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ALLERGY AND HYPERSENSITIVITY IMMUNE RESPONSE IN WHICH THE ANTIGEN IS AN ENVIRONMENTAL AGENT, FOOD OR DRUG THAT IS NOT INTRINSICALLY HARMFUL. MOST WIDESPREAD IMMUNOLOGICAL DISORDER IN HUMANS; RAPIDLY INCREASING – 27% INCIDENCE; INDIVIDUAL SUSCEPTABILITY ?? WIDE RANGE OF SERVERITY MOST EFFECTIVE THERAPY: ALLERGEN AVOIDANCE HYGIENE HYPOTHESIS OF ALLERGY RECOGNIZED IN 1989, LACK OF INFECTION FAVORS THE DEVELOPMENT OF ALLERGIC DISEASE. MYCOBACTERIA AND HELMINTHS ARE IMPORTANT IN THIS HYPOTHESIS AS INFECTIONS CAUSED BY THESE AGENTS GENERATE REGULATORY MECHANISMS THAT CAN RESTORE IMMUNE BALANCE. MULTIPLE AND REPETITIVE INFECTIOUS FACTORS DURING CERTAIN PERIODS OF IMMUNE SYSTEM DEVELOPMENT INFLUENCE ALLERGY AND ASTHMA DEVELOPMENT. TYPE I ALLERGIC RESPONSES – IMMEDIATE HYPERSENSITIVITY. MEDIATED BY IgE AND CAUSES THE RELEASE OF HISTAMINE, LEUKOTRIENES AND PROSTAGLANDINS FROM MAST CELLS AND BASOPHILS. USUALLY ATOPIC (FAMILIAL DISPOSITION. 1. IgE BINDS TO MAST CELLS 2. ANTIGEN CROSS BRIDGING 3. HISTAMINE RELEASE (MAST CELL DEGRANULATION) EFFECTS OF MAST CELL DEGRANULATION EFFECTS OF MAST CELL DEGRANULATION HISTAMINE – INCREASES VASCULAR PERMEABILITY EOSINOPHIL CHEMOTACTIC FACTOR – ATTRACTS EOSINOPHILS TO THE AREA, EOSINOPHILS RELEASE: 1. MAJOR BASIC PROTEIN –CAUSES BRONCHIAL CONSTRICTION AND HYPERRESPONSIVENESS, INHIBITS CILIAL FUNCTION, TOXIC FOR RESPIRATORY EPITHELIAL CELLS AND PNEUMOCYTES. 2. EOSINOPHIL PEROXIDASE – TOXIC FOR RESPIRATORY EPITHELIAL CELLS AND PNEUMOCYTES. LEUKOTRIENES – SLOW REACTING SUBSTANCE OF ANAPHYLAXIS, CONSTRICTION OF SMOOTH MUSCLE PLATELET ACTIVATING FACTOR – PLATELET AGGREGATION AND LYSIS, MACROPHAGE AND NEUTROPHIL ACTIVATION EXAMPLES: ACUTE ANAPHYLAXIS, HAY FEVER, FOOD ALLERGIES MEDIATORS OF ALLERGY A. IgE – ANTIBODY PRODUCED BY B CELLS, SENSITIZES MAST CELLS FOR MEDIATOR RELEASE, USUALLY IN VERY LOW AMOUNTS IN SERUM. B. HISTAMINE - SECRETED BY MAST CELLS, CAUSES VASODILATION, INC. VASCULAR PERMEABILITY OF VENULES AND MUCUS PRODUCTION, CONTRICTS BRONCHIAL AIRWAYS, STIMULATES NERVE ENDINGS. H1 RECEPTORS RESPONSIBLE FOR MOST ALLERGIC RESPONSES, H4 RECEPTORS MAY PLAY A ROLE C. PLATELET ACTIVATING FACTOR - LIPID MEDIATOR, SECRETED BY BASOPHILS, NEUTROPHILS, MONOCYTES, MACROPHAGES, ENDOTHELIAL