Miscellaneous 2 Flashcards
Be able to define an adverse drug effect (ADR)
Be aware of how new drugs are tested before being licenced
Be aware of the epidemiology of ADRs and at risk groups
Know the Rawlins-Thompson classification of ADRs
Know the classification of hypersensitivity reactions
Know about anaphylactoid reactions
Understand how medication errors can contribute to ADRs
Know how to identify an ADR
Know how to report an ADR
Know how to avoid an ADR
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Be able to define an adverse drug effect (ADR)
‘ A response to a drug that is noxious and unintended and occurs at a dose normally used in man for the prophylaxis, diagnosis or therapy of a disease or for the modification of physiological function.’
Know the Rawlins-Thompson classification of ADRs
Type A (Augmented / accentuated) Type B (Bizarre)
Type C (Chronic) Type D (Delayed) Type E (End-of-Use) Type F (Failure)
Type A:
- Dose-dependent
- Predictable from pharmacology of the drug
- Host independent
- Common
- Usually mild
- Low morbidity and mortality
- Reproducible in animal studies
- E.g. Bleeding/bruising on warfarin or aspirin
- Reduce dose or withhold
Type B:
- Dose independent
- Unpredictable
- Host dependent
- Uncommon
- Can be severe
- High morbidity and mortality
- No animal models
- E.g. Anaphylaxis to penicillin
- Withhold and avoid in future / put in notes
- allergic reactions
describe pharmacogenetics in type B ADRs
- Glucose-6-phosphate dehydrogenase deficiency > haemolysis of RBCs with oxidizing agents - Porphyria - Malignant hyperthermia > 1:20 000, abnormal response to GA - Coumarin (warfarin) resistance - Aminoglycoside induced deafness - Long QT Syndrome
pharmacogenetics in Type A ADRs
- Poor metabolizers
- Extensive metabolisers
> CYP2D6
> CYP2C19
> acetylation “fast”/”slow”
> methylation
> non-hepatic metabolism (pseudocholinesterase)
Know the classification of hypersensitivity reactions
Allergic / hypersensitivity reactions Gell and Coombs’s classification
Type I (immediate) - IgE -> mast cell release -> anaphylaxis
Type II (antibody-mediated cytotoxic) - drug induced haemolysis
Type III (immune complex) - fever, rash, arthropathy, glomerular damage
Type IV (delayed/cell mediated) - drug acts as hapten, rash common
ADR lecture slide 48 for image
describe type 1 hypersensitivity reaction
Anaphylaxis is:
– A severe, life-threatening, generalized or systemic hypersensitivity reaction
Anaphylaxis is characterised by: Rapidly developing, life threatening, - Airway and/or - Breathing and or - Circulation problems – Usually with skin and/or mucosal changes
treatment of anaphylactic shock
ABC - airway breathing circulation
0.5 ml 1:1000 adrenaline IM
Chlorphenamine 10mg IV
Hydrocortisone 100mg IV
Regular review
describe type II hypersensitivity reactions
Type-II reactions are caused by cytotoxic antibodies, which are primarily IgM, or IgG. Cell damage results from two main mechanisms:
- the direct action of macrophages, neutrophils and eosinophils that are linked to immunoglobulin-coated target cells (essentially blood cells) through the Fc receptor of the antibody.
- antibody-mediated activation of the complement classical pathway that results in cell lysis
In sensitized patients, the delay of onset after subsequent exposure to the drug is short, but the clinical manifestations of the reaction, such as fever and infection due to agranulocytosis, or purpura due to thrombocytopenia, are actually diagnosed only after a few days.
describe type III hypersensitivity reactions
- Type-III hypersensitivity reactions involve tissue injury by immune complexes.
- This response occurs when the antigen reacts in the tissue spaces with potentially precipitating antibodies (mostly IgM), forming microprecipitates in and around small vessels, causing secondary damage to cells.
- Immune complexes are primarily deposited in the lung, joints, kidneys and the skin.
- Tissue injury is initiated by the local inflammatory response involving activation of the complement. Various cells, such as macrophages, neutrophils and platelets, are subsequently attracted to the deposition site, and further contribute to the tissue damage.
Serum sickness which develops 9–11 days following the administration of heterologous therapeutic sera, such as antithymocyte globulins is the most typical example of type-III hypersensitivity reactions. Serum sickness has also been suspected to develop following the administration of low-molecular-weight drugs.
describe type IV hypersensitivity reactions
In contrast to the three previous types of hypersensitivity drug reactions, no antibodies are involved in type-IV reactions, even though they can be present in the sera of patients.
Type-IV reactions typically manifest as skin eruptions (contact dermatitis) in response to drugs, cosmetics and environmental chemicals, to which the skin is often exposed. The symptoms usually develop within 2–14 days after exposure to the (drug) allergen depending whether the patient is already sensitized or not. Type-IV reactions are triggered when the (drug) allergen encounters T-lymphocytes, and is presented to T-lymphocytes by antigen-presenting cells, which results in lymphocyte stimulation and cytokine release.
