Drug Toxicity - Prof. Coleman

Question 1

What are type-A adverse drug reactions?

Answer 1

Reversible adverse reactions.

Question 2

How many subclasses of type-A adverse drug reactions are there?

Answer 2

Two; type A1 and type A2.

Question 3

Define type A1 adverse drug reactions.

Answer 3

Effects linked to pharmacological action - pharmacological over action. 95% of toxicity.

Question 4

Define type A2 adverse drug reactions.

Answer 4

Effects unrelated to drug action. Can be off target reactions/effects.

Question 5

What are type-B adverse drug reactions?

Answer 5

Irreversible, toxic responses. Can present as an illness and may be treated incorrectly.

Question 6

How many subclasses of type-B adverse drug reactions are there?

Answer 6

Three; type B1, type B2, and type B3.

Question 7

Define type B1 adverse drug reactions.

Answer 7

Direct necrotic injury. Can result from overdosage (paracetamol), oxidation to reactive species (troglitazone), causes outside of drug metabolism (tacrine).

Question 8

Define type B2 adverse drug reactions.

Answer 8

Immune-mediated toxicity.

Question 9

Define type B3 adverse drug reactions.

Answer 9

Cancer.

Question 10

Per year, how many overdoses of paracetamol are there?

Answer 10

70,000.

Question 11

How many deaths from paracetamol overdose are there per year?

Answer 11

300-500.

Question 12

What percentage of paracetamol is cleared to glucuronide?

Answer 12

50%.

Question 13

What percentage of paracetamol is cleared to a sulphate?

Answer 13

45%.

Question 14

What percentage of paracetamol is cleared to N-acetyl, p-benzoquinoneimine (NAPQI)?

Answer 14

5%.

Question 15

What dose of paracetamol is defined as an overdose?

Answer 15

12g/day in adults.

Question 16

What metabolite of paracetamol is the one that leads to liver toxicity?

Answer 16

NAPQI.

Question 17

What substance in the liver quenches toxic paracetamol metabolites?

Answer 17

Hepatic GSH. Becoming gradually depleted.

Question 18

What syndromes/conditions are type B2 adverse drug reactions?

Answer 18

Anticonvulsant syndrome, blood dyscrasias, aplastic anaemia, cutaneous toxicity, hepatotoxicity, agranulocytosis.

Question 19

What are the symptoms of anticonvulsant syndrome?

Answer 19

Symptoms, rashes, fever, hepatitis, liver failure.

Question 20

What drugs cause blood dyscrasias?

Answer 20

NSAIDS, penicillins, cephalosporins.

Question 21

What is aplastic anaemia and what drugs can cause it?

Answer 21

Destruction of the bone marrow by the immune system. Caused by chloramphenicol, chlorpromazine, antineoplastic agents.

Question 22

What drugs cause cutaneous toxicity?

Answer 22

Sulphonamides.

Question 23

What drugs cause hepatotoxicity?

Answer 23

Statins, halothane, INH, phenytoin.

Question 24

What drugs cause agranulocytosis?

Answer 24

Clozapine, sulphones, chlorpromazine, antithyroid agents.

Question 25

What two hypothesises have been proposed as to how drugs trigger an immune response?

Answer 25

The stranger hypothesis. The danger hypothesis.

Question 26

Explain the stranger hypothesis.

Answer 26

The immune system reacts to non-self (anything that is non-human). However, this doesn't account for the destruction of cancer cells and the rejection of organs.

Question 27

Explain the danger hypothesis.

Answer 27

The immune system 'listens'. It detects certain trigger molecules associated with danger. If enough trigger molecules are detected, a response is initiated.

Question 28

What is the hapten hypothesis of how drugs/substances lead to an immune response?

Answer 28

Haptens are reactive species which bind to macromolecules. The immune system responds to the hapten/macromolecule combination.

Question 29

What is the pharmacological interaction hypothesis of how drugs/substances lead to an immune response?

Answer 29

Some immune responses are so fast that antigen presentation could not have occurred. The drug/metabolite binds directly to MHC molecules and triggers effects. However, this doesn't explain how sensitization occurs.

Question 30

Describe type B3 adverse drug reactions (cancer).

Answer 30

Drugs are rarely implicated in cancer. Some reactive species formed by CYPS and reductive pathways can damage DNA unless Phase II detoxified. DNA is either repaired or retained as damaged, and malignancy can result, sometimes 20-50 years later.