DRUG ALLERGY: - USAFP
DRUG ALLERGY:
PCN/ASA/NSAID/RCM/Local Anesthetics
OVERVIEW
Background
Epidemiology
Classification
Clinical manifestations of drug reactions
Specific drugs:
Penicillin
ASA/NSAID’s
Radio contrast media
Local anesthetics
Summary
Background
Adverse reactions to drugs are not uncommon
“Allergy” or hypersensitivity to a drug is defined as “any immunologic response to a drug or its metabolites that results in an adverse reaction”
True allergic reactions require previous sensitization
Caused by a variety of drug classes
Present in a wide array of clinical syndromes
Able to affect any tissue or organ
Epidemiology
Adverse reactions to drugs are not uncommon
15% inpatients with ADE
Outpatient data lacking (17-25% ADE)
Immune-mediated rxns comprise up to 6-10% of observed ADE’s
Up to 33% of all Rx ADE’s are possibly allergic
Individual risk of an allergic reaction to a drug is 1-3%
Drug associated fatalities are reported in 0.1% of inpatients and 0.01% of surgical patient
Classification
Predictable (Type A)- Reactions that occur in most normal patients given sufficient dose and duration of therapy
Account for 80% of adverse drug reactions
Usually dose dependent
Due to the pharmacologic properties of the drug
Examples:
Overdosage – “exaggerated but characteristic pharmacologic effect produced by administering a supratherapeutic dose” i.e. Tylenol OD hepatic necrosis
Side effects – “excessive expression of known pharmacologic effects of a drug that occur at recommended doses” i.e. albuterol induced tremor
Secondary effects – “indirect pharmacologic effects of the primary drug action that are not attributable to overdosage, idiosyncratic reactions, hypersensitivity or intolerance” i.e. clindamycin induced C. difficile
May involve disease factors
Drug interactions – “unusual effects due to the simultaneous activity of 2 or more drugs” i.e. Seldane + E-mycin induced torsades
Unpredictable (Type B)- Uncommon hypersensitivity reactions seen in susceptible patients
Minority of drug reactions
Most (except intolerance) are unrelated to the drug’s pharmacologic actions and are not dose dependent
Examples:
intolerance – “undesirable pharmacologic effect that occurs at a subtherapeutic drug dose” i.e. ASA induced tinnitus
Idiosyncratic reaction – “uncharacteristic response to administration of a drug, unrelated to the pharmacologic actions of the drug” i.e. Chloroquine hemolytic reaction in G6PD
Hypersensitivity/allergic reactions – “immune-mediated reactions” 5-10%
Allergic Drug Reactions
Allergic or hypersensitivity drug reactions are immune-mediated and share the following characteristics:
Occur in a small number of patients
Require previous sensitization
Develop rapidly after re-exposure
Produce clinical syndromes associated with immunologic reactions
* Rxn may occur at much lower dose than normal
Concepts of drug hypersensitivity
* Hapten- covalent binding to carrier protein
* Pro-Hapten- enzymatic or non-enzymatic conversion to reactive intermediate
* Danger- drug-related cytotoxicity resulting in enhanced immune response + co-stimulatory signal i.e. virus
* Pharmacological interaction (p-i) concepts- non-covalent binding to MHC peptides
* Immune response humoral (ab), cellular (T cell) or both
Allergic reactions are more likely to occur with:
High molecular weight drugs (insulin)
Proteins (carbohydrates are less immunogenic)
Presence of inflammation (enhances the immune response)
Prolonged or repeated enteral or parental treatment
Certain HLA phenotypes
Gell and Coombs Classification
Type I: IgE-mediated mast cell degranulation causing immediate hypersensitivity or anaphylaxis
IgE specific antibodies cross-link; cell activiation
Usually occurs within 30 min of administration
May occur immediately in prior sensitization
Wheezing, urticaria/angioedema
Diagnose via history, PE, PST/RAST
Treatment: avoidance vs. desensitization
Examples: PCN (immediate reaction), Blood products, Vaccines
Type II: Cytotoxic reactions mediated by binding of IgG or IgM to cell bound antigens, leading to activation of complement
Usually due to blood products or rapidly haptenating drugs (PCN, Quinidine, Sulfonamides, Methyldopa)
Coomb’s positive hemolytic anemia/thrombocytopenia, AIN, pneumonitis
Diagnose by clinical syndrome and in vitro demonstration of antibody
Treatment: removal of offending agent, steroids
Type III: Immune-complex mediated by binding of antigens to antibody (IgG and IgM), with subsequent tissue deposition and complement activation
Local or disseminated inflammatory reactions
Due to high-dose, prolonged use of drug
Example: serum sickness (fever, LAD, arthralgias, nephritis, hepatitis etc.)
