Allergic drig reactions

Question 1

What is an adverse drug reaction?

Answer 1

An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which produces hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen or withdrawal of the product

Question 2

How many adverse drug reactions are believed to be the result of immunological reactions?

Answer 2

Potentially 20% of adverse drug reactions however it is difficult to quantify because reports are based on clinical symptoms rather than the demonstration of drug specific immunological responses

Question 3

Why are adverse drug reactions often attributed to an immunological mechanism?

Answer 3

The time course of the reaction
The need for repeated exposure
The presence of circulating antibodies that recognize the drug/drug-protein conjugate or auto-antibodies

Question 4

What are the different target tissues are associated with hypersensitivity reactions in humans?

Answer 4

Cutaneous, Liver, Blood and systemic anaphylaxis

Question 5

What are the classes of allergic reactions?

Answer 5

Anaphylatic which causes Urticaria, asthma and anaphylaxis
Cytotoxic Pemphigus, Blood cell penias: haemolytic anaemia, neutropenia and thrombocytopenia
Immune Complex which causes vasculitis- hypersensitivity vasculitis and Henoch-Schonlein purpura
Delayed many clinical patterns often involving the skin

Question 6

What occurs in anaphylactic reactions?

Answer 6

Antigen combines with IgE antibodies bound to receptors on the surface of mast cells and basophils
Bridging of the IgE receptors triggers the cell to degranulate with release of mediators such as histamine
The symptoms may develop within minutes of drug administration

Question 7

What are the features of anaphylaxis of the skin?

Answer 7

Pruritus or itching of the skin which may be localised or general
Urticara (hives), red rash and swelling
Skin may feel hot

Question 8

What are the features of respiratory anaphylaxis?

Answer 8

Shortness of breath, throat tightness, coughing, sneezing, wheeze
Upper airway obstruction indicated by nasal congestion, swelling of lips or tongue, hoarseness

Question 9

What are the features of anaphylaxis of the heart?

Answer 9

Chest pains, rapid or irregular heart beat, low blood pressure

Question 10

What are the features of the anaphylaxis of the gastrointestinal system?

Answer 10

Stomach cramps

Nausea, vomiting and diarrhoea

Question 11

What are the features of systemic anaphylaxis?

Answer 11

Confusion, dizziness, tremor and collapse

Question 12

What are type 2 cytotoxic reactions?

Answer 12

Antibodies react with antigens on the surface of target cells leading to complement activation and hence damage to the cell
Surface antigens may be haptens or neoantigens that result in autoimmune reactions
Cell toxicity may also occur as a consequence of antigen-antibody complexes adhering to the cell surface

Question 13

What are the symptoms of type 2 cytotoxic reactions?

Answer 13

Hemolytic anemia
Agranulocytosis
Thrombocytopenia
Hepatitis

Question 14

What drugs have been reported to cause haemolytic anemia?

Answer 14

Chlorpromazine, methyldopa, penicillins and quinine

Question 15

What are drugs which cause hepatotoxicity through type 2 hypersensitivity reactions?

Answer 15

Halothane and tienilic acid are thought to produce hepatitis as a consequence of metabolism by CYP
A reactive metabolite binds to the isozyme (CYP2E1 and CYP2C9 respectively) which is then presented on the cell surface acting as a neoantigen elicting an immune response
Anti-liver and anti-kidney microsomal autoantibodies found in serum of patients on tienilic acid which are cross reactive with CYP2C9

Question 16

What are type 3 Immune complex reactions?

Answer 16

These are a result of free antibodies reacting with an excess of free antigen
The immune complexes formed may precipitate in the vascular endothelium with subsequent activation of complement and PMN infiltration

Question 17

What are the symptoms of type 3 immune complex reactions?

Answer 17

Local tissue damage, serum sickness (rash, fever, joint swelling) and skin involvement

Question 18

How common is drug induced lupus?

Answer 18

As many as 10% of 500,000 cases of lupus erythematous in the US may be drug induced
More whites than blacks develop drug induced lupus while more blacks than whites present with systemic lupus
Incidence in males and femals of drug induced lupus is equal while systemic lupus more commonly affects women
Patients with drug induced lupus tend to be older (50-70) then the average age of those with systemic lupus (29) this may be due to elderly being more susceptible to drug induced systemic lupus due to higher rates of disease treated with medications which may result in drug induced lupus

Question 19

What are the symptoms of drug induced lupus?

Answer 19

Most patients will have one or more clinical symptoms of systemic lupus
As many as 90% of patients with drug induced lupus have severe but usually non-inflammatory joint pain, it is possible that synovitis may be present
Arthralgias are often the only clinical manifestation of drug induced lupus
As many as 50% of patients with drug induced lupus experience muscle pain
There is a typical absence of CNS and Renal involvement can distinguish drug induced lupus from traditional lupus
Clinical improvement also rapidly occurs upon removal of the drug and anti-nuclear antibodies will decrease to normal

Question 20

What is the mechanism of drug induced lupus?

