Lecture 3: Principles of Drug action 1 - the conc-response relationship

Question 1

Describe the conc-response relationship

Answer 1

drug effects quantified by relationship between dose & response

• log drug conc graph : S shape
• dose response threshold (aka smallest amount that has effects) = just before effects
• there’s a point above which no additional response

Question 2

what are 3 important points regarding the conc-response response curve?

Answer 2

• there’s a conc of drugs below which doesn’t do much (haven’t reached threshold where drug produces effect)
• between ~20% and 80% there’s a linear relationship between response and log conc so easy to analyse relationship
• conc above which no more amount of the drug you give will give a bigger response (has reached MAX)

Question 3

Response to drug concentration is determined by the type of experiment performed. What are the three main types of pharmacological experiments

Answer 3

1) in vitro (in test tube)
2) in vivo (in living)
3) ex vivo (in between)

Question 4

in vitro

Answer 4

study drug effects on tissue -> tissue dissected & kept alive in lab
- most common
- focus on cells
examples of responses measured: tension of muscle, changes in enzyme

Question 5

in vivo

Answer 5

drug effects studied on whole living organism (animal or human)
- complicated
- tightly regulated
- relevant to clinical trials
examples of responses that might be measured: increase in BP, reduction in pain threshold, reduction in allergen-induced bronchoconstriction

Question 6

ex vivo

Answer 6

tissue/organ removed from animal treated w/ drug (in vivo) (i.e. tissue/organ has been treated with drug and then removed)

• effects of drug then tested in vitro
• tightly regulated
  examples: experiments to see whether long-term treatment w/ drug induces liver damage or alters aspect of brain biochemistry

Question 7

describe the concentration axis for concentration-response curves

Answer 7

for log conc curve:

- (in vitro experiments)conc expressed in moles per lire i.e. molar (M) (to ensure same number of molecules)

Question 8

very potent drugs act at what concentration?

Answer 8

low concs

• 1 x 10^-6 M to 1 x 10^-12 M
• more doses in lower potency = better

Question 9

constructing conc-response curve (in vitro)

Answer 9

• put ileum (part of gut) into organ bath, connect via thread to receptor
• tug on force transducer as it contracts, measure contractions
• w = wash, can wash tissue in between measures
• can get cumulative response by not washing between measures

Question 10

measurements for doses in vivo

Answer 10

can’t use molar conc as diff vol of solvent

• instead weight drug/weight animal (eg. 1 mg/kg)
• allows for extrapolation fm animals -> humans (dosage)

Question 11

What is the maximal effect (Emax)?

Answer 11

max response drug produces
- units: Emax = y-axis (fraction of release)
note: increasing conc of the drug produces no greater effect
also note: top of curve conc-response curve is what indicated the Emax

Question 12

what is the EC50?

Answer 12

50% response

• Molar conc of drug that produces 50% of max response for that drug (EC90 and others exist)
• gives position of curve on conc axis as rest of curve = similar in all
• y-axis units = Molar (microL)

Question 13

What are the two key parameters of pharmacodynamics

Answer 13

• the maximum response (Emax) and the concentration producing 50% of Emax (C50)

Question 14

how is the potencty of a drug found and what does it describe?

Answer 14

found by EC50

• describe conc that effective
• potent drug = effective in very small amounts (low EC50 = high potency)
• range where drug = effective (therapeutic window)

Question 15

how are relative potencies found?

Answer 15

compare EC50 values of drugs w/ same action

Question 16

why is it not possible to use molar concentrations for experiments in vivo?

Answer 16

because the volume of the solvent (e.g. blood) isn’t known

Question 17

a lower EC50 indicates what about the potency of a drug?

Answer 17

the lower the EC50, the more potent the drug is

Question 18

how is the potency ratio calculated?

Answer 18

• comparing EC50 values for two drugs with the same action allows us to calculate their relative potencies (described by potency ratio (M))

M= EC50(test)/EC50(standard)
or log M = logEC50(test) - logEC50(standard)

Question 19

what does it mean if drug A is 20x more potent than drug B?

Answer 19

need 20x more of drug to achieve same sized response

Question 20

what does an M value of less than 1.0 indicate?

Answer 20

means that the test drug is more potent than the standard

the equation:
M= EC50(test)/EC50(standard)

Question 21

What is M (potency ratio) when drug A has an EC50 of 15μm and drug B has an EC50 of 300μm?

Answer 21

M= EC50(test)/EC50(standard) 
15/300 = 0.05

M less than 1 therefore means drug A (test drug) is more potent than drug B (standard)

Question 22

what is a bioassay?

Answer 22

• techniques used to determine relative potency of drug
• measured via biological response drug produces
• ranges from cells growing in tissue culture to clinical trials in humans
  e. g. 2 + 2 bioassay

Question 23

what is the “2+2 bioassay” ?

Answer 23

• simplest bioassay for determining the relative potency of 2 drugs
• 2 conc of 2 drugs
• if lines parallel than should be same mechanism (that drugs act by)
• quickly determine M (potency ratio)
• makes use of linear part of S in log drug conc graph

Question 24

what is the “therapeutic index?”

Answer 24

• ratio between toxic dose of drug & dose that produces desired therapeutic effect
• high = lower chance drug produces toxic side effects
• = LD50/ED50 (LD lethal dose in 50% of population, ED50 = effective dose in 50% of population)

Question 25

why is the ratio used to calculate the therapeutic index no longer used?

Answer 25

• other side effects to consider apart from just death

- unethical to kill animals to obtain LD50 values in animals

Question 26

what is the ratio used to calculate the therapeutic index?

Answer 26

TI = LD50/ED50

Question 27

what does it mean if a drug has a therapeutic index (TI) of 1000?

Answer 27

• would have to take 1000x more times the drug to cause harm than produce desired TI
  (note: unlikely for patient to OD b/c they’ve taken 1000x too much of drug - so drug is quite safe)

Question 28

In humans how can the therapeutic index be calculated?

Answer 28

TI (in humans) = TD50/ED50

- the TD50 is the “toxic” dose in 50% of the population (look for dose that produces some sign of toxicity e.g. nausea)

Question 29

when calculating TI in humans using TD50, why do we still need to treat it with caution?

Answer 29

• wide person to person variation in both toxic and beneficial effects of drugs
• drug can have different ED50 values depending on conditions being treated (e.g. ibuprofen treating headache or arthritis)