Immune complex reactions can cause drug induced lupus syndromes (Hydralazine, Procainamide, Isoniazid, Phenytoin)
Treatment: removal of offending agent, steroids
Future administration of the offending agent is a relative contraindication
Type IV: Delayed hypersensitivity reaction mediated by T-cells (cell-mediated immunity)
Requires memory T cells for drug allergen (7-20 days initially; 8-120 hrs subsequent)
Examples: contact dermatitis, drug fever, drug-induced vasculitis
Diagnosis: clinical syndrome, patch test, in vitro test for antibody
Treatment: removal of offending agent, steroids
Future administration of offending agent is a relative contraindication
Risk Factors for Drug Allergy
Parenteral medications are more likely than oral to cause IgE-mediated reactions
Prophylactic doses are less likely to sensitize than high doses
Frequent courses of an antibiotic are more likely to induce reactions than rare courses
Women have a 35% higher incidence of reaction than men
HLA type may influence drug allergy when associated with certain diseases (HLA-DR3 associated drug-induced nephropathy in RA patients taking gold or penicillamine; abacavir reactions are highly associated with the presence of the HLA-B*57 allele)
A positive history of immune-mediated drug reaction in a parent increases the child’s risk of drug allergy 15-fold
Patients with SLE or HIV- increased risk
Clinical Manifestations
Multiple Organ System Patterns
Erythema Multiforme, Stevens-Johnson syndrome
Toxic Epidermal Necrolysis (TEN)
Hypersensitivity syndrome
Drug fever
Cutaneous patterns (most common)
Multiple drug allergy syndrome
Multiple Organ System Patterns
Anaphylaxis: IgE-mediated “acute, life-threatening immunologic reaction that consists of diffuse erythema, pruritis, urticaria, angioedema, bronchospasm, laryngeal edema and hypotension, alone or in combination”
Anaphylactoid: direct mast cell release of histamine; clinical syndrome identical to anaphylaxis
Thiamine, opiates, RCM, muscle relaxants, vancomycin
Erythema Multiforme
Erythematous, polymorphic eruption caused by drugs in 50% of cases; Lymphocyte cell mediated rxn; 1-2 wks after Rx
Target lesions, maculopapular rash, urticaria, vesicles
Three zones:
Erythematous central papule that may blister
Edematous middle ring
Erythematous outer ring
Symmetric; predilection for extremities
Major and minor forms
Stop the offending drug immediately and avoid in the future
Stevens-Johnson Syndrome (SJS)
Severe form of EM with mucosal and conjunctival involvement; 5% mortality
Fever and flu-like symptoms precede rash by 1-3 days
Epidermal loss 30% of BSA
High mortality rate (30-40%)
May be difficult to differentiate from SJS, as many of the same drugs cause both
Re-administration of drug for SJS/TEN is an ABSOLUTE CONTRAINDICATION
Steroids are not helpful and contraindicated in TEN
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
Formerly Hypersensitivity Syndromes (HSS)
Specific syndrome associated with anticonvulsants, sulfasalazine, allopurinol etc.
