1: Basic Principles I

Question 1

Drug action - molecular action - _______. Drug effect - pharmacologic effect - _______ response.

Answer 1

Drug action - molecular action - invisible. Drug effect - pharmacologic effect - visible response.

Question 2

Selectivity is the property of a drug to cause a _______ effect-_______ drugs produce a single effect. Primary effect - _______ effect. _______ effects or “side effects” may or may not be desired. See figure 2 pg.1.

Answer 2

Selectivity is the property of a drug to cause a specific effect-few drugs produce a single effect. Primary effect - desired effect. Secondary effects or “side effects” may or may not be desired. See figure 2 pg.1.

Question 3

Pharmacokinetics = _______ course of drug absorption, actions and elimination.

Answer 3

Pharmacokinetics = Time course of drug absorption, actions and elimination.

Question 4

Pharmacodynamics = Types of drug _______.

Answer 4

Pharmacodynamics = Types of drug actions.

Question 5

Physiochemical actions are simple chemical interactions ie - antacids, antiseptics & _______ very specific. Receptor interactions are interactions of drugs with specific physiologic _______-macromolecule most drugs.

Answer 5

Physiochemical actions are simple chemical interactions ie - antacids, antiseptics & not very specific. Receptor interactions are interactions of drugs with specific physiologic receptors-macromolecule most drugs.

Question 6

We Create Drugs that Mimic the _______ Agonists or antagonists.

Answer 6

We Create Drugs that Mimic the Endogenous Agonists or antagonists.

Question 7

1 mole

Answer 7

6.02x12^23 molecules/mol

Question 8

In toxicology, the median lethal dose, LD50 (abbreviation for “lethal dose, 50%”), LC50 (lethal concentration, 50%) or LCt50 (lethal concentration and time) of a toxin, radiation, or pathogen is the dose required to kill _______ the members of a tested population after a specified test duration.

Answer 8

In toxicology, the median lethal dose, LD50 (abbreviation for “lethal dose, 50%”), LC50 (lethal concentration, 50%) or LCt50 (lethal concentration and time) of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration.

Question 9

Molecules/mole ÷ grams/mole

Answer 9

Molecules/ grams. See slides 11 & 12 on PP.

Question 10

_______ different types of receptors within a class may coexist in a single cell.

Answer 10

Several different types of receptors within a class may coexist in a single cell.

Question 11

Drug - Receptor interactions cause molecular events to occur in each cell, enough of the events cause a change in cell function, ultimately resulting in a change in _______ function.

Answer 11

Drug - Receptor interactions cause molecular events to occur in each cell, enough of the events cause a change in cell function, ultimately resulting in a change in tissue function.

Question 12

Receptors are _______ molecules, particularly proteins. May be on or in a cell or free in the plasma or extracellular fluid. These are present as part of the normal biochemical and physiologic mechanisms and usually interact with endogenous compounds. They are specific. They function both as ligand _______ and as an _______. The natural ligand (agonist) or a drug which resembles it can bind to a receptor and modulate its usual activity. Each receptor occupied might be stimulated (agonist) or inhibited (antagonist).

Answer 12

Receptors are Macromolecules, particularly proteins. May be on or in a cell or free in the plasma or extracellular fluid. These are present as part of the normal biochemical and physiologic mechanisms and usually interact with endogenous compounds. They are specific. They function both as ligand binder and as an effector. The natural ligand (agonist) or a drug which resembles it can bind to a receptor and modulate its usual activity. Each receptor occupied might be stimulated (agonist) or inhibited (antagonist).

Question 13

Each cell in a tissue contains a large population of receptors that are easily accessible to drugs. Each drug receptor interaction produces a small change in the biochemical or electrochemical homeostasis of the cell. The cumulative effects of many drug receptor interactions will lead to a change in the _______ of the cell. When enough cells in a tissue are affected then the function of the tissue is altered and an _______ pharmacologic response can be noted. A maximal response is eventually achieved which is related to the _______ of drug receptor interactions and the physiologic _______ of the tissue (normal vs diseased).

