Drug induced allergy and hypersensitivity

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twinklemuse
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65983
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Drug induced allergy and hypersensitivity
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2011-02-16 16:05:50
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Drug induced allergy hypersensitivity
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Drug induced allergy and hypersensitivity
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  1. what is antigen?
    substance that is recognized and processed by immune system
  2. what is hapten?
    • drug or metabolite that must bind to a tissue or protein to serve as a complete antigen
    • (too small to be recognized by itself)
  3. Is there humoral or cellular immune response in pseudoallergy?
    NOPE
  4. does anaphylactoic reaction involve immune mediated reaction?
    • NOPE
    • this is a type of pseudoallergy that mimics anaphylaxis
  5. does anaphylaxis involve immune mediated reaction?
    • Yes.
    • this is the most severe and life threatening form of drug allergy (a form of hypersensitivity)
    • histamine mediated
  6. what is the mechanism of hypersensitivity?
    • Not completely understood
    • because difficult to study (many animal models), single drug can have many mechanisms and reactions, and it is difficult to identify the antigen
  7. what are the hallmark characteristics of drug hypersensitivity?
    • drug is the antigen; "individual drug related"
    • 1) onset from 5-21 d after initial exposure (sensitization period)
    • 2) associated with usual or standard dose of drug
    • 3) presence of histamine related or immune mediated S&S, including eosinophilia
    • 4) reversibility of symptoms after d/c of drug
    • 5) faster appearance of reaction (within hours to days) after reintroduction of the drug
  8. what are the 5 stages of immune response to a drug during hypersensitivity?
    • 1) formation of complete antigen
    • 2) processing of the complete antigen by antigen presenting cells
    • 3) recognition of the antigenic determinants by the T-lymphocytes
    • 4) generation of a drug specific antibody or sensitized T cells
    • 5) clinical presentation of immune reaction
  9. how do haptens form? (part of the first stage of hypersensitivity)
    • via metabolism in liver, skin keratinocytes, WBC
    • hapten binds with higher weight protein to form a complete antigen
    • (note: binding of a drug to plasma protein, like albumin, does not count)
  10. what should happen when hapten major histocompatibility complex on the APC surface interact with T-helper cells to induce a clinical reaction? (part of the 3rd stage of hypersensitivity)
    • cytokines should be released to differentiate T-helper cells to type 1 and type 2 for a clinical reaction.
    • otherwise, cells are just sensitized and no reaction will occur.
  11. T helper type 1 cells secrete cytokines favoring ___, ___ and ___. And this is called ____ response. (part of 4th stage of hypersensitivity)
    • CD4+, CD8+, memory cells
    • cellular response
  12. T helper type 2 cells secrete cytokines favoring ___, ___ and ___. And this is called ____ response. (part of 4th stage of hypersensitivity)
    • antibodies IgE, IgG, IgM
    • humoral response
    • (aka delayed immune response becdause makes antibodies)
  13. During stage 5 of hypersensitivity, there is clinical presentation of immune reaction. How are these classified?
    • classified by mechanism and clinical presentation.
    • (note: you must have a clinical response to proceed to stage 5)
  14. How long do stages 1-4 for hypersensitivity take?
    5-21 days
  15. what are the 4 types of immune reaction for hypersensitivity? (this is stage 5)
    • type I: immediate hypersensitivity
    • type II: cytotoxic reaction
    • type III: immune complex reaction
    • type IV: delayed and cellular immune response
  16. what is type I immune reaction called?
    what is the timing?
    what antibodies are released?
    what are the targeted cells?
    what is the presentation?


    T helper type 1 cells secrete cytokines favoring ___, ___ and ___. And
    this is called ____ response. (part of 4th stage of hypersensitivity)
    • immediate hypersensitivity (severe)
    • minutes to 2 hour, up to 48 h
    • IgE (histamine mediated)
    • mast cells (lungs, GI, connective tissue), basophils (blood)
    • anaphylaxis, urticaria, angioedema, bronchospasm, CV collapse, resp collapse
  17. what is type II immune reaction called?
    what is the timing?
    what antibodies are released?
    what are the targeted cells?
    what is the presentation?