S/Sx’s- fever, papular rash, LAD (75%), hepatitis (50%), nephritis, eosinophilia 2-6 wks after starting new Rx
Morbilliform rash, often indurated/infiltrated, facial swelling, exfoliative dermatitis, bullae and purpura
Acute liver failure is most common cause of mortality, which is 18-40% in those with hepatitis
Alveolar or interstitial Pneumonitis
Felt to be immune-mediated, but cause unknown
Treat by stopping the drug, supportive care and steroids
Re-exposure to drug is contraindicated
* In some, is due to an inherited deficiency of epoxide hydrolase needed to metabolize toxic arene oxide made by cytochrome P-450 from parent drug (anticonvulsants)
* Slow acetylators may be at increased risk
Drug Fever
Idiosyncratic reaction
Variable pattern: Low grade/continuous; Spiking/intermittent
Eosinophilia, leukocytosis, rash
Elevated ESR
Almost always resolves within 48-72 hours of discontinuing the offending drug
Cutaneous Patterns
Urticaria/angioedema – common manifestation
Rapid onset after drug is given, resolves when drug is discontinued
Skin testing may confirm Dx
IgE-mediated, direct mast cell release, or bradykinin-mediated (ACEI)
Does not involve other organs, afebrile
Treatment: antihistamines, epinephrine if laryngeal involvement suspected
Morbilliform, maculopapular exanthems
Most common drug-induced skin reaction
Usually symmetric, confluent macules/papules- spare palms and soles
Predilection for dependent areas in hospitalized patients
Onset 4-10 days after Rx; up to 14 days after Rx completion
Common drugs: PCN, NSAIDs, (-lactams, sulfonamides, anticonvulsants, allopurinol
Maculopapular reactions occur more often (10%) with amoxicillin than other PCN’s and in 50-80% of patients with EBV, CMV, CML, hyperuricemia or allopurinol
Treatment: removal of offending drug with future avoidance
If necessary, can continue drug if no evidence of mucosal involvement, vasculitis (‘treating through’)
Allergic contact dermatitis
Most common example of delayed hypersensitivity
Caused by topical medications
Pruritic, erythematous, vesicular or maculopapular rash
Sensitization occurs in 5-7 days, with repeat topical or systemic exposure producing rash within 24 hours
Causes: neomycin, local anesthetics, parabens, ethylenediamine, PABA-containing sunscreen, corticosteroids (frequency of 3-5%)
* Fixed drug eruptions
* Consist of single or multiple round sharply demarcated plaques that appear soon after drug exposure and recur in exactly the same site with subsequent drug exposure
* Pruritus and burning are common
Multiple Drug Allergy Syndrome
Occurs primarily with antibiotics
General tendency to respond to haptens rather than specific classes of drugs
No treatment/difficult to diagnose
Prevention of reactions via prevention of infection and avoidance of unnecessary use of antibiotics
Diagnosis of Drug Allergy
Index of Suspicion!
History, including timing of drug administration/onset of rxn
Name of Rx
Timing?
Systems involved?
Why Rx given?
Other Rx?
Tx required for rxn?
Rx exposure before/since rxn?
S/Sx’s w/o Rx?
PMHx?
Caveats of PST to invalidated drugs (most drugs except PCN and some cephalosporins):
Not indicated for non-IgE-mediated reactions
Uninformative if negative
Must rule-out an irritant reaction if positive
Delay skin testing 2-4 weeks after anaphylactic episode to avoid refractory period
RAST testing often not available and not sensitive/specific
Serum tryptase and/or histamine in acute reaction
IgG, IgA and IgM to specific drugs are not useful
+ PST suggests Dx/may predict greater risk for future rxn
[pic]
Management of Drug Allergy
Identify and withdraw the offending drug
Treat anaphylactic reactions appropriately
Supportive care – most reactions resolve without treatment once the drug is removed
Can consider steroids if extensive dermal or systemic involvement
Educate patient on avoidance of drug and cross-reacting drugs (provide letter)
Recommend Medic Alert for severe reactions
Alternatives for Drug Allergic Patients
Recommend an unrelated alternative medication
Most common approach
Educate patient on avoidance of drug and cross-reacting drugs (provide letter, document in chart!)
