Lecture 2 Part 1 Flashcards
therapeutic and/or toxic effects of drugs result from what?
their interactions with molecules within patient
true or false
all drugs act by associating with specific receptors (macromolecules) in ways that alter the receptor’s biochemical or biophysical activities
FALSE
most, but not all
“the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects”
drug receptor
what is the “chain of biochemical events” that occurs when the receptor interacts with the drug
signal transduction pathway
what has become the central focus of investigation of drug effects and their mechanism of action?
drug receptors
(pharmacodynamics)
what 2 people observed things that made drug receptors the central focus of investigation of drug effects/mechanism of action
John Langley
Paul Erlich
what did john langley notice
Curare did not prevent the electrical stimulation of muscle contraction, but DID block contraction that was triggered by nicotine
what did Paul Erlich discover
some synthetic organic agents had anti-parasitic effects while other agents didn’t
name 4 ways in which the receptor has important practical consequences for the development of new drugs and therapeutic decisions
-receptors are sites of binding for drugs
-receptors are responsible for selectivity of drug action
-receptors mediate the actions of both AGONISTS AND ANTAGONISTS (both need to bind)
-receptors determine the quantitative relationships between dose/concentration of a drug and pharmacological effects
what properties are important for selectivity
size
shape
charge
atomic composition
true or false
receptors mediate the action of agonists but not antagonists
FALSE - both.
both need to bind to the receptor
true or false
all receptors are proteins
FALSE - most receptors are proteins
what are the BEST CHARACTERIZED drug receptors?
regulatory proteins that mediate the actions of endogenous chemicals signals
(like neurotransmitters, hormones, and autacoids)
besides regulatory proteins that mediate actions of endogenous chemicals, name 3 other classes of proteins that have been clearly identified as drug receptors
-enzymes
-transport proteins
-structural proteins
true or false
enzymes are receptors
true
true or false
enzymes are receptors that may be inhibited or activated by drugs
true, but inhibit is more common
give an example of an enzyme that is a receptor for a drug
DHFR (dihydrofolate reductase) is the receptor for methotrexate (antineoplastic)
give an example of how transport proteins can be drug receptors
the receptor for cardioactive digitalis glycosides = Na+/K+ ATPase
how can structural proteins function as drug receptors
tubulin = protein involved to maintain cellular integrity.
tubulin = receptor for colchicine – an anti-inflamm agent for gout
what is the receptor for colchicine
tubulin (a structural protein)
what is the receptor for methotrexate
DHFR (enzyme)
dihydro folate reductase
when is the relationship between dose and response potentially quite complex? when is it simple and can be described with mathematical precision
complex - when administered to a human
simple - in vitro studies
in intact patients or animals, the responses to low doses of drug usually ________ in proportion to dose.
however….
increases in direct proportion
as the dose continues to increase, the response increment diminishes and doses can finally be reaches at which no further increase in response can be achieved
what is an “idealized” system
in vitro
in idealized/in vitro systems, how is the relationship between drug concentration (C) and effect (E) described?
by a hyperbolic curve.
equation:
E = Emax * C / C + EC50
what is EC50
the concentration of drug at which HALF OF MAXIMAL response is observed
true or false
EC50 is 50% of the response
false – doesn’t fit if it’s a partial agonist
should be - “Half of maximal response” or “drug conc that produces half of maximal effect”
what is Emax
the maximal response that can be produced by a drug
what is the formula for the relation between bound and unbound drug?
explain
B = Bmax * C/ C + KD
B = drug bound to receptors
Bmax = total conc of receptor sites
C = conc of unbound drug
KD = equilibrium dissociation constant, represents the conc of FREE DRUG at which half-maximal binding is observed
explain what KD is
equilibrium dissociation constant
represents the concentration of FREE DRUG at which HALF MAXIMAL BINDING is observed
characterizes the receptor’s affinity for binding the drug
if KD is high, what does this say about binding affinity
LOW
bc KD represents the concentration of FREE DRUG at which half maximal binding is observed
KD characterizes the receptor’s ______
AFFINITY for binding the drug (RECIPROCAL - meaning the higher the KD the lower the affinity)
true or false
when a receptor is occupied by an agonist, the resulting conformational change is the only step required to produce a pharmacological effect
FALSE
this is the first of many steps.
