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DRUG ALLERGY: MAKING SAFE TREATMENT DECISION William Chui Chief of Pharmacy Service, HKW Cluster 1 2 Adverse Drug Reaction Adverse drug reactions are classified as predictable or unpredictable. A predictable drug reaction is related to the pharmacological actions of the drug. An unpredictable reaction is related to immunological response ( hypersensitivity reactions ) or nonimmunological response 3 Adverse Drug Reactions Drug Hypersensitivity Drug Allergy Drug Intolerance 4 Definition of drug allergy It is defined as an adverse reaction to a drug by a specific immune response either directly to the drug or one or more of its metabolites alone, or to a drug bound to a body protein such as albumin, (Hapten). Such binding alters the structure of the drug/protein complex, rendering it antigenic. 5 Distinctive features of allergic drug reactions No correlation with known pharmacological properties of the drug No linear relationship with drug dosage Often include a rash, angioedema, the serum sickness syndrome, anaphylaxis and asthma which are reactions similar to those of classical protein allergy 6 Distinctive features of allergic drug reactions Require an induction period on primary exposure but not on readministration Disappear on cessation of therapy and reappear after readministration of a small dose Occur in a minority of persons receiving the drug Desensitization may be possible 7 Classification of hypersensitivity The criteria of the classification 1) Based on the time required for the symptoms or skin test reactions to appear after exposure--- immediate and delayed hypersensitivity. 2) Based on the nature of organ involvement. •Fewer than 10 percent of adverse drug reactions are allergic. 8 Hypersensitivity Reactions I (immediate) II (cytotoxic) III (immune complex) IV (delayed) V (stimulating/blocking) # Antigens Pollens, moulds, mites, drugs, food and parasites Cell surface or tissue bound Exogenous (viruses, bacteria, fungi, parasites) Autoantigens Cell/tissue bound Cell surface receptors Mediators IgE and mast cells IgG, IgM and complement IgG, IgM, IgA and complement TD, Tc activated macrophages and lymphokines IgG Diagnostic tests Skin-prick tests: wheal and flare Specific IgE in serum Coombs’ test Indirect immunofluorescence (antibodies) Red cell agglutination Precipitating antibodies ELISA Immune complexes Skin test: erythema induration (e.g. tuberculin test) Indirect Immunofluorescence Time taken for reaction to develop 5-10min 6-36 hours 4-12 hours 48-72 hours Variable #Type V hypersensitivity may also be classified with type II reactions 9 I (immediate) II (cytotoxic) III (immune complex) IV (delayed) V (stimulating/blocking) Immunopathology Oedema, vasodilation, mast cell degranulation, eosiniophils Antibody-mediated damage to target cells Acute inflammatory reaction, neutrophils, vasculitis Perivascular inflammation, mononuclear cells, fibrin Granulomas Caseation and necrosis in TB Hypertrophy or normal Diseases and conditions produced Asthma (extrinsic) Urticaria/oedema Allergic rhinitis Anaphylaxis Autoimmune Haemolytic anaemia Transfusion reactions Haemolytic disease of newborn Goodpasture’s syndrome Addisonian pernicious anaemia Myasthenia gravis Autoimmune (e.g. SLE, glomerulonephritis, rheumatoid arthritis) Low-grade persistent infections (e.g. viral hepatitis) Disease caused by environmental antigens (e.g. farmer’s lung) Pulmonary TB Contact dermatitis Graft-versus-host disease Insect bites Leprosy Neonatal hyperthyroidism Graves’ disease Myasthenia gravis Treatment Antigen avoidance Antihistamines Corticosteroids (usually topical) Sodium cromoglicate Epinephrine for lifethreatening conditions Exchange transfusion Plasmapheresis Immunosuppressives /cytotoxics Corticosteroids Immunosuppressives Plasmapheresis Immunosuppressives Corticosteroids Removal of antigen Treatment of individual disease RAST, radioallergosorbent test; SLE, systemic lupus erythematosus; TB, tuberculosis; Tc, T cytotoxic; TD, T delayed hypersensitivity 10 Overview of Drug Allergy Drug allergy is an uncommon and unwanted side effect of medication. Reactions to drugs range from a mild localized rash to serious effects on vital systems. The body’s response can affect many organ systems, but the skin is the most frequently involved. 