Recommend Medic Alert for severe reactions
Recommend a medication not identical to, but potentially cross-reactive with, the drug in question
10 years, frequently in 3rd to 4th decade
Scripps Clinic reviewed 300 AERD patients between 1995-2001 and found 57% were female and nasal polyps and asthma first presented at an average age of 34 years
European study of AERD:
Rhinitis appeared at an average of 30 years of age
Asthma followed the onset of rhinitis
ASA/NSAID-induced respiratory symptoms followed the onset of asthma
Nasal polyps developed last
Female:male was 2.3:1
Females had earlier onset and more severe disease
Atopy present in 1/3 with family history of AERD in 6%
Prevalence in asthmatic adult population is 9-20%
Prevalence in adult asthmatics with nasal polyps is 34%
Adult asthmatics with history of respiratory symptoms to ASA/NSAID’s will have a positive oral challenge to ASA/NSAID’s 66-97% of the time
Clinical presentation: ingestion of ASA or cross-reacting NSAID in setting of an asthmatic with rhinitis and nasal polyps induces:
Intense rhinorrhea
Nasal congestion
Conjunctival injection
Periorbital edema
Laryngospasm
Bronchospasm (wheeze, SOB, chest tightness)
Reactions can be slow in onset, occurring 30-120 minutes after ingestion
Patient may experience only lower respiratory tract symptoms, upper respiratory tract symptoms, or both
Most experience symptoms of both
The dose of ASA or NSAID that provoked the symptoms is the most important indicator of severity
Pathogenesis
Although the history may suggest a type I reaction, thus far IgE mediated mechanisms have NOT been clearly demonstrated
skin test responses with ASA are typically negative (only 1 case report)
Usually no serum Ab against ASA or its derivatives in affected patients
ASA and most NSAID’s, as non-specific COX-inhibitors, inhibit COX-1 more potently than COX-2
All NSAID’s that inhibit COX-1 cross-react with ASA, even on first exposure to the new NSAID
Degree of cross-reactivity is proportional to the amount of NSAID required to inhibit COX-1
Selective COX-2 inhibitors (rofecoxib and celecoxib) do not cross-react in AERD
Partially selective COX-2 inhibitors (nimesulide, meloxicam) don’t cross-react at small doses where inhibition of COX-2 is felt to be predominant, but do cross-react with ASA at higher doses, where inhibition of COX-1 is predominant
COX-1 is expressed in all mammalian cells, whereas COX-2 is inducible by inflammatory mediators
With inhibition of COX-1 and COX-2, excess arachidonic acid is shunted via the 5-lipooxygenase pathway to produce leukotrienes, specifically LTC4, LTD4, and LTE4
Evidence supporting LO “shunt” theory
BAL fluid shows ( LTC4 in patients with AERD compared to non-AERD asthmatics
LTE4 is elevated in urine of AERD patients even before ingestion of ASA/NSAID, as compared to non-AERD asthmatics
AERD patients have decreased levels of anti-inflammatory lipoxins (also generated by LO from arachidonic acid)
Therapy with LT-antagonists can inhibit AERD bronchoconstriction
On exposure to ASA/NSAID’s, COX-1 is inhibited, causing a decrease in production of PGE2
PGE2 inhibits 5-LO, so in its absence, with ongoing production of arachidonic acid, excess leukotrienes are produced
Leukotrienes result in bronchoconstriction, vasodilation, mucous secretion and eosinophil chemotaxis
[pic]
Diagnosis
Based primarily on history of respiratory symptoms in an asthmatic after ingestion of ASA/NSAID’s
If the diagnosis is unclear, confirm with an Aspirin Challenge
Must be done in hospital setting
Prefer asthma be under good control
May continue current medications, although leukotriene modifiers may decrease the lower respiratory response (not upper respiratory)
Up to 25% of patients with convincing history may have a negative oral challenge
Lysine-ASA, a soluble form of aspirin, has been used for nebulized bronchoprovocation challenge in outpatient setting, but is not available in the United States
Treatment:
The usual guidelines for asthma therapy also apply to the ASA/NSAID-intolerant asthmatic
Avoid all routes of ASA/NSAID administration
Tylenol is generally a safe substitute
Case reports: patients who are very sensitive to ASA have also reacted to tylenol (which has very low but detectable COX activity)
Magnesium salicylate and Salicylic acid also have very low COX activity and are alternatives
COX-2 inhibitors:
