Pharm 1-2: Receptors I And Ii

Front 1

what is the differnece between pharmacodynamics and pharmacokinetics

Back 1

dynamics-What does the drug do to the body? (mech of action, therapeutic uses, side effects); kinetics-what does the body do to the drug (absorption, distribution, metabolism, elimination)

Front 2

The "three S's" describe why receptors are excellent targets for drugs. Name each and describe  wh

Back 2

specificity-only a subset of receptors are affected by the drug; selectivity-only a subset of signal transduction pathways will be affected; sensitivty-effects at receptors are amplified within the cell, only small amount of drug is needed

Front 3

define Kd

Back 3

Kd=k2 (dissociation)/k1 (association), Kd=[L]*[R]/[LR] it is the equilibrium, dissociation constant which describe the goodness of fit between ligand and receptor, it is the concentration of L at which 1/2 of Rt is acheived it is inversley related to afffinity,

Front 4

what is the relationship between Kd and affinity

Back 4

inverse, a low Kd is a high affinity

Front 5

What is the occupancy at Kd

Back 5

50%, Kd is definted at the [L] at which 1/2 Rt is acheived

Front 6

which type of bond is the major determinant of K1, the association constant

Back 6

ionic bonds

Front 7

Which type of bond is the major determinant of K2, the dissociation constant

Back 7

Van der Waals interactions

Front 8

define mathematically the concentration of LR complexes

Back 8

[LR]= (Rt *[L])/ (Kd +[L])

Front 9

Why is the concept of intrinsic activity necessary?

Back 9

occupancy theory states that maximal effect occurs when all receptors are bound. this does not explain the effects of ligands that do not produce an effect or any effect at all. Intrinsic activity states describes the effect as proportional to the fraction of occupied receptors and the ligands ability to lead to the effect

Front 10

E/Emax is proportional to

Back 10

E/Emax= a*(LR/Rt)

Front 11

what is the difference between affinity and intrinsic activity

Back 11

affinity-does the key fit the lock? IA-does the key turn the lock? E.g. a full antagonist has a high affinity but no intrisic activity, it binds the receptor but does not induce the effect

Front 12

What are the alpha values for an agonist, antagonist and partial agonist

Back 12

agonist=1, antagonist=0, partial 0<a<1

Front 13

define Ec50

Back 13

the concentration of ligand at which 1/2 of the maximal effect is achieved. Analogus to Kd, the concentration of L at which 1/2 of the receptors are occupied. Note however that these are not equal since occupancy does not necesarily equal effect

Front 14

How could Ec50 nto equal Kd

Back 14

Kd is the concentration where 1/2 of the receptors are occupied, EC50 is the concentratoin at which 1/2 of the max effect is achieved. Because of varying intrinsic activities, occupancy does not necesarily equal effect. Therefore, a concentration at which 1/2 of the receptors are occupied may not achieve 1/2 of the Emax

Front 15

What is the function of spare receptors in a cell

Back 15

Spare receptors increase the sensitivity of the cell to a low concentration of ligand. For a given [L], we know that the % occupancy will be the same, thus a cell with more receptors will have a high aboslute number of receptors bound to ligand. Assuming the cells have the same number of effectors, the cell with more receptors engaged will activate more effectors

Front 16

How is occupancy calculated

Back 16

[LR]/Rt=[L]/(Kd+[L])

Front 17

Antagonists include chemical, physiological, and pharmacological. Describe how each works

Back 17

1. chemical=combines with the agonist to prevent interaction with site of action 2. physiological-activates an opposing physiological input 3. pharmacological-blocks the effects of teh agonist at its site of action

Front 18

Where does a competitive antagonist bind

Back 18

exactly the same site as the agonist

Front 19

Conceptually, how can you tell if an inhibitor will affect the Emax of the receptor

Back 19

Ask whether or not increase the substrate concentration can overcome the effect of the inhibitor/ did you modify the ability of the enzyme to carrry out its action when given the chance? For competitive inhibitors, increase the substrate concentration overcomes the effect so Emax is unchanged. For non-competitive, the enzyme/ receptor is modify in such a way that it cannot achieve Emax even when [S] is high

Front 20

Conceptually, how can you tell if an inhibitor will change Ec50

Back 20

Ask if the inhibitor interfers with substrate binding. If

Front 21

How is EC50' calculated

Back 21

EC50'=EC50 (1+ ([antagonist])/ ki), the impact of the antagonist on the EC50 depends on both the concentration of the antagonist and its affinity for the receptor

Front 22

What is the effect of a competitive inhibitor on Emax

Back 22

no change, increasing the substrate concentration can overcome the inhibitor, the ability of the receptor to carry out the function is unchanged

