Rashes Flashcards
Haptens
A drug substance that is capable of reacting with a specific antibody but cannot induce the formation of antibodies unless bound to a carrier protein or other molecule.
Also called incomplete antigen, or partial antigen.
Formation of drug haptens Pathway A
In pathway A, nonreactive drugs are taken up by host cells, such as hepatocytes, and are chemically activated by phase I metabolism (a). The activated form can be detoxified by a phase II enzyme (b), or can become conjugated with a host cell protein, possibly in the endoplasmic reticulum (ER; c), and be transported to the cell surface as a neo-antigenic hapten (d).If the activated form escapes from the cell, it can react with a soluble host cell protein (e) to form a soluble neo-antigenic hapten (f). The hapten can then be taken up into the proteasome of antigen-presenting cells (APCs) to be cleaved by proteases (g). The peptide–hapten conjugate can then be transported to the ER, become associated with a MHC protein, and be transported to the cell surface (h)
Formation of drug haptens Pathway B
In pathway B, chemically reactive xenobiotics can bind to host cell proteins without metabolic activation to form haptens.
Coombs and Gell classification of hypersensitivity reactions - Type I
Type I reactions are caused by the formation of drug/antigen-specific IgE that cross-links with receptors on mast cells and basophils leading to immediate release of chemical mediators, including histamine and leukotrienes.
Clinical features include pruritus, urticaria, angio-oedema and, less commonly, bronchoconstriction and anaphylaxis.
The drugs most commonly responsible for type I hypersensitivity are aspirin, opioids and penicillins.
Coombs and Gell classification of hypersensitivity reactions - Type II
Type II or cytotoxic reactions are based on IgG or IgM-mediated mechanisms.
These involve binding of antibody to cells with subsequent binding of complement and cell rupture.
This mechanism accounts for blood cell dyscrasias such as hemolytic anemia and thrombocytopenia.
Caused by: aspirin, chloroquine, primaquine (antimalarial), dapsone (leprosy), methyldopa (HBP), levodopa (antiparkinsonian)
Coombs and Gell classification of hypersensitivity reactions - Type III
Type III reactions are mediated by intravascular immune complexes that arise when drug antigen and antibodies, usually of IgG or IgM class, are both present in the circulation, with the antigen present in excess.
Slow removal of immune complexes by phagocytes leads to their deposition in the skin and the microcirculation of the kidneys, joints and gastrointestinal system.
Serum sickness and vasculitis are examples of type III reactions.
penicillin, cephalosporin, sulfonamide, loop and thiazide-type diuretics, phenytoin and allopurinol
Coombs and Gell classification of hypersensitivity reactions - Type IV
Type IV reactions are mediated by T cells causing ‘delayed’ hypersensitivity reactions.
Typical examples include contact dermatitis or delayed skin tests to tuberculin.
Drug-related delayed-type hypersensitivity reactions include Stevens–Johnson syndrome and toxic epidermal necrolysis (TEN).
sulfonamides, nonsteroidal anti-inflammatory drugs,allopurinol, methotrexate
The clinical manifestations of drug hypersensitivity depend on various factors, including:
The chemical or structural features of a drug
The genetic background of the affected individual
The specificity and function of the drug-induced immune response.
Drug Hypersensitivity - PCN
Penicillins, are the classic drugs acting as haptens, but are reported to cause type 1 IgE mediated (immediate-type) hypersensitivity reactions as well as non-IgE mediated reactions, including morbilliform eruptions, erythema multiforme and Stevens–Johnson syndrome.
Certain patient groups appear to be predisposed to cutaneous adverse drug reactions (ADRs):
There is a high incidence of hypersensitivity reactions in patients with altered immune status, for example due to viral infections (Epstein–Barr virus or HIV).
A well-documented example is the increased risk of trimethoprim/sulfamethoxazole hypersensitivity in HIV patients.
Drugs Rarely Causing Cutaneous Eruptions
Antacids Muscle relaxants Antihistamines (oral) Nitrates Atropine Nystatin Benzodiazepines Oral contraceptives Corticosteroids Propranolol Digoxin Spironolactone Ferrous sulphate Theophylline Insulin Thyroid hormones Laxatives Vitamins Local anaesthetics (other than topical)
Rash associated with demeclocycline and chlorpromazine
A morbilliform rash (macular lesions that are red and usually 2–10 mm in diameter but may be confluent in places) may be due to a viral infection or an antibiotic, and this may unnecessarily limit the future use of a particular medication.
Some drugs are more likely to be the cause of a particular type of eruption than others. For example, if a patient taking both demeclocycline and chlorpromazine develops a photosensitivity reaction the chances are that demeclocycline is the cause, although both drugs are capable of producing the reaction.
However, if the patient develops skin hyperpigmentation then chlorpromazine is more likely to be implicated.
Relationship of timing and diagnosis
The timing of skin reactions is a useful diagnostic tool. In general, the onset occurs soon after the introduction of the causative drug.
If a medicine has been taken for many years without a problem then it is much less likely to be responsible.
When examining a list of medicines taken by a patient with a rash, new drugs taken within the previous month are the most likely cause.
Notable exceptions:
-Hypersensitivity reactions to penicillins can occur several weeks after the drug has been discontinued.
-Gold can also cause very late reactions.
Signs suggestive of a severe reaction include:
Signs suggestive of a severe reaction include: mucous membrane involvement blisters or skin detachment high fever angio-edema or tongue swelling facial edema skin necrosis lymphadenopathy dyspnoea.
Drugs commonly Causing Exanthematous Reactions
Acetaminophen Allopurinol Antimicrobials: cephalosporins, penicillins, chloramphenicol, erythromycin, gentamicin, amphotericin, antituberculous drugs, nalidixic acid, nitrofurantoin, sulfonamides Antifungals (allylamine type: Terbinafine) Barbiturates Captopril Carbamazepine Furosemide Gold salts Lithium Phenothiazines Phenylbutazone Phenytoin Thiazides