Theoretically should not cross-react because of preservation of PGE2
Experience is limited but small reports show that although safer than COX-1, they may not be completely specific for COX-2, especially at higher doses
Should be used with caution
Leukotriene-inhibitors
5-lipoxygenase inhibitors
zileuton
Cysteinyl LT receptor antagonists (LTD4)
Zafirlukast, montelukast
ASA-desensitization:
all AERD patients can be desensitized
Eliminate the respiratory reaction by increasing exposure to oral ASA
Requires hospital admission ~ 2-3 days
May become resensitized if ASA stopped >2-5 days
Useful in patients requiring continuous ASA/NSAID treatment
Stroke or CAD prophylaxis, rheumaic dz, etc
Has also been shown to improve both upper and lower airway disease in patients with AERD
Asthma not well controlled on steroids/LT/B-agonists
Repeated nasal polypectomies and sinus operations
Type 2: NSAID-induced Urticaria/angioedema in patients with chronic urticaria
In patients with chronic idiopathic urticaria, ASA-induced urticaria reported in 21-30%
Usually occurs 2-4 hours following ingestion
Dose-dependent
Increased with high activity of underlying urticaria
Antihistamines and leukotriene receptor antagonists prevent or modify these reactions
Diagnosis:
Oral challenge is only diagnostic tool
Most people react to doses of 325-650mg
Reactions are later (6hrs) so challenge is modified to start with higher doses (100mg)
Treatment:
Avoidance of ASA/NSAIDS decreases acute flares but usually patient continues to have chronic urticaria
Desensitization to ASA is NOT effective
Type 3: ASA/NSAID-induced cross-reacting urticaria in normal individuals
Urticaria or angioedema with NSAID’s that inhibit COX-1
May develop chronic urticaria at a later date
Type 4: Blended reactions in normal individuals
Urticaria, angioedema, rhinitis, bronchospasm
May be due to one or more NSAID’s
Type 5: Single NSAID-induced urticaria/angioedema in normal individuals
Requires prior sensitization
No cross-reaction between ASA and other NSAIDs
Atopy may be a risk factor
More common if NSAID is taken intermittently than chronically
Type 6: Single NSAID-induced anaphylaxis
IgE-mediated reaction to a single NSAID
Patient may be challenged to a structurally different NSAID or ASA
Sulindac, tolmetin and zomepirac share a common acetic acid structure and may cross-react
Type 7: Aseptic Meningitis caused by a specific NSAID
Diagnosis of exclusion
Presentation involves a patient with recurrent bouts of meningitis within 12-24 hours of the same NSAID
Symptoms resolve when the NSAID is discontinued
Reported with ibuprofen, sulindac, tolmetin and naproxen
Cross-reactions do not occur
Type 8: Hypersensitivity Pneumonitis
Due to specific NSAIDS (not ASA)
Often seen in patients with chronic arthritis
Patients will often tolerate a different NSAID
Strict Avoidance of offending NSAID
Radiocontrast Material (RCM)
First used by Swick, an American urologist, in 1928
1950’s, ionic monomeric RCM was introduced and became the standard RCM
1980’s, ioxaglate became the first ionic low-osmolar RCM
1986, nonionic lower osmolar RCMs were introduced in the United States (iopamidol, iohexol)
1996, FDA approved iodixanol, a nonionic RCM (iso-osmolar to blood)
Over 10 million contrast studies annually in US
Adverse reaction rate 2-3% with low osmolar RCM, up to 12.66% with high osmolar RCM
Most reactions minor
Moderate reactions in 1.0%
Life-threatening reactions 0.01 -0.1%
10,000 patients annually
Mortality rate 1/75,000 - 1/170,000
130 patients annually
Classification of RCM
Ionic or nonionic
Monomeric or dimeric
Hyperosmolar or lower osmolar
Benzoic acid with iodine in 3 positions of the benzene ring
Ionic monomers have a tri-iodinated benzene ring – are also hyperosmolar (>1400 mOsm/kg)
Ionic dimer (ioxaglate) are lower osmolar
Nonionic monomers (iohexol, iopamidol, ioversol, iopromide and ioxilan) are lower osmolar
Nonionic dimer (iodixanol) – lowest rate of reactions
Iso-osmolar: iodixanol (visipaque)
Decrease of anaphylactoid reactions from 2.5% to 0.7% in study of 1411 patients
Decrease in adverse reaction from 20% to 6.7% in another study of 120 patients
Most RCM non-ionic
Lower rate of reaction with non-ionic RCM
Large Japanese study
Ionic RCM group (169,284 cases) vs nonionic RCM group (168,363 cases)
Adverse reactions were 12.66% (severe 0.22%) with ionic RCM and 3.13% (severe 0.04%) with nonionic RCM