17 The most common drug to cause allergy Analgesics, such as codeine, morphine, nonsteroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen or indomethacin), and aspirin Antibiotics such as penicillin, sulfa drugs, and tetracycline 18 Risk factors for Drug Allergy Frequent exposure to the drug Large doses of the drug Drug given by injection rather than pill Family tendency to develop allergies and asthma. 19 Drug Allergy Symptoms Drug allergies may cause many different types of symptoms It depends on the drug and how often you have taken it. 20 Most common allergic reactions Rash Fever Muscle and joint aches Lymph node swelling Inflammation of the kidney Anaphylactic shock 21 Allergic reactions on skin Measles-like rash Hives - Slightly red and raised swellings on the skin, irregular in shape, itchy Photoallergy - Sensitivity to sunlight, an itchy and scaly rash when you go out in the sun Erythema multiforme - Red, raised and itchy, sometimes look like bull's-eye targets, sometimes with swelling of the face or tongue 24 Allergic reactions on skin Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) -A manifestation of acute graft versus host disease -Medications with longer half-lives are more likely than those with shorter half-lives to pose a risk for SJS and TEN 25 Stevens Johnson’s syndrome 26 Toxic epidermal necrosis 28 SJS & TEN SJS & TEN develop 1-3 weeks after the culprit medication is initiated Sulphonamides, other antibiotics, NSAIDs, anticonvulsant and antiretroviral agents are the most common causative medications. 29 Signs and Symptoms of SJS & TEN Mucosal erosions Asymmetric skin involvement with blisters Widespread of skin distribution <10% total body surface area affected Mucosal erosions Flaccid blisters and denuded skin Widespread of skin distribution > 30% total body surface area affected 30 Signs and Symptoms of SJS & TEN Fluid and electrolyte imbalance Compromised cutaneous integrity promotes bacterial colonization and infection of the skin with the risk for sepsis. Debilitated, bedridden patients are susceptible to aspiration pneumonia, deep vein thrombosis and pulmonary embolism Ocular involvement may manifest to blindness 31 Guideline for Treatment of SJS & TEN Admit to intensive care or burn unit Discontinue culprit medication and all unnecessary medications Sterile technique in handling patient Place intravenous or central line in area of uninvolved skin if possible 32 Guideline for Treatment of SJS & TEN Culture skin, blood, urine daily Avoid prophylactic systemic antibiotics and silver sulfadiazine to skin Fluid and electrolyte monitoring and replacement Initiate total parenteral nutrition or nasogastric feedings if unable to take po 33 Guideline for Treatment of SJS &TEN Remove oral and nasal debris daily; antiseptic mouthwashes or oral sprays daily Antiseptic eye drops daily and ophthalmology consultation Anticoagulation to prevent deep vein thrombosis and pulmonary embolism 35 Anaphylactic Reaction Life threatening Almost all anaphylactic reactions occur within 4 hours of the first dose of the drug. Most occur within 1 hour of taking the drug, and many occur within minutes or even seconds. 36 Symptoms of anaphylactic shock Skin reaction - Hives, redness/flushing, sense of warmth, itching Difficulty breathing - Chest tightness, wheezing, throat tightness Fainting - Light-headness or loss of consciousness due to drastic decrease in blood pressure ("shock") Rapid or irregular heart beat Swelling of face, tongue, lips, throat, joints, hands, or feet 37 The causative antigens causing anaphylaxis Blood products ß-lactam antibiotics X-ray contrast agent Other drugs 38 Prophylaxis of anaphylaxis Routine skin testing before giving serum is mandatory. When a drug or serum is essential, rapid desensitization. For x-ray contrast agent anaphylaxis, the patient is pretreated with prednisolone 50mg q 6h for 3 doses, diphenhydramine 50mg po 1h beforehand and adrenaline 25 mg po 1h beforehand for adult. 46 Urticaria What is urticaria? It is local wheals and erythema in the superficial dermis Urticaria induced by drug is generally acute and is limited to the skin and subcutaneous tissues. 