2MB+Imunopharmacology+III-allergic+disorders%281%29.pdf

Drugs for Allergic Disorders Prof. L.J. Egan What is allergy?  Altered bodily reactivity (such as hypersensitivity) to an antigen in response to a first exposure eg a bee venom allergy so severe that a second sting may be fatal Exaggerated or pathological immunological reaction (as by sneezing, dif...

Drugs for Allergic Disorders Prof. L.J. Egan What is allergy?  Altered bodily reactivity (such as hypersensitivity) to an antigen in response to a first exposure eg a bee venom allergy so severe that a second sting may be fatal Exaggerated or pathological immunological reaction (as by sneezing, difficult breathing, itching, or skin rashes) to substances, situations, or physical states that are without comparable effect on the average individual  Merriam Webster  Spectrum of allergic reactions Anaphylaxis     Severe acute allergic, IgE-mediated, immediate hypersensitivity reactions Accounts for 1% A&E visits Life-threatening (5000-10,000 deaths per year in US) Commonest allergens      Insect stings Foods Drugs Protein drugs Radiocontrast agents Milder allergic reactions      Confined to body surfaces Sites of contact with allergens Very common Symptoms trivial and recurrent Commonest allergens    Pollen House dust mite dander Latex Clinical examples of allergic diseases  Food allergy    Asthma     Fungal spores… Nasal congestion, mild Drug allergy    House dust mite dander, pollen……. Wheezing, can be life threatening Allergic rhinitis   Peanut, shell fish, kiwi, strawberry………. GI upset …………….Anaphylaxis PCN……. Rash………………Anaphylaxis Contact dermatitis   Latex….. Rash Allergy: Hypersensitivity reactions   Immunological priming Further exposure to antigen  Secondary boosting of immune response (good!)   Eg vaccination producing active immunity Hypersensitivity or damaging response (bad!)  Types of reactions Hypersensitivity type I    Histamine   Specific IgE generated Binds to Fc receptors on mast cells Subsequent exposure to allergen cross-links IgE on mast cells, causing mediator release Histamine: Vasodilatation, bronchoconstriction Eicosanoids eg LTs, PGs: Inflammation, bronchoconstriction Histamine    Basic amine Stored in mast cell granules Acts on specific histamine receptors H1, H2….   G protein couples receptors H1 receptors present on    Bronchial smooth muscle – contraction Endothelial cells – vasodilatation & vascular permeability Vomiting centres in brain Hypersensitivity type I reactions     Anaphylactic or immediate hypersensitivity reaction Develops only in genetically susceptible individuals Mediated by allergen-specific IgE antibodies Central role of local histamine release in mild allergic reactions  Increased capillary permeability   Vasodilatation   Wheal, urticarial (hives) Erythema Itch  Sensory nerve irritation SYSTEMIC ALLERGY: ANAPHYLAXIS Anaphylaxis: Clinical presentation   5-60 minutes after exposure to allergen Urticaria and angioedema   Bronchospasm causing wheezing   Histamine-induced bronchoconstriction Hypotension and CV collapse   Capillary leakage of plasma Hypovolemia, myocardial depression Vomiting, diarrhea Concerning allergy, which statement is false? 1. 2. 3. 4. 5. Allergic reactions are antigen-specific IgE triggers histamine release from mast cells Histamine acts on H1 receptors to cause bronchodilatation and vasoconstriction Allergic diseases range from mild everyday symptoms to life-threatening emergencies Can to diagnosed by skin prick testing Anaphylaxis: Pharmacotherapy  Epinephrine  Stimulates        adrenoceptors - vasoconstriction 1 adrenoceptors – increased cardiac contractility 2 adrenoceptors – bronchodilation Life saving No absolute contraindication Needs to be administered rapidly  Epi-Pen, Ana-Pen devices Epi-Pen EpiPen controversy in Ireland  New Legislation    Allows