Drug Hypersensitivity

Question 1

What is the difference between HSR and SEs?

Answer 1

SEs: predictable drug reaction related to pharmacologic actions of the drug
HSR: unpredicted immunologic reaction

Question 2

What are drug related risk factors for HSRs?

Answer 2

1. chemical / drug class (PCNs)
2. biologics increase risk

Question 3

What are patient related risk factors for HSRs?

Answer 3

1. hereditary (parent allergic and so is child)
2. previous drug reactions
3. genetic predisposition (metabolism, MCH alleles)

Question 4

What are disease related risk factors for HSRs?

Answer 4

1. alteration of metabolic pathways
2. variations in immunologic responses

Question 5

How are anti-drug antibodies generated?

Answer 5

1. haptenation
2. sensitization
3. Ellicitation

Question 6

What is haptenation?

Answer 6

small molecules that elicit immune response only when attached to a larger carrier (PCN molecules on carrier protein)

Question 7

What is sensitization?

Answer 7

1. haptenation
2. B cells and T cells must recognize the same antigen
3. epitope on an allergen is recognized by surface Ig on B cell
4. allergen is internalized and degraded by B cell and presented to CD4 T cells by MHC-II molecules
5. activaed CD4 T cells help B cells differentiate into plasma cells
   6, plasma cells release anti-drug antibodies

Question 8

What is elicitation?

Answer 8

1. pre-existing anti-drug antibodies
2. memory B cells capture drug-bound proteins –> rapid production of new anti-drug antibodies

Question 9

How are IgE and IgG antibodies different?

Answer 9

IgE: t1/2= 2-5 days; engage FcE Receptors
IgG: t1/2=21 days; engage FcY receptors

Question 10

What are the steps of a type 1 HSR?

Answer 10

1. mast cells and basophils express FcERs
2. receptor has high affinity for IgE
3. each allergen-IgE2 complex binds to 2 FcE receptors (dimerization)
4. tyrosine phosphorylation –> signaling –> degranulation –> histamine (minutes) –> synthesis of pro-inflammatory mediators (hours)

Question 11

What are the steps of a type 2 HSR?

Answer 11

1. binding of dug molecules on circulating blood cell membranes
2. IgG mediated cytotoxic
3. effectors (natural killer macrophage, neutrophils) cells that express FcYR
4. Destruction of RBCs and platelets
5. s/s of hemolytic anemia and thrombocytopenia can occur days after exposure

Question 12

What are the steps of a type 3 HSR?

Answer 12

1. formation of IgG- drug immune complexes in blood
2. deposition immune complexes tissues
3. activation of complement proteins, serum sickness
4. tends to occur over 24-72 hours after initial exposure

Question 13

What are the steps of a type 4 HSR?

Answer 13

1. medicated by antigen specific T cells
2. contact sensitizing agents (lipophilic highly reactive molecules)
3. modification of CD4 or CD8 T cell epitopes (MCH-I or MCH-II ligands)
4. SJS/ Tens occurs 1-3 weeks after exposure and lasts 4-8 weeks

Question 14

What determines the type of allergic reaction that results?

Answer 14

dose and route of allergen (IV vs. oral)

Question 15

What type of HSR is hemolytic anemia most associated with?

Answer 15

type 2

Question 16

What is anaphylaxis?

Answer 16

most severe type 1 reaction; massive amount of histamine released in short amount of time

Question 17

How can you recognize anaphylaxis?

Answer 17

skin/ mouth/ throat + airway and/or cardiovascular distress within minutes

Question 18

How are type 1 reactions biphasic ?

Answer 18

1. within minutes histamine is released causing hypotension, mucus production, smooth muscle contraction, and vascular leakage
2. histamine triggers production of inflammatory mediators (leukotrienes, cytokines)
3. within hours eosinophils and neutrophils infiltrate

Question 19

How can someone be desensitized to reduce recurrent risk of HSR?

Answer 19

1. start with low dose 1/10,000
2. double q15-20 min (6-17 steps)
3. slowly degranulate mast cells
4. down regulation of receptors
5. transient depletion of histamine from cells

Question 20

Why is epinephrine used for immediate management of anaphylaxis?

Answer 20

alpha, beta1 and beta2 agonist; prevent/ reverse anaphylactic reactions

Question 21

How is probability of cross-reactivity of PCNs and cephalosporins characterized?

Answer 21

relatively low if patient does not have PCN allergy; 4-7 fold increase of allergic reaction in those with PCN allergy

Question 22

What factors may increase likelihood of allergic reaction with cephalosporins?

Answer 22

Risk depends on cephalosporin generation and side chains;
1st > 2nd > 3rd;
amino hydroxyphenyl side chains

Question 23

What cephalosporin would Amoxicillin most likely react with?

Answer 23

Cefadroxil due to amino-hydroxyphenyl R group

Question 24

What cephalosporin would Ampicillin most likely react with?

Answer 24

Cephalexin, Cefaclor, and Cephaloglycin due to amino-phenyl R group

Question 25

What reactions are associates with recombinant monoclonal antibodies?

Answer 25

Type 3