Adverse Drug Reactions (Immune Hypersensitivity) - PDF

IMMUNE HYPERSENSITIVITY REACTIONS  HYPERSENSITIVITY REACTIONS ❖ Hypersensitivity reaction: is an exaggerated undesirable reaction produced by the normal immune system in response to a benign antigen. ❖The immune response NOT the antigen is actually harmful. ❖ Hypersensitivity reacti...

IMMUNE HYPERSENSITIVITY REACTIONS  HYPERSENSITIVITY REACTIONS ❖ Hypersensitivity reaction: is an exaggerated undesirable reaction produced by the normal immune system in response to a benign antigen. ❖The immune response NOT the antigen is actually harmful. ❖ Hypersensitivity reactions are usually referred to as an over-reaction of the immune system, and these reactions may be damaging ,uncomfortable, or occasionally fatal.  HYPERSENSITIVITY REACTIONS Hypersensitivity occurs in two phases : 1. Sensitization phase: initial encounter with an antigen (first encounter). 2. Effector phase: immunologic memory and results in tissue pathology.  HYPERSENSITIVITY REACTIONS Hypersensitivity can be classified as: 1. Antibody-mediated: three types of hypersensitivity (types I – III). 2. Cell-mediated: one type of hypersensitivity (type IV). TYPES OF HYPERSENSITIVITY REACTIONS Type Alternative Mediators Names Type I “Immediate IgE hypersensitivity reaction” (Allergy) Type II “Cytotoxic hypersensitivity IgM or IgG reaction” Type III “Immune Complex IgG hypersensitivity reaction” Type IV Delayed type T-cells hypersensitivity (DTH) “Cell mediated” “Antibody independent”  TYPE I HYPERSENSITIVITY It is also known as anaphylactic reaction. Type I hypersensitivity or immediate hypersensitivity is mediated by IgE antibodies specific for allergens. The route and location of allergen exposure determine the ensuing symptoms.  TYPE I HYPERSENSITIVITY 1. Inhaled allergens may exacerbate allergic rhinitis or asthma by causing nasal congestion, rhinorrhea, sneezing, and bronchospasm. 2. Topical contact with allergens can cause urticaria.  TYPE I HYPERSENSITIVITY 3. Exposure to allergen via the oral or intravenous route typically produces systemic symptoms: ✓ Anaphylaxis is a life-threatening type I systemic allergic response to allergens such as foods, medications, or stinging insect venoms. ✓characterized by urticaria, angioedema, bronchospasm, nausea, vomiting, diarrhea, hypotension, and, rarely, shock. PATHOPHYSIOLOGY  PATHOPHYSIOLOGY 1. On the 1st exposure to the antigen (Ag), dendritic cells (Ag-presenting cells) will pick it up, process it and express part of it on its surface. 2. Dendritic cells will then carry the Ag to nearby lymphoid tissue (e.g. lymph nodes) and present the Ag to naïve T- helper (Th) cells that develop into Th2 cell phenotype. 3. Th2 cells will respond by secreting cytokines such as IL- 4, IL-5 and IL-13 that will: Stimulate eosinophils to secret cytokines and leukotrienes. Activate B cells to transform into the antibody-producing plasma cells.  PATHOPHYSIOLOGY 4. Plasma cells are now IgE-secreting, releasing IgE antibodies that bind to specific receptors on the surface of mast cells and basophils. 5. Upon subsequent (2nd) exposure to the same antigen, IgE antibodies that are bound to the surface of mast cells and basophils will recognize the Ag, bind with it (Free antigen binds to two adjacent IgE antibodies =crosslinking) causing degranulation and release of histamine, leukotrienes and other inflammatory mediators such as prostaglandins from mast cells and basophil granules.  PATHOPHYSIOLOGY (CONT..) Increased smooth muscle contraction + peripheral vasodilation + increased vascular permeability → bronchospasm , abdominal cramping, and rhinitis → hypovolemia , hypotension Extravasation of capillary blood → erythema Fluid shift into the interstitial space → edema Pruritus Eosinophil and neutrophil chemotaxis induced by basophil and mast cell mediators → eosinophilia  TYPE II HYPERSENSITIVITY REACTION It is also known as cytotoxic reaction. It is an antibody-mediated process in which IgG and IgM antibodies are directed against antigens. These antigens are typically found on circulating blood cells, such as red blood cells, platelets, neutrophils, or on epithelial cells in mucosal surfaces and basement membranes.  