there is a transduction process called COUPLING
the efficiency of receptor occupancy-response coupling is partially determined how?
by the initial conformational change in the receptor
explain what spare receptors are
receptors are “spare” when the maximum response can be obtained by an agonist at a concentration that DOES NOT RESULT IN FULL OCCUPANCY OF THE AVAILABLE RECEPTORS
TRUE OR FALSE
spare receptors are different from nonspare receptors
false - they’re the exact same
the drug (agonist) is just very efficient bc it is able to produce a full response without occupying all of them
true or false
spare receptors are not hidden or unavailable
true – they’re there and available, just not needed
true or false
when spare receptors ARE occupied, they can be coupled to a response
true
true or false
KD is the concentration of the agonist at which half the receptors are bound
TRUE
when the agonist binds to its receptor, it elicits what?
this enables what?
a change in receptor conformation enables the receptor to bind to and activate a TRANSDUCING MOLECULE
In the case of having spare receptors, this means that there are less drug receptors than receptor-effector molecules
TRUE OR FALSE
FALSE – more drug receptors than receptor-effector molecules
a cell has 4 receptors and 4 effectors
are there any spare receptors?
no.
what can you say when an agonist is present in concentration EQUAL TO KD
50% of the receptors will be occupied.
half of the effectors will be activated, and thus a half maximal response will be produced
an agonist is present at a concentration equal to KD.
the number of receptors increases 10 fold, and the total number of effectors remains constant.
are there any spare receptors?
yes - most of them are spare
this means that the drug is producing its maximal effect, even though only half of the available receptors are occupied
true or false
when there is a situation with spare receptors, a low concentration of agonist is usually sufficient to produce a maximal response
true
true or false
antagonists have affinity but no efficacy
true
explain the effect of antagonists
they bind to the receptor but do not activate it.
they essentially BLOCK agonists (drugs/other endogenous regulatory molecules) from binding to and activating receptors
how can antagonists be divided?
reversible antagonists (competitive inhibitor)
irreversible antagonists (non competitive inhibitor)
true or false
reversible antagonists are also known as noncompetitive inhibitors
FALSE
competitive. they are competing for the same binding site.
therefore, increasing the concentration of the agonist can “reverse” the effects of the reversible antagonist
explain the difference you would expect to see in a graph of agonist effect vs agonist concentration with:
-agonist
-agonist + competitive inhibitor
EC50 would be pushed to the right once the competitive inhibitor enters the picture
a higher dose of agonist would be needed to produce the normal agonist effects.
true or false
EC50 is higher in the agonist than with agonist + competitive inhibitor
FALSE - higher with competitive inhibitor. more drug needed to produce same response
true or false
for any fixed concentration of competitive antagonist, the emax will remain the same for the agonist
true – the concentration effect curve will just shift to the right and more dose will be needed to produce the SAME EMAX
in a fixed concentration of competitive antagonist, a higher concentration of agonist is needed to produce a given effect (higher than the dose needed with just the agonist itself).
how can the ratio of these 2 agonist concentrations be estimated?
the SCHILD EQUATION
C’/C = 1 + ([I]/KI)
KI = dissociation constant of the antagonist
C’ = agonist concentration
I = concentration of antagonist
true or false
in the presence of a fixed concentration of competitive antagonist, lower concentrations of agonist are required to produce a given effect
FALSE - higher concentrations are needed
the degree of inhibition produced by a competitive antagonist is dependent on what?