    • cytotoxic reaction
    • 7-21 days
    • IgG and IgM
    • blood cells
    • cytopenia (hemolytic anemia, thrombocytopenia, neutropenia), vasculitis
  18. what is type III immune reaction called?
    what is the timing?
    what antibodies are released?
    what are the targeted cells?
    what is the presentation?
    • immune complex reaction
    • 5-21 days
    • IgG and IgM
    • skin, joint, kidney, liver
    • serum sickness illness, morbilliform or maculopapular rash, glomerulonephritis, interstitial nephritis, erythema multiformes, SJS
  19. what is type IV immune reaction called?
    what is the timing?
    what antibodies are released?
    what are the targeted cells?
    what is the presentation?
    • delayed and cellular immune response
    • 24-48h
    • sensitized T lymphocyte (no Ig)
    • skin, liver, lung, kidney
    • contact dermatitis, maculopapular rash, bullous or pustular eruptions, SJS, TEN, interstitial pneumonitis
  20. which type of immune reaction during stage 5 of hypersensitivity do NOT involve immunoglobulin antibody?
    • type IV (delayed and cellular immune response)
    • has sensitized T lymphocyte
  21. what are the 3 mechanisms of pseudoallergy?
    • 1) direct stimulation of mast cells (often in skin) causes histamine release
    • 2) non-immunologic activation of complement cascade
    • 3) alteration of metabolism or production of inflammatory mediators
    • ****does NOT involve the immune system
  22. what kind of reaction does opiates cause? (hypersensitivty or pseudoallergy)
    what is the mechanism?
    • pseudoallergy
    • direct stimulation of mast cells to release histamine
  23. what kind of reaction does protamine cause (antidote for heparin)?
    what is the mechanism?
    • pseudoallergy
    • direct stimulation of mast cells to release histamine
    • also non-immunologic activation of complement cascade
  24. what kind of reaction does pentamidine cause?
    what is the mechanism?
    • pseudoallergy
    • direct stimulation of mast cells to release histamine
  25. what kind of reaction does polymyxin cause?
    what is the mechanism?
    • pseudoallergy
    • direct stimulation of mast cells to release histamine
  26. which 4 medications have pseudoallergy wtih the mechanism of direct stimulation of mast cells to release histamine?
    • opiates
    • polymixin
    • pentamidine
    • protamine
    • this mechanism is mostly dose related
  27. what kind of reaction does contrast media have?
    what is the mechanism?
    • pseudoallergy
    • nonimmunologic activation of complement cascade
  28. what 2 medications may have pseudoallergy with mechanism of non-immunologic activation of complement cascade?
    • contrast media
    • protamine
  29. what kind of reaction does NSAIDs have?
    what is the mechanism?
    • pseudoallergy
    • alteration of metabolism or production of inflammatory mediators
  30. what kind of reaction does ACEi have?
    what is the mechanism?
    • pseudoallergy
    • alteration of metabolism or production of inflammatory mediators
  31. what two medications have pseudoallergy with mechanism of alteration of metabolism or production of inflammatory mediators?
    • ACEi
    • NSAIDs
  32. Does psedoallergy have to do with an individual drug or the class of drug?
    • the class
    • (hypersensitivity has to do with individual drug)
  33. what are signs and symptoms of anaphylaxis?
    • early: urticaria +/- angioedema, bronchospasm, stridor, elevated tryptase
    • late: erythema, laryngeal edema
    • general: hypotension, arrhythmia, eosinophilia, reflex tachycardia
    • this is medical emergency
  34. what are the S&S of urticaria?
    • asymmetric, circumscribed erythematous papular lesions of variable size with raised borders, pruritis
    • red rim and central cleaning
  35. what are s&s of angioedema?
    • asymmetric non-pitting edema of head and neck usually
    • periorbital edema, laryngeal edema
    • difficulty swallowing
    • hoarseness and difficulty speaking
    • rarely edema of extremities and genitalia
    • involves deep dermis
  36. what are S&S of blood disorders?
    • hemolytic anemia with positive Coombs test
    • thrombocytopenia (<100,000), neutropenia
    • decreased C3 and C4
    • antiplatelet or antineutrophil antibodies
    • occurs within 5-21 days
  37. what are the S&S of serum like sickness?
