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AUTACOIDS : Receptor- and Non Receptor-Mediated Therapeutics 201, Learning Unit IV Semester 1, AY 2009-2010 Department of Pharmacology & Toxicology UP College of Medicine July 13, 2009 Autacoids : Agonists, Antagonists Objectives: At the end of the session, students are expected to: • Review concepts pertaining to the inflammatory process • Define an autacoid • Describe the different autacoids in terms of (emphasis on histamine, serotonin, eicosanoids) 1. 2. 3. 4. 5. 6. Distribution/site in the body Synthesis/storage/release/metabolism Factors that stimulate synthesis, release Specific receptors Pharmacologic action/effect of agonists, antagonists and enzyme inhibitors Clinical applications Concept MAP : Maintaining/Restoring Balance in Health/Disease Sick Person Healthy Person Normal Tissue (Structure & Fxn) Mechanisms In Disease : External/Internal milieu => Body response => S/S <Basic Pharmacology> Management & Therapeutics Goal : Dx, Relief & Restoration, Prevention Drug & Non-Drug (Surgery, Rehab) <Clinical Pharmacology> Clinical illness is produced by: Direct invasion of tissue Toxic compounds liberated by the organism The body’s response to the organism The manifestations of disease are usually produced by various inflammatory mediators produced by: •the initiating organism or •the host The resulting inflammation may be: •helpful in localising the causative infection or •harmful Autacoids “Autacoids” : a varied group of endogenous substances occurring in minute amounts and possessing distinct chemical structure with distinct biologic/ pharmacologic activity Autos = self; Akos = medicinal agent or remedy (Greek). AUTACOIDS • Naturally occurring substances • Localized in tissues • Do not normally circulate • Diverse physiological and pharmacological activities • Differ from hormones and neurotransmitters • Short duration of action • Usually involved in response to injury • Sites of action restricted to the synthesis area Examples of autacoids • Amines: histamine, serotonin (5HT) • Polypeptides: kinins, oxytocin, angiotensin II, vasopressin, atrial natriuretic factor, endothelins. • Fatty acids: prostaglandins, leukotrienes, thromboxanes, platelet activating factor (PAF). • Others: endothelium-derived relaxing factor (NO), cytokines (proteins). G-protein-coupled receptors (GPCRs)* • Major target of drug development • Signalling mechanism & potential target sites for drug action 1. Basal state (“switch off”) 2. Receptor-mediated GDP release 3. Subunit dissociation & effector regulation 4. Deactivation & return to basal state Histamine (-aminoethylimidazole): a basic amine COOH Histamine is formed from histidine by histidine decarboxylase. Small amounts of histamine formed by bacteria in the gastrointestinal tract (GIT) is broken down in the gut wall and liver. Distribution of histamine • • • • • Widely distributed in: - bacteria - plants - animals - venoms and stinging fluids (stinging nettle, insect stings, bee venom). Histamine • Signal involved in local immune response, also a neurotransmitter • synthesized by the decarboxylation of histidine • Either stored or quickly inactivated by histamine-Nmethyltransferase and diamine oxidase • Release of histamine from mast cells is stimulated by IgE antibodies which respond to foreign antigens in the body Synthesis • Decarboxylation of amino acid L-histidine catalyzed by pyridoxal PO4-dependent Lhistidine decarboxylase. • Ingested from food or formed by bacteria in the GIT • Storage