Chap 2 Pharmacodynamics

Question 1

Receptor

Answer 1

A molecule to which a drug binds to bring about a change in function of the biologic system

Question 2

Inert binding molecule or site

Answer 2

A molecule to which a drug may bind without changing any function

Question 3

Receptor site

Answer 3

Specific region of the receptor molecule to which the drug binds

Question 4

Spare receptor

Answer 4

Receptor that does not bind drug when the drug concentration is sufficient to produce maximal effect; present when Kd > EC50

Question 5

Effector

Answer 5

Component of a system that accomplishes the biologic effect after the receptor is activated by an agonist; often a channel, transporter, or enzyme molecule, may be part of the receptor molecule

Question 6

Agonist

Answer 6

A drug that activates its receptor upon binding

Question 7

Pharmacologic antagonist

Answer 7

A drug that binds without activating its receptor and thereby prevents activation by an agonist

Question 8

Competitive antagonist

Answer 8

A pharmacologic antagonist that can be overcome by increasing the concentration of agonist

Question 9

Irreversible antagonist

Answer 9

A pharmacologic antagonist that cannot be overcome by increasing agonist concentration

Question 10

Physiologic antagonist

Answer 10

A drug that counters the effects of another by binding to a different receptor and causing opposing effects

Question 11

Chemical antagonist

Answer 11

A drug that counters the effects of another by binding the agonist drug (not the receptor)

Question 12

Allosteric agonist, antagonist

Answer 12

A drug that binds to a receptor molecule without interfering with normal agonist binding but alters the response to the normal agonist

Question 13

Partial agonist

Answer 13

A drug that binds to its receptor but produces a smaller effect (Emax) at full dosage than a full agonist

Question 14

Constitutive activity

Answer 14

Activity of a receptor-effector system in the absence of an agonist ligand

Question 15

Inverse agonist

Answer 15

A drug that binds to the non-active state of receptor molecules and decreases constitutive activ- ity (see text)

Question 16

Graded dose-response curve

Answer 16

A graph of the increasing response to increasing drug concentration or dose

Question 17

Quantal dose-response curve

Answer 17

A graph of the increasing fraction of a population that shows a specified response at progres- sively increasing doses

Question 18

EC50, ED50, TD50, etc

Answer 18

In graded dose-response curves, the concentration or dose that causes 50% of the maximal effect or toxicity. In quantal dose-response curves, the concentration or dose that causes a speci- fied response in 50% of the population under study

Question 19

Kd

Answer 19

The concentration of drug that binds 50% of the receptors in the system

Question 20

Efficacy, maximal efficacy

Answer 20

The largest effect that can be achieved with a particular drug, regardless of dose, Emax

Question 21

Potency

Answer 21

The amount or concentration of drug required to produce a specified effect, usually EC50 or ED50

Question 22

Graded dose-response and dose-binding graphs

Answer 22

FIGURE 2–1 Graded dose-response and dose-binding graphs. (In isolated tissue preparations, concentration is usually used as the measure of dose.) A. Relation between drug dose or concentration (abscissa) and drug effect (ordinate). When the dose axis is linear, a hyperbolic curve is commonly obtained. B. Same data, logarithmic dose axis. The dose or concentration at which effect is half-maximal is denoted EC50, whereas the maximal effect is Emax. C. If the percentage of receptors that bind drug is plotted against drug concentration, a similar curve is obtained, and the concentration at which 50% of the receptors are bound is denoted Kd, and the maximal number of receptors bound is termed Bmax.

Question 23

graded dose-response curve

Answer 23

A graph of increasing response to increasing drug concentration or dose

Question 24

What parameters are created from the graded dose-response curve

Answer 24

The efficacy (Emax) and potency (EC50 or ED50) parameters are derived from these data.

The smaller the EC50 (or ED50), the greater the potency of the drug.

Question 25

(ED50)

Answer 25

median effective dose (ED50)

Question 26

(TD50)

Answer 26

median toxic dose (TD50)

Question 27

(LD50)

Answer 27

median lethal dose (LD50)

Question 28

maximal efficacy is measured with ?

Answer 28

- greatest effect (Emax) an agonist can produce if the dose is taken to the highest tolerated level - can be *measured* with a *graded dose-response curve* but **not** with a *quantal dose-response curve*.

Question 29

Spare receptors are said to exist if :

Answer 29

the determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the concentration for 50% of maximal binding (Kd). If the EC50 is less than the Kd, spare receptors are said to exist

Question 30

spare receptors Graph

Answer 30

FIGURE 2–3 In a system with spare receptors, the EC50 is lower than the Kd, indicating that to achieve 50% of maximal effect, less than 50% of the receptors must be activated. Explanations for this phenomenon are discussed in the text.

Question 31

Activity in the absence of ligand is called

Answer 31

constitutive activity

Question 32

full agonist In the presence of a full agonist

Answer 32

is a drug capable of fully activating the effector system when it binds to the receptor ## Footnote In the presence of a full agonist, a partial agonist acts as an inhibitor

Question 33

Competitive antagonists

Answer 33

Competitive antagonists are drugs that bind to, or very close to, the agonist receptor site in a reversible way without activating the effector system for that receptor

Question 34

Competitive antagonists increase\_\_\_\_

Answer 34

Competitive antagonists increase the ED50; irreversible antagonists do not (unless spare receptors are present).