TYPE II HYPERSENSITIVITY REACTION This subsequently leads to cell lysis, tissue damage or loss of function through mechanisms such as: 1. Complement activation via the classical complement pathway. 2. Antibody dependent cell-mediated cytotoxicity. 3. Target cell dysfunction.  1. COMPLEMENT ACTIVATION Complement system: A group of serum proteins that circulate in an inactive state. The activated complement components participate in a controlled enzymatic cascade that results in membrane –damaging reactions which destroy pathogenic organisms by formation of a membrane attack complex (MAC). 2. ANTIBODY DEPENDENT CELL- MEDIATED CYTOTOXICITY 3. TARGET CELL DYSFUNCTION 3. TARGET CELL DYSFUNCTION  EXAMPLES OF CYTOTOXIC REACTIONS (1) Erythroblastosis fetalis : Hemolytic disease of the newborn. It is an autoimmune condition that develops in a fetus and caused by Rh incompatibility. When IgG antibodies that have been produced by the Rh -ve mother and have passed through the placenta include ones which attack the red blood cells in the fetal circulation. Red blood cells are broken down and the fetus can develop anemia and sometimes can result in death of the fetus.  Prevention is by administration of anti-Rh (anti –D) globulin just after birth or maximum 72 hours after each delivery of the Rh +ve fetus. These antibodies attach to the Rh antigens now circulating in the mother’s bloodstream and prevent her own immune cells from recognizing the antigen. This in turn prevents the mother from forming her own antibodies against the Rh antigen, protecting the next child from Rh incompatibility related disease. This disease could also happen with the first fetus if the Rh-ve mother received previously a Rh +ve blood. EXAMPLES OF CYTOTOXIC REACTIONS (2) Faulty blood transfusion: The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies.  THE ABO SYSTEM Blood transfer arrangement of ABO system  TYPE III HYPERSENSITIVITY It is also known as immune complex hypersensitivity reaction. In type III responses, IgG and IgM antibodies bind to antigens to form immune complexes (antigen-antibody complexes). ❖ The antigen-antibody complexes formed in the circulation should be removed. ❖ Otherwise, the immune complexes may accumulate in tissues and such situation is harmful to the host. ❖ Binding of antibody with the antigen activates the classical complement system. ❖ Activation of complement system by immune complexes helps in efficient removal of immune complexes from circulation. ❖ As long as the immune complexes are present in the circulation, they are not harmful to the host. ❖ The undesirable effects occur when the immune complexes deposit in tissues. ❖ Once deposited in tissues, the complexes activate a variety of potent mediators of inflammation causing an influx of neutrophils and monocytes to the site of deposition. ❖ The neutrophils and monocytes try to engulf the immune complexes. ❖ During their attempt to engulf the immune complexes, the phagocytes release toxic products of oxygen metabolites , various proteases and enzymes which cause tissue damage around the site of immune complex.  TYPE III HYPERSENSITIVITY Common sites of complex deposition include small arteries, renal glomeruli, and synovial capsules of joints, thereby causing vasculitis, glomerulonephritis, and arthritis, respectively. Thus, the symptoms associated with type III reactions are determined by the site of immune complex deposition and not by the source of the antigen. PATHOPHYSIOLOGY  TYPE IV HYPERSENSITIVITY Type IV hypersensitivity responses are collectively termed delayed hypersensitivity reactions. The reaction takes several days to develop (usually 48- 72 hrs.) It’s a cell-mediated immune reaction. It does NOT involve the participation of antibodies but is due primarily to the interaction of T cells with antigens. Involve T cells as the major effector cells.  TYPE IV HYPERSENSITIVITY Effector T cells, macrophages and other leukocytes infiltrate a site of antigen exposure and induce a delayed form of inflammatory tissue damage through the production and release of reactive oxygen species, lysosomal enzymes, and inflammatory cytokines. PATHOPHYSIOLOGY  EXAMPLES OF DELAYED HYPERSENSITIVITY Allergic contact dermatitis: o It results from exposure of certain individuals to metals and reactive chemicals. o Such substances are only antigenic after combination with serum proteins.