CELLS, CAUSES RELEASE OF MEDIATORS FROM PLATELETS, NEUTROPHIL AGGREGATION, NEUTROPHIL SECRETION AND SUPEROXIDE ANION PRODUCTION, INCREASES VASCULAR PERMEABILITY, CONSTRICTS BRONCHIAL AIRWAYS. D. PROSTAGLANDINS – DERIVED FROM ARACHIDONIC ACID PGD2 – CONSTRICTS BRONCHIAL AIRWAYS PGE2 – CAUSES VASODILATION, POTENTIATES EFFECTS OF HISTAMINE AND LEUKOTRIENES. E. LEUKOTRIENES – DERIVED FROM ARACHIDONIC ACID VIA 5-LIPOXYGENASE PATHWAY, MOST CONTRIBUTE TO INC. VASCULAR PERMEABILITY, CAN INDUCE BRONCHOCONSTRICTION, “SLOW REACTING SUBSTANCE OF ANAPHYLAXIS”. LTB4 – CHEMOTACTIC FOR NEUTROPHILS, INC. VASCULAR PERMEABILITY IN THE PRESENCE OF PGE2. LTC4 – INC. VASCULAR PERMEABILITY, INDUCES BRONCHOCONSTRICTION. LTD4 & LTE4 – INC. VASCULAR PERMEABILITY LTC4, LTD4 & LTE4 – TOGETHER WERE CONSIDERED SRSA F. CYTOKINES – 1. INTERLEUKIN 3 – STIMULATES EOSINOPHILS, MAST CELL GROWTH FACTOR. 2. INTERLEUKIN 4 – STIMULATES PRODUCTION OF IgE BY B CELLS, INDUCES B & T CELL PROLIFERATION, INDUCES T HELPER CELLS, HAS INHIBITORY EFFECT ON MACROPHAGES, ACTIVATES MAST CELLS, INC. MUCUS PRODUCTION, BASEMENT MEMBRANE THICKNESS AND SMOOTH MUSCLE HYPERTROPHY IN BRONCHIAL TISSUE. 3. INTERLEUKIN 5 – EOSINOPHIL GROWTH FACTOR, INC. IL-4 INDUCED IgE PRODUCTION 4. INTERLEUKIN 13 – STIMULATES IgE SYNTHESIS BY B CELLS, HAS INHIBITORY EFFECT ON MACROPHAGES, SIGNIFICANTLY INC. MUCUS PRODUCTION, BASEMENT MEMBRANE THICKNESS AND SMOOTH MUSCLE HYPERTROPHY IN BRONCHIAL TISSUE. 4. GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR – INC. GRANULOCYTE (INCLUDING EOSINOPHIL) AND MONOCYTE COLONY FORMATION, ACTIVATES MACROPHAGES 5. TUMOR NECROSIS FACTOR-a – INCREASES NEUTROPHIL PHAGOCYTOSIS & DEGRANULATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, CHEMOTACTIC FOR BOTH MACROPHAGES AND NEUTROPHILS, INC. PGE2 PRODUCTION BY MACROPHAGES. ALLERGY TREATMENTS IMMUNOLOGIC APPROACHES ALLERGIC DESENSITIZATION - INDIVIDUAL VARIATION - MULTIPLE ALLERGEN ISOFORMS (ANTIGEN SPECIFIC PEPTIDE THERAPY) ANTI-IgE THERAPY: OMALIZUMAB (XOLAIR), GOOD FOR AEROALLERGINS AND ASTHMA TREATMENT, EFFICACY NOT SHOWN IN OTHER ALLERGIC CONDITIONS. HUMAN IgG1 BINDS TO IgE TO REMOVE IT FROM CIRCULATION, INHIBITS BINDING OF IgE TO HIGH AFFINITY RECEPTORS ON MAST CELLS AND BASOPHILS. ALLERGY TREATMENTS IMMUNOLOGIC APPROACHES (CONT.) SOLUBLE IL-4Ra: DEC. DEVELOPMENT OF T CELLS, REMOVES CIRCULATING IL-4 BY TRAPPING IL-4 MUTEIN: IL-4 VARIENT, CAN BIND TO CELL SURFACE RECEPTOR BUT NOT TRIGGER RESPONSE SOLUBLE IL-13Ra2: DEC. AIRWAY RESPONSIVENESS IN MOUSE STUDIES, REMOVES CIRCULATING IL-13 CHEMICAL APPROACHES - ANTIHISTAMINES ASTHMA DISEASE CHARACTERIZED BY REVERSIBLE OBSTRUCTION OF THE BRONCHI. ACCOMPANIED BY NONSPECIFIC BRONCHIAL HYPERRESPONSIVENESS OR “IRRITABILITY”, ASSOCIATED WITH ATOPY, SPONTANEOUS RELEASE OF MEDIATORS FROM MAST CELLS IS INCREASED PATHOPHYSIOLOGY OF ASTHMA PATHOGENESIS OF ASTHMA PATHOLOGY EARLY RESPONSES - RAPID RELEASE OF PREFORMED INFLAMMATORY MEDIATORS BY MAST CELLS, SYNTHESIS OF EICOSANOIDS, BRONCHOCONSTRICTION LATE RESPONSE - SECOND ROUND OF BRONCHOCONSTRICTION ACUTE ATTACK CAN BE FATAL, ACUTE ASPHYXIATION, MARKED CONSTRICTION AND OCCLUSION OF THE BRONCHI. ASTHMATIC AIRWAY OBSTRUCTION NORMAL ASTHMA AIRWAY OBSTRUCTION MUCUS PLUGGING MUCUS CAST OF BRONCHIAL TREE CHRONIC ASTHMA MARKED THICKENING OF THE BASEMENT MEMBRANE OF BRONCHIAL MUCOSA, HYPERTROPHY OF BRONCHIAL SMOOTH MUSCLE, HYPERTROPHY OF BRONCHIAL MUCOUS GLANDS, EOSINOPHILS AND CHRONIC INFLAMMATORY CELLS IN THE BRONCHIAL WALL, INC. NUMBER OF MAST CELLS, PRESENCE OF MUCOUS IN BRONCHI CONTAINING LARGE NUMBERS OF EOSINOPHILS. TISSUE INJURY IN ASTHMA EPITHELIAL INJURY IN ASTHMA NORMAL TRACHEA ASTHMATIC TRACHEA EOSINOPHILIC INFILTRATION HYPERTROPHIED AIRWAY MUSCLE EXTRINSIC ASTHMA- TRIGGERED BY EXPOSURE TO ALLERGENS, IgE MEDIATED FACTORS PREDISPOSING TO DEVELOPMENT OF EXTRINSIC ASTHMA 1. HEREDITY 2. PRENATAL EFFECTS - high cord blood IgE levels, prenatal exposure to allergens 3. HIGH POSTNATAL IgE SERUM LEVEL 4. BIRTH DURING POLLEN SEASON 5. BIRTH IN URBAN ENVIRONMENT 6. STRESSFUL PERINATAL PERIOD 7. EARLY DIET - early exposure to eggs, wheat, bovine products 8. LOW SERUM IgA LEVELS AT 3 MONTHS OF AGE 9. LOW LEVELS OF T LYMPHOCYTES AT 3 MONTHS OF AGE 10. EARLY SURGERY OR HOSPITALIZATION 11. EXPOSURE TO ANIMALS, MOLDS, TOBACCO SMOKE, AND POLLEN 12. FREQUENT INFECTIONS INTRINSIC ASTHMA NON-ATOPIC, ORIGINALLY THOUGHT TO BE NON-IgE MEDIATED, MAY BE DUE TO LOCAL PRODUCTION OF IgE WITHIN AIRWAYS TRIGGER UNKNOWN BUT MAY DEVELOP FROM SEASONAL ALLERGY, MAY BE DUE TO IMBALANCE OF PHYSIOLOGICAL CONTROL OF SMOOTH MUSCLE TONE. INTRINSIC ASTHMA