Question 35

Agonist dose-response curves graph

Answer 35

Agonist dose-response curves in the presence of competitive and irreversible antagonists. Note the use of a logarithmic scale for drug concentration. A. A competitive antagonist has an effect illustrated by the shift of the agonist curve to the right. B. An irreversible (or noncompetitive) antagonist shifts the agonist curve downward.

Question 36

Describe the difference between a pharmacologic antagonist and an allosteric inhibitor. How could you differentiate these two experimentally

Answer 36

Allosteric antagonists do not bind to the agonist receptor site; they bind to some other region of the receptor molecule that results in inhibition of the response to agonist . They do not prevent binding of the agonist. In contrast, pharmacologic antagonists bind to the agonist site and prevent access of the agonist. The difference can be detected experimentally by evaluating competition between the binding of radioisotopically labeled antagonist and the agonist. High concentrations of agonist displace or prevent the binding of a pharmacologic antagonist but not an allo- steric antagonist.

Question 37

therapeutic index define & what does it represent determined from what curve?

Answer 37

The *therapeutic index* is the ratio of the TD50 (or LD50) to the ED50, determined from *quantal dose-response curves.* The *therapeutic index represents* an estimate of the safety of a drug, because a very safe drug might be expected to have a very large toxic dose and a much smaller effective dose.

Question 38

Example of Therapeutic Index

Answer 38

For example, in Figure 2–2: The ED50 is approximately 3 mg, and the LD50 is approximately 150 mg. Therefore the **therapeutic index** is approximately 150/3, or 50, in mice.

Question 39

therapeutic window is clinically useful index for \_\_\_\_

Answer 39

The therapeutic window, a more clinically useful index of safety, describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose

Question 40

tachyphylaxis

Answer 40

acute drug desensitization describes an acute, sudden decrease in response to a drug after its administration, i.e. a rapid and short-term onset of drug tolerance. It can occur after an initial dose or after a series of small doses.

Question 41

Several Mechanisms are responsible for **tachyphylaxis**

Answer 41

1. intracellular molecules may block access of a G protein to the activated receptor molecule 2. Second, agonist-bound receptors may be internalized by endocytosis, removing them from further exposure to extracellular molecules. The internalized receptor molecule may then be either reinserted into the membrane (eg, morphine receptors) or degraded 3. Third, continuous activation of the receptor-effector system may lead to depletion of some essential substrate required for downstream effects

Question 42

downregulation

Answer 42

Long-term reductions in receptor number (**downregulation**) may occur in response to continuous exposure to agonists

Question 43

upregulation

Answer 43

(**upregulation**) occurs when receptor activation is blocked for prolonged periods (usually several days) by pharma- cologic antagonists or by denervation.

Question 44

Graded vs quantal responses

Answer 44

Responses are **graded** when they increment gradually (eg, heart rate change) as the dose of drug increases Respones are **quantal** when they switch from no effect to a specified effect at a certain dose (eg, from arrhythmia to normal sinus rhythm) or if they are measured as positive upon reaching a specified response

Question 45

Graded vs quantal dose response curves

Answer 45

**Graded dose response curves** plot the increment in physiologic or biochemical response as dose or concen- tration is increased. **Quantal dose response curves** plot the increment in the percent of the population under study that responds with a specified effect as the dose is increased

Question 46

Efficacy vs potency

Answer 46

**Efficacy** represents the maximal effect (Emax) of a drug at the highest tolerated dose **Potency** reflects the amount of drug (the dose or concentration) required to cause a specific amount of effect, eg, the EC50 for a half-maximal effect. A drug may have high efficacy but low potency or vice versa

Question 47

Agonism and antagonism

Answer 47

The ability to activate (**agonism**) or inhibit (**antagonism**) a biologic system or effect. Different drugs may have very different effects on a receptor. The effect may be to activate, partially activate, or inhibit the receptor’s function. In addition, the binding of a drug may be at the site that an endogenous ligand binds that receptor, or at a different site

Question 48

Transmembrane signaling

Answer 48

Many drugs act on intracellular functions but reach their targets in the extracellular space. On reaching the target tissue, some drugs diffuse through the cell membrane and act on intracellular receptors. Most act on receptors on the extracellular face of the cell membrane and modify the intracellular function of those receptors by transmembrane signaling

Question 49

Receptor regulation

Answer 49

Receptors are in dynamic equilibrium, being synthesized in the interior of the cell, inserted into the cell membranes, sequestered out of the membranes, and degraded at various rates. These changes are noted as **upregulation** or **downregulation** of the receptor numbers and usually take days to accomplish. More rapid changes (minutes or hours) in response to agonists may occur as a result of block of access of intracellular coupling molecules to activated receptors, resulting in tachyphylaxis or tolerance