    • skin rash (urticarial or maculopapular) with prodromal fever and malaise, arthralgia, lymphadenopathy
    • elevated ESR, decreased C3 and C4
    • rarely glomerulonephritis
  38. what are S&S of vasculitis?
    (also known as Churg Strauss syndrome)
    • purpuric or maculopapular rash with prodromal fever, arthralgia, sore throat
    • nausea, abdominal pain, synovitis, proteinuria with casts and RBCs, hemoptysis, wheezing, pleuritic pain, infiltrate and CXR
  39. what are the S&S of SJS and TEN?
    • prodrome of nausea, vomiting, sore throat, cough, arthralgia, myalgia, fever, burning sensation of skin, facial edema, mucosal lesions, epidermal detachment (<10% with SJS, >30% with TEN), + Nikolsky's sign
    • organ failure and metabolic abnormality in TEN
    • iris lesion
    • dermatologic EMERGENCY
  40. what are the risk factors for hypersensitivity?
    • prior reaction is the most reliable risk factor
    • antigenicity (drug related): increased MW (>4000Da), chemical composition including proteins or polypeptides, ability of drug or metabolite for covalenty binding to carrier protein
    • patient related: route, dose, frequency, age, gender, genetics, concurrent viral infection
    • atopy is NOT implicated as a risk factor
  41. Which has more risk for developing hypersensitivity?
    continuous dosing vs single dosing
    continuous dosing
  42. is atopy a risk factor for increased hypersensitivty?
    • no
    • however, due to high IgE response in atopic patient, once allergy develops, it would be more severe
  43. what are the risk factors for pseudoallergy?
    • prior reaction to drug is most reliable risk factor
    • more dependent on specific causative drug
  44. Pseudoallergy.
    Increased risk anaphylactoid reaction from contrast agents in ___, ____, ___ and ___.
    • women
    • atopy
    • asthma
    • BB therapy
  45. Pseudoallergy.
    Increased risk of angioedema from ACEi in ___, ___, and ___.
    • black american
    • hx angioedema
    • longer acting ACEi
  46. Pseudoallergy.
    increased risk of aspirin induced asthma due to aspirin in ___.
    hx asthma
  47. Pseudoallergy.
    increased risk of urticaria or angioedema from NSAIDs in ___.
    atopic pt with previous hx
  48. what is the mechanism of penicillin hypersensitivity?
    • rapidly hydrolyzed to major and minor determinants and either may elicit IgE mediated response (penicillin itself does not cause)
    • side chain specific reactions may occur with aminopcn and piperacillin (not related to b-lactam ring)
    • skin test to rule out b-lactam allergy
  49. how do you rule out b-lactam allergy for penicillin hypersensitivity?
    • 1) scratch skin with lancet
    • 2) administer pre-pen (major determinant) and penicillin G. also use histamine and saline controls)
    • 3) wait 15 min and see if itching, erythema, or wheal are present.

    • 4) if negative, perform intradermal test. wait 15 min for symptoms
    • 5) if none, tolerate penicillin; if yes, do not continue high risk IgE response with pcn re-exposure

    4) if positive, do not continue high risk IgE response with pcn re-exposure
  50. is there a cross reactivity between pcn and aztreonam?
    NOPE
  51. is there a cross reactivity between pcn and carbapenem?
    • unknown
    • if confirmed IgE mediated allergy with pcn via skin test, avoid carbapanem as wel
    • cross sensitivity within the carbapenem class is unknown.
  52. is there a cross reactivity between pcn and cephalosporin?
    • low risk (<10%), especially with 2nd and 3rd generation cephalo so may use these if pcn-associated maculopapular rash
    • 1st generation has a higher sensitivity due to similar substitution group
    • however, if IgE mediated reaction history, avoid cephalo!
  53. when is penicillin medically necessary?
    if type I hypersensitivity is suspected for these patients, what should you do?
    • treatment of syphilis in pregnant women
    • patient with cystic fibrosis and pneumonia
    • can perform epicutaneous skin test to assess likelihood of anaphylaxis reaction on re-exposure (IgE mediated response)
  54. what is the limitation of skin test for penicillin?
    • it does not indicate IgG, IgM or cell mediated
    • only IgE is indicated
  55. when should you NOT skin test for penicillin? why not?
