Term
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Definition
• All unintended pharmacologic effects of a drug
• Excludes: therapeutic failures, intentional overdose, drug abuse, or administration errors |
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Term
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Definition
| • Immunologically mediated response to a drug or excipient in a sensitized person |
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Term
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Definition
• Immediate systemic reaction in a previously sensitized individual post allergen re-exposure
• IgE mediated immune response |
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Term
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Definition
• Immediate systemic reactions that mimic anaphylaxis
• Non-IgE mediated release of mediators from mast cells and basophils |
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Term
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Definition
• Undesirable pharmacologic effect occurring at low or usual doses of drug
• Not mediated by humoral/cellular immune response |
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Term
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Definition
• Abnormal and unexpected effect unrelated to pharmacologic action of a drug
• Unknown mechanism |
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Term
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Definition
[IgE-Mediated]
mechanism: • Drug IgE complex binds to mast cells
• Release of histamine,
inflammatory mediators
clinical manifestations: • Urticaria
• Pruritis
• Angioedema
• Bronchospasms
• Vomiting, diarrhea
• Anaphylaxis
reaction time:
• Minutes to hours after
drug exposure |
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Term
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Definition
[Cytotoxic]
mechanism:
• Specific IgG or IgM antibodies directed at drug-hapten coated cells
clinical manifestations:
• Hemolytic anemia • Neutropenia
• Thrombocytopenia
reaction time:
• Variable |
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Term
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Definition
[Immune Complex]
mechanism:
• Drug-antibody complexes deposit in tissuesà complement activation and inflammation
clinical manifestation:
• Serum sickness
• Fever
• Rash
• Arthralgias
• Lymphadenopathy
• Urticaria
• Glomerulonephritis
• Vasculitis
reaction time:
• 1–3 weeks post drug exposure |
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Term
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Definition
[Delayed, Cell- Mediated]
mechanism:
• MHC presentation of drug molecules to T cellsà cytokine and inflammatory mediator release
clinical manifestations
• Allergic contact dermatitis
• Maculopapular drug rash
reaction time:
• 2–7 days post cutaneous
drug exposure |
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Term
History and Physical (H&P) Examination
• Important components of drug hypersensitivity clinical evaluation: |
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Definition
• H&P
• Objective clinical signs/symptoms
• Laboratory tests
- History should focus on:
• Previous and current drug use
• Toxicity and allergenicity of previous and current drugs
• Sequence of events between initiation and symptom onset
- Physical exam:
• Include all systems that could account for clinical presentation
• Cutaneous manifestations are the most common |
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Term
| Your patient reports an “upset stomach” when they take ibuprofen. This is an example of a |
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Definition
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Term
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Definition
• Antibiotics
- β-lactams
- Non-β-lactams
• Opiates
• Heparin
• Aspirin (ASA) and nonsteroidal anti- inflammatory drugs (NSAIDs)
• Angiotensin-converting enzyme inhibitors (ACEIs) |
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Term
β-Lactams
• Classification: |
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Definition
• Penicillins
• Aminopenicillins (ampicillin/amoxicillin)
• Cephalosporins
• Monobactams
• Carbapenems |
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Term
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Definition
- 10%ofpatientsreportreactingtopenicillin (PCN)
• 90% of these individuals are able to tolerate PCN
-Reasonsforallergydiscrepancy?
• IgE antibodies rapidly wane over time
• Some reactions result from: • Underlying viral/bacterial infection • Interaction between infectious agent and antibiotic
• Mislabeling of actual antibiotic received as PCN
• Predictable reactions (i.e., diarrhea) labeled as allergic |
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Term
| Allergic Reaction Mechanism: PCN |
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Definition
Naturalstate:chemicallyinert
• Undergoes conversion to reactive intermediates spontaneously under physiologic conditions
Diagnosis:
• PCN skin testing—most reliable method for evaluating IgE mediated allergy
- (-) Predictive value for serious immediate type reactions near 100%
- (+) Predictive value between 40–100%
• Ideally would use both major and minor PCN determinants
• Should only be performed by personnel skilled in the application and interpretation of skin testing |
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Term
| What is the most common manifestation of a sulfonamide allergy? |
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Definition
| Delayed maculopapular eruption |
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Term
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Definition
Approach to patients with history of PCN allergy:
1. Reaction history
2. Need for treatment with PCN
History of time elapse since reaction is useful
• IgE antibodies decrease with time
• Sensitivity loss to IgE mediated PCN allergy with time:
- 5years:50%
- 10years:80%
• Patients with distant (>10 years) or questionable histories— potential candidates to receive PCN via graded challenge
• Convincing history of anaphylaxis, particularly recent— administer PCN via drug tolerance procedure |
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Term
Induction of Drug Tolerance
• Drug tolerance: |
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Definition
state where a patient with drug allergy is able to tolerate a drug without adverse reaction
• Induction of drug tolerance procedures modify a patient’s response to a drug to allow safe temporary treatment
• Indication?
