BIMM118Drugs against Allergies• Antihistamines• Leukotriene Modulators• Glucocorticoids• EpinephrineBIMM118AllergyAllergy:represents a sensitivity to a specific substance, called anallergen, that is contacted through the skin, inhaled into thelungs, swallowed, or injected.Anaphylaxis:is a severe whole-body allergic reaction that occurs within minutes ofexposure, progresses rapidly and can lead to anaphylactic shock and death.BIMM118Allergy - SymptomsBIMM118Allergy - PathophysiologyBIMM118Allergy - 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 epitopeswith foods: banana, avocado,chestnutAllergy - LatexBIMM118Hymenoptera (hymen=membrane; ptera=wings): ants, bees, waspsAllergy - Hymenoptera stingsWaspYellow 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, endothelialcells and lymphocytes => Vasodilation, bronchoconstriction, seperation ofendothelial cells, pain and itching, allergic rhinitis, motion sickness.•H2-Receptor–Gs coupled to Adenylyl Cyclase–Parietal cells; vascular smooth muscle cells => mediate histamine induced gastricacid 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; alsocontrols 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 vasoconstriction H1 - increased permeability of post capillary venules => edemaHeart: H1 - decreased AV conduction H2 - increased chronotropy H2 - increased inotropyLung: H1 - bronchoconstriction H1 - increased mucus viscosity H1 - stimulation of vagal sensory nerve endings: cough and bronchospasmGastrointestinal System: H2 - acid, fluid and pepsin secretion H1 - 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 AntagonistsActually 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 sicknessBIMM118H1-Antagonists (“Antihistamines”)First generation drugs:• Doxylamine (Unisom®, Nyquil®):– Antiallergy: as good as diphenhydramine– Most potent OTC sedative/sleep aid (better than barbiturates!)• Clemastine (Tavist®):BIMM118H1-Antagonists (“Antihistamines”)First generation drugs:• Chlorpheniramine (Chlor-Trimeton®):– Also anti-depressant (inhibits serotonin re-uptake)• Meclizine (Dramamine II®):– Antiemetic: Less drowsiness than original Dramamine• Hydroxyzine (Atarax®):– Antihistamine action due to metabolite: CetirizineSecond generation drugs:• Cetirizine (Zyrtec®):BIMM118H1-Antagonists (“Antihistamines”)Second generation drugs:• Loratadine (Claritin®):– Does not enter CNS => NO drowsiness!– t1/2=8h => Active metabolite: Desloratadine (t1/2=28h)• Desloratadine (Clarinex®):• Fexofenadine (Allegra®):– Highly selective for H1-Receptor– $ 2B in sales/year !!BIMM118Mast Cell Stabilizers• Cromolyn=Cromoglycate (Intal®, Nasalcrom®):– Only prevents asthma, but can NOT stop an attack in progress– Acts by preventing mediator release
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