    • if reaction hx is SJS (type 4), TEN (type 4), or exfoliative dermatitis (type 4), serum-like sickness (type 3), cytopenia (type 2), hepatitis, nephritis
    • because these are NOT type 1
  56. if you have a late forming nonpruritic maculopapular rash, should you skin test?
    not necessary b/c low risk of severe reaction
  57. regarding penicillin,
    what should you do when type 1 hypersensitivity is suspected?
    what should you do when type 2-4 are suspected?
    how about you late forming nonpruritic maculopapular rash?
    • type 1: skin test
    • type 2-4: avoid test and avoid drug
    • late rash: can try test dose
  58. what is the general desensitization guide?
    • only if medically necessary
    • closely monitored setting with epinephrine, antihistamine, NS, O2, large bore IV
    • discontinue beta blockers (b/c hypotension so interfere with epinephrine)
    • use oral route for lower risk
    • administer two-fold dose every 15-30 min starting with a very low dose (0.05mg) and observe. 15-20 doses given to escalate to therapeutic range
  59. what should you d/c when you use epinephrine for penicillin anaphylaxis or in close monitoring due to desensitization of pcn?
    beta blockers
  60. what is the mechanism of cephalosporin hypersensitivity?
    • caused by the beta-lactam ring or side chains
    • all generations share a common b-lactam ring and as with pcn
    • groups of cephalo share structurally similar side chains and this predict risk of cross reactivity
  61. groups of cephalo share structurally similar side chains. what does this predict?
    risk of cross reactivity
  62. how do you prevent cephalo hypersensitivity?
    • if the previous reaction was potentially IgE mediated, pcn skin test may be performed. if negative, may be due to the side chain. if positive, follow skin test algorithm.
    • alternative cephalo use should be clinically decided. think about severity of allergic rxn, availability of equally effective non b-lactam abx, side chain structure of choice agents
  63. what is the first definition of "sulfa" medication?
    what does it include?
    • refers to medications containing a sulfamoyl moiety (SO2NH2)
    • includes sulfonamide antibiotic,
    • oral sulfonylurea hypoglycemia,
    • carbonic anhydrase inhibitor, metolazone, loop diuretic, thiazide
    • celecoxib, sumatriptan, zonisamide
  64. what is NOT a sulfa drug?
    • sulfate salts
    • sulfites
    • sulfides
    • (i.e morphine sulfate, atropine sulfate)
  65. what is the second definition of sulfa drug?
    what are the drug examples?
    what kind of reaction may these have?
    • aromatic amine at N4 position
    • sulfonamide antibiotics (i.e. sulfadiazine, sulfamethoxazole, sulfapyridine)
    • associated with more severe and IgE-mediated reactions (type 1 reaction)
  66. Is the risk of cross reactivity between the sulfa subclasses high?
    considered low
  67. how do you prevent sulfa hypersensitivity?
    • depends on history and medication
    • history of allergy to sulfa abx seems to have slight increased risk of allergy to sulfa non-abx.
    • poor ability to predict hypersensitivity risk and cross reactivity. no reliable agent for skin testing
  68. do you have a risk for sulfa non-abx if you have a hx of allergy for sulfa abx?
    • just slight increase
    • unless you have an anaphylaxis reaction to sulfa, you can give other medications
  69. which medications cause hypersensitivity? (that we learned in Hugh's class)
    • penicillin
    • cephalosporin
    • sulfa drugs
    • salicylate
  70. which medications cause pseudoallergy that we learned in Hugh's class?
    • ACEi
    • salicylate
    • contrast media
  71. which one can you pretreat and which one can you not?
    hypersensitivity vs. pseudoallergy
    • hypersensitivity: cannot pretreat
    • pseudoallergy: can pretreat (because you can expect)
  72. how do you prevent angioedema by ACEi?
    • this is pseudoallergy
    • Avoid all ACEi in the future (re-exposure can cause more severe reaction)
  73. can you get angioedema with ARB?
    • yes there are reports
    • however, not contraindicated so use with caution
  74. what are the mechanisms of salicylate reaction?
