Lecture 2

Question 1

what is a drug receptor

Answer 1

the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drugs observed effects

Question 2

Drug receptor properties

Answer 2

1) Receptors largely determine the quantitative relations between the dose or concentration of a drug and its pharmacologic effects.

2) Receptors are responsible for the selectivity of drug action

3) Receptors are the sites of binding of pharmacologic agents

Question 3

what is affinity?

Answer 3

property of attraction of a drug for a receptor

1/KD

Question 4

what is the equation of KD?

Answer 4

Rate constant for offset / rate constant for onset
= ( k-1) / (k+1)

Question 5

what is selectivity?

Answer 5

Degree to which a given drug acts on a particular receptor compared to other sites of action of the drug.

Question 6

T/F: Absolute selectivity is likely

Answer 6

False; it is unlikely

Question 7

most receptors are what?

Answer 7

Proteins

Question 8

what does the structure of polypeptides provide?

Answer 8

both the necessary diversity and the necessary specificity of shape and electrical charge.

Question 9

regulatory proteins mediate the action of what?

Answer 9

endogenous chemical signals such as neurotransmitters, autacoids, and hormones

this class of receptors mediates the effects of many of the most useful therapeutic agents

Question 10

Enzymes may be inhibited by

Answer 10

by drugs (e.g. dihydrofolate reductase- DHFR- the receptor for the antineoplastic drug methotrexate)

Question 11

transport proteins are involved in

Answer 11

the transport of ions or other biological molecules Na+/K+ ATPase: the membrane receptor for cardioactive digitalis glycosides

Question 12

structural proteins are involved in the maintenance of what?

Answer 12

cellular integrity

ex: tublin ; the receptor for colchicine, an anti-inflammatory agent

Question 13

what are orphan receptors?

Answer 13

receptors for which no ligands known

Question 14

in carefully-controlled in vitro systems the relationship between __________ of a drug and its ______ is often simple and can be described with mathematical precision

Answer 14

concentration; effect

Question 15

what is an agonist?

Answer 15

A molecule that binds to a receptor and ACTIVATES the receptor and produces biological response

Question 16

Biological molecules are which type of agonist?

Answer 16

endogenous

Question 17

Drug

Answer 17

isoproterenol binding to adrenergic receptor

Question 18

In ideal or in vitro systems, the relationship between drug concentration (C) and effect (E) is described by

Answer 18

a hyperbolic curve according to the equation:

E = Emax x C / C + EC50

Question 19

know this slide

Answer 19

Question 20

the relation between drug bound to receptors (B) and the concentration of unbound drug (C) is described by the equation:

Answer 20

Bmax x C
B = ————-
C + Kd

Question 21

what is Bmax?

Answer 21

the total concentration of receptor sites bound to the drug at infinitely high concentrations of free drug.

Question 22

what is Kd?

Answer 22

the equilibrium dissociation constant represents the concentration of free drug at which half-maximal binding is observed

Question 23

What does Kd characterize?

Answer 23

the receptor’s affinity for binding the drug in a reciprocal fashion

Question 24

If Kd is high, binding affinity is

Answer 24

low

Question 25

If Kd is low, binding affinity is

Answer 25

high

Question 26

know this slide

Answer 26

Question 27

what is coupling?

Answer 27

The transduction process between occupancy of receptors and drug response

Question 28

The relative efficiency of receptor occupancy-response coupling is partially determined

Answer 28

by the initial conformational change in the receptor.

Question 29

the effects of full agonists can be considered

Answer 29

more efficiently coupled to receptor occupancy than are the effects of partial agonists.

Question 30

what are spare receptors?

Answer 30

the maximal response can be elicited by an agonist at a concentration that does not result in occupancy of the full complement of available receptors.

Question 31

spare receptors are NOT qualitatively different from nonspare receptors

Answer 31

*not hidden or unavailable *when they are occupied, they can be coupled to response

Question 32

spare receptors may be demonstrated by using

Answer 32

irreversible/higher affinity antagonist to prevent binding of agonist to a proportion of available receptors and showing that high concentrations of agonist can still produce an undiminished maximal response.

Question 33

Receptor-Effector Coupling and Spare Receptors

Answer 33

Thus, a maximal ionotropic response of heart muscle to catecholamines can be elicited even under conditions where 90% of the B-adrenoceptors are occupied by an irreversible antagonist.

Question 34

Myocardium is said to contain a large proportion of what?

Answer 34

spare B-adrenoceptors

Question 35

know this slide

Answer 35

Question 36

know this slide

Answer 36

Question 37

B = C ----- --------- Bmax C + Kd

Answer 37

The KD of the agonist-receptor interaction determines what fraction (B/Bmax) of total receptors will be occupied at a given free concentration (C) of agonist, regardless of the receptor concentration:

Question 38

Answer 38

Logarithmic transformation of the dose axis and experimental demonstration of spare receptors, using different concentrations of an irreversible antagonist. Curve A shows agonist response in the absence of antagonist. After treatment with a low concentration of antagonist (curve B), the curve is shifted to the right. Maximal responsiveness is preserved, however, because the remaining available receptors are still in excess of the number required. In curve C, produced after treatment with a larger concentration of antagonist, the available receptors are no longer “spare”; instead, they are just sufficient to mediate an undiminished maximal response. Still higher concentrations of antagonist (curves D and E) reduce the number of available receptors to the point that maximal response is diminished. The apparent EC50 of the agonist in curves D and E may approximate the Kd that characterizes the binding affinity of the agonist for the receptor.

