L19 - Immunosuppressants & Allergy Lecture Notes PDF

Drugs in Immune Disorders, Allergy & Anaphylaxis ILOs By the end of this lecture, students will be able to 1. Predict benefits of drugs activating immune response in control of immunodeficiency, prevention of infection. 2. Correlate different phases of immune response to mechanism used in co...

Drugs in Immune Disorders, Allergy & Anaphylaxis ILOs By the end of this lecture, students will be able to 1. Predict benefits of drugs activating immune response in control of immunodeficiency, prevention of infection. 2. Correlate different phases of immune response to mechanism used in control & treatment of graft rejection and autoimmune disorders 3. Appraise the benefits of blocking the effect of allergic mediators to control different allergic diathesis 4. Correlate the mechanism of action of drugs acting on allergic pathways to their selection in the different allergic diseases. 5. Identify rescue strategies needed in anaphylaxis and tools for prevention After studying the immune response and immune disorders there is a need to determine therapeutics that act as Immunostimulants, to control cases of immune deficiency and others acting as Immunosuppressants to control hyper or exaggerated immune reactions. Within, the control of exaggerated response to non-pathogenic antigens that manifest as type I Immediate Hypersensitivity reaction; are controlled by drugs termed Anti-Allergics. IMMUNOSTIMULANTS Used to boost basal immunity, when fighting against infections and inflammation or to activate suppressed immune response as in immunodeficiency or cancer. They achieve that by; IMMUNIZATION: Adopting an active process by using Specific Bacterial/Viral Antigens (Vaccination) or a passive process using Preformed Antibodies (Serum or Immunoglobulins) CYTOKINE-BASED THERAPY: by using Recombinant Proteins that mimic the natural interferons, interleukins, colony-stimulating-factors…... etc OTHERS: whether naturally existing or synthetically manufactured. IMMUNOSUPPRESSANTS Used to suppress exaggerated immune response as in cases of autoimmune disorders, graft rejection or in cancer arising from some hematopoietic cells. They achieve that by Non-Selective or Selective inhibition of steps of the immune response. A) NON-SELECTIVE IMMUNOSUPPRESSANTS I. By Corticosteroids; Prednisone the global Inhibitor of lymphocytes, macrophages and other effectors’ or targets’ cell Gene Expression to control immune inflammatory mediators. II. By Conventional Response Modifiers; A. Inhibitors of Lymphocyte Activation Signalling: 1. Phase 1 Inhibitors: Calcineurin Inhibitors;. 2. Phase 2 Inhibitors: m-TOR Inhibitors; B. Inhibitors of Lymphocyte Cell-Cycle Progression: 1. Anti-Metabolites; exerting effect on steps of cell-cycle. 2. Alkylating Agents; introducing an alkyl group to cross-link DNA and RNA 1 B) SELECTIVE IMMUNOSUPPRESSANT: BIOLOGICS Are drugs prepared by biotechnology from living sources (genes, cellular or tissue components, small proteins, …etc) that can suppress selective components of immune system. I. Cytokine Inhibitors; as TNF and IL-Inhibitors II. Inhibitors of Immune Cell Adhesion; as Lymphocyte Function Associated Antigen (LFA-1) Inhibitors III. Inhibitors of Surface antigens; as against CD 20, CD28, CD3 ….etc. Therapeutic Uses of immunosuppressants: 1- Glucocorticoids and conventional response modifiers are mainly used in autoimmune disorders, in preventing graft rejection, and in selected cases of cancer specially of hematopoietic origin, viral infections, or inflammatory disorders. They are used as single agents or in combination but with the hazard of increased ADRs 2- Biological agents are preserved to second line treatment in severe resistant autoimmune disorders, in acute graft rejection. ANTI-ALLERGICS Are drugs used in Allergic Disorders that vary in severity of manifestations ranging from hay fever, urticaria, to asthma, to the severest being anaphylaxis. They belong to Type I Immune Hypersensitivity Reactions ▪ If manifestations are repeatedly modest-moderate; drugs intend to stop actions of prevailing mediators released. (Controlling Agents) ▪ If manifestations are acute moderate- severe; drugs intend to physiologically antagonise them (Relieving Agents) + Controlling Agents. ▪ If anaphylactic manifestation appear; immediate rescue procedures to support respiratory or circulatory collapse (Supportive Management) + Relieving Agents + Controlling Agents. A. CONTROLLING AGENTS: Suppress Histamine Actions by; ▪ Inhibiting Mast Cell Degranulation; Mast Cell Stabilizers: Ketotifen ▪ Competitively Blocking H1 Receptors; Antihistamines Suppress Leukotriene Actions by; ▪ Inhibiting their Synthesis; LOX inhibitors ▪ Blocking their Receptors; Leukotriene Receptor Antagonists. Suppress Gene Expression of Most Mediators by; Glucocorticoids (Prednisone) Bind IgE Immunoglobulins by; Monoclonal antibodies: that binds circulating IgE B. RELIEVING AGENTS Physiological Antagonism of Life Threatening Manifestation; Adrenergic Agonist: Epinephrine Relievers of Bronchoconstriction; 2 Adrenergic Agonists Muscarinic receptor agonists Relievers of Refractory Hypotension; Dopamine, if needed in shock state. C. Supportive Management Respiratory Support; Opening airway; specially in laryngeal edema + O2 Inhalation Circulatory Support; Positioning; Head down / Legs up + Fluid Replacement 2  ANTIHISTAMINES Are reversible Competitive inhibitors of histamine on H1 Receptors Some possess other mechanisms as; Anticholinergic &/or α-Adrenergic Blocking Actions. Their 1st generation introduced were Non-Selective but 2nd & 3rd generations are more Selective Generations of 1st: Chlorpheniramine 2nd : Loratidine 3rd: Fexofenadine Antihistamine Block H1 Block only H1 Block only H1 > anti-Ach M1 Mechanism > α- ADR & 5-HT2A/C > ion channel modulation. Cross BBB / lipophilic < crossing / hydrophilic in overdose) due to prolongation of the cardiac action potential duration secondry to blockade of K+ channels during repolarization. If 3rd generation; They are potentially the safest as they are metabolites of 2 nd generation. Contraindications: depend on the generation used aside the side effects of concern. For instant if 1st generation are used, their anticholinergic side effect can be contraindicated in elderly men who have prostatic enlargement least they develop urine retention or who have elevated intraocular pressure least they develop glaucoma. _______________ 4