Lecture 3

Question 1

What is Synergy?

Answer 1

Two drugs causing a greater than expected effect
-compared to the additive effect: 1U + 1U = 2
for synergy: 1U + 1U = 4

Question 2

What could be a benefit of Synergy?

Answer 2

-Two drugs to get a greater effect, so that the dose can be reduced -> which would decrease side effects f.e. in chemotherapy

-or for antibiotics: add a drug to get synergy against bacteria that got resistant to one drug

Question 3

How can two drugs be tested for synergy?

Answer 3

Step 1: get ED50 of drug A and ED50 of drug B
Step 2: Isobolograph
-Plotting one x-axis of the Drug-response relationship (Drug A)with another x-axis of the drug-response relationship (Drug B) and draw a line (Isobole) between the two ED50 (of drugs A and B)

Step 3: then test with an increasing amount of drug A with a constant amount of drug B -> and get ED50 (combo)

Step 4: put ED50 combo on the Isobolograph-> if there is synergy the ED50 would be shifted to the left (less dose needed for the same effect)

Step 5: mark how much of drug B was added in the combo trial y-axis of Isobolograph

Step 6: mark the intercept between ED50 (drug B) and ED50 (combo), if the point is to the left of the Isobole -> Synergy
if it is to the right of the Isobole -> Antagonistic
if it is on the isobole -> Additive effect (the effect is not multiplied or subtractive)

Question 4

What is the combination index?

Answer 4

Test for synergy of two drugs acting together
-take some dose of A and some dose of B
-see how efficacious it is -> that would be the ED
-use the formula: a (some dose of A) / A (ED A) + b (some dose B) / B (ED b)

Question 5

Why does the risk increase of adverse effects with multiple drug intake?

Answer 5

Because of tolerance the dose will be shifted to the right, nearer to side effects

Question 6

What are the mechanisms of tolerance?

Answer 6

-Pharmacodynamic: What happens to the receptor (ß-arrestin downregulates the sensitivity of the G-proteins and the receptor population)

-Pharmacokinetics: Drug metabolism: rate increases due to enzyme induction (more enzymes)

-Behavioral tolerance -> Learning

Question 7

What are extension effects?

Answer 7

an extension effect is an adverse effect that also contributes to the intended effect: f.e. ß-blockers used to reduce the cardiac output of the heart -> patients with lower cardiac output don’t have the energy to exercise as much -> which will also reduce the stress of the heart

Question 8

What are Idiosyncratic effects?

Answer 8

Effects that are not predictable
-drug tested for 1000 people -> very few patients will have a drug-related side effect
-didn’t happen often enough in the trial to be predictable
-f.e. antidepressant causing loss of sense of smell