Allergic Reactions

Predictable drug reactions

related to the pharmacological actions of the drugs

Unpredictable reactions

Non-immunological and immunological

Non immunological

non-specific, idiosyneratic, intolerance

Immunological

allergy hypersensitivity

Idiosyncratic

unusual or abnormal response to a substance or medicine that is not normally seen in the entire population

Risk Factors- Drugs

-Chemical/drug class= penicillin, NSAIDs, sulfonamide, ACE inhibitors account for >80% of drug allergic reactions

-Increases cases of biologics related to reactions (mAb)

Epitopes

a specific region on an antigen that an antibody or T cell receptors bind to

Risk factors- Patient Factors

-Genetic Predisposition

-Metabolism

-MHC alleles= presentation of drug allergen epitopes to T cells

Risk factors- disease factors

-Alteration of metabolic factors

-variations in immunologic responses

____ following a response by the _____ to an otherwise innocuous _____

disease; immune system; antigen

Distinctive features of drug hypersensitivity

-No correlation with know pharmacological actions of the drug

-No clear relationships with drug dosage

-Severity is drug and patient-specific

-Initial exposure may be asymptomatic, mild, or severe

-Past severity does not always predict future reactions

Type 1 mediator

IgE

Type 2 Mediator

IgG

Type 3 Mediator

IgG

Type 4 Mediator

activated T cells

Type 1 Antigen

soluble Ag

Type 2 Antigen

cell associated Ag

Tyep 3 antigen

Ag-IgG complex

Type 4 Antigen

modified T cell epitopes

Type 1 effectors

mast cells, basophils

Type 2 effectors

complement lekuocytes

Type 3 effectors

complement leukocytes

Type 4 effectors

T lymphocytes

Type 1, 2, and 3 hypersensitivity reactions are mediated by what

antibodies

Macromolecule drug allergens

-Recombinant proteins= monoclonal antibodies, growth factors

-Aggregated proteins= increased risk factors

How do small molecule drugs become allergens

haptenation

Hapten

-a small molecule that elicits immune reactions only when attached to a larger carrier

-drug or its metabolite reacts with protein to form covalent linkages

-resultant protein displays multiple drug molecules (multivalent antigen)

-cross-linked antibodies—→ immune activation

How are anti-drug antibodies generated

senixation and elicitation

Senization

-small molecule drug reacts with proteins (haptent carrier)

-B cells and helper T cells must recognize same antigen

-An epitpe on an allergen is recognized by surface Ig on a B cell

-The allergen is internalized and degraded by the B cell, and presented to CD4 T cells via MHC-2 molecules

-Activated CD4 T cells help B cells differentiate into plasma cells

-Plasma cells release anti-drug antibodies

Elicitation

-pre-existing anti-drug antibodies

-memory B cells capture drug-bound proteins —→ rapid production of new anti-drug antibodies

-severity depends Ab titer and B cell memory pool

How are IgE and IgG different

-both bridge drug allergen with unique Fc receptors on leukocytes

-antigen (drug allergen) specific

-produced by activated B cells with help by CD4 T cells

-Half lives determine duration of reactions

-Bind drug-protein or drug-cell complex via bivalent variable regions (Fab)

-Engage complement proteins or unique Fc receptors (FcR) on cells

IgE FCR

FcER

IgG FCR

RcYR

IgG half life

is greater (21 days) to the IgE half life (2.5 days)

Type 1 hypersensitivity is mediated by

IgE

Type 1 hypersensitivity

-immediate hypersensitivity

-there is an immediate and late phase response

-localized exposure (can manifest in systemic reactions)

Type 1 hypersensitivity is characterized by

urticaria/hives

Primary effectors of Type 1 hypersensitivity

mast cells and basophils

Both mast and basophils originate in the

bone marrow

Mast cells reside in

mucosal tissues and skin

Basophils are found

circulating in the blood

Both mast and basophils have

histamine (stored in granules)

Degranulations of both mast and basophils lead to

histamine

Mast and basophils are activated by

IgE allergen complex via Fc receptors

Specialized Fc Receptors for IgE of Type 1

-Mast cells and basophils express= tetrameric Fc esilon receptors

-Fc epsilon receptors have a high affinity for= IgE (most IgE are cell bound)

-Drug-protein complex “cross links” two IgEs

-Each allergen-IgE2 complex binds two FCE receptors on cells

Dimerizations of Type 1

Tyrosine phosphorylation to signaling to degranulation to histamine (minutes) to synthesis of pro-inflammatory mediators (hours)

what is the most severe systemic allergic reaction

anaphylaxis

What to look for with anaphylaxis

skin/mouth/throat to airway and/or cardiovascular (within minutes)

Classic Allergic Reaction

Flushing, hypotension, increased mucus production, pruritis, smooth muscle contraction, vascular leakage

Late Phase Reaction

eosinophil infiltration, neutrophil infiltration, fibrin deposition, mononuclear infiltration, tissue destruction

Clinical Presentation of Type 1

-rash—→ airway GI—→ cardiovascular

-Anaphylaxis= massive amounts of histamine released in a short time

Cellular Elements of Type 1 reactions

-mast cells and basophils (Early 1 hour)

-eosinophils and neutrophils (late 24 hours)

Molecular mechanisms of Type 1 reactions

-drug + protein——> allergen

-IgE recognizes rug molecules bound to protein carrier

-histamine release and production of inflammatory mediators

Type 2 hypersensitivity reactions are mediated by

IgG

Type 2 hypersensitivity reactions effectors

NK, macrophage, neutrophil, cells that express FCYR

Type 2 hypersensitivity reactions of destruction of

-RBC (hemolytic anemia)

-Platelets (thrombocyteopenia )

Type 2 hypersensitivity reactions

-signs and symptoms can occur days after exposure

-binding of drug molecules on circulating blood cell membrane

Type 3 hypersensitivity are mediated by

IgG

Type 3 hypersensitivity

-Formation of IgG-drug aggregates (immune complexes) in blood circulating Ag-IgG

-Deposition of immune complexes in tissues

-Immune complexes activate complement proteins

-Serum sickness (Systemic transient): chills, fever, rash, arthritis, nephritis, vasculitis (inflamed blood vessels)

-Tends to occur 24-72 hours after initial exposure

Type 4 hypersensitivity reactions

-delayed typed hypersensitivity

-contact-sensitizing agents: highly reactive liophilic molecules

-modification of CD4,CD8,and cell epitopes (MHC 1 and MHC 2 ligands)

-dermatitis, muscular rash, blisters, organ damage

-SJS and TEN

Type 4 hypersensitivity reactions are mediated by

CD8 and cytotoxic T cells

SJS and TEN

-mucocutaneous eruption

-epidermal detachment and skin loss (third-degree burn)

-mucosal erosions and organ damage

-occurs 1 to 3 weeks after drug administration lasting 4 to 8 weeks

Drugs that have to do with SJS and TEN

Allopurinol, sulfonamides, carbamazepine/HLA-B*1502