Local hormones 1_Inflammation.ppt

Local hormones 1: Inflammation Dr Omar Janneh Email: [email protected] Tel: 0208 725 5614 Office: Jenner Wing, First Floor, Corridor 4, Room: 1.118 Learning objectives • Describe the role of histamine and 5-hydroxytryptamine (5-HT) in inflammation • Outline the clinical utility of H1 and H2 rece...

Local hormones 1: Inflammation Dr Omar Janneh Email: [email protected] Tel: 0208 725 5614 Office: Jenner Wing, First Floor, Corridor 4, Room: 1.118 Learning objectives • Describe the role of histamine and 5-hydroxytryptamine (5-HT) in inflammation • Outline the clinical utility of H1 and H2 receptor antagonists and their major side effects • Define the terms eicosanoid, prostanoid and leukotriene • Describe the major enzymatic pathways leading to the formation of prostaglandins and leukotrienes, with special reference to areas where drug therapy can be applied • Outline the main effects of eicosanoids with reference to their roles in inflammation, haemostasis and gastric cytoprotection • Describe the effects of aspirin on gastric cytoprotection Outline of Lecture • • Inflammation- what is it? Local hormones: – Role of histamine in acute inflammation/gastric acid secretion – H1 and H2 antagonists • • 5-HT – synthesis, metabolism and effects Lipid mediators of inflammation: Eicosanoids (actions of eicosanoids; physiology, pathology, diversity and modulation of other systems) Eicosanoids; terms, clinical importance Formation of prostanoids; arachidonic acid, cyclooxygenases, synthases Formation of leukotrienes; lipoxygenases Actions of eicosanoids; physiology, pathology, diversity and modulation of other systems • • • • NSAIDs (aspirin and ibuprofen): Pharmacological mechanism of action What is Inflammation? Function of inflammation? It is the body’s defence response to: 1) Invasion – pathogens (disease-causing), allergens (non-disease) 2) Injury - heat, ultraviolet, chemicals Signs: Calor - Warmth ( blood flow) Rubor- Redness ( blood flow) Dolor - Pain (Sensitisation/activation of sensory nerves) Tumor - Swelling ( post-capillary venule permeability) Functio laesa - Loss of function (pain/injury) •Chronic inflammation - severe tissue damage e.g. atherosclerosis •Acute responses - e.g. anaphylaxis, sepsis •Anti-inflammatory drugs are regularly prescribed Cardinal signs of Inflammation: Summary Timescale of Events in Inflammation Injury Hours 0 12 24 days 2 3 4 5 Mediator release Microvascular Cell accumulation & activation Systemic effects Steps of inflammation (5Rs) •Recognition of the injurious agent •Recruitment of leukocytes •Removal of the agent •Regulation (control) of response •Resolution (repair) Repair/healing Microvascular Actions 1-24 hr - Influx of immune cells to area requiring ‘defence’ Capillary bed Venule Arteriole Local hormones e.g. Histamine, Prostaglandins Local hormones e.g. Histamine, bradykinin Local Hormones Many of the signs of inflammation are produced by chemical mediators that orchestrate the complex responses involved: ‘local hormones’ or ‘autacoids’ • Produced in response to a wide range of stimuli • Synthesised or released only as and when required • Local release for local action • Inactivated locally to minimise systemic effects Histamine • Synthesised from histidine amino acid by histidine decarboxylase • Metabolised by imidazole-N-methyltransferase (INMT) and diamine oxidase • Synthesised, stored and released from: – Mast cells, which express receptors for IgE on cell surface (connective tissues) – Basophils (blood) – Neurons in brain – Histaminergic cells in gut • Pre-made, ‘ready-to-go’ in secretory granules composed of heparin and acidic proteins Histamine Released by allergic reactions (IgE-mediated), insect stings, trauma, etc. through a rise in [Ca2+]i. Wheal (depends on soluble, chemical mediator) The Triple Response: dermatographia Pointed object firmly depressed on the skin: Red line, flare around the line, wheal Demonstration of Lewis triple reaction: •Make a line on the skin using a pointed object •Histamine is a mediator Histamine receptors • Four types of histamine receptors- H1, H2, H3, H4 • All G-protein-coupled receptors which produce physiological effects by activating second messenger systems • Differential expression of receptors • Stimulation of H1 and H2 receptors produce many of the actions of histamine-mediated inflammation • H1 and H2 antagonists are clinically important Effects of Stimulation of H1 and H2 Receptors • TPR = total peripheral resistance Cardiovascular BV= blood volume BP= blood pressure – dilates arterioles, TPR (H1) – Increased permeability of post-capillary venules, BV (H1) – Increase in heart rate (H2) (- tachycardia) – Generally involved in BP (↓ vascular resistance) • Non-vascular smooth muscle (airways, gut, etc.) – Contraction (H1), e.g. bronchoconstriction • Algesia – Pain, itching, and sneezing caused by stimulation of sensory nerves (H1) • Gastric acid – Increase secretion (H2) • Associated exocrine secretions – Increased, due to  blood flow Pathological Roles of Histamine The most important clinical roles of histamine are Acute inflammation (H1 effects) and Stimulating gastric acid secretion (H2) Histamine & Gastric Acid Secretion HCO3- H1 Antagonists – Treat Acute Inflammation • ‘1st generation’ – mepyramine, diphenhydramine, promethazine • ‘2nd & 3rd generation’ – Terfenadine,  Fexofenadine, active, non-toxic metabolite of terfenadine • Therapeutic & side effects – Reduce minor inflammatory reactions (e.g. insect bites, hay fever), BUT NO significant value in asthma – 1st generation drugs are sedative; sometimes used as a therapeutic effect – Some (e.g. promethazine) are anti-emetic – ‘motion sickness’ – Anti-muscarinic actions (1st generation drugs) e.g. atropine-like effects of blurred vision, constipation, etc. H2 Antagonists – Gastric Problems – Cimetidine, famotidine • Therapeutic & side effects – Reduce gastric acid secretion in treatment of duodenal and gastric ulcers and Zollinger-Ellison syndrome – Increases breakdown of histamine – Mental confusion, dizziness, tiredness & diarrhoea sometimes as side effects – Cimetidine - ↓ P450 activity, gynecomastia Biosynthesis and metabolism of 5-hydroxytamine Neurotransmitter derived from tryptophan 5-hydroxy-L-tryptophan 5-hydroxytryptophan decarboxylase Distribution of 5-HT • Platelets release 5-HT (and TXA2) → platelet aggregation • The mucosal EC cells of gastrointestinal tract (mediates gut movement, diarrhoea) • Brain (cognition, aggression, mating, vomiting, and regulation of behaviour) • Some tumours (e.g. carcinoid) proliferation, and cell survival feeding, secrete sleep, excess 5-HT pain, →↑ EC = enterochromaffin Inflammatory actions of 5-HT • 5-HT promotes inflammation by increasing the number of mast cells at the site of tissue injury • 5-HT stimulates mast cell adhesion and migration • 5-HT enhances inflammatory reactions of skin, lungs and gut • 5-HT may synergise with TXA2 to stimulate platelet activity and vasoconstriction • Activation of TXA2 receptors responses in blood vessels increases 5-HT-mediated • Basically, injured arteries and arterioles constrict due to the release of 5-HT from platelets which plug the injured site Eicosanoid ‘family tree’ EICOSANOIDS Cyclooxygenases Prostaglandins & Thromboxanes = prostanoids Lipooxygenases Leukotrienes & Lipoxins Why are Eicosanoids Important? • Molecules with powerful inflammatory actions • Targets of major anti-inflammatory drugs – NSAIDs – Glucocorticoids – Lipoxygenase inhibitors – Leukotriene antagonists Formation of Prostanoids (Prostaglandins & Thromboxane) • Prostanoids are not ‘ready-to-go’ (unlike histamine) • Prostanoids are generated from arachidonic acid (AA, polyunsaturated fatty acid). • AAs are produced from phospholipids (PLs) Cyclooxygenases • Conversion of AA to prostanoids requires the enzyme cyclooxygenase (COX) • Two main isoforms COX-1 and COX-2 • COXs are fatty acids, attached to endoplasmic membrane • COX-1 - Constitutively active - Responsible for ‘physiological’ roles of PGs/TXs such as regulation of peripheral vascular resistance, renal blood flow, platelet aggregation, gastric cytoprotection • COX-2 - Needs to be stimulated (e.g. by inflammatory cytokines- IL-1, TNF) - Responsible for role of PGs/TXs in inflammation responses (pain and fever) • COX-3 - Variant of COX-1; pain perception of CNS Eicosanoid synthesis l Cyc ic hw pat ay Lin ear pat hw ay No need to memorise this pathway. Just note the function of the key mediators Actions of Eicosanoids – Local Hormones • Cells specialise in making particular eicosanoids - mast cells: PGD2 - platelets: TXA2 - endothelial cells: PGI2, PGE2 • Act at specific G-protein-coupled receptors - PGs subtypes mediate their effects by acting at their receptors • - TXs at TP receptors - LTs: LTB4 at BLT receptors; LTC4, LTD4 & LTE4 at CysLT receptors (-chemotactic; bronchoconstrictor & ↑ vascular permeability; oedema, ↑secretion of thick, viscous mucus) • Exert diverse and often contradictory actions in inflammation • Subjected to local inactivation Effects of the mediators on bronchospasm Comparing SRSA (LTD4, LTC4, LTE4) with histamine in the lung Effects of LTC4, LTE4, LTD4 and histamine on the contraction of guinea pig lung strip: a section of peripheral lung tissue LTD4 LTE4 LTC4 Tension [Agonist] histamine • ↑ cellular infiltration of eosinophils, neutrophils • ↑ mucus secretion • ↑ bronchoconstriction • ↑ airway oedema Summary of results: Leukotrienes are much more potent than histamine SRSA = slow reacting substances of anaphylaxis Leukotriene receptor antagonists Examples: Zafirlukast Blocks receptor for cysteinyl LTs (LTC 4, LTD4, LTE4) These LTs cause airway oedema, secretion of thick mucus and smooth muscle contraction Receptor blockade is useful in following: – Prevention of mild to moderate asthma – Early to late bronchoconstrictor effects of allergens – Exercise-induced asthma and asthma provoked by NSAIDs Side effects: – GI upset – Irritability – Dry mouth, thirst – Rashes, oedema Diverse Actions of Eicosanoids Vascular smooth muscle cells Endothelial cells platelets Vessel lumen TXA2 BK, 5-HT +Haemostatic balance TXA2 Endothelial cells PGI2 TP receptor Contraction Shear Stress IP receptor Ca2+ cAMP Relaxation Describe the major enzymatic pathways leading to the formation of prostaglandins and leukotrienes, with special reference to areas where drug therapy can be applied We shall briefly review the pathways, functions of the mediators and sites of action of the drugs Textbooks for lectures 1 and 2 In addition to the lecture slides, you may find the following titles useful: •Rang & Dale's Pharmacology by Humphrey P. Rang and James M. Ritter, 8th edition Paperback – 21 January 2015 ; chapters 17 and 26 •Pharmacology by Humphrey P. Rang, Maureen M. Dale, James M. Ritter and Philip Moore; 5th edition; 20 March 2003; chapters 15 and 16