    • true hypersensitivity reaction (i.e anaphylaxis, interstitial nephritis) (reacting to a specific NSAID and not a structurally dissimilar NSAID)
    • pseudoallergy reaction (i.e. asthma exacerbation, urticaria, angioedema) due to COX-1 inhibition that shift AA metabolism towards LT path
  75. how do you prevent salicylate hypersensitivity reaction?
    avoid structurally similar NSAIDs (due to risk of cross reactivity)
  76. how do you prevent NSAID-induced asthma? (pseudoallergy mechanism of salicylate)
    • avoid all COX-1 inhibitor
    • COX-2 inhibitor may be used
    • low dose APAP (<1g) may be an alternative
  77. what is the mechanism of contrast media?
    • anaphylactoid reaction
    • non immunologic activation of complement cascade
  78. how do you prevent anaphylactoid reaction by contrast media?
    • use low osmolar agent
    • pretreat: (PED)
    • prednisone 50mg po 13, 7, 1 hr before admin
    • ephedrine 25mg po 1 hr before procedure (avoid if unstable angina, HTN, arrhythmia)
    • diphenhydramine 50mg po/iv/im 1 hr before procedure
    • in emergency, hydrocortisone 200mg iv STAT and q4h and diphenhydramine
  79. how do you generally manage acute hypersensitivity? (provide adult doses)
    • avoid suspected medication if possible
    • establish and maintain airway
  80. are the hypersensitivity and pseudoallergy treated differently?
    they are treated similary
  81. how do you manage anaphylaxis?
    place in recumbent position and elevated lower extremities

    • O2 4-10L/min
    • if hypotensive, IV fluid
    • Epinephrine 0.2-1mg/dose SC/IM q10-15min
    • diphenhydramine 25-50mg/dose IM/IV then q4-6h (max 400mg/d)
  82. what do you use for anaphylaxis for preventing late phase and those also with asthma and angioedema?
    • methylprednisolone 1-2 mg/kg IV q6-8h for 24h (max 125 mg q6h)
    • then 1-2mg/kg/day IV or PO
  83. what do you use if anaphylaxis is not responsive to diphenhydramine and epinephrine?
    ranitidine 50mg in 20ml D5W IV q6-8h
  84. If the patient is beta-blocked, epinephrine may not work as well for hypersensitivity. what can you use instead?
    • glucagon 1-5mg IV followed by 5-15mcg/min
    • this is a positive inotrope
  85. what can you use for urticaria?
    • combination of antihistamine
    • 1st line: nonsedating H1 blockers (cetirizine 5-20mg qd, loratidine 5-10mg qd, fexofenadine 180mg qd or 60mg tid)
    • 2nd line: hydroxyzine 10-00mg qd or div, diphenhydramine 12.5-100mg q46h prn
    • 3rd line: doxepin 25-100mg/d (off label)
  86. how do you manage angioedema?
    • H1 blocker
    • epinephrine
    • corticosteroids
    • nebulized B2 agonsit
  87. how do you manage vasculitis?
    • H1 blocker
    • corticosteroids (prednisone 1mg/kg) in div doses x 7-14d
  88. how do you manage SJS/TEN?
    • nutrition support (b/c high metabolic rate due to a lot of calorie burning to recover)
    • pain control, intranasal saline, oral hygiene (for mucosal lesion)
    • topical antiseptic and wound care
    • surgical debridement
  89. what should you avoid in SJS/TEN management? why?
    steroids due to infection risk
  90. Epinephrine autoinjector direction for use:
    1) grasp pen with black tip pointing down and form a fist
    2) with other hand, pull off gray safety release
    3) hold black tip near outer thigh
    4) swing arm and jab firmly at ___ angel with outer thigh
    5) hold in place for ___.
    6) remove and massage for ___
    7) seek immediate medical attention and notify that you have taken this injection.
    • 4) 90 degree
    • 5) 10 seconds
    • 6) 10 seconds
  91. abacavir
    hypersensitivity or pseudoallergy?
    hypersensitivity
  92. anticonvulsants
    ´╗┐´╗┐hypersensitivity or pseudoallergy?
    allergy
  93. azathioprine
    hypersensitivity or pseudoallergy?
    allergy
  94. allopurinol
    hypersensitivity or pseudoallergy?
    allergy
  95. amphotericin B
    hypersensitivity or pseudoallergy?
    allergy
  96. anesthetics
    hypersensitivity or pseudoallergy?
    al

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