- Only when an alternate non-cross-reacting drug can not be used
• Processinvolvesadministrationofincremental
doses of the drug |
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Term
Induction of Drug Tolerance
Example: |
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Definition
| penicillin oral immunologic IgE induction of drug tolerance protocol. 15 steps, start at .05 mg and slowly increase |
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Term
| Graded Challenge (Test Dosing) |
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Definition
• Objective: cautiously introduce a drug in patients who are unlikely to be allergic
• Does not modify an individual’s immune response to a medication
• Starting dose: higher than for induction of drug tolerance
• Number of steps involved: two or several
-Interval between doses depends on type of previous reaction |
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Term
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Definition
• Some individuals with amoxicillin/ampicillin immediate-type reactions may tolerate other penicillin class drugs
- Reaction may be due to R-group side chain
• Associated with a delayed maculopapular rash in 5–10% of patients
- Rash not related to IgE mediated allergy
- Suggested that rash requires the presence of concurrent viral illness |
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Term
| Managing Aminopenicillin Allergy |
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Definition
Consider PCN skin test prior to administration
• Even if history is suggestive of amoxicillin/ampicillin- associated maculopapular rash
• Negative:
- Consider administering aminopenicillin via graded challenge depending on history
• Positive:
- Administer alternate antibiotic
- Undergo induction of drug tolerance to PCN |
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Term
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Definition
• Rate of allergic reactions 10 times lower versus PCN
• R-group side chains implicated in causing allergic reactions |
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Term
| Groups of Beta-Lactam Antibiotics That Share R1-Group Side Chains |
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Definition
Amoxicillin Cefadroxil Cefprozil Cetirizine
Ampicillin Cefaclor Cephalexin Loracarbef
Ceftriaxone Cefotaxime Cefpodoxime
Cefoxitin
Ceftazadime Aztreonam |
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Term
| Groups of Beta-Lactam Antibiotics That Share R2-Group Side Chains |
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Definition
Cephalexin Cefadroxil
Cefotaxime Cephalothin
Cefuroxime Cefoxitin
Cefotetan Cefamandole
Cefaclor Loracarbef |
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Term
| Managing Cephalosporin Allergy |
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Definition
Patientwithhistoryofcephalosporinallergy requires treatment with another cephalosporin
• Ensure two cephalosporins do not share R-group side chains
1. Performgradedchallengewithnewcephalosporin
2. Performcephalosporinskintest(withagentto be used)
• Positive: indicates presence of drug specific IgE antibodies
• Negative: does not rule out presence of drug specific IgE antibodies
3. Performcephalosporininductionofdrugtolerance (especially with history of severe anaphylaxis) |
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Term
| Cross-Reactivity: Cephalosporins and PCN |
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Definition
Share common beta-lactam ring structure
- Moderate cross-reactivity documented in vitro • Most commonlywithPCNandfirst/secondgeneration cephalosporins
• Infrequent clinically significant cross-reactivity between PCN and cephalosporins
• Since 1980, reaction rates in PCN history-positive and skin test-positive patients treated with cephalosporin = 2%
• Patients with history of allergy to PCN + not skin tested
but given cephalosporin directly, chance of reaction
probably <1% |
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Term
Cross-Reactivity: Cephalosporins and PCN
Management of administering cephalosporin to PCN allergic patient |
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Definition
1. Administer non-beta-lactam antibiotic
2. Perform penicillin skin testing
• Negative:administercephalosporin
• Positive:givecephalosporinviagradedchallengeordesensitize
3. Cephalosporin skin testing
• Negative:givecephalosporinviagradedchallenge
• Positive:givealternatedrugordesensitize
4. Treat with cephalosporin
• Onlyintheabsenceofsevereand/orrecentpenicillinallergy reaction history |
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Term
| Cross-Reactivity: Cephalosporins and PCN |
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Definition
Penicillin administration to patients with history of cephalosporin allergy
• Amoxicillin/ampicillin allergic patients:
1. Avoid cephalosporins with identical R-group side chains