sites: – perivascular tissue – mast cell – circulation – basophil (bound to chondroitin SO4) – others – GIT, lungs, skin, heart, liver, neural tissue, reproductive mucosa, rapidly growing tissues and body fluids Storage of histamine • ‘Slow-turnover’ histamine is stored as heparin-histamine complex in cytoplasmic granules in mast cells (lungs, GIT, skin) and basophils. • ‘Fast-turnover’ histamine is stored in CNS neurons, skin and enterochromaffin-like cells (ECL) of stomach. Release of ‘Slow turnover’ histamine Allergic reaction: Antigen combines with IgE antibodies on the surface of mast cells or basophils. Mechanical–induced degranulation: e.g., scratch. Non-exocytotic: displacement of histamine from storage site by a drug, e.g., tubocurarine, morphine. Metabolism : Histamine receptors Receptor Mechanism H1 Gq H2 Gs 2+ ↑ Ca H3 Gi H4 Gi Function Antagonists •ileum contraction •modulate circadian cycle •systemic vasodilatation •bronchoconstriction (asthma) •H1-receptor antagonists •Diphenhydramine •Loratadine •Cetirizine •speed up sinus rhythm •Stimulation of gastric acid secretion •Smooth muscle relaxation •Inhibit antibody synthesis, T-cell proliferation and cytokine production •H2-receptor antagonists •Ranitidine •Cimetidine •Neurotransmitter in CNS •Presynaptic autoreceptors •H3-receptor antagonists •ABT-239 •Ciproxifan •Clobenpropit •mediate mast cell chemotaxis. [2] •H4-receptor antagonists •Thioperamide •JNJ 7777120 Histamine H1-receptors • Present in endothelium, smooth muscles cells, nerve endings. • Receptor activation → diacylglycerol and IP3 • Contract smooth muscles: intestine, bronchi • V/d: direct + NO release → flushing, headache • Vascular permeability : contract endothelial cells in venules) • Triple response: flush, flare and wheal. • Stimulate nerve endings: pain, itch; release epinephrine and norepinephrine from adrenal medulla; central excitation. Triple response (Lewis,1927) Response Action 1 Loczd red spot “flush” relaxation of vasodilation vasc smooth m 2 Swelling or edema “wheal” contrxn endoth cells, postcap 3 Brighter red halo, “flare” local axon reflx venl Effect increased “cap” perm or leakage Indirect vasodilation Pathophysiological action of histamine • Mediate type 1 hypersensitivity reactions: hives and hay fever. • Emesis: mediation of motion sickness • Histamine shock (hypotension): systemic anaphylaxis. The Allergic Reaction An Allergic Reaction • Early phase reaction: occurs within minutes of exposure to an allergen and lasts for 30-90 minutes • Late phase reaction: begins 4-8 hours later and can last for several days, often leading to chronic inflammatory disease Symptoms • • • • • • Allergic Rhinitis Conjunctivitis Bronchoconstriction Urticaria Atopic Dermatitis Anaphylaxis http://allergy.healthcentersonline.com/nasalsinus/allergicrhiniti s.cfm Symptoms:anaphylaxis, swelling (skin, mucosa); itching, bronchospasm, hypotension, shock, phospholipase C and A2 activation. Liberators: large molecules (proteins – egg white, serum, venom, toxins); surface active agents, proteolytic enzymes, drugs etc. Clinical uses: diagnosis of achlorhydria, diagnosis of pheochromocytoma, and to verify integrity of axon reflexes. Histamine H2-receptors Receptor activation: stimulation of adenylyl cyclase cAMP. • Parietal cells: H+ secretion. • Vascular smooth muscle cells: vasodilatation • Heart: force of contraction, HR. Histamine H3-receptors • • • Largely presynaptic receptors in brain, myenteric plexus and other neurons. Autoreceptors: negative feedback inhibition