Lecture 3: Principles of Drug action 1 - the conc-response relationship Flashcards
Describe the conc-response relationship
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
what are 3 important points regarding the conc-response response curve?
- 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)
Response to drug concentration is determined by the type of experiment performed. What are the three main types of pharmacological experiments
1) in vitro (in test tube)
2) in vivo (in living)
3) ex vivo (in between)
in vitro
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
in vivo
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
ex vivo
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
describe the concentration axis for concentration-response curves
for log conc curve:
- (in vitro experiments)conc expressed in moles per lire i.e. molar (M) (to ensure same number of molecules)
very potent drugs act at what concentration?
low concs
- 1 x 10^-6 M to 1 x 10^-12 M
- more doses in lower potency = better
constructing conc-response curve (in vitro)
- 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
measurements for doses in vivo
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)
What is the maximal effect (Emax)?
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
what is the EC50?
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)
What are the two key parameters of pharmacodynamics
- the maximum response (Emax) and the concentration producing 50% of Emax (C50)
how is the potencty of a drug found and what does it describe?
found by EC50
- describe conc that effective
- potent drug = effective in very small amounts (low EC50 = high potency)
- range where drug = effective (therapeutic window)
how are relative potencies found?
compare EC50 values of drugs w/ same action
why is it not possible to use molar concentrations for experiments in vivo?
because the volume of the solvent (e.g. blood) isn’t known
a lower EC50 indicates what about the potency of a drug?
the lower the EC50, the more potent the drug is
how is the potency ratio calculated?
- 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)
what does it mean if drug A is 20x more potent than drug B?
need 20x more of drug to achieve same sized response
what does an M value of less than 1.0 indicate?
means that the test drug is more potent than the standard
the equation:
M= EC50(test)/EC50(standard)
What is M (potency ratio) when drug A has an EC50 of 15μm and drug B has an EC50 of 300μm?
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)
what is a bioassay?
- 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
what is the “2+2 bioassay” ?
- 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
what is the “therapeutic index?”
- 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)
why is the ratio used to calculate the therapeutic index no longer used?
- other side effects to consider apart from just death
- unethical to kill animals to obtain LD50 values in animals
what is the ratio used to calculate the therapeutic index?
TI = LD50/ED50
what does it mean if a drug has a therapeutic index (TI) of 1000?
- 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)
In humans how can the therapeutic index be calculated?
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)
when calculating TI in humans using TD50, why do we still need to treat it with caution?
- 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)