OCCUPATIONAL ASTHMA EXPOSURE TO SMALL PROTEINS OR MOLECULAR WEIGHT MOLECULES AT WORK PRESENTATION OF OCCUPATIONAL ASTHMA • • • • IMMEDIATE HYPERSENSITIVITY REACTION IMMEDIATE BRONCHOSPASM ISOLATED LATE RESPONSE (USUALLY SENSITIZR INDUCED) SLEEP DISORDER TYPES OF OCCUPATIONAL ASTHMA • NEW ONSET • SENSITIZER-INDUCED • IRRITANT INDUCED • AGGRAVATION OF UNDERLYING ASTHMA • REACTIVE AIRWAYS DYSFUNCTION SYNDROME (RADS) • COLD AIR- OR EXERCISE-INDUCED SYNDROME • AIRWAYS REACTIVITY SECONDARY TO HYPERSENSITIVITY PNEUMONITIS INDUCERS OF OCCUPATIONAL ASTHMA SENSITIZER-INDUCED • SPECIFIC ANTIGEN • LOW MW, “HAPTEN” • HIGH MW • MINIMAL EXPOSURE • < OCCUPATIONAL EXPOSURE LIMITS • IgE MEDIATED • PRIOR HISTORY OF ATOPY NOT PREDICTIVE • PPE OFTEN INSUFFICIENT TO CONTROL SYMPTOMS • MEDICAL REMOVAL USUALLY NECESSARY IRRITANT-INDUCED • ANY IRRITANT • MODERATE TO HEAVY EXPOSURE • USUALLY HISTORY OF INTOLERANCE TO SECOND HAND TOBACCO SMOKE • OFTEN VARIABLE • PPE OFTEN EFFECTIVE IN PREVENTING EPISODES • MEDICAL REMOVAL THE LAST RESORT • MOST COMMON COMMON SENSITIZERS (INCOMPLETE LIST) LOW MW • ISOCYANATES • ANHYDRIDES • METAL SALTS • EPOXY RESINS • FLUXES • PERSULFATE • ALDEHYDES HIGH MW • PHARMACEUTICALS • ANIMAL PROTEINS • LATEX • CEREALS • SEAFOOD • PROTEOLYTIC ENZYMES • WOOD CONSTITUENTS TREATMENT OF ASTHMA I. CROMOLYN SODIUM MAST CELL STABILIZER, PREVENTS ANTIGEN INDUCED HISTAMINE RELEASE FROM MAST CELLS, APPEARS TO PREVENT TRANSMEMBRANE FLUX OF CALCIUM TRIGGERED BY IgE INTERACTION WITH MAST CELL SURFACE. SPECIFIC FOR MAST CELLS, BEST USED PROPHYLACTICALLY. INHIBITS BRONCHOSPASM AND APPEARANCE OF IL-8 (NEUTROPHIL CHEMOTACTIC FACTOR) TRADE NAMES: INTAL - PULMONARY AEROSOL NASALCROM - NASAL AEROSOL GASTROCROM - ORAL II. NEDOCROMIL SODIUM TRADE NAME: TIDADE SIMILAR TO CROMOLYN SODIUM IN STRUCTURE AND ACTIVITY, INHIBITS MEDIATOR RELEASE FROM INFLAMMATORY CELLS (MAST CELLS, EOSINOPHILS, NEUTROPHILS & MACROPHAGES), USED PROPHYLACTICALLY BY INHALATION. NOT USED FOR ACUTE ATTACKS. III. METHYLXANTHINE DRUGS CAUSE BRONCHODILATION, SMOOTH MUSCLE RELAXATION, INHIBITS PHOSPHODIESTERASES, INHIBITION OF ADENOSINE RECEPTORS, DOWN REGULATION OF ADENYL CYCLASE ACTIVITY, MAY TRIGGER EOSINOPHIL APOPTOSIS. ADVERSE EFFECTS: A. CENTRAL NERVOUS SYSTEM – NERVOUSNESS, TREMOR, INSOMNIA B. CARDIOVASCULAR – IMPAIRMENT