of histamine synthesis and release. Heteroreceptor: release of norepinephrine, dopamine, serotonin and acetylcholine. Selected Actions of Histamine in Humans Organ Tissue CARDIOVASCULAR Vascular Facial cutaneous Forearm Gastric mucosa Carotid artery Pulmonary artery Basilar artery Coronary artery Other pre & post cap Arterioles Postcapillary venules Heart Action Receptor TPR Vasodilatation Blood flow H1, H2 H2 H1, H2 Blood flow,relaxation Constriction Relaxation Constriction Constriction Vasodilatation Permeability SA rate Force of contraction Atrial & vent automaticity H2 (?) H1 H2 H2 H1 H1 H2 H2 Selected Actions of Histamine in Humans Organ Tissue RESPIRATORY Bronchiolar smooth muscle Action Receptor Contraction (more prominent) Relaxation H1 H2 Acid and pepsin secretion, If Relaxation & Contraction (more prominent) Relaxation (?) H2 H1 CUTANEOUS NERVE ENDINGS (Sensory) Pain & itching (esp to insect bites & needle stings) H1, H2 (?) ADRENAL MEDULLA Epinephrine release H1 BASOPHILS Inhibition of IgE – dependent degranulation H2 GASTROINTESTINAL Oxyntic mucosa GI smooth muscle Gallbladder smooth muscle H2 (?) Histamine & Agonists : Chemical Structure Histamine Antagonists 1. Physiologic antagonism – epinephrine 2. Release inhibitors – cromolyn sodium, Beta 2 adrenoceptor agonists 3. Histamine receptor antagonists Histamine H1-receptor antagonists • Competitive; some are antimuscarinic, some block -adrenoceptors, and receptors for bradykinin, serotonin, and some have local anesthetic properties. • First generation antihistamines: lipid soluble → sedative (children may experience excitation) • Second generation antihistamines: Non-sedative: loratadine First Generation Antihistamines • Small, lipophilic molecules that could cross the BBB • Not specific to the H1 receptor • Groups: – – – – – Ethylenediamines Ethanolamines Alkylamines Piperazines Tricyclics • Common structural features of classical antihistamine – – – – – – • 2 Aromatic rings Connected to a central Carbon, Nitrogen or CO Spacer between the central X and the amine Usually 2-3 carbons in length Linear, ring, branched, saturated or unsaturated Amine is substituted with small alkyl groups eg CH3 Histamine Antagonists First Generation Agents A. Ethanolamines 1. Carbinoxamine maleate 2. Clemastine fumarate 3. Diphenhydramine HCl 4. Dimenhydrinate B. Ethylenediamines 1. Pyrilamine maleate 2. Tripelennemine HCL/citrate 3. PPA C. Alkylamines 1. Chlorpheniramine maleate 2. Brompheniramine maleate D. Piperazines 1. Hydroxyzine HCl/pamoate (long acting) 2. Cyclizine HCl/lactate 3. Meclizine HCl 4. Chlorcyclizine E. Phenothiazines 1. Promethazine HCl Second Generation Antihistamines • Modifications of the First Generation Antihistamines to eliminate side effects resulted in the Second Generation Antihistamines • More selective for peripheral H1 receptors • Examples: – – – – – terfenadine loratadine cetirizine mizolastine astemizole Second Generation Agents A. Alkylamines • Acrivastine B. Piperazines • Cetirizines HCl C. Piperidines • Astemizole • Levocabastine • Loratadine • Terfenadine • Fexofenadine “Next” Generation Antihistamines • Metabolite derivatives or active enantiomers of existing drugs • Safer, faster acting or more potent than Second Generation drugs • Examples: – Fexofenadine – Desloratadine – Levocetirizine Therapeutic Uses: 1. 2. 3. 4. 5. 6. 