LEC12-13: Pharmacodynamics I & II

Question 1

what’s the broad definition of a drug?

Answer 1

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

Question 2

what is pharmacodynamics?

Answer 2

“what the drug does to the body”

the principles relating drug concentration (dose) to effect

based on principles of enzyme kinets

Question 3

what is pharmacokinetics?

Answer 3

“what the body does to the drug”

Question 4

what is pharmacotherapeutics?

Answer 4

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

Question 5

how do drugs tend to produce their effects?

Answer 5

by binding to protein targets

4 major drug targets are: enzymes, receptors (transmembrane), carriers, ion channels

Question 6

what is a drug’s “receptor”? what is the receptor’s “ligand”?

Answer 6

a drug’s target. commonly:

enzymes, channels, GPCRs

drug is a “ligand”

Question 7

what kind of graph do we use to plot effect of a drug?

Answer 7

Question 8

are drugs specific or selective for a target?

Answer 8

**never specific, only selective, **for a particular target

and, at sufficiently high dose (sometimes within the therapeutic range), all drugs significantly affect multiple targets

Question 9

what is the michaelis-menten equation for drugs? explain the variables

Answer 9

B_max: maximum # of binding sites available to the drug, the maximum effect

K_D: drug concentration at which 1/2 sites are bound

Question 10

what are drug agonists?

Answer 10

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)

Question 11

why does an agonist’s binding and effect curve look exactly the same, usually?

Answer 11

because there’s usually linearityy between binding and effect

Question 12

what is the EC₅₀ of a drug?

what is its in vivo metric?

Answer 12

the concentration that produces 50% of the maximum effect that this drug can produce

invivo equivalent is ED₅₀, the dose effect

Question 13

what is E_max?

Answer 13

the maximum effect that this drug can produce

Question 14

what is a full agonist?

Answer 14

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

Question 15

what is efficacy re: drugs?

Answer 15

the limit to the effect that can be produced by a drug in a given tissue, organ, or cell

Question 16

what are partial agonists?

Answer 16

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

Question 17

what distinguishes full agonists from each other?

Answer 17

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

Question 18

what is the difference btwn a full and partial agonist?

Answer 18

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

Question 19

what are spare receptors?

Answer 19

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”

Question 20

what is the relationship btwn a full agonist’s binding and effect curve?

relationship between K_D and EC₅₀?

Answer 20

binding curve is to the right of effect curve

EC₅₀ < K_D

Question 21

what is the relationship between the binding and effect curve for a partial agonist?

what’s the relationship between K_D and EC₅₀?

Answer 21

they are on top of each other

b/c every available receptor must be saturated in order to get the downstream effect

K_D=EC₅₀

Question 22

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

Answer 22

metric by which full agonists differ

affinity is inversely proportional to K_D

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

Question 23

what is potency of a full agonist?

relationship between concentration of a drug needed for a given response and potency?

Answer 23

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

Question 24

what determines potency?

what do the most potent full agonists have re: these factors?

Answer 24

1) affinity
2) intrinsic efficacy

most potent full agonists have high affinity and high intrinsic efficacy

Question 25

which drug is more potent?

Answer 25

agonst A is more potent than agonist B because its EC₅₀ is smaller

Question 26

which drug is more potent?

if the therapeutic goal is to reduce bp by 30 mmHg, which is more potent?

Answer 26

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

Question 27

what is an inverse agonist?

Answer 27

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*

Question 28

what is the intrinsic efficacy of a full vs. partial agonist?

Answer 28

full agonist intrinsic efficacy > partial agonist intrinsic efficacy

Question 29

what is an antagonist?

Answer 29

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

Question 30

what is a competitive vs noncompetitive antagonist?

Answer 30

competitive: competes w/ an agonist for a binding site
noncompetitive: binds elsewhere, even on a different protein, and blocks response to agonist that way

Question 31

what are reversible vs irreversible antagonists?

Answer 31

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

Question 32

what is a reversible competitive antagonist’s effect on an agonist’s binding and effect curves?

what is the extent of this shift?

Answer 32

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

Question 33

what is the extent of the shift of the concentration-response curve for an agonist in case of a reversible competitive antagonist?

Answer 33

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

Question 34

what is pA₂?

Answer 34

parameter used to compare the abilities of different competitive antagonists to inhibit agonist-induced responses

pA₂ = pK_a

Question 35

what does it mean if pA₂ is large?

Answer 35

if pA₂ is relatively large, a relatively **low **antagonist concentration is sufficient to effectively block the response to an agonist

Question 36

does an antagonist’s pA₂ hold for the antagonist at all receptors?

Answer 36

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

Question 37

can an antagonist have potency?

Answer 37

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”

Question 38

how can a partial or inverse agonist act as a reversible competitive antagonist?

Answer 38

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

Question 39

what is a noncompetitive antagonist?

Answer 39

binds to a site other than the agonist binding site

antagonism lasts only as long as the antagonist is present

Question 40

what is an irreversible antagonist?

Answer 40

covalently modifies the receptor

the longer the exposure, the more receptors modified

effect outlasts the antagonist; recovery only when new receptors are synthesized

Question 41

what is an irreversible or noncompetitive (allosteric) antagonist’s effect on the dose-effect curve?

Answer 41

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

Question 42

what does this curve show?

Answer 42

effect of an antagonist on drug effectiveness decreases over time even in presence of an agonist

Question 43

what % of drugs exist as stereoisomers?

do the enantiomers behave the same?

Answer 43

50% of all drugs exist as stereoisomers

the different enantiomers have very different effects; 1 is many more times effective than theother

Question 44

how do individuals respond to drugs re: each other?

Answer 44

for any drug, individuals differ w/ respect to their responsiveness, due to genetic variations, age, disease, gender, & other factors

Question 45

what is quantal dose-response relationship?

Answer 45

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

Question 46

what does the spread of the distribution represent? what is its variable in the curve?

Answer 46

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

Question 47

what is this curve?

Answer 47

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

Question 48

what is the population ED₅₀?

how about ED₉₉? TD₅₀? LD₅₀?

Answer 48

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)

Question 49

what is a safety index for a drug? how is it calculated?

Answer 49

compare effective doses for therapeutic and lethal effects

therapeutic index = TD₅₀/ED₅₀

certain safety factor = LD₁/ED₉₉

Question 50

which drug has a larger therapeutic index?

Answer 50

penicillin