Relationship btw amount of drug and effect Flashcards
what relationships are linear?
dose of drug and [drug] at target site
[drug-receptor complex] and response
Dose response causal chain
dose of drug -> drug at target site -> drug-receptor complex -> response
what relationships are non linear?
[drug] at target site -> [drug receptor complex]
what is the dominant non linear relationship in the causal chain?
formation of the drug-receptor complex
what does the drug-receptor complex determine?
the shape of the dose-effect and the concentration-effect relationships
A plot of [D]free versus [R-D] is
hyperbolic
A plot of log [D]free versus [R-D] is
sigmodial
A plot of [D]free versus response is
hyperbolic
A plot of log [D]free versus response is
sigmoidal
The [drug] which causes 1/2 maximal response is called
EC50 and corresponds to the Kd if there is a linear relationship between [D-R] and response
Potency refers to
EC50 of a drug
when the assumption of linearity does not hold, the EC50
no longer approximates the Kd
Spare receptors
when present, the EC50 will be much smaller than the Kd
Tissue express “spare receptors” when
only a small fraction of the receptor population must be occupied by drug to give a maximal response
The lower the Ec50, the
greater the potency
A low Kd and high number of spare receptors increases
the potency of the drug
Efficacy
refers to the maximal response of a drug
the greater the maximal response,
the greater the efficacy
The more effectively a drug engages signal-transduction systems in a cell per unit receptor occupied, the
greater is the efficacy of that drug
best in class
Full agonist and any drug that generates a maximal response equal to the “best in class” is also referred to as “full agonist”
Partial agonist
any drug that generates a maximal response less than that elicited by the “best in class”
Even if Drug A is a full agonist and Drug B is a partial agonist, they can still the same what?
Potency
Shape of dose versus Response
Hyperbolic
shape of Log dose vs. Response
sigmoidal
ED50
dose which causes 1/2 maximal response
affected by Kd and EC50 it is greatly influenced by apparent volume in which drug is distributed
ED50 is never equal to
EC50 or Kd
characteristics of surmountable antagonist
produces parallel shift in concentration-response curve of agonist
Full effect of agonist can be restored by increasing concentration of agonist
Common mechanism of surmountable antagonism
competitive interaction between agonist (potency and efficacy) and antagonist (potent but no or little efficacy) at binding site on receptor
The net effect of a competitive antagonist is to increase the apparent
Kd, or said differently to decrease the apparent potency of the agonist
Addition of competitive antagonist causes
apparent shift in EC50 for the agonist
because takes higher concentration for a response
Characteristics of insurmountable antagonist
produce non-parallel shift in concentration-response curve of agonist
full effect of agonist cannot be restored by increasing concentration of agonist
Common mechanism of insurmountable antagonism
competitive but irreversible binding of antagonist to binding site on receptor
allosteric modulation of receptor by antagonist so as to attenuate coupling of receptor to signal transduction
blockade of signal transduction “downstream” of receptor
Quantal effect
is an effect that is either present or absent
Quantal concentration
or dose response curve is a plot of concentration or dose versus % patients in the population who exhibit the quantal response at the given concentration or dose
we represent the effect of a drug in an Individual as a concentration or
dose response curve in which the graded effects of the drug are related to concentrations or doses of the drug
we represent the effect of a drug in a Population as a concentration or
dose response curve in which the Quantal effect of the drug is related to concentrations or doses of the drug
If quantal response happens to be death then ED50 is called
LD50
Although both graded and quantal relationships have ED50s and EC50s, the parameter are
NOT the same for graded and Quantal relationships
Graded relationships
Ed50s and EC50s indicate doses and concentrations that cause 1/2 maximal response in a given individual
Quantal relationships
ED50s and Ec50s indicate doses and concentrations that cause 1/2 of the population to respond
Since the log dose-response curve is sigmoidal, increasing
the dose of a drug when the response is submaximal will enhance the therapeutic effect
Since the log dose-response curve is sigmoidal, increasing
the dose of a drug when the response is maximal will not improve the therapeutic effect but may subject the patient to toxicity
The log dose-response curve is sigmoidal, regardless of whether the
“response” is therapeutic or toxic
The safety of a drug can be assessed by examining the log dose-response curves for
therapeutic versus toxic effects
The more separation between the therapeutic log dose-response curves and the toxic log dose-response curves, the
safer the drug
A drug with low potency and high efficacy may be better than a drug with
low efficacy and high potency
Potency is a determinant of
how much of the drug must be given to obtain a “ceiling” effect
Efficacy refers to the magnitude of
the “ceiling” effect
In an antagonist is being employed to block the effect of an agnoist, it is important to know whether the antagonist is of
surmountable or insurmountable type
Dose of insurmountable antagonist usually does not need upward adjustment as amount of
agonist in body increases
Dose of surmountable antagonist must be increased if amount of agonist (endogenous or exogenous) in the patient
increases
Graded dose/concentration relationships help to understand
how changing dose of drug will effect the degree of response of an individual patient
Quantal dose/concentration relationships help to understand
how changing dose of drug will effect the % of your patients who will experience a defined response