7. Dermatosis Allergic rhinitis Motion sickness & emesis Parkinson’s disease EPS Insomnia Adverse reactions Adverse Reactions and Side Effects • First Generation Drugs: – Anticholinergic CNS interactions – Gastrointestinal reactions – Common side effects: sedation, dizziness, tinnitus, blurred vision, euphoria, lack of coordination, anxiety, insomnia, tremor, nausea and vomiting, constipation, diarrhea, dry mouth, and dry cough • Second Generation Drugs: – Common side effects: drowsiness, fatigue, headache, nausea and dry mouth • Side effects are far less common in Second Generation drugs Adverse Effects: 1. 2. 3. 4. 5. 6. CNS : sedation, agitation, nervousness, delirium, tremors, incoordination, hallucinations, & convulsions - common in first generation antihistamines GIT : vomiting, diarrhea, anorexia, nausea, epigastric distress, constipation - dryness of mouth, throat & airway, urinary retention first generation Headache, faintness Chest tightness, palpitations, hypotension Visual disturbances Hematological - leukopenia, agranulocytosis, HA Structural Class Prototype Characteristics Diphenhydramine Significant antimuscarinic activity Sedation, somnolence Incidence of GI symptoms Effective in emesis & motion First Gen. Agents: 1. Ethanolamine sickness 2.Ethylenediamine/ Ethylamine 3. Alkylamine Pyrilamine Mepyramine Pyranesamine Most specific H1 antagonist Anticholinergic activity Feeble CNS effects Chlorpheniramine Pheniramine Most potent Not so prone to develop drowsiness More suitable for older patients Chlorphenamine Somnolence GI s/s common Sedation/CNS stimulation 4. Piperazine Chlorcyclizine Oldest member More prolonged action Incidence of drowsiness Structural Class Prototype Hydroxyzine Characteristics Long acting Widely used for skin allergies CNS depressant More prominent antipruritic action Cyclizine Counters motion sickness (primarily) Meclizine/Meclozine Counters motion sickness & emesis Structural Class Prototype Characteristics Anticholinergic Prominent sedation Counters motion sickness primarily antiemetic 5. Phenothiazine Promethazine Second Gen.Agents Terfenadine Highly selective for H1 receptor Non-sedating (-) anticholonergic action (-) pass BBB incidence of S/E Acrivastine Rapid onset of action (30 mins) (-) anticholinergic effects Reduce both wheal & flare response Potential to penetrate BBB Skin allergy 1. Piperidine 2. Alkylamine Allergic rhinitis 3. Piperazine Cetirizine Rhinitis, urticaria (-) pass BBB Histamine H2-receptor antagonists • Competitive • Cimetidine, ranitidine, famotidine. Uses of histamine H2-receptor antagonists Secretion of H+ and pepsin: more effective on nocturnal (due to histamine) than food-induced (due to ACh, gastrin and histamine) secretion. - Gastric ulcer: normal H+, mucosal defense. - Duodenal ulcer: H+, Helicobacter pylori infection? - Reflux esophagitis - Zollinger-Ellison syndrome (gastrin producing tumor) Side effects of histamine H2-receptor antagonists • Cimetidine (Tagamet) – antiandrogenic (gynecomastia in man), inhibit several cytochrome P450 drug metabolism pathways - hepatic [O] of many drugs (e.g., propranolol, alcohol). • Ranitidine (Zantac) – 5x more potent than cimetidine; reversible liver dysfunction. • Famotidine (Pepcid) – 5x more potent than ranitidine. BIOGENIC AMINES SEROTONIN Source: plants (banana, pineapple, plums) & animals (mollusks, arthropods, mammals (platelets, not in mast cells). Biosynthesis: Hydroxylation of tryptophan, then decarboxylation to serotonin(5-hydroxy tryptamine;5HT). Rapidly absorbed into secretory granules. Accumulated in platelets, degradation by oxidative deamination. Uses: No therapeutic use. Antagonists are highly useful. Serotonin Synthesis 5-HT Precursor