Answer 20

Drugs involved include hydralazine, isoniazid, penicillamine and procainamide these can bind got C4 and thereby inhibit complement cascade leading to immune complexes deposition
Procainamide and hydralazine both inhibit T cell DNA methylation and induce autoreactivity cloned in CD4+ T cells

Question 21

Could there be a genetic predisposition for drug induced lupus?

Answer 21

Acetylator phenotype is an important factor in the development of this adverse reaction, slow acetylators develop symptoms faster than rapid acetylators
Hydralazine-induced drug induced lupus has been seen with increased frequency in association with HLA-DR4

Question 22

What is delayed type 4 hypersensitivity?

Answer 22

These reactions involve the uptake and presentation of antigen specific, sensitized T cells
This leads to the release of cytokines that in turn increase capillary permeability and mast cell reactivity as well as monocyte infiltration
This type of reaction is responsible for contact sensitivity seen with CDNB, DNFB, neomycin, picryl chloride, poison ivy and nickel

Question 23

What is the most frequently targeted organ in delayed hypersensitivity reactions?

Answer 23

The skin which results in cutaneous adverse drug reactions

Question 24

What are the different forms of cutaneous drug reactions?

Answer 24

Morbiliform reactions which commonly occur within 2 weeks of drug use
Urticara which is the second most common form
Fixed drug eruption which results in skin lesions within hours and often recurs at the same anatomical site like the lips and genitalia
Acute generalized pustulosisthsi is a rare widespread macular erythemathous rash with fever and blood leucocytosis
Erthyemia multiform/ stevens Johson syndrome/toxic epidermal necrolysis

Question 25

What are the subclassifications of delayed hypersensitivity reactions (type 4)?

Answer 25

4a which can result in contact dermatitis and the tuberculin reaction
4b which can result in maculopapular rash, exanthemata with eosinophilia
4c contact dermatitis maculopapular rash and drug induced exanthemata and bullous eruptions
4d which can result in acute generalized exanthematous pustulosis

Question 26

What are the immune mediators involved in type 4a reactions?

Answer 26

Th1 type T-cells activate macrophages by IFN-gamma secretion which drives the production of complement fixing antibody isotypes and act as co-stimulators for proinflammatory CD8 T cell responses

Question 27

What are the immune mediators involved in type 4b reactions?

Answer 27

Th2 T-cells secrete IL-4, IL-13 and IL-5 cytokines which promote B cell production of IgE and IgG4, Macrophage deactivation and mast cell and eosinophil responses

Question 28

What are the immune mediators involved in type 4c reactions?

Answer 28

T cells act as effector cells, they emigrate into the tissue and kill cells such as hepatocytes or keratinocytes in a perforin/granzyme B and/or FasL-dependent manner

Question 29

What are the immune mediators involved in type 4d reactions?

Answer 29

CXCL8 and GM-CSF producing T cells recruit neutrophilic leucocytes and prevent their apoptosis via GM-CSF release

Question 30

What are the putative mechanisms of immune-mediated hepatotoxicity which involve T cells?

Answer 30

T cell involvement requires covalent adducts presented on surface of the cell
Internalisation of hepatocyte by macrophage and presentation with MHCII
Release of cytokines resulting in clonal expansion
Protein fragment associated with MHC I is recognized by T cells
Th cells release cytokines which activate macrophages and NK cells

Question 31

What are the putative mechanisms of immune-mediated hepatotoxicity which involve B cells?

Answer 31

Presentation of modified protein with MHC
B cells undergo clonal expansion followed by maturation and secretion of Ig
Complement activation and activation of macrophages/NK cells

Question 32

What role might a second signal play in the putative mechanisms of immune-mediated hepatotoxicity?

Answer 32

Concurrent infection has been postulated
In animal models, LPS can sensitize animals to the effects of drugs to produce liver toxicity with the onset of toxicity in the ranitidine model occurs in hours while idiosyncratic liver toxicity and adaptive immune-mediated reactions require a week or more to become evident on first exposure

Question 33

What are the different between immune mechanisms of drug toxicity or direct drug toxicity?

Answer 33

Although anti-drug or antihost antibodies have been detected after administration of a number of drugs an immunological mechanism has only been proven for a limited number of drugs
The incidence of immunologically-mediated drug reactions is often low and may reflect inter-individual differences in drug metabolism like genetic polymorphisms

Question 34

What is hypersensitivity to asprin and NSAIDs?

Answer 34

This was first described as a syndrome in 1922
It presents in either the airways (as recurrent rhinitis associated with nasal polyposis followed by asthma attacks) or the skin (where it manifests as urticarial and angioedema)
The prevalence of this condition is at most 2.5% I the general population but up to 10-20% of adult asthmatics
There is evidence for the involvement of mast cells, basophils and eosinophils but hypersensitivity not associated with IgE and instead results from inhibition of cyclooxygenase in the airways or the skin of hypersensitive patients
Normally acts as a brake on the production of sulphidoleukotrienes
There is cross reactivity between asprin and NSAID in sensitive individuals