Lecture 4 ADRs and Drug Interactions

Question 1

What did Paracelsus say?

Answer 1

All substances are poisons, there is none that is not a poison. The right dose distinguishes a poison and a remedy

Question 2

What is warfarin used for?

Answer 2

Warfarin is an anticoagulant drug, blood thinner to reduce blood clots. Warfarin inhibits clotting factors in the clot cascade. Decreases risk of stroke and heart attack.

Question 3

How does the interaction of benefits and side effects interplay in the effect of warfarin?

Answer 3

As the concentration of warfarin administered increases, the clotting risk decreases exponentially. However simultaneously the risk of bleeding increases exponentially. Analysing the combined risk we can set a therapeutic range of warfarin concentration.

Question 4

What is the therapeutic index?

Answer 4

Relative measure of the safety of a drug

LD50/ED50 (lethal dose/effective dose)

Question 5

Which CYP enzyme clears warfarin?

Answer 5

CYP2C9

Has multiple alleles with varying amounts of activity

Question 6

What are the key identifying conditions of Phase I Trials

Answer 6

Studied pharmacokinetic / dynamics.

Known tolerated dose range

Question 7

What are the key identifying conditions of Phase II Trials

Answer 7

Pilot studies in disease states.
Placebo controlled studies
Anticipated drug interactions

Question 8

What are the key identifying conditions of Phase III Trials

Answer 8

Further safety research
Large scale clinical trials
Extended research: pharmacoeconomics, life quality

Question 9

What are the key identifying conditions of Phase IV Trials

Answer 9

Post marketing
Surveillance for ADRs
Actual drug-disease interactions

Question 10

Which enantiomer of warfarin is active?

Answer 10

S warfarin

Question 11

What is the antiplatelet effect of warfarin?

Answer 11

Inhibit cyclooxygenase in platelets

Question 12

What does CYP2C9 polymorphism affect other than warfarin and increased risk of haemorrhage?

Answer 12

Increase sulfonylureas toxicity (diabetes drugs) -> leading to hypoglycemia
Increase phenytoin toxicity (anti-epileptic drugs)

Question 13

Describe Type A ADRs

Answer 13

Augmented
Dose related: increase dose, increase risk
Predictable
High incidence and morbidity
Low mortality

Question 14

Describe Type B ADRs

Answer 14

Bizarre
Not dose-dependent. Unpredictable, because based mostly on the individual’s characteristics e.g. enzyme or receptor polymorphism, organ failure
Low incidence (rare) and morbidity
High mortality

Question 15

Describe Type C ADRs

Answer 15

Chronic

Not obvious due to delayed onset or high background prevalence

Question 16

What is the Rule of 3’s?

Answer 16

If on average the adverse event occurs 1 in 100 subjects, then you must observe 300 subjects to confirm there is a >95% chance of observing one such adverse event

Question 17

TRUE OR FALSE: a narrow therapeutic range exists for all anticoagulants

Answer 17

True, so not much we can do about the adverse effects of warfarin