PCPA: inhibits TH Synthesis: Tryptophan Hydroxytryptophan 5 hydroxytryptamine (Serotonin) 5-hydroxyindole acetaldehyde 5-hydroxyindole acetic acid (principal metabolite) acid 5-hydroxytrytophol N-acetyl- 5-HT Melatonin Synthesis and Metabolism • Competition at the level of brain and neuronal uptake • Rate limiting enzyme not saturated usually • No end-product negative feedback • 5-OHTr decarboxylase same as DOPA decarboxylase • 5-OHIAA actively extruded from CNS (probenecid-sensitive) and excreted in urine. BIOGENIC AMINES SEROTONIN Actions • • • • • • • Neurotransmitter in the CNS Precursor of melatonin Induces sleep, Intestinal motility Involved in Temperature regulation Affects mood and behavior (humans) Deficiency causes depression Hemostasis : 5-HT2 receptors → aggregation and vasoconstriction of platelets • Carcinoid syndrome (tumor of serotonin producing cells) large amounts released leading to diarrhea, bronchoconstriction and edema Serotonin Receptors • • • • • At least 15 types and subtypes Multiple transduction mechanisms 5HT-1A: role in anxiety/depression 5HT-1D: role in migraine 5HT-2: role in CNS various behaviors, and in cardiovascular system • 5-HT3: role in nausea and vomiting esp. due to Chemotherapy. Serotonin Pharmacological Effects • Respiratory system: bronchoconstriction if asthmatic; stimulation of aortic and carotid chemoreceptors → ↑ RR and minute vol. • GI tract: small intestine very sensitive to serotonin → intense rhythmic contractions due to direct and indirect (ganglia in wall) effects. Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally). Serotonin Pharmacological Effects -2 • 1. 2. 3. 4. Cardiovascular system: Multiple direct and indirect effects: Direct vasoconstriction (large arteries) and indirect vasodilation (NO and PGI2 – mediated) Heart: direct inotropic and chronotropic effects Reflex mechanisms due to change in BP Stimulation of sensory nerve endings in baroreceptors and in vagal afferents in coronary circulation (Bezold Jarrisch reflex) → bradycardia and hypotension Serotonin in the Central Nervous System • Pain perception • Sleep/Wakefulness • Various behaviors normal/abnormal: depression, schizophrenia, obsessive compulsive behavior, etc. • Neuroendocrine regulation – controls hypothalamic cells involved in release of several anterior pituitary hormones. Serotonin Agonists • Sumatriptan: 5-HT1D agonist; contraindicated in patients with angina • Fluoxetine: Selective serotonin uptake inhibitors for depression and other indications • Buspirone: 5-HT1A agonist for anxiety • Cisapride: 5-HT4 agonist to ↑ GI motility and decrease G-E reflux (Removed from US market due to fatal arrhythmias) • LSD: 5HT1A – hallucinogen • Ergot alkaloids: 5-HT1 and 2 and other receptors Serotonin Antagonists • Methysergide and Cyproheptadine. 5HT2 antagonists. In carcinoid, migraine. • Ketanserin: 5HT2 and Alpha antagonist – used as antihypertensive. • Ondansetron: 5-HT3 antagonist for chemotherapy induced nausea and vomiting • Clozapine: 5HT2A/2C antagonist: for schizophrenia. Serotonergic Drugs: Primary Actions and Clinical Uses (Table 11-4, G&G 11 ed) th Receptor Action Prototype Clinical dis 5-HT1A P.Agonist Buspirone Anx, dep 5-HT1D Agonist Sumatriptan Migraine 5-HT2A/2C Antagonist Risperidone Mig,dep,shz 5-HT3 Antagonist Ondansetrn Chem emes 5-HT4 Agonist Cisapride GI disorder 5-HTtransp Inhibitor Fluox,sert Dep,oc,pts The Pharmacology of INFLAMMATION Cyclooxygenase Enzyme & Other Tales The inflammatory reaction • Complex series of integrated phenomena • Cellular components & chemical mediators • Events : arteriolar dilatation, increased vascular permeability, leukocyte interaction with endothelium, diapedesis and migration (chemotaxis) • Symptoms : dolor, rubor, calor, tumor EICOSANOIDS hormones localized to tissues where they are produced. prostaglandins, thromboxanes and leukotrienes. derived from arachidonic acid arachidonic acid from linoleic acid an essential fatty acid Table 1. Physiological functions of eicosanoids. Eicosanoid Functions prostaglandins inflammation, fever production, prevent platelet aggregation (prevent clotting); induce labor thromboxanes produced by platelets to promote their aggregation (blood clotting) leukotrienes allergic reactions Eicosanoids: The Arachidonic Acid Derivatives •All C-20 Derivatives of 5,8,11,14 Eicosatetraenoic Acid •Three classes: Prostaglandins, Thromboxanes, Leukotrienes •Generated by cleavage of C-2 ester of phosphatidyl inositol in membrane-associated signaling events •Active at very low concentrations – regulate blood pressure, coagulation, reproduction, pain & fever •Tissue-specific generation – often opposing actions Eicosanoids: The Arachidonic Acid Derivatives COOH (5,8,11,14) Arachidonic Acid PGH2 Synthase = Prostaglandin endoperoxide synthase (cyclooxygenase) Prostacyclins and Prostaglandins Cyclization to 5-membered ring Leukotrienes: (Asthmatic Symptoms) Hydroxylation; no cyclization Thromboxanes Cyclization to 6-membered ring Eicosanoids: The Arachidonic Acid Derivatives Cortisteroids- block PLA2 to block the release of Arachidonic Acid Arachidonic Acid Prostacyclins and Prostaglandins (Pain & Fever) Leukotrienes: (Asthmatic Symptoms) Thromboxanes (Clotting) *Leukotrienes are not aspirin-inhibited and are responsible for inflammatory and hypersensitivity disorders Eicosanoids: The Arachidonic Acid Derivatives Arachidonic Acid Leukotrienes: (Asthmatic Symptoms) PGH2 Synthase = Site of actions for aspirin (enzyme acetylation) and non-steroidal antiinflammatory drugs including Acetominophen & Ibuprofen (noncovalent binding) Prostacyclins and Prostaglandins (Pain & Fever) Thromboxanes (Clotting) *Leukotrienes are not aspirin-inhibited and are responsible for inflammatory and hypersensitivity disorders Membrane Phospholipid Phospholipase A2 inhibited by glucocorticoids Leuokotrienes Arachidonic acid Lipoxygenase Cyclooxygenase inhibited by aspirin, ibuprofen PGH2 Thromboxanes in platelets Prostaglandins in many cells Conversion of arachidonic acid to eicosanoids. Inflammatory Conditions : Drug therapy • Nonsteroidal antiinflammatory drugs (NSAIDs) or aspirin-like drugs • Corticosteroids • Drugs modifying acute rheumatic diseases (DMARDs) • Antigout therapy ASA : A century hence • Turn of the century drug • 1971 : landmark discovery of COX (Vane) • 1992 : discovery of COX-2, an inducible isoform vs COX-1 which is constitutively expressed COX-1 and COX 2 : Fraternal Enzymes • COX-1 : widely distributed throughout the GIT, believed to be gastroprotective (as in kidneys); “housekeeper” • COX-2 : minimal amts in GIT; detectable in leukocytes, synovium, CNS (site of inflam, fever & pain); inducible, upregulated in response to growth factors & cytokines; “homewrecker” COX-mediated effects of Aspirin (acetylsalicylic acid) • • • • Analgesic-antipyretic Antiinflammatory Antiplatelet Adverse Effects : gastric/duodenal ulcers, bleeding, nephropathy Outline: Bringing concepts together • Problem : Inflammation (eg, joints) • Pathophysiology : Phases => s/s=>Dx • Cellular Events : Cells, mediators ; enzymes, receptors => • Targets for drug action => • Drugs : Steroids, NSAIDs, DMARDs, & Biologics (basic pharmacology) • Clinical Pharmacology & Therapeutics : Evidence of efficacy, safety, suitability CONCEPT MAP: INFLAMMATION Sick Person (Inflamed Joint: s/s) Healthy Person Pathophysiology: cells, mediators, cytokines etc Targets for drug action (Normal/Fxnal Joint) THERAPY Goal: Relief & Restoration, Prevention Drugs : Symptomatic (Steroids, NSAIDs), Disease-Modifying (Gold, Mtx, Tetracyc), Biologics Surgery, Rehab/PT, Exercise Alternative therapies (Acu, Glucosamine, Chondroitin) Assessment: Proof of Efficacy & Safety Antiinflammatory Agents : Nonsteroidal AntiinfIammatory Drugs (NSAIDs) NSAIDS: Nonsteroidal Antiinflammatory Drugs • Prototype: Aspirin (circa 1899) • Mechanism of NSAIDS or aspirin-like drugs revolves around the enzyme prostaglandin synthase or cyclooxygenase (C0X) • Shared properties: 1 antiinflammatory, analgesic, antipyretic actions 2 side effects INFLAMMATION: Friend or Foe? • Essential for survival versus environmental pathogens and injury (ie, beneficial effect) • May be exaggerated and sustained for no apparent beneficial reason (ie, problem/ disease) INFLAMMATION: Stimuli & S/S (review) • Series of events elicited by numerous stimuli (infectious agent, ischemia, ag-ab interaction, thermal/other physical injury) leading to a characteristic pattern of response • Accompanied by clinical signs/symptoms: erythema (rubor), pain (dolor), edema (tumor), fever (calor), tenderness (hyperalgesia) 3 Phases of Inflammatory Response (review) 1 Acute transient phase local vasodilation & increased capillary permeability (floodgates open) 2 Delayed, subacute phase infiltration of leukocytes & phagocytic cells (chemotaxis & diapedesis) 3 Chronic proliferative phase tissue degeneration & fibrosis (± repair) Proinflammatory AUTACOIDS • • • • • • Histamine (early transient phase) Bradykinin & serotonin (5-HT) Leukotrienes Platelet Activating Factor (PAF) Eicosanoids : Prostaglandins Nitric oxide (NO) Pharmacologic Properties : LEUKOTRIENES SITE ACTION EFFECT CVS Contraction, coronary & pulm, mesent vasc Hypotension Airway Smooth m ; Bronchial glands; Bld vessels Inflam & Immunity (major) Contraction of smooth m; Stimulate secretion; Airway narrowing Inc mucus Mucosal edema Stim aggreg of pmn, neutr adhesion to endoth wall, transendoth migration; stim synth proinflam cytokines Chemotaxis Functions of endogenous leukotrienes • Inflammatory & Immune Response: LTs are generally proinflammatory • CysLTs prob dominate during allergic constriction of the airway Proinflammatory Cells & Factors (review) • Endothelial Cell (EC), Leukocytes • Cell Adhesion Molecules (CAMs): E-, P-, L-selectins • ICAM-1, VCAM-1 • Cytokines : IL-1, TNFa, chemokines) • Leukocyte integrins • NO synthase (iNOS vs nNOS,eNOS) • Complement factor (C5a) Natural Antiinflammatory factors => homeostasis • IL-1 receptor antagonist (IL-1ra) • Other cytokines & growth factors : transforming growth factor(TGF-ß1), IL-10, Interferon gamma • Targets for novel antiinflammatory agents Lipid-Derived AUTACOIDS EICOSANOIDS & PAF Products of COX Pathway: Active Compounds • • • • • PGD2 PGE1, PGE2 PGF2a PGI2 via prostacyclin synthase TXA2 via thromboxane synthase Prostaglandin Receptor Diversity • Distinct receptors for specific activity • Subtypes/Agonists/G protein/2nd mssgr DP EP1 EP2 EP3 EP4 FP IP TP PGD2 PGE2 PGE2 PGE2 PGE2 PGF2a PGI2(E2) TXA2,H2 Gs cAMP Gq (?) Ca2+;IP3/DAG (?) Gs cAMP Gi,Gs,Gq all of above