48 Urticaria 49 Urticaria Signs and symptoms Pruritus (generally the first symptom) Crops of hives Lesion (if lesion persists more than 24 hours, the possibility of vasculitis should be considered) Diagnostic tests are seldom required 50 Urticaria Treatment for acute urticaria Symptoms subside in 1 to 7 days, treatment is chiefly palliative. All nonessential drugs should be stopped until the reaction has subsided. Symptoms can be relieved by oral antihistamine and glucocorticoid. 51 Drugs for Acute Urticaria Oral antihistamine: diphenhydramine 50-100mg q4h, hydroxyzine 25-100mg bid or cyproheptadine 4-8mg q4h Glucocorticoid for more severe reactions, especially when associated with angioedema (prednisone 30-40 mg/ day po) 52 Angioedema What is angioedema? It is a deeper swelling due to edematous areas in the deep dermis and subcutaneous tissue and may also involve mucous membranes. 55 Signs & Symptoms of Angioedema Diffuse and painful swelling of loose subcutaneous tissue, dorsum of hands or feet, eyelids, lips, genitalia and mucous membranes. Edema of the upper airways may produce respiratory distress 56 Angioedema 57 Management for Angioedema Glucocorticoid (e.g. prednisone 3040mg/day po) Adrenaline 1:1000, 0.3ml subcutaneously should be the 1st line treatment for acute pharyngeal or laryngeal angioedema IV antihistamine (e.g. diphenhydramine 50100mg) to prevent airway obstruction Intubations or tracheotomy and oxygen administration may be necessary 58 Example of Drug Allergy 59 Penicillin Allergy Symptoms Fever Rash Urticaria Angioedema Nephritis Lymphadenopathy Arthralgias 60 Immunological reactions resulting in signs and symptoms Type I : immediate hypersensitivity Antigens with specific IgE antibodies that are bound to mast cells or basophils and lead to the release of histamine and leukotrienes. Clinical presentation : urticaria, laryngeal, edema, bronchospasm, hypotension and cardiovascular collapse, anaphylaxis. 61 Immunological reactions resulting in signs and symptoms Type II : Cytotoxic reaction Cytotoxic reactions result when IgG or IgM β-lactam specific antibodies become attached to circulating blood cells or renal interstitial cells which have β-lactam antigens bound to their surface. Clinical presentation: hemolytic anemia, thrombocytopenia, granulocytopenia or drug-induced nephritis. 62 Immunological reactions resulting in signs and symptoms Type III :immune complex reactions β-lactam specific IgG or IgM antibodies may form circulating complexes with β-lactam antigens. These complexes causing serum sickness like reaction and possibly drug fever. Clinical presentation: fever, rash, urticaria, lymphadenopathy and arthralgias 63 Immunological reactions resulting in signs and symptoms Type IV: cell-mediated hypersensitivity T lymphocytes recognize the β-lactam antigen through an antigen-specific Tcell receptor, triggering cytokine release, resulting in tissue inflammation. Clinical presentation: contact dermatitis. 64 Mechanism of Penicillin Allergy Only proteins and large polypeptide drugs can stimulate specific antibody production by straightforward immunologic mechanisms. The drug, or one of its metabolites must be chemically reactive with protein can act as haptens and bond covalently to proteins. 65 Mechanism of Penicillin Allergy The breakdown products can bond to ε-amino groups of lysine residues, most importantly globulins. This binding leads to a spectrum of potentially immunologically active moieties on serum proteins that can cross-link with a variety of preformed anti-penicillin IgE bond to mast cells. 66 Cross-reactivity The most important part of penicillin antigen appears to be the core structure The structure of the penicillin is a βlactam ring with the five-membered thiazolidine ring 67 The structure of Penicillin 68 Cross-reactivity Carbapenems have a bicyclic nucleus containing β-lactam ring and an adjacent five-membered ring. It showed 50% cross-reactivity in allergy skin testing between penicillin major and minor determinants and the analogous imipenem reagents. Patients especially with positive penicillin skin test should withhold carbapenems 69 The Structure of Carbapenem 70 Cross-reactivity The structure of cephalosporin contains a βlactam ring with a six-membered dihydrothiazine ring. Side chain antigens may be more significant and probably dominate in cephalosporin (patients with positive penicillin skin test results who were given cephalosporin had a cross reaction rate of 10%-20%) 71 72 Prophylaxis of Penicillin Allergy Skin test Skin tests for immediate-type (IgE-mediated) hypersensitivity are very useful in diagnosis of reactions to penicillin, enzymes, and some vaccines. 