Answer 13

Each cell in a tissue contains a large population of receptors that are easily accessible to drugs. Each drug receptor interaction produces a small change in the biochemical or electrochemical homeostasis of the cell. The cumulative effects of many drug receptor interactions will lead to a change in the function of the cell. When enough cells in a tissue are affected then the function of the tissue is altered and an observable pharmacologic response can be noted. A maximal response is eventually achieved which is related to the number of drug receptor interactions and the physiologic capacity of the tissue (normal vs diseased).

Question 14

Types of Receptors: 1) _______ bound - eg. in neural synapse, ion channels 2) _______ - intracellular or extracellular 3) _______ macromolecules - eg. microtubules 4) _______ macromolecules - eg. steroid receptors, RNA 5) _______ itself - change electrical potential, fluidity. See figure 6 pg. 5.

Answer 14

Types of Receptors: 1) Membrane bound - eg. in neural synapse, ion channels 2) Enzymes - intracellular or extracellular 3) Structural macromolecules - eg. microtubules 4) Intracellular macromolecules - eg. steroid receptors, RNA 5) Cell membrane itself - change electrical potential, fluidity. See figure 6 pg. 5.

Question 15

Drug - Receptor Bonds: _______ = ionic, Van der Waals, Hydrogen. _______ = covalent

Answer 15

Drug - Receptor Bonds: Reversible = ionic, Van der Waals, Hydrogen. Irreversible = covalent

Question 16

Receptor Amplification and Transduction. Drug - Receptor interactions - fractions of seconds activate G protein activity that lasts for seconds. See figure 7.

G Proteins (GTP binding proteins) - regulate the activity of:

a. Distinct _______ proteins in the cell eg - enzymes
channels transport proteins.

b. There can be _______ G proteins in a single cell.
c. Act as switches that are turned on by the _______ and turn themselves off in a few seconds.
d. Several drugs can stimulate different receptors but ultimately influence the same _______ protein through the mediation of a G protein that is shared by the _______ receptors. Thus stimulus averaging or modulation can be achieved.

Answer 16

Receptor Amplification and Transduction. Drug - Receptor interactions - fractions of seconds activate G protein activity that lasts for seconds. See figure 7.

G Proteins (GTP binding proteins) - regulate the activity of:

a. Distinct effector proteins in the cell eg - enzymes
channels transport proteins.

b. There can be multiple G proteins in a single cell.
c. Act as switches that are turned on by the receptor and turn themselves off in a few seconds.
d. Several drugs can stimulate different receptors but ultimately influence the same effector protein through the mediation of a G protein that is shared by the different receptors. Thus stimulus averaging or modulation can be achieved.

Question 17

Second Messengers:

1. produce _______ of the drug receptor interaction
2. Converts an event that happens _______ the cell (ie. receptor binding) into a change that happens _______ the cell. Some second messengers can cause different effects in different tissues.

Answer 17

Second Messengers:

1. produce amplification of the drug receptor interaction
2. Converts an event that happens outside the cell (ie. receptor binding) into a change that happens inside the cell. Some second messengers can cause different effects in different tissues.

See figure 8 Interactions between the second messengers cyclic AMP and Ca2+.

Question 18

Changing the biochemical balance of substrates in metabolic pathways and activating or deactivation enzyme systems can have profound effects on the function of the cells in a tissue. eg. cAMP, Ca2+. Second messenger may be stimulated or inhibited by _______.

Answer 18

Changing the biochemical balance of substrates in metabolic pathways and activating or deactivation enzyme systems can have profound effects on the function of the cells in a tissue. eg. cAMP, Ca2+. Second messenger may be stimulated or inhibited by G proteins.

Question 19

The structure of the drug determines how it will fit into the receptor. The better the fit, the _______ the stimulation. Subtle changes in structure amongst a class of drugs can greatly influence the drugs’ effects.

Answer 19

The structure of the drug determines how it will fit into the receptor. The better the fit, the better the stimulation. Subtle changes in structure amongst a class of drugs can greatly influence the drugs’ effects.

Question 20

In stereoisomery imagine that when the S, inert isomer, binds partially to receptor it could _______ the active R form.

Answer 20

In stereoisomery imagine that when the S, inert isomer, binds partially to receptor it could inhibit the active R form.

Question 21

See equation on pg. 8 and note that we give so much drug that we drive rxn _______—le chataliers concept.

Answer 21

See equation on pg. 8 and note that we give so much drug that we drive rxn right—le chataliers concept.

See figure 10 under equation