Adverse drug reactions (toxicology 2)

Question 1

What is an adverse drug reaction?

Answer 1

Harmful, unintended reactions to medicines that occur at doses normally used for treatment

Question 2

What is an adverse drug event?

Answer 2

They occur while a patient is taking a drug,

but are not necessarily related to drug (Includes unintentional harm to patients due to misuse or non-use of drugs)

Question 3

What is the contribution of ADRs to hospital admissions?

Answer 3

~ 6% of general hospital admissions (5.6%)

1/3 of admissions in >75yo

Question 4

What are the risk factors for ADRs?

Answer 4

Age (elderly)
Use of narrow therapeutic window drugs
Metabolism abnormalities (slow acetylators)

Question 5

What are the 2 types of ADRs?

Answer 5

Type A ("augmented")
Type B ("bizarre")

Question 6

A person taking warfarin is admitted into emergency with HAEMORRHAGE. What kind of ADR is this?

Answer 6

Type A - adverse effect is related to the primary pharmacological action of the drug (warfarin is an anticoagulant)

Question 7

What category of ADR is “acetylator status”? Give an example of how acetylator status leads to an ADR.

Answer 7

Type B - non-immune related - metabolic abnormality.

Slow acetylators have reduced ability to clear hydralazine from their system. This causes drug induced lupus.

Question 8

Explain how acetylator status affects ADRs.

Answer 8

Some drugs require an acetyl group to be added in order to be excreted (a process called acetylation occurring in the liver)

Acetylation is catalysed by N-acetyltransferase (NAT) which exists in fast and slow forms.

Slow acetylators have increased drug-half lives and are at higher risk of ADRs

Question 9

What category of ADR is “CYP450 status”? Give an example of how acetylator status leads to an ADR.

Answer 9

Type B - non-immune related - drug metabolism abnormalities

CYP2D6 and 3A4 are examples of CYP450 proteins that are subject to polymorphisms.

Some variants have reduced ability to clear the drug from the plasma.

Causes accumulation of the drug/metabolites to toxic levels

Question 10

What category of ADR is pseudoporphoria? What symptoms result and what drugs are involved?

Answer 10

Type B - non-immune related - inability to compensate

Many drugs (e.g. NSAIDS, tetracyclines) can induce symptoms of the porphyrias including skin blistering and fragility.

Question 11

What category of ADR is malignant hyperthermia? How does it occur?

Answer 11

Type B - non-immune related - inability to compensate

Volatile anaesthetics trigger massive Ca2+ release, causing metabolic stimulation, contractile response and hyperthermia (high body temp).

Caused by inherited variation in RYR1 (ryanodine receptor isoform 1) Ca2+ channel in skeletal muscle.

Question 12

Give an example of an immediate and a non-immediate immune reaction induced by drugs. What are the mediators involved in each?

Answer 12

Immediate:
Anaphylaxis, urticaria, bronchospasm
IgE

Non-immediate:
Stevens Johnson syndrome or toxic epidermal necrolysis
T cells

Question 13

When does an immediate drug hypersensitivity reaction occur?

Question 14

When does a non-immediate drug hypersensitivity reaction occur?

Answer 14

> 1hr and up to several days after the last drug dose