Front 23

What is the effect of a competitive inhibitor on EC50

Back 23

the EC50 increases because more substrate is needed to reach 1/2 Emax because the inhibitor is getting in the way

Front 24

WHat is the effect of an irreversible competitive antagonist on Emax

Back 24

Emax is reduced (after the spare receptors are used up) because there are less receptors available to complete the function

Front 25

What is the effect of an irreversible competitive antagonist on EC50- assuming all spare receptors are used up

Back 25

The EC50 is not changed because the remaing receptors function normally, the receptors that have not been bound by the inhibitor function at their full capacity

Front 26

What are the therapeutic implications of a non-equilibrium (irreversible competitive) antagonist

Back 26

1. new receptor synthesis is the only way to overcome the effects, this takes time so effect lasts longer 2. the degree of inhibition produced is not influenced very much by the concentration of agonist present THese drugs are good for treating conditions where there is too much agonist or the concentration of agonist is very variable e.g. pheochromocytoma and phenoxybenzamine

Front 27

what is the effect of a noncompetitive pharmacological antagonist on Emax

Back 27

Emax is reduced, adding more agonist will not overcome the effect, the ability of the receptor to carry out its function is decreased

Front 28

What is the effect of noncompetitive pharmacological antagonist on EC50

Back 28

no change-the antagonist does not prevent the substrate from binding to the receptor, for the given possible Emax, the same EC50 is required

Front 29

What are therapeutic implications of a noncompetitive pharmacological antagonist

Back 29

1. antagonist effet is essentially indpendent of agonist concentration at the receptor 2. can be used to inhibit the effects of multiple agonists that use the same signal transduction cascasde

Front 30

A partial agonist/ antagonist can have both an agonist and antagonist effect. How is this possible?

Back 30

WHen a partial agonist is present alone, it acts like an agonist (something is better than nothing). When the PA is present in combintaion with a full agonist, there is an antagonist like effect because the partial presents the full from eliciting the full possible Emax, similar to a compeitive antagonist (no change in emax, increase in EC50)

Front 31

Describe how agonists and antagonists influce tonically active receptors

Back 31

agonists shifts the equilibrim of the receptor towards the active form, a true antagonist has no effect and does not effect the equilibrium. Do not confuse an antagonist with an inverse agonist which shifts the equilibrium towrads the inactive form of a receptor

Front 32

Given that some receptors can be tonically active, what is the difference between an antagonist and an inverse agonist

Back 32

an antagonist prevents the receptor equilibirum from shifting towards one form or another. An inverse agonist decreases the tonic activity of the receptor by shifting the equilibrium towards the inactive form (contrast to agonist which shifts towards the active form)

Front 33

define potency

Back 33

the relationship between the amount of drug administered and its effect, mirroed by the position of the  efficacy curve on the X axis, inversley related to the EC50

Front 34

what is the relationship between EC50 and potency

Back 34

inverse. a low EC50 is a highly potent drug

potency is the relationship between the amount of drug administered and its effect

Front 35

define efficacy

Back 35

the maximal effect that is produced by  a drug

Front 36

What do the axis in the dose response curve represent

Back 36

x=potency, described by the EC50, y axis= efficacy

Front 37

describe a log normal distribuiton

Back 37

in a population, the frequency of response to a drug vs. the log of the dose follows a normal distribution curve, 68%, 95%

Front 38

describe a cumulative frequency distribution

Back 38

Graphs the relationship between % of total population responding to the log dose

Front 39

list two determinants of potency

Back 39

affinity of drug for site of action, ability to reach site of action (metabolic rate , can have high affinity but low potency)

Front 40

List three determinants of efficacy

Back 40

intrinsic activity, characteristics of the effector, limitations on the amount of drug that can be used

Front 41

List some reasons why a drug may derrivated from an idealized dose response curve

Back 41

additive effects, threshold effects, antagonist effects

Front 42

list some reasons why induvidual responses to drugs vary

Back 42

pharmoacokinetic, variations in endogenous receptor amount,  changes in number or function of drug target, differences in a component distal to the drug target

Front 43

Define idiosyncratic drug responses

Back 43

unexpcted response based on the mechanism of action of the drug

Front 44

Define hyporeactive or hyperreactive response

Back 44

individual at the tail ends of the frequency distribution, require very low/ high doses for response

Front 45

Define hypersensitivity

Back 45

allergic or inflammatory response to the drug

Front 46

define tolerance

Back 46

slowly developing resistance to the drug
(contrast to tachyphylaxis, a rapid resistance)

Front 47

define tachyphylaxis

Back 47

rapidly developing resistance to the drug

Front 48

Define therapeutic index

Back 48

TI=TD50/ ED 50, safer drugs have higher TI values