emergency medication to be administered in a pharmacy without a prescription EpiPens Others EpiPen controversy over pricing Anaphylaxis: Pharmacotherapy contd  Anti-histamines  Diphenhydramine     H1 receptor antagonist Administered IV or orally Continue for duration of symptoms Inhibit vasodilation, vascular leakage and bronchospasm Anaphylaxis: Pharmacotherapy   2 adrenoceptor agonists Wheezing patients    Salbutamol Nebulised Not a substitute for epinephrine Anaphylaxis: Pharmacotherapy  Corticosteroids     2nd phase of anaphylaxis often occurs 8-72 hours after initial symptoms Markedly inflammatory Mediated in part by eicosanoids and cytokines Corticosteroids    Inhibit the 2nd phase Must be administered early Methylprednisolone IV, high dose Anaphylaxis: Summary of management  Early       Epinephrine Anti-histamines 2 adrenoceptor agonist Corticosteroid Aggressive fluid resuscitation Airway management Anaphylaxis 1. 2. 3. 4. 5. Is difficult to diagnose Should only be treated in a hospital setting Causes severe hypertension Requires immediate administration of anti-histamines and corticosteroids Should be treated with IM adrenaline LOCALIZED ALLERGIES Allergic diseases other than anaphylaxis  Fundamental principle   If avoidance not possible or effective   Avoidance of allergen Pharmacotherapy Atopic individuals    Often have multiple allergies Allergens Sites Atopic diseases      Skin: eczema Airways: asthma GIT: food allergy (differentiate disease from common use of this term) Eyes: conjunctivitis Nose: allergic rhinitis Drugs for atopy  Corticosteroids     Administered at time/season of symptoms Slow-acting – must be used prophylactically Inhibit recruitment of immune cells eg mast cells, lymphocytes etc Topical use minimizes systemic exposures    Nasal spray Cream/ointment Eye drops Drugs for atopy Drugs for atopy   Corticosteroids contd. Fluticasone, triamcinolone, beclomethasone…….  Structural modification of hydrocortisone to      lipophilicity  first-pass metabolism Glucocorticoid potency > mineralocorticoid ADR:   Some systemic exposure even with topicals Skin – thinning with chronic use Drugs for atopy  Mast cell stabilizers  Cromolyn sodium and nedocromil     Inhibit Cl channel on mast cells, and others Prevents mast cell degranulation and histamine release Ineffective once that has already happened Used prophylactically Drugs for atopy  Mast cell stabilizers      Inhalation: Allergic asthma Nasal spray: Allergic rhinitis Ophthalmic drops: Allergic conjunctivitis Mastocytosis: Oral ADR  Few Drugs for atopy: Anti-histamines: H1 receptor partial agonists  First Generation      Used for    diphenhydramine, chlorpheniramine………. others Lipophilic, cross BBB Act as “inverse agonists” Drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist Anaphylaxis Nausea and vomiting Adverse effects   Sedation Dry mouth Drugs for atopy: Anti-histamines: contd   Second generation: Cetirizine, loratadine, fexofenadine    Lipophobic, don’t cross BBB Additional anti-inflammatory effects Uses:  Allergic rhinitis     ↓ sneezing, rhinorrhoea Urticaria Orally administered Available OTC Terfenadine: History     First non-sedating anti-histamine Early 1990s: reports of sudden cardiac deaths QT prolongation Withdrawn from market Drugs for atopy  Topical calcineurin inhibitors    Tacrolimus (FK506) ointment Inhibits production of IL-2 by activated T lymphocytes Uses:   Atopic eczema dependent on corticosteroids ADR:   Burning sensation in skin ?lymphoma Which statement about anti-histamines is false? 1. 2. 3. 4. 5. Diphenhydramine is a H1 receptor antagonist Diphenhydramine crosses the blood brain barrier Loratadine does not cross the blood brain barrier Terfenadine can be subject to a clinically significant drug-drug interaction Many anti-histamines are available over the counter b Questions?