Flashcards in Allergic drig reactions Deck (34):
What is an adverse drug reaction?
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
How many adverse drug reactions are believed to be the result of immunological reactions?
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
Why are adverse drug reactions often attributed to an immunological mechanism?
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
What are the different target tissues are associated with hypersensitivity reactions in humans?
Cutaneous, Liver, Blood and systemic anaphylaxis
What are the classes of allergic reactions?
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
What occurs in anaphylactic reactions?
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
What are the features of anaphylaxis of the skin?
Pruritus or itching of the skin which may be localised or general
Urticara (hives), red rash and swelling
Skin may feel hot
What are the features of respiratory anaphylaxis?
Shortness of breath, throat tightness, coughing, sneezing, wheeze
Upper airway obstruction indicated by nasal congestion, swelling of lips or tongue, hoarseness
What are the features of anaphylaxis of the heart?
Chest pains, rapid or irregular heart beat, low blood pressure
What are the features of the anaphylaxis of the gastrointestinal system?
Nausea, vomiting and diarrhoea
What are the features of systemic anaphylaxis?
Confusion, dizziness, tremor and collapse
What are type 2 cytotoxic reactions?
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
What are the symptoms of type 2 cytotoxic reactions?
What drugs have been reported to cause haemolytic anemia?
Chlorpromazine, methyldopa, penicillins and quinine
What are drugs which cause hepatotoxicity through type 2 hypersensitivity reactions?
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
What are type 3 Immune complex reactions?
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
What are the symptoms of type 3 immune complex reactions?
Local tissue damage, serum sickness (rash, fever, joint swelling) and skin involvement
How common is drug induced lupus?
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
What are the symptoms of drug induced lupus?
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
What is the mechanism of drug induced lupus?
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
Could there be a genetic predisposition for drug induced lupus?
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
What is delayed type 4 hypersensitivity?
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
What is the most frequently targeted organ in delayed hypersensitivity reactions?
The skin which results in cutaneous adverse drug reactions
What are the different forms of cutaneous drug reactions?
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
What are the subclassifications of delayed hypersensitivity reactions (type 4)?
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
What are the immune mediators involved in type 4a reactions?
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
What are the immune mediators involved in type 4b reactions?
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
What are the immune mediators involved in type 4c reactions?
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
What are the immune mediators involved in type 4d reactions?
CXCL8 and GM-CSF producing T cells recruit neutrophilic leucocytes and prevent their apoptosis via GM-CSF release
What are the putative mechanisms of immune-mediated hepatotoxicity which involve T cells?
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
What are the putative mechanisms of immune-mediated hepatotoxicity which involve B cells?
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
What role might a second signal play in the putative mechanisms of immune-mediated hepatotoxicity?
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
What are the different between immune mechanisms of drug toxicity or direct drug toxicity?
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