Drugs against AllergiesAllergyPowerPoint PresentationSlide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Allergy - Drugs Targeting HistamineH1-Antagonists (“Antihistamines”)Slide 17Slide 18Slide 19Slide 20Mast Cell StabilizersSlide 22Allergy - LeukotrienesSlide 24BIMM118Drugs against Allergies•Antihistamines•Leukotriene Modulators•Glucocorticoids•EpinephrineBIMM118AllergyAllergy:represents a sensitivity to a specific substance, called an allergen, that is contacted through the skin, inhaled into the lungs, swallowed, or injected.Anaphylaxis:is a severe whole-body allergic reaction that occurs within minutes of exposure, progresses rapidly and can lead to anaphylactic shock and death.BIMM118Allergy - SymptomsBIMM118Allergy - PathophysiologyQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.BIMM118Allergy - Food• Allergic reactions to foods almost always occur immediately• The majority of reactions are not fatal• In general, reactions worsen with ageBIMM118Latex: milky sap from the rubber tree hevea brasiliensisAllergy - LatexBIMM118Latex has cross-reactive epitopes with foods: banana, avocado, chestnutAllergy - LatexBIMM118Hymenoptera (hymen=membrane; ptera=wings): ants, bees, waspsAllergy - Hymenoptera stingsWasp Yellow jacketBeeBumble BeeBIMM118Allergy - DrugsPredominantly against beta-lactam antibiotics and NSAIDs:BIMM118Allergy - DiagnosisBIMM118Allergy - MediatorsBIMM118Allergy - HistamineReceptors:part of the super family of G-protein coupled receptors•H1-Receptor–Gq coupled to Phospholipase C–CNS, smooth muscle cells of airways, GI tract, cardiovascular system, endothelial cells and lymphocytes => Vasodilation, bronchoconstriction, seperation of endothelial cells, pain and itching, allergic rhinitis, motion sickness.•H2-Receptor–Gs coupled to Adenylyl Cyclase–Parietal cells; vascular smooth muscle cells => mediate histamine induced gastric acid secretion; vasodilation •H3-Receptor–Gi/o coupled to AC, also to N-type voltage gated Ca channels and reduce Ca influx–CNS => Presynaptic, feedback inhibition of histamine synthesis and release; also controls release of other neurotransmitters•H4-Receptor–coupled to Gi/o in mast cells, can trigger calcium mobilization–found primarily in bone marrow and immune cells => mast cell chemotaxisBIMM118Allergy - HistamineHistamine:Endogenous bioactive amine: synthesized, stored and released in–mast cells, which are abundant in the skin, GI, and the respiratory tract–basophils in the blood–neurons in the CNS and peripheral NS•Physiological actions –Primary stimulant for gastric acid and pepsin secretion (acid secretion is further enhanced by gastrin and vagal stimulation)–Neurotransmitter (both in the CNS and peripheral sites)•Pathophysiological actions –Mediator of immediate hypersensitivity reactions and acute inflammatory responses–Anaphylaxis–Duodenal ulcersBIMM118Allergy - Histamine EffectsActions of Histamine:Vascular:H1 - vasodilation mediated by NO and PGs (via endothelial cells)H2 - vasodilation mediated by cAMP (vascular smooth muscle cells)H1 - coronary vasoconstrictionH1 - increased permeability of post capillary venules => edemaHeart:H1 - decreased AV conductionH2 - increased chronotropyH2 - increased inotropyLung:H1 - bronchoconstrictionH1 - increased mucus viscosityH1 - stimulation of vagal sensory nerve endings: cough and bronchospasmGastrointestinal System:H2 - acid, fluid and pepsin secretionH1 - increased intestinal motility and secretionsCutaneous Nerve Endings:H1 - pain and itchingSymptoms range from mild allergic symptoms to anaphylactic shock:•mild/cutaneous: erythema, urticaria, and/or itching •moderate: skin reactions, tachycardia, dysrhythmias, moderate hypotension, mild respiratory distress•severe/anaphylactic: severe hypotension, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrestBIMM118•H1 Receptor Antagonists Actually inverse agonists (H-receptors display baseline activity!)–1st Generation (Sedating):•Ethylenediamines: 1st antihistamines => obsolete•Ethanolamines: Diphenhydramine, Doxylamine, Clemastine•Alkylamines: Chlorpheniramine•Piperazines: Meclizine, Hydroxyzine –2nd Generation (Non-sedating):•Piperazines: Cetirizine•Piperidines: Loratadine, Fexofenadine•(H2 Receptor Antagonists => GI drugs)•(H3 Receptor Agonist and Antagonists: potential new drugs being developed)•Mast Cell StabilizersAllergy - Drugs Targeting HistamineBIMM118H1-Antagonists (“Antihistamines”)First generation drugs:•Applications:–Adjunctive in anaphylaxis (H2 antagonists and epinephrine also used) –Antiallergy (allergic rhinitis, allergic dermatoses, contact dermatitis)–Sedative/sleep aid–Prevention of motion sickness•Adverse effects:–Sedation (Paradoxical Excitation in children)–Dizziness, Fatigue–Peripheral anti-muscarinic effects: (also block muscarinic Ach receptors)•Dry Mouth•Blurred Vision•Constipation•Urinary Retention•Drug interactions:–Additive with classical muscarinic Ach receptor antagonists–Potentiate CNS depressants•opioids•sedatives•general and narcotic analgesics•alcoholBIMM118H1-Antagonists (“Antihistamines”)First generation drugs:•Diphenhydramine (Benadryl®):–Allergic rhinitis (=seasonal allergies); skin allergies (=contact dermatitis); cough relief–Penetrates blood/brain barrier => Sedative/sleep aid•Dimenhydrinate (Dramamine®):–1:1 ratio Diphenhydramine : 8-Cl-Theophylline => Slower action–Anti H1 and anti-muscarinic activity => good antiemetic–Used to treat nausea, motion sicknessQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.BIMM118H1-Antagonists (“Antihistamines”)First generation drugs:•Doxylamine (Unisom®, Nyquil®):–Antiallergy: as good as diphenhydramine–Most potent OTC sedative/sleep aid (better than
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