Question 39

receptor antagonists ______but do not activate it

Answer 39

bind to the receptor

Question 40

what are effects of antagonists?

Answer 40

result from preventing agonists (other drugs or endogenous regulatory molecules) from binding to and activating receptors

Question 41

what are the two classes of antagonists

Answer 41

-reversible antagonists -irreversible antagonists (non-surmountable) *These two classes of antagonists produce quite different concentration-effect and concentration-binding curves *Based on competition with agonist

Question 42

In the presence of a fixed concentration of agonist

Answer 42

increasing concentrations of a competitive antagonist progressively inhibits the agonist response

Question 43

high antagonist concentrations

Answer 43

prevent response completely.

Question 44

sufficiently high concentrations of agonist

Answer 44

can completely surmount the effect of a given concentration of the antagonist.

Question 45

Competitive and Irreversible Antagonists

Answer 45

the Emax for the agonist remains the same for any fixed concentration of competitive antagonist

Question 46

because the antagonism is competitive, the presence of antagonist

Answer 46

increases the agonist concentration required for a given degree of response, and the agonist concentration-effect curve shifts to the right

Question 47

The concentration (C’) of an agonist required to produce a given effect in the presence of a fixed concentration [I] of competitive antagonist

Answer 47

is greater than the agonist concentration (C) required to produce the same effect in the absence of antagonist

Question 48

SCHILD EQUATION: C’ = 1 + ( [I] / KI ) --- C

Answer 48

The ratio of these two agonist concentrations (the “dose ratio”) is related to the dissociation constant (KI) of the antagonist

Question 49

know this slide about agonist

Answer 49

Question 50

know this slide about antagonist

Answer 50

Question 51

competitive antagonist slide

Answer 51

Question 52

A competitive antagonist binds ______ to the same receptor as the agonist

Answer 52

reversibly

Question 53

Some receptor antagonists bind to the receptor in an ________ or nearly irreversible fashion (i.e. NON-Competitive)

Answer 53

irreversible

Question 54

The antagonist’s affinity for the receptor may be so high

Answer 54

that for practical purposes, the receptor is unavailable for binding of agonist

Question 55

WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist'

Answer 55

After occupancy of some proportion of receptors by such an antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit maximal response.

Question 56

Once the irreversible antagonist has occupied the receptor

Answer 56

it need not be present in unbound form to inhibit agonist responses.

Question 57

the_______ of such an irreversible antagonist is relatively independent of its own rate of elimination and more dependent upon the _______ of receptor molecules

Answer 57

duration of action rate of turnover

Question 58

what are partial agonists?

Answer 58

produce a lower response at full receptor occupancy than do FULL agonists *it will never achieve the full effect * partial agonists may occupy all receptor sites

Question 59

The percentage of receptor occupancy resulting from full agonist (present at a single concentration) binding to receptors in the presence of increasing concentrations of a partial agonist.

Answer 59

Because the full agonist (purple) and partial agonist (yellow) compete to bind the same receptor sites, when occupancy by the partial agonist increases, binding of the full agonist decreases.

Question 60

How can an agonist be partial?

Answer 60

partial agonists have higher affinity for receptors with inactive conformation

Question 61

partial agonist bind to what?

Answer 61

both inactive and active receptor conformations… in effect, decreasing their maximum effects relative to full agonists.

Question 62

The higher the affinity for inactive receptor conformation,

Answer 62

the less efficacious the partial agonist

Question 63

Antagonists binds to what?

Answer 63

inactive receptor conformations?

Question 64

what are chemical antagonists?

Answer 64

one drug may antagonize the actions of a second drug by binding to and inactivating the second drug

Question 65

what is heparin

Answer 65

an anticoagulant that is negatively charged

Question 66

protamine

Answer 66

a protein that is positively charged at physiologic pH

Question 67

protamine can be used clinically to counteract the effects of what?

Answer 67

heparin *One drug antagonizes the effects of the other simply by binding it and making it unavailable for interactions with proteins involved in the formation of a blood clot.

Question 68

Physiologic Antagonists

Answer 68

physiologic antagonism takes advantage of endogenous regulatory pathways -many physiological functions are controlled by opposing regulatory pathways

Question 69

example of physiologic antagonists

Answer 69

To treat bradycardia (abnormally slow heartbeat) that is caused by increased release of acetylcholine from vagus nerve endings (after an event such as a myocardial infarction) the physician could use isoproterenol beta-adrenoceptor agonist that increases heart rate by mimicking sympathetic stimulation of the heart. The use of this physiologic antagonist would be less rational than would use of a receptor-specific antagonist such as atropine (atropine is a competitive antagonist at the receptors at which acetylcholine slows heart rate).