Key concepts in Toxicology

Question 1

What are the two categories of unwanted effects in using drugs?

Answer 1

1. Side-effects - non-deleterious consequences

2. Toxic effects - deleterious

Question 2

What is the difference between adverse effect of a drug and toxicity?

Answer 2

Toxicity causes unwanted events at supratherapeutic doses - they’re dose related, whereas adverse effects are at normal therapeutic doses and not normally dose-related

Question 3

What is the shape of the curve that most toxic responses to drugs occurs on?

Answer 3

Sigmoidal

Question 4

What is the therapeutic window?

Answer 4

The difference between the minimum effectice concentration and the minimum effective concentration

Question 5

What are some types of drug-induced toxicity?

Answer 5

Organ specific injury
Cancer (carcinogenicity)
Prenatal toxicity
Allergic hypersensitivity

Question 6

What is the therapeutic index?

Answer 6

Drug dose causing a toxic effect in 50% patients - Drug dose causing therapeutic effect in 50% patients

Question 7

What does susceptibility to bioactivation cause?

Answer 7

Toxic effects
Some drugs become more toxic after metabolism in the liver = toxicological bioactivation.
These products are often electrophillic or electron-deficient metabolites, and termed “adducts”
These adducts have been implicated in toxicity and cancer

Question 8

Which organ is most vulnerable to reactive metabolites?

Answer 8

The liver, as it has a high metabolic capacity

Question 9

What are the three classes of drug-induced liver injury?

Answer 9

1. Hepatocellular
2. Cholestatic
3. Hepatocellular-cholestatic

Question 10

Variations in which enzyme expression may explain some drug induced liver injury?

Answer 10

CYP isoforms

Question 11

What are the main five consequences of polymorphisms in the CYP450 genes?

Answer 11

1. No metabolism of drugs
   2&3. Lower/Normal metabolism of drugs
2. Novel metabolites produced
3. Increased metabolism

Question 12

What is Gilbert’s syndrome?

Answer 12

A common condition involving mild hyperbilirubinemia, as a result of lower hepatic levels of the enzyme UGT1A1, which catalyses the glucuronidation of bilirubin in the liver.
The syndrome affects the hepatic clearance of paracetamol, and the cancer drug Irinotecan. This leaves the patient open to toxicity