what's the broad definition of a drug?
a substance of known identity that produces a biological effect,
excuding known nutrients and/or essential dietary constituents
may be endogenous substances - i.e. hormones, neurotransmitters
what is pharmacodynamics?
"what the drug does to the body"
the principles relating drug concentration (dose) to effect
based on principles of enzyme kinets
what is pharmacokinetics?
"what the body does to the drug"
what is pharmacotherapeutics?
the uses of specific drugs to treat disease
including: drug mechanism of action, conditions that contraindicate use of a drug, interactions w/ other drugs and dietary factors
how do drugs tend to produce their effects?
by binding to protein targets
4 major drug targets are: enzymes, receptors (transmembrane), carriers, ion channels
what is a drug's "receptor"? what is the receptor's "ligand"?
a drug's target. commonly:
enzymes, channels, GPCRs
drug is a "ligand"
what kind of graph do we use to plot effect of a drug?
are drugs specific or selective for a target?
never specific, only selective, for a particular target
and, at sufficiently high dose (sometimes within the therapeutic range), all drugs significantly affect multiple targets
what is the michaelis-menten equation for drugs? explain the variables
Bmax: maximum # of binding sites available to the drug, the maximum effect
KD: drug concentration at which 1/2 sites are bound
what are drug agonists?
produce a response by changing the rate of a biological process from its basal rate
almost always, increase above basal activity
has an intrinsic effect on its target
(except inverse agonists, which depress activity below basal rate)
why does an agonist's binding and effect curve look exactly the same, usually?
because there's usually linearityy between binding and effect
what is the EC50 of a drug?
what is its in vivo metric?
the concentration that produces 50% of the maximum effect that this drug can produce
invivo equivalent is ED50, the dose effect
what is Emax?
the maximum effect that this drug can produce
what is a full agonist?
can stimulate a signaling pathway to the maximum extent possible in that tissue
drugs that can produce the full effect
usually, endogenous drugs are full agonists
what is efficacy re: drugs?
the limit to the effect that can be produced by a drug in a given tissue, organ, or cell
what are partial agonists?
drugs that cannot produce the full effect of a system, even when its concentration is sufficient to beind all receptors, because have low intrinsic efficacy
what distinguishes full agonists from each other?
the drug's intrinsic efficacy: the effect that is produce per molecule of an agonist binding to its receptor
full agonist w/ lower intrisic efficacy needs to bind more receptors than a full agonist with higher intrinsic efficacy
what is the difference btwn a full and partial agonist?
the intrinsic efficacy
a receptor bound to a full agonist couples v. efficiently to its downstream molecule- when enough receptors are bound by agonist, the downstream signaling pathway's fully activated, and no larger effect is possible
whereas if that receptor is bound by a partial agonist, even when all receptors are bound by a partial agonist, the downstream mechanism isn't fully activated
what are spare receptors?
for a full agonist, more receptors are available than are needed to produce the maximal effect; those in excess are spare receptors
full agonist w/ low intrinsic efficacy is said to have "fewer spare receptors"
what is the relationship btwn a full agonist's binding and effect curve?
relationship between KD and EC50?
binding curve is to the right of effect curve
EC50 < KD
what is the relationship between the binding and effect curve for a partial agonist?
what's the relationship between KD and EC50?
they are on top of each other
b/c every available receptor must be saturated in order to get the downstream effect
what is affinity of a full agonist?
compare the [drug] needed between a full agonist with high affinity for a receptor versus one with low affinity for a receptor
metric by which full agonists differ
affinity is inversely proportional to KD
full agonist w/ relatively low affinity for a receptor requires a higher [drug] to occupy the same number of receptors as another agonist w/ higher affinity
what is potency of a full agonist?
relationship between concentration of a drug needed for a given response and potency?
its EC50: the [drug] required to prodce 50% of the maximum response or a therapeutically relevant criterion response
the lower required concentration for a given response, the higher the potency
what determines potency?
what do the most potent full agonists have re: these factors?
2) intrinsic efficacy
most potent full agonists have high affinity and high intrinsic efficacy
which drug is more potent?
agonst A is more potent than agonist B because its EC50 is smaller
which drug is more potent?
if the therapeutic goal is to reduce bp by 30 mmHg, which is more potent?
