Drug hypersensitivity

Question 1

The Gell and Coombs classification system

Answer 1

Type I reactions (IgE-mediated);

Type II reactions (cytotoxic);

Type III reactions (immune complex);

and Type IV reactions (delayed, cell-mediated)

Question 2

Immunologic Drug Reactions

Answer 2

Type I reaction (IgE-mediated)

Type II reaction (cytotoxic)

Type III reaction (immune complex)

Type IV reaction (delayed, cell-mediated)

Specific T-cell activation

Fas/Fas ligand-induced apoptosis

Other (Drug-induced, lupus-like syndrome

Anticonvulsant hypersensitivity syndrome)

Question 3

Nonimmunologic Drug Reactions

Answer 3

Predictable

Pharmacologic side effect

Dry mouth from antihistamines

Secondary pharmacologic side effect

Thrush while taking antibiotics

Drug toxicity

Hepatotoxicity from methotrexate

Drug-drug interactions

Seizure from theophylline while taking erythromycin

Drug overdose

Seizure from excessive lidocaine (Xylocaine)

Unpredictable

Pseudoallergic

Anaphylactoid reaction after radiocontrast media

Idiosyncratic

Hemolytic anemia in a patient with G6PD deficiency after primaquine therapy

Intolerance

Tinnitus after a single, small dose of aspirin

Question 4

□ Basic understanding of how small molecule drugs interact with the immune system

Answer 4

MHC-peptide complex in order to trigger an immune response. Rather, some drugs may bind directly and reversibly to immune receptors like the major histocompatibility complex (MHC) or the T cell receptor (TCR), thereby stimulating the cells similar to a pharmacological activation of other receptors. This concept has been termed pharmacological interaction with immune receptors the (p-i) concept

Question 5

Type A reactions

(predicatable)

Answer 5

Pharmacological adverse effects

Drug interactions

Otherss

Question 6

NSAID hypersensitivity reactions

Answer 6

Non Steroidal Anti-inflammatory Drugs (NSAID)

• 1) Aspirin NSAID exacerbated respiratory disease (AERD)
• 2) Aspirin/NSAID induced urticaria/angioedema
• 3) NSAID induced anaphylaxis (especially diclofenac)
• 1 and 2 likely pharmacological idiosyncrasy; natural history of “3” suggests specific sensitisation but direct evidence minimal

Question 7

Type B adverse drug reactions

Answer 7

Immune and non-immune mediated

Question 8

IgE-Mediated Drug Hypersensitivity (Type I)

Answer 8

Drugs act as haptens

Prohaptens are inert drugs that undergo metabolism (bioactivation) and become reactive metabolites (haptens), which then can bind covalently to proteins.

hapten-carrier complexes) are taken up by antigen-presenting cells (APCs) and then transported into the local draining lymphoid tissue, where they are processed and presented on major histocompatibility complexes (MHCs

aïve T cells with the appropriate specificity recognize these complexes, are induced to proliferate, and expand as primed T cells

In the presence of specific T-cell help, drug-specific B cells may proliferate and differentiate into plasma cells

In a T-helper 2 cytokine milieu (interleukin [IL] 4, IL-5, IL-10), a class switch to IgE production may occur

renewed contact with small amounts of antigens (drugs) may induce symptoms

Question 9

IgG-Mediated Cytotoxicity (Type II)

Answer 9

IgG-mediated cytotoxicity directed to the membranes of erythrocytes, leukocytes, platelets, and probably hematopoietic precursor cells in the bone marrow

The antibody-coated cells are sequestered to the reticuloendothelial system in the liver and spleen by Fc or complement-receptor binding

More infrequently, intravascular destruction may occur by complement-mediated lysis. Different pathways of antibody recognition of target T cells have been proposed

Question 10

Immune Complex Deposition (Type III)

Answer 10

Formation of immune complexes, a common event in a normal immune response, usually occurs without symptoms.

On rare occasions, immune complexes bind to endothelial cells and lead to immune complex deposition with complement activation in small blood vessels.

Why and under what circumstances an immune complex disease develops is unclear.

The clinical symptoms of a type III reaction include serum sickness (eg, β-lactams), drug-induced lupus erythematosus (eg, quinidine), and vasculitis (eg, minocycline).

Question 11

T-Cell-Mediated Drug Hypersensitivity (Type IV)

Answer 11

T-cell-mediated drug hypersensitivity may have a variety of clinical manifestations, ranging from involvement of the skin alone to fulminant systemic diseases. Frequently, the drugs involved are sulfa antibiotics and β-lactams.

Question 12

Penicillin and NSAID hypersensitivity

Answer 12

Type B hypersensitivity reaction

Type 1 G and C

Question 13

ACEinduced angioedema

Answer 13

Inhibitors of drugs responsible for bradykinin breakdown; not mediated by adaptive immunity –

ACEI angioedema without rash or other anaphylaxis phenotypes OR cough (different syndrome); (less frequently with A2R inhibitors, mechanism not clear)

Question 14

Acute Generalised Exanthematous Pustulosis

Offending Drugs

Answer 14

Amoxycillin

Antimalarials

Ca channel blockers

Question 15

Drug reaction with eosinophilia and systemic symptoms (DRESS)

offending drugs

Answer 15

Allopurinol Antiepileptics Sulfasalazine Dapsone Abacavir Minocycline

Question 16

Type 4 – Cell-mediated (Delayed-Type Hypersensitivity, DTH)

Answer 16

Type 4 hypersensitivity reactions are often called delayed type as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response.

CD8+ cytotoxic T cells and CD4+ helper T cells recognise antigen in a complex with either type 1 or type 2 major histocompatibility complex. The antigen-presenting cells in this case are macrophages which secrete IL-1, which stimulates the proliferation of further CD4+ T cells

Re-exposure to the allergen results in a Th1 mediated response which stimulates the proliferation of the allergen-specific memory Th1 CD4+ T helper lymphocyte via recognition of complexes of peptide on antigen presenting cells (APCs) (See figure 4b).

CD4+ T cells secrete IL-2 and interferon gamma, further inducing the release of other Type 1 cytokines, thus mediating the immune response. Activated CD8+ T cells destroy target cells on contact while activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells