Miscellaneous 2

Question 1

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

Answer 1

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Question 2

Be able to define an adverse drug effect (ADR)

Answer 2

‘ 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.’

Question 3

Know the Rawlins-Thompson classification of ADRs

Answer 3

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

Question 4

describe pharmacogenetics in type B ADRs

Answer 4

- 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

Question 5

pharmacogenetics in Type A ADRs

Answer 5

• Poor metabolizers
• Extensive metabolisers
  > CYP2D6
  > CYP2C19
  > acetylation “fast”/”slow”
  > methylation
  > non-hepatic metabolism (pseudocholinesterase)

Question 6

Know the classification of hypersensitivity reactions

Answer 6

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

Question 7

describe type 1 hypersensitivity reaction

Answer 7

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

Question 8

treatment of anaphylactic shock

Answer 8

ABC - airway breathing circulation

0.5 ml 1:1000 adrenaline IM

Chlorphenamine 10mg IV

Hydrocortisone 100mg IV

Regular review

Question 9

describe type II hypersensitivity reactions

Answer 9

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.

Question 10

describe type III hypersensitivity reactions

Answer 10

• 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.

Question 11

describe type IV hypersensitivity reactions

Answer 11

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.