OF Ca++ SEQUESTRATION BY SARCOPLASMIC RETICULUM C. GASTROINTESTINAL – STIMULATE SECRETION OF GASTRIC AND DIGESTIVE ENZYMES D. KIDNEY – WEAK DIURETICS ** E. SMOOTH MUSCLE - BRONCHODILATION, INHIBITION OF HISTAMINE RELEASE F. SKELETAL MUSCLE – REVERSES DIPHRAGM FATIGUE AMINOPHYLLINE THEOPHYLLINE ETHYLENEDIAMINE, 79% THEOPHYLLINE THEOPHYLLINE TRADE NAMES: ELIXOPHYLLIN, SLO-PHYLLIN DYPHYLLINE PENTXIFYLLINE TRADE NAME: TRENTAL IV. SYMPATHOMIMETIC DRUGS ADENORECEPTOR AGONISTS, RELAX AIRWAY SMOOTH MUSCLE, INHIBIT RELEASE OF BRONCHOCONSTRICTING COMPOUNDS. A. EPINEPHRINE - BRONCHODILATOR, RAPIDLY ACTING, STIMULATES BOTH b1 & b2 RECEPTORS, CAN CAUSE TACHYCARDIA, ARRHYTHMIAS AND ANGINA, TRADE NAME: PRIMATINE MIST B. EPHEDRINE - LONGER DURATION AND LOWER POTENCY THAN EPINEPHRINE, USED INFREQUENTLY, CAN BE USED WITH THEOPHYLLINE & A SEDATIVE. C. ISOPROTERENOL – POTENT BRONCHODILATOR, CAN CAUSE CARDIAC ARRHYTHMIAS, TRADE NAME: ISUPREL D. $2-SELECTIVE AGENTS - BRONCHODILATORS, LONG LASTING, BRONCHODILATION WITHIN 30 MIN, PERSISTS FOR 3-4 HR, MOST WIDELY USED SYMPATHOMIMETICS. 1. METAPROTERENOL – TRADE NAMES: ALUPENT, METAPREL 2. TERBUTALINE - TRADE NAME: BRETHINE, BRICANYL 3. ALBUTEROL - TRADE NAMES: PROVENTIL, VENTOLIN 4. BITOLTEROL - TRADE NAME: TORNALATE 5. PIRBUTEROL ACETATE - TRADE NAME: MAXAIR 6. SALMETEROL - LONGER ACTING, HIGH LIPID SOLUBILITY, MAY ALSO INHIBIT EOSINOPHILS, TRADE NAME: SEREVENT 7. FORMOTEROL – LONG ACTING, HIGH LIPID SOLUBILITY, TRADE NAME: FORADIL V. MUSCARINIC ANTAGONISTS INHIBIT EFFECT OF ACETYLCHOLINE AT MUSCARINIC RECEPTORS, BLOCKS CONTRACTION OF AIRWAY SMOOTH MUSCLE, BRONCHODILATORS, INC. MUCUS SECRETION. 1. ATROPINE 2. IPRATROPIUM BROMIDE - TRADE NAME: ATROVENT VI. CORTICOSTEROIDS POTENTIATE EFFECTS OF $-RECEPTOR AGONISTS, REDUCE BRONCHIAL REACTIVITY, DECREASE NUMBER & ACTIVATION OF INFLAMMATORY CELLS (MAY TRIGGER EOSINOPHIL APOPTOSIS, INHIBIT CYTOKINE SYNTHESIS. INHALED STEROIDS ARE LIPID SOLUBLE SO LESS LIKELY TO HAVE SYSTEMIC EFFECTS COMMONLY USED STEROIDS 1. PREDNISONE – ORAL 2. BECLOMETHASONE – TRADE NAME: BECLOVENT, VANCERIL, AEROSOL 3. TRIAMCINOLONE - TRADE NAME: AZMACORT, AEROSOL 4. BUDESONIDE – TRADE NAME: PULMICORT, AEROSOL 5. FLUNISOLIDE - TRADE NAME: AEROBID, AEROSOL 6. FLUTICASONE PROPIONATE – TRADE NAME: FLOVENT, AEROSOL 7. MOMETASONE – TRADE NAME: ASMANEX, AEROSOL 8. METHYLPREDNISONE - INTRAVENOUS VII. CALCIUM INFLUX BLOCKING DRUGS INHIBIT BRONCHOCONSTRICTION, NOT COMMONLY USED 1. NIFEDIPINE – TRADE NAMES: PROCARDIA, ADALAT 2. VERAPAMIL VIII. LEUKOTRIENE INHIBITORS INHIBIT BRONCHOCONSTRICTION, MICROVASCULAR LEAKAGE, EDEMA, MUCUS SECRETION, AND LEUKOCYTE ACCUMULATION A. BIOSYNTHESIS INHIBITORS - INHIBIT 5-LIPOXYGENASE 1. BENSOFURANS – DIRECT INHIBITION OF 5-LIPOXYGENASE 2. N-HYDROXYUREA DERIVATIVES – EFFECTIVE COLD, EXERCISE INDUCED, ASPIRIN SENSITIVE & CHRONIC ASTHMA, ZILEUTON, TRADE NAME: ZYFLO 3. INDAZOLINONES – INHIBIT CYSTEINYL-LEUKOTRIENE (LTC4, D4, & E4) COMPONENT OF ANTIGEN-INDUCED BRONCHOCONSTRICTION. 4. HYDROXAMATES - INHIBIT CYSTEINYL-LEUKOTRIENE (LTC4, D4, & E4) COMPONENT OF AG-INDUCED BRONCHOCONSTRICTION, INHIBIT LTB4 SYNTHESIS 5. METHYLOXYALKYL-THIAZOLES – SELECTIVE INHIBITOR OF 5-LIPOXYGENASE B. RECEPTOR ANTAGONISTS - BLOCKS RECEPTORS FOR LEUKOTRIENE B4 (BLT RECEPTORS) AND/OR LEUKOTRIENE C4, D4, AND E4 (CYS LT RECEPTORS). 1. ZAFIRLUKAST (ICI-204219) – INHIBITS LTD4-INDUCED BRONCHOCONSTRICTION, INHIBITS EARLY & LATE RESPONSES TO ALLERGEN, EFFECTIVE AGAINST EXERCISE & COLD INDUCED, & CHRONIC ASTHMA, TRADE NAME: ACCOLATE 2. MONTELUKAST SODIUM – INHIBITS LTD4-INDUCED BRONCHOCONSTRICTION, INHIBITS EARLY & LATE RESPONSES BUT IS MORE EFFECTIVE AGAINST EARLY, TRADE NAME: SINGULAIR 3. QUINOLONES (MK-571) - INHIBITS LTD4-INDUCED BRONCHOCONSTRICTION 4. PRANKULAST (ONO-1078) - INHIBITS LTD4-INDUCED BRONCHOCONSTRICTION RELATIVE POTENCIES OF ANTILEUKOTRIENE AGENTS AS DETERMINED BY THEIR ABILITY TO BLOCK LEUKOTRIENE D4-INDUCED BRONCHCONSTRICTION: ZILEUTON<PRANKULAST<MK-571<ZAFIRLUKAST IX. ANTI-IgE THERAPY OMALIZUMAB (XOLAIR) - SUBCUTANEOUS INJECTION, USED PREDOMINANTLY FOR ASTHMA TREATMENT, USED PROPHYLACTICALLY, WILL NOT HAVE EFFECT ON ACUTE ATTACKS HUMAN IgG1 BINDS TO IgE TO REMOVE IT FROM CIRCULATION, INHIBITS BINDING OF IgE TO HIGH AFFINITY RECEPTORS ON MAST CELLS AND BASOPHILS. POSSIBLE NEW TARGETS FOR ASTHMA THERAPIES T cell Eosinophil Recruitment Chemotaxis (eotaxin) Eosinophil survival (IL-5) Immumodulators cyclosporins Anti-IL-5 (Mepolizumab) Adhesion blockers Anti-VLA-4 Anti-selectins CCR3 antagonists (receptor responsible for Th2 recruitment) Corticosteroids Apoptosis-inducers