2. Administer cephalosporin via rapid induction of drug tolerance (depending on reaction history)
• Immediate type-reaction to cephalosporin:
1. Undergo penicillin skin testing
• Negative:administerpenicillin
• Positive:givealternatedrugorundergodesensitization
2. Cautious graded challenge |
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Term
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Definition
• Aztreonam
• Less immunogenic than penicillin and cephalosporins
- Allergic reactions uncommon with administration
• No standardized skin testing available for aztreonam
• In vitro tests, skin tests, patient challenges: negative for cross-reactivity between PCN/cephalosporins and aztreonam
- Exception: ceftazadime shares an identical R-group side chain with aztreonam
- Ceftazadime allergic patients should not
receive aztreonam |
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Term
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Definition
• Immunogenicity or frequency of allergic reactions have not been formally evaluated
• No standardized skin tests available
• Clinical cross-reactivity between carbapenems and other beta-lactams appears low
- Retrospective study of hospitalized patients with history of penicillin allergy: 10% developed possible allergic reaction with carbapenems• Nolife-threateningreactionsdocumented
• Penicillin skin testing
- Negative: administer carbanepnem
- Positive: administer via graded challenge |
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Term
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Definition
• Overall incidence of hypersensitivity estimated to be approximately 1–3%
• No validated skin tests available
- Multiple end products exist for an antibiotic • Relevant allergenmaybemetabolitenotparentdrug
- Evaluation of allergy is not performed electively
• If clinically warranted, induction of drug tolerance or graded challenge may be employed based on history
• Readministration in cases of severe non-IgE mediated reactions (SJS, TEN):
- Contraindicated unless treatment benefit outweighs the risk of
life-threatening reaction |
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Term
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Definition
• All sulfonamides contain NH2-SO2 moiety
- Antibiotics: sulfamethoxazole, sulfadiazine
- Non-antibiotics, bumetanide, hydrochlorothiazide, glyburide, celecoxib
• Up to 4% of sulfonamide-antibiotic treated patients experience allergic reactions
• Most common reaction is delayed maculopapular eruption
• Cross-reactivity with non-antibiotic sulfonamides?
- Sulfonamide antibiotics contain an aromatic amine and a
substituted ring • Thesemolecularchanges—essentialforallergicreactionswith sulfonamide antibiotics |
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Term
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Definition
Associated with red man syndrome:
- Characterized by: • Pruritis
• Erythema
• Flushing of the face, neck, upper chest • Occasional hypotension
• Non-IgE medicated histamine release related to peak concentration
• Prevention:
1. Slow-infusion rate
2. May premedicate with antihistamine |
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Term
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Definition
- Opiates and their analogues: common cause of pseudoallergic reactions
- Opiates directly stimulate mast cell-mediated release of histamine
• Not associated with a specific immunologic mechanism
• Symptoms include:
• Pruritis
• Urticaria
• Occasionalmildwheezing • Whealsattheinjectionsite • Flushing
• Hypotension |
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Term
| Opiate Structural Subclasses |
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Definition
| • True opiate allergy: consider using opiates from another structural class or use non-narcotics |
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Term
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Definition
Natural- codeine morphine
Semi-synthetic- hydrocodone, hydromorphone, oxycodone, oxymorphone |
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Term
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Definition
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Term
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Definition
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Term
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Definition
Documented adverse drug reactions include: • Thrombocytopenia
• Various cutaneous eruptions
• Hypereosinophilia
• Anaphylaxis (rare)
Thrombocytopenia
• Type II: caused by immune complexes
- Key component is heparin-dependent IgG specific for platelet factor 4
- Occurs after ~5 days of therapy with unfractionated heparin - Associated with thrombosis and necrosis |
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Term
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Definition
1. Aspirin-exacerbated respiratory disease (AERD)
2. Exacerbation of urticaria and angioedema in chronic idiopathic urticaria