74 Prophylaxis of Penicillin Allergy Skin test It should be performed in patients With a history of penicillin allergy β-lactam antibiotic is indicated drug of choice. 75 Prophylaxis of Penicillin Allergy Skin test The major degradation product of penicillin, benzylpenicillenic acid, can combine with tissue proteins to form benzylpenicilloyl ( BPO ), the major antigenic determinant of penicillin. 76 Prophylaxis of Penicillin Allergy If the patient has a history of a severe explosive reaction, the reagents should be diluted 100-fold for initial testing. 78 Prophylaxis of Penicillin Allergy Intradermal test 0.5 or 1 ml dilute is injected to produce a 1 or 2 mm bled. Each set of skin tests should include the diluents alone as a negative control and histamine as a positive control. 79 Intradermal Test 80 Prophylaxis of Penicillin Allergy Intradermal test A skin test is considered positive if it produces a wheal and flare reaction in 15 min with a wheal diameter at least 5 mm larger than the control. 81 Prophylaxis of Penicillin Allergy If skin tests are positive, the patient risks an anaphylactic reaction if treated with penicillin Negative skin tests minimize but do not exclude the risk of a serious reaction. 82 Caution with the skin test Antihistamines, tricycle antidepressants and adrenergic drugs can inhibit skin tests results and should be discontinued before the testing procedure. Patients using β-adrenergic blocking drugs or angiotensin-converting enzyme inhibitors at the same time of skin testing may not respond to emergency treatment with adrenaline if a systemic reaction occurs. 84 When will desensitization perform? When penicillin is the drug of choice. The alternate drugs fail, induce unacceptable side effects or are less effective. When anaphylaxis of the penicillin present 85 Contraindication of Desensitization Patients with a history of StevensJohnson syndrome and toxic epidermal necrolysis present an almost absolute contraindication to the readministration of any β-lactam antibiotic since an accelerated lifethreatening reaction may occur. 86 Procedure of desensitization Baseline evaluation Intravenous access, electrocardiogram, spirometry, blood pressure, pulse, respiratory rate and clinical status should be reevaluated prior to the next dose. 87 Procedure of desensitization Premedication with antihistamine or steroids is not recommended 1) They are not effective in preventing severe reactions and may mask early signs of reaction that would otherwise result in a modification of the protocol 88 Procedure of desensitization Dose that causes mild systemic reactions, such as pruritus, urticaria, rhinitis or mild wheezing should be repeated until the patient tolerates the dose without systemic symptoms or signs. More serious reactions, such as hypotension, laryngeal edema, asthma and if desensitization is continued, withheld until the patient is stable. 89 Procedure of desensitization Once desensitized, the patient’s treatment with penicillin should not lapse because the risk of an allergic reaction increases when restarting treatment. If the patient requires β-lactam antibiotic in the future and his skin test result remains positive, desensitization is required again. 90 The protocol of desensitization 91 Latex allergy Latex is derived from natural rubber, which is itself composed of various polymers of isoprene. The potential contamination of medications and the fact that latexallergic reactions in some situations could be mistakenly interpreted as medication allergies or allergic reactions to general anesthesia. 96 100 101 Conclusion As drug allergy can pose risk to patients’ health, Healthcare professions should… Be aware of patients’ drug allergy history Record such information properly Double check patients’ drug allergy history before drug administration 102 Thank You 103