THE CONCENTRATION OF THE ANTAGONIST
true or false
in the case of a reversible antagonist, increasing the concentration would increase the inhibition of agonist
true
what is a source of variability in clinical response to a competitive antagonist?
the concentration of agonist that is competing for binding to the receptors
the higher the concentration of the agonist, the better the response
phenoxybenzamine
will destroy the receptor
under circumstances where there is only agonist, only agonists can bind to the receptor.
when all the receptors are saturated, what do we see?
the maximal effect (EMAX)
TRUE OR FALSE
antagonists bind to receptors, but do not activate those receptors
true
true or false
when there is both agonist and antagonist, they can both bind to the receptor
true
in the presence of competitive antagonists, the maximum effect will be diminished.
is there any way to over come this and still produce the maximum effect?
yes – by adding more agonist
true or false
even at very low concentrations of reversible antagonist, the efficacy is still diminished
FALSE
if there is a lot of agonist, little amounts of competitive antagonist won’t affect the efficacy
at higher concentrations, efficacy will eventually start to decrease
true or false
if there is a high enough concentration of competitive antagonist, ALL of the agonist may be displaced and replaced with antagonist
true
true or false
in the presence of noncompetitive antagonist, increasing the concentration of agonist won’t do anything
true
true or false
in the case of noncompetitive/irreversible antagonists, the antagonist’s affinity for the receptor may be so high that, for practical purposes, the receptor is UNAVAILABLE for binding of agonist
true
give an example of irreversible antagonist
they produce covalent bonds with the receptor – irreversible effects (phenoxybenzamine)
is EMAX decreased in the case of noncompetitive antagonists?
YES
at a certain point, when a lot of receptors are occupied by antagonist, the # of remaining unoccupied receptors may be too low for the agonist to elicit a maximal response (EVEN AT HIGH CONCENTRATION)
true or false
with noncompetitive inhibitor, EC50 increases
false
it may remain the same
true or false
covalent binding is an example of a competitive antagonist
FALSE – noncompetitive/irreversible
in what case would a lower dose of irreversible antagonist still allow the achievement of a maximum response to the agonist?
if spare receptors are present
when all receptors have been saturated with an irreversible antagonist, the addition of MORE AGONIST will NOT re-establish the response
TRUE OR FALSE
TRUE
true or false
an agonist is unable to displace an irreversible antagonist, even at very high concentrations of agonist
true
give a specific example of an irreversible antagonist and how it works
Phenoxybenzamine
an irreversible alpha adrenoceptor antagonist.
used to control hypertension caused by catecholamines released from a tumor of the adrenal medulla
give the name for a tumor of the adrenal medulla.
what drug can be used to treat it?
pheochromocytoma
phenoxybenzamine – an irreversible alpha-adrenoceptor antagonist
give an example of how the irreversible antagonist - phenoxybenzamine - provides a therapeutic advantage
even when the administration of phenoxybenzamine lowers, blood pressure will still be maintained, even when the tumor releases very large amounts of catecholamine
(bc it is an irreversible antagonist!!)
explain a major therapeutic disadvantage of the irreversible antagonist - phenoxybenzamine
overdose can cause major issues
if the blockade of the alpha-adrenoceptor cannot be overcome, the excess effects of the drug must be antagonized “physiologically” – by using a pressor agent (anti hypotensive agent) that does NOT act via alpha receptors
catecholamines cannot displace phenoxybenzamine to combat its function bc it is an IRREVERSIBLE antagonist
what happens when catecholamines bind to alpha adrenoceptors?
catecholamines act as agonists to stimulate an increase in blood pressure
what happens in the case of a patient with pheochromocytoma
this adrenal medulla tumor will secrete excess catecholamines
these act as agonists to the alpha adrenoceptor and cause an excess increase in blood pressure
true or false
catecholamines can displace phenoxybenzamine from the alpha adrenoceptors
FALSE
phenoxybenzamine is an irreversible antagonist and thus cannot be displaced by agonist