3. Selective ASA or single NSAID-induced urticaria or angioedema (other NSAIDs are tolerated)
4. Nonselective urticaria or angioedema caused by all drugs that inhibit COX-1 |
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Term
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Definition
• Characterized by ASA and NSAIDs- induced respiratory reactions in patients with chronic rhinosinusitis and asthma
1. Starts as severe perennial rhinitis
2. Development of nasal and/or sinus polyps 3. Disease progression to include asthma
• Severe upper and lower tract symptoms can occur after ASA/NSAIDs administration
• Mechanism: related to abnormal arachidonic acid metabolism due to loss of prostaglandin E2 increased production of leukotrienes
• Management:
• Avoidance of ASA/NSAIDs
• Aggressive medical/surgical management of underlying asthma, rhinitis or sinusitis
• ASA desensitization in clinically warranted cases |
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Term
| Angiotensin-Converting Enzyme Inhibitors |
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Definition
- Two major adverse effects: 1. Cough
2. Angioedema
- Incidence of angioedema = 0.1–0.7% • Involves the face or upper airway
• Unpredictable temporal relationship
• Management includes:
• Discontinue medication
• Supportive care with careful management of airway
• MostpatientsabletotolerateARBs
• Occasional case reports of ARB-related angioedema after switching from ACEI |
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Term
| Prevention of Allergic Reactions |
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Definition
1. Carefulhistorytodeterminehostriskfactors
2. Avoidance of cross-reactive drugs
3. Application of predictive tests when available
4. Proper and prudent prescribing of drugs frequently associated with adverse reactions
5. Use of oral drugs when possible
6. ProperdocumentationofADRinthepatient’s medical record |
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Term
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Definition
• Anaphylaxis: acute, life-threatening systemic reaction due to release of mediators from mast cells and basophils
• History: most important tool to determine anaphylaxis cases and causes of episode
- Should include:
• Timeandsettingofattack
• Treatmentrequiredduringattack
• Durationofepisode
• Documentationofallmedicationstakenwithin6hoursofevent
• More rapid anaphylaxis: more likely to be severe or life-threatening reaction |
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Term
| Anaphylaxis: Frequency of Signs and Symptoms |
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Definition
Cutaneous
Urticaria and angioedema
85–90%
Flushing
45–55
Pruritis without rash
2–5
Respiratory
Dyspnea, wheezing
45–50
Upper airway angioedema
50–60
Rhinitis
15–20
Dizziness, syncope, hypotension
30–35
Abdominal
Nausea, vomiting, diarrhea, cramping
25–30 |
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Term
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Definition
Epinephrine - Drugofchoiceinanaphylaxis
- Mechanismofaction:
• Beta-receptor agonist of the heart, vasculature, and
other smooth muscle
• Beta-1: positive inotropic and chronotropic cardiac effects
• Beta-2: bronchodilation and increase in cAMP in mast cells and basophils (decreasing inflammatory mediator release)
• Peripheral alpha receptor agonistàincreases peripheral vascular resistance (improves blood pressure and coronary perfusion)
-IM or SQ |
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Term
Anaphylaxis Management: Epinephrine
• Precautions |
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Definition
- Caution during injection
• Donotinjectintravenously
• Donotinjectintobuttock,digits,handsorfeet
- Adverse reactions
• Increasedheartrate,palpitations
• Sweating,nausea,andvomiting
• Weakness,shakiness,anxiety,apprehension
• Coronaryarterydisease—mayexperienceangina
• Diabetics—maydevelopincreasedbloodglucose
• Arrhythmiashavebeenreported
• Rapidrisesinbloodpressuremayproducecerebralhemorrhage
- Blunted response to epinephrine may occur in patients taking
beta-blockers |
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Term
| Anaphylaxis Management: Supportive Care |
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Definition
-Positioning of patient
• Place patient in supine position and elevate lower extremities • Especiallyifthereisconcernforhemodynamiccompromise
• Slows the progression of hemodynamic compromise 1. Preventsorthostatichypotension
2. Helpsshuntcirculationfromperiphery
• Cases of death reported with premature upright sitting
- Oxygen
• Should be administered with prolonged reactions
• Administration can be considered for any anaphylaxis case
-Fluid resuscitation
• Administer in cases of persistent hypotension despite epinephrine injections
• One to two liters normal saline, 5–10 mL/kg in the first five minutes
• Caution in patients with heart failure
- Vasopressors
• Consider in cases when hypotension is refractory to epinephrine
and fluid resuscitation
- Inhaledbeta-2adrenergicagonists
• Useful in patients who develop bronchospasms
• Especially if non-responsive to epinephrine (• Adverse reactions: • CNS:tremors,dizziness,nervousness • GI:nausea,dyspepsia • Cardiovascular:tachycardia) |
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Term
| Anaphylaxis Management: Antihistamines |
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Definition
-Supportive therapies and do not replace epinephrine
-Second line agents: can be given post-epinephrine
• Useful for controlling cutaneous and cardiovascular manifestations
H1 antagonists
• Diphenhydramine
• Mechanism of action: histamine1 antagonist
-Alleviatessymptomsofbronchoconstriction,vasodilation,increased
capillary permeability, and GI smooth muscle spasms
• Dosing: Adults = 25–50 mg, Pediatrics = 1 mg/kg (up to 50 mg)
• Administration: Oral, intramuscular or intravenous
• Precautions: sedating, confusion (especially older adults) |
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Term
Anaphylaxis Management: Antihistamines
• H2 antagonists |
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Definition
• Famotidine, ranitidine
• Mechanism of action: histamine2 antagonist - Believed to potentiate H1 antagonists effects
• Dosing:
- Famotidine: 20 mg once (Adults), 0.5 mg/kg
(Pediatrics, maximum 20mg)
• Administration: Oral, intravenous
• Precautions:
- Reported adverse reactions: headache, dizziness,
constipation, diarrhea
- CNS effects: confusion, hallucinations, agitation |
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Term
| Anaphylactic Management: Corticosteroids |
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Definition
• Glucocorticoids: not shown to be effective for acute treatment
• Theoretically can prevent protracted anaphylaxis through reduction of the inflammatory response |
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Term
| Anaphylaxis: Observation and Follow-Up |
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Definition
• Biphasic anaphylaxis: recurrence of anaphylaxis symptoms hours after resolution of the initial phase
- Most recur within 10 hours
- Frequency: occurs 1–23% of anaphylactic episodes
• Observation periods post anaphylactic reactions are individualized
- No consistently reliable predictors of biphasic reactions or protracted anaphylaxis episodes
- Follow-up is individualized
• Post-discharge patients should receive a prescription and counseling for injectable epinephrine |
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Term
| Exanthematous Drug Reactions |
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Definition
• “Morbilliform”rash
• Mostcommonofallcutaneousdrugeruptions
• Symptoms
- Widespread, symmetric, erythematous macules and papules on the trunk and extremities
- Pruritis and mild fever
• Rashappears>2daysafterdruginitiation
- Usually around day 8 or day 11
- May persist several days after stopping the drug |
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Term
| Treatment: Exanthematous Drug Reactions |
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Definition
Topical steroids
• Low potency: safest for long-term use, large surface areas, and sensitive skin (face, thinner skin)
• Lowest potency
• Hydrocortisone 1– 2.5%
• Low potency
• Triamcinolone 0.1%
High potency: beneficial for severe disease, thicker skinned areas
• High potency
• Desoximetasone 0.25%
• Very high potency • Clobetasol 0.05% |
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Term
Treatment: Exanthematous Drug Reactions • Topicalsteroids
• Mechanism of action: |
|
Definition
• Decrease IgE-mediated release of histamine, leukotrienes
and cytokines from basophils |
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Term
Has ADE:
• Atrophy of the epidermis (prolonged administration) • Drying, cracking or tightening of the skin |
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Definition
|
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Term
| Treatment: Exanthematous Drug Reactions: moisturizing lotions |
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Definition
| • Lubriderm (mineral oil) • Cetaphil (glycerin) |
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Term
Treatment: Exanthematous Drug Reactions
• Oral antihistamines |
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Definition
• Diphenhydramine 25–50 mg every 4–6 hours as needed
• May consider standing dosing |
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Term
Treatment: Exanthematous Drug Reactions
reassurance |
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Definition
• Usually resolves without sequelae
• Extensive scaling/desquamation can occur |
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Term
| Select the most appropriate treatment for anaphylaxis. |
|
Definition
| Epinephrine 0.3 mg injection IM x 1 |
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