Drug A is more potent than Drug B, its EC50 is smaller
HOWEVER: if therapeutic goal isn't reachable by A (as is the case), drug A cannot be called more potent
what is an inverse agonist?
an agonist that intrinsically decreases the activity of a target protein below its basal activity
requires that the receptor has some activity even when no drug is present
*note that can also get this effect if the drug happens to interfere w/ an endogenous effect; so be careful that this is really the drug*
what is the intrinsic efficacy of a full vs. partial agonist?
full agonist intrinsic efficacy > partial agonist intrinsic efficacy
what is an antagonist?
drug without any intrinsic effect on the activity of its target
produce effect by preventing an exogenous ligand from exerting its effect -
binds to receptor and doesn't changes its activity, but prevents agonist from producing a response
analoous to inhibitors in enzyme kinetics
what is a competitive vs noncompetitive antagonist?
competitive: competes w/ an agonist for a binding site
noncompetitive: binds elsewhere, even on a different protein, and blocks response to agonist that way
what are reversible vs irreversible antagonists?
reversible: antagonists that readily dissociate from their receptors, leaving target protien intact
irreversible: antagonists that caovalently modify receptor, render it permanently inactive; recovery depends on synthesis of new enzyme
what is a reversible competitive antagonist's effect on an agonist's binding and effect curves?
what is the extent of this shift?
if antagonist is competitive and reversible, its antagnoism can be overcome by increasing agonist concentration; antagonist's effect is surmountable
the antagonist shifts the concentration-response curve for the agonist to the RIGHT
what is the extent of the shift of the concentration-response curve for an agonist in case of a reversible competitive antagonist?
extent of shift to the right! depends on [antagonist] and its affinity for the receptor
a given concentration of an antagonist will produce the same size shift for any agonist at that receptor
what is pA2?
parameter used to compare the abilities of different competitive antagonists to inhibit agonist-induced responses
pA2 = pKa
what does it mean if pA2 is large?
if pA2 is relatively large, a relatively low antagonist concentration is sufficient to effectively block the response to an agonist
does an antagonist's pA2 hold for the antagonist at all receptors?
no, the pA2 is a property of the antagonist acting at a specific receptor
its binding to a different receptor will be characterized by a different pA2, since its dissociation constant depends on the receptor type
can an antagonist have potency?
technically, no! antagonists have no intrinsic activity, therefore no potency
however, competitive antagonist with a high pA2 means less antagonist is needed for the desired response- so "more potent"
how can a partial or inverse agonist act as a reversible competitive antagonist?
by occupying receptors, they prevent a full agonist from producing its maximum effect
some drugs even were described 1st as pure antagonists, later became known they were inverse agonists
what is a noncompetitive antagonist?
binds to a site other than the agonist binding site
antagonism lasts only as long as the antagonist is present
what is an irreversible antagonist?
covalently modifies the receptor
the longer the exposure, the more receptors modified
effect outlasts the antagonist; recovery only when new receptors are synthesized
what is an irreversible or noncompetitive (allosteric) antagonist's effect on the dose-effect curve?
if there are spare receptors, can lose receptors to the covalent modification without decreasing the maximum effect of the agonist
the more spare receptors - the higher the intrinsic efficacy of the agonist - the greater the number of receptors that must be modified before 1 sees a decrease in maximal response
what does this curve show?
effect of an antagonist on drug effectiveness decreases over time even in presence of an agonist
what % of drugs exist as stereoisomers?
do the enantiomers behave the same?
50% of all drugs exist as stereoisomers
the different enantiomers have very different effects; 1 is many more times effective than theother
how do individuals respond to drugs re: each other?
for any drug, individuals differ w/ respect to their responsiveness, due to genetic variations, age, disease, gender, & other factors
what is quantal dose-response relationship?
used to quantify the effect of the drug on a population
note the dose that is sufficient to produce the criterion response for an individual, graph these observations as frequency dsitribution for lowest effective dose
what does the spread of the distribution represent? what is its variable in the curve?
spread reflects the variance in the population
= slope of the cumulative curve
steep slope indicates that most individuals response at about the same minimum dose
what is this curve?
population dose-response relationship
spread of distribution reps the variance in the population
narrow spread would indicate that individuals response at abt the same minimum dose
have danger zone- where some ppl respond adversely to effect, some people don't
what is the population ED50?
how about ED99? TD50? LD50?
the dose at which 1/2 the subjects respond to the drug
ED99 is dose at which 99% respond
TD50 is toxic effect in 50% of pop
LD50 is lethal effect in 50% of pop (in animal studies)
what is a safety index for a drug? how is it calculated?
compare effective doses for therapeutic and lethal effects
therapeutic index = TD50/ED50
certain safety factor = LD1/ED99
which drug has a larger therapeutic index?