Gs cAMP Gq IP3/DAG/Ca2+ Gs cAMP Gq IP3/DAG/Ca2+ Endogenous Eicosanoids: Possible Fxns in Physiol/Pathol Processes • Platelet-vessel wall interaction, hemostasis • Reproduction & Parturition • Vascular and pulmonary smooth muscle tone modulation • Renal blood flow modulation, urine regulation, renin • Inflammatory and Immune Response • Malignancy (eg, colon, breast ca) Therapeutic Uses of Eicosanoids • Induction of labor at term : PGE2 or PGF2a • Gastric cytoprotection: PGE1 analog (misoprostol) • Impotence: PGE1 (alprostadil) • Maintenance of PDA: PGE1 in some neonates with congenital heart disease • Primary pulmonary hypertension: PGI2 (epoprostenol) Outline: Bringing concepts together • Problem : Inflammation (eg, joints) • Pathophysiology : Phases => s/s=>Dx • Cellular Events : Cells, mediators ; enzymes, receptors => • Targets for drug action => • Drugs : Steroids, NSAIDs, DMARDs, & Biologics (basic pharmacology) • Clinical Pharmacology & Therapeutics : Evidence of efficacy, safety, suitability ANALGESIC-ANTIPYRETIC & (NONSTEROIDAL) ANTIINFLAMMATORY AGENTS Chemical Classification • Nonselective COX Inhibitors : aspirin, paracetamol, indomethacin, diclofenac, ibuprofen,mefenamic acid, meloxicam, nabumetone • Selective COX-2 Inhibitors : rofecoxib, celecoxib, nimesulide, etodolac Aspirin vs tNSAIDs (How Aspirinlike are they?) • Aspirin covalently modifies both COX-1 and COX-2 => irreversible inhibition of COX activity. For COX-1 => serine 530; for COX-2 => serine 516 • Platelets are especially susceptible to aspirin; they cannot regenerate COX • In contrast to aspirin, most NSAIDs act as reversible, competitive inhibitors of COX NSAIDs: Shared Properties (THERAPEUTIC Effects) • 1 antipyretic • 2 analgesic, for low-to-mod intensity like dental pain, postop pain or pain from inflammatory conditions. Not visceral pain. • 3 antiinflammatory, symptomatic relief in musculoskeletal disorders (eg, rheumatoid arthritis, osteo-arthritis, ankylosing spondylitis) (except paracetamol, which is effective vs brain COX only, not antiinflam in peripheral tissues) Other Therapeutic Uses of NSAIDs • Indomethacin for postnatal closure of PDA (not during pregnancy) • Relief of cramps in primary dysmenorrhea • Emerging use: prevention of colon/breast cancer, Alzheimer’s (?) with COX-2 inhibitors Shared Properties of NSAIDs: SIDE EFFECTS (due to COX inhibition) 1 Gastric or intestinal ulceration due to loss of cytoprotective - PGI2 & PGE2 2 Disturbance in platelet function - TXA2 3 Prolongation of gestation/spont labor (COX2 inh) 4 Premature closure of ductus 5 Renal function changes, critical in CHF, cirrhosis, chronic renal dis, hypovolemic *(not shared/less risk with highly selective COX-2 inhibitors) COXibs : Continuing Issues & Food for Thought • The present coxibs (COX2 Inhibitors) do not appear to be more efficacious than older NSAIDs • They are the drugs of choice for those with gastric sensitivity;their claimed advantage seems to be in reducing ulcerogenic effect • Adverse effect profile similar to other NSAIDs (even increased cardiac risk?) • Emerging use: vs cancer , Alzheimer’s Summary • 1. Autacoids are part of a heterogenous group of substances that participate in homeostasis. • 2. Autacoids have different sources, fates, and biologic activities. • 3. Autacoids play an important role in health and disease. • 4. Understanding the pharmacologic properties of these agonists, antagonists & inhibitors using prototype drugs is important to effectively utilize these agents in the clinical setting.