Pharmacodynamics Flashcards
why is the “magic range” of drug MW value between 100 and 1,000
too large, drug has a hard time getting around in the body
too small, drug has too many off-target interactions and binding is too loose because it is tiny (trouble with specificity)
what is the intrinsic response of antagonists
none - they only block action of agonists by binding to receptors, they do not produce any pharmacological response
_____ determines the quantitative relationship between drug dose and pharmacological response
what 2 factors dictate this relationship
RECEPTORS determine quantitative relationship between drug dose and pharmacological response
dictated by:
1. number of drug-bound receptors (dependent on affinity)
2. total number of receptors (determines maximal effect)
number of drug-bound receptors is determined by ______
equilibrium dissociation constant, Kd
measure of affinity of drug for receptor
[remember that LOW Kd = HIGH affinity]
how do you describe the quantitative relationship between drug effect (E) and drug dose (D)
E = [D]xEmax
————-
[D] + EC50
EC50 = effective drug concentration that produces 50% of max effect
when are semilog plots of E (effect) vs log[D] (drug concentration) useful?
allows for greater range of drug concentrations to be examined
shape of curve changes from hyperbolic to sigmoidal
EC50 is found at inflection point of curve (where slope stops increasing, starts decreasing)
Emax is found at plateau (just like in hyperbolic curve)
drug potency is determined by ___ value
low EC50 = HIGHER potency
less drug required to produce desired effect
also minimizes potential for adverse effects to arise (because less drug is needed)
drug efficacy is determined by ____ value
HIGH Emax = HIGH efficacy
drugs that elicit higher max effect are more efficacious
potency vs efficacy
potency: how much drug do I need to elicit a response? (depends on EC50)
efficacy: what is the largest response this drug can elicit? (depends on Emax)
by definition, a partial agonist has lower _____ than a full agonist
partial agonists are ALWAYS less EFFICACIOUS (Emax) than agonists
however, potency (EC50) may be the same or more
because antagonists have no intrinsic activity, how do you measure their impact?
plot graded dose-response curve of an agonist in the presence of differing concentrations of antagonist
log[D] on x-axis of dose-response curve will ALWAYS ALWAYS be an agonist**
2 types of antagonist and their definitive principle (in pharmacology)
competitive - reversible (and can be overcome by high concentrations of agonist)
non competitive - irreversible
what is a characteristic limitation of competitive antagonists
effect is reversible, and with a high enough concentration of agonist present antagonist can be overcome
in a graded dose-response curve of an agonist in the presence of a competitive antagonist, what parameter will NOT change
Emax will NOT change - inhibition can be overcome by increasing concentration of agonist (efficacy is unchanged)
EC50 will increase, making the agonist appear less potent
match:
beta-blocker
proton pump inhibitor
competitive antagonist
non-competitive antagonist
beta-blocker: competitive antagonist of NE/E
proton pump inhibitors (Prilosec): non competitive/irreversible antagonist of proton pump in stomach lining, preventing acidification of gut
what is the effect of noncompetitive antagonists on the graded dose-responses curve of an agonist
EC50 (potency) is unchanged (curve is NOT shifted right)
Emax (efficacy) is DECREASED (curve does not reach maximal plateau)
irreversible antagonists bind receptors permanently, effectively taking those out of the pool of available receptors (this is not overly toxic because cells can make more receptors)
chemical antagonism
one drug may antagonize the actions of a second drug (by binding to it)
example: Protamine (positively charged) antagonizes anticoagulant actions of Heparin (negatively charged) by binding Heparin in electrostatic manner
pharmacokinetic antagonism
referred to as drug-drug interaction
drugs induce metabolism of other drugs, thereby antagonizing actions of metabolized drugs
example: Phenobarbital induces metabolic clearance of anticoagulant Warfarin
drug selectivity for a certain tissue can arise from over-expression of a given receptor, in which case the tissue has ______
what is the effect of this
spare receptors
basically means extra receptors, enhance tissue sensitivity to drug
expression of more receptor than is needed for max response —> agonist can induce maximal response without binding all available receptors
you can use a low dose and target this specific tissue without effecting anything else!
how can you demonstrate (using dose-response curve) the presence of spare receptors?
create graded dose-response curve of agonist in presence of increasing irreversible antagonists
irreversible antagonist SHOULD decrease Emax
BUT, when there are spare receptors, Emax is unchanged until there are no more spare receptors (at high antagonist concentration)
ALSO, there will be a right shift (increasing EC50) as irreversible antagonist decreases number of spare receptors, until there are none left, and EC50 begins to stay the same
how will EC50 and Emax appear on a graded-dose response curve of an agonist in the presence of an irreversible antagonist, when the agonist is acting in a tissue with spare receptors?
until irreversible antagonist blocks the rest of the spare receptors (at high concentrations)…
EC50 INCREASES (less potent) with increasing [antagonist]
and
Emax says the SAME
2 key limitations of graded dose-response curves
- difficult to construct when pharmacological response is “either-or” (aka, quantal event)
- graded dose-response profile in an individual may have limited applicability to others (inter-individual variability)
how can limitations of graded dose-response curves be overcome
quantal dose-response curve: determining dose of drug required to produce specific response in multiple individuals
plots cumulative % of individuals responding versus log(dose)
quantal dose response = done in a person, information comes from clinical trails
median effective dose (ED50): dose at which 50% of individuals exhibit response
%max: max percentage of individuals that ultimately exhibit the response
what parameters are measured in quantal dose-response curves
quantal = done in people (clinical trials)
ED50: median effective dose, dose at which 50% of individuals exhibit response (measures potency)
%max: max % of individuals that ultimately exhibit response (measures efficacy)
in quantal dose-response curves, what measures potency and what measures efficacy
ED50 = potency
%max = efficacy
how do you measure how safe a drug is
therapeutic index = TD50/ED50
TD50: median toxic dose, dose at which 50% of individuals experience toxic response
TI is the margin of safety, should be HIGH
Penicillin has a therapeutic index of 25-30… is this drug safe?
YES
TI = TD50/ED50
so safe drugs have high TI (wide margin of safety)
you want the toxin dose-response curve to be very far right of the effective dose-response curve
what therapeutic index indicates a toxic drug?
less than 5
TI = TD50/ED50
*ideally, want a TI of at least 10
drug prescriptions must have 3 pieces of information (regarding the drug):
- identity of drug
- dose of drug
- frequency of administration
in pharmacotherapeutic decision making, drug selection is based on ____ and ____ ,
dose of drug is determined by _____ ,
and frequency of drug is dictated by _____
drug selection: efficacy and toxicity
dose: potency
frequency: pharmacokinetic properties
