibited, this protective mechanism is lost, making the stomach lining susceptible to damage from acid and pepsin, which can lead to ulcers and bleeding. Selective COX-2 inhibitors such as Celecoxib tend to produce fewer gastrointestinal side effects because they spare COX-1 activity.
Q2. What Is the Difference Between COX-1 and COX-2?
Cyclooxygenase-1 (COX-1) is a constitutive enzyme present under normal physiological conditions and is responsible for functions such as gastric mucosal protection, platelet thromboxane production, and maintenance of renal blood flow. Cyclooxygenase-2 (COX-2) is an inducible enzyme that is upregulated during inflammation and produces prostaglandins responsible for pain, fever, and inflammatory responses. Selective COX-2 inhibitors such as Rofecoxib were developed to reduce gastrointestinal toxicity but were later associated with increased cardiovascular risk.
Q3. How Does Colchicine Work in Acute Gout?
Colchicine binds to tubulin and inhibits microtubule polymerization in neutrophils. This prevents migration of neutrophils to the inflamed joint, inhibits phagocytosis of urate crystals, and reduces release of inflammatory mediators. Its action is specific to gouty inflammation rather than general analgesic or anti-inflammatory effects. A common adverse effect is severe gastrointestinal disturbance such as diarrhea.
Q4. Why Is Ondansetron Effective for Chemotherapy-Induced Vomiting?
Chemotherapy damages intestinal enterochromaffin cells, causing release of serotonin (5-HT), which stimulates 5-HT₃ receptors on vagal afferent nerves and triggers the vomiting center in the brain. Ondansetron blocks these receptors both peripherally and centrally, preventing activation of the vomiting reflex and making it highly effective for chemotherapy-induced nausea and vomiting.
Q5. What Is Reye’s Syndrome and Why Is Aspirin Contraindicated in Children?
Reye syndrome is a rare but serious condition that can occur in children who take Aspirin during viral infections such as influenza or chickenpox. It causes acute liver failure and cerebral edema, leading to vomiting, confusion, and potentially coma. Because of this risk, antipyretics such as Paracetamol are preferred for fever management in children.