Types of reactions
Vasovagal reactions
Reactions due to physiochemical properties (i.e. osmolality) of the agent
Anaphylactoid reactions
Anaphylactoid reaction
Non-IgE mediated mechanism
Reactions may occur with first exposure
Otherwise identical to anaphylaxis
Can still be fatal
Hyperosmolality seems to play central role
Direct correlation between osmolality and adverse reactions
Actual mechanism uncertain
Possible etiologies:
Direct mast cell activation with release of histamine and other mediators
Activation of coagulation, kinin and complement cascades
Inhibition of platelet aggregation also occurs
Red cell aggregation and endothelial disruption
Shown in vitro
Clinical Presentation:
Onset of symptoms
Typically during or within a few minutes of IV administration
Rarely after 20 minutes
Most common symptoms
Likely due to vagal stimulation
Nausea, emesis, flushing, urticaria, pruritis, sneezing, cough, pain at site of infusion, palpitations, facial edema, rigor, hoarseness, chest pain and abdominal pain
Others: pallor, diaphoresis, lightheadedness, dyspnea, hypotension, cardiac arrest
Diagnosis made by history / exam alone
NO in vitro / in vivo tests are available
Skin testing is NOT helpful
“Test doses” NOT helpful
Severe / fatal reactions have occurred with a 1-2 ml IV test dose
Severe reactions have followed negative test doses
Identifying higher risk patients is the best way to prevent or minimize future reactions
|Factor |Risk |
|Previous anaphylactoid reaction to RCM |17-60% |
|Heart disease |2-5x |
|Atopy |3x |
|Asthma |10x |
|Beta-blockers | |
| |2.5x |
| |(may increase severity) |
Management of acute reactions:
STOP THE INFUSION
Treat identically to IgE-mediated anaphylaxis
EPINEPHRINE
Antihistamines
Steroids
Other supportive measures as indicated
Most reactions respond promptly
Do not ignore potential for fatal outcome!!!
Perform procedures with trained personnel and emergency equipment
Prevention of future reactions:
Premedication
Use of low osmolar contrast agents
Use of alternative contrast agents
RCM Premedication
[pic]
Treatment of patients needing RCM for emergency procedures:
Document need for particular study and that alternatives are unsatisfactory (i.e. MRI)
Document informed consent
Recommend nonionic, low osmolar RCM
Pre-treat: steroids, antihistamines, ephedrine
Successful emergency regimen used in past
Hydrocortisone 200mg IV Q4 hrs until study done
AND benadryl 50mg IM 1 hour before RCM
+/- ephedrine
Document
There has not been time for conventional pretreatment
There is limited experience w/ rapid schedules
Emergency equipment available
Study of 657 procedures in 563 patients
Rate of anaphylactoid reactions on repeat exposure in patient with previous reaction to RCM:
Low-osmolar Nonionic RCM:
Evaluated 800 studies with high osmolar vs. 200 studies with low osmolar RCM
Other Agents - Gadolinium
Gadolinium (GAD)- based media are the primary contrast agents used in MRI
Incidence of reactions is MUCH lower than RCM, on the order of 0.0003% - 0.01%
Non-IgE mechanism, again NO testing available
Do NOT need to pre-treat when giving GAD in patients with prior RCM reaction
In rare patient with actual anaphylactoid reaction to GAD, may consider pretreatment as with RCM
Final thoughts:
Anaphylactoid reactions may occur when RCM administered by nonvascular routes
Retrograde pyelograms, hysterosalpingograms, myelograms, arthrograms
Pretreatment doesn’t work for:
ARDS, noncardiogenic pulmonary edema, renal protection
Reaction to RCM does not mean:
Allergy to topical iodine cleansers or other iodides
Immediate hypersensitivity to shellfish
Shellfish allergy is a reaction to the shellfish protein, not to iodine
Local Anesthetic Reactions
Drugs anesthetize the area to which they are applied by blocking nerve conduction and preventing depolarization of cell membranes
Incidence:
2-3% of local anesthesias
True allergies are exceedingly rare
................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related searches
- allergy eye drops prescription names
- prescription allergy eye drops list
- zicam allergy relief nasal spray
- peanut allergy drug fda approval
- drug induced lupus drug list
- drug allergy symptoms
- drug allergy icd 10
- drug to drug interaction examples
- how long does a drug allergy last
- drug to drug interactions
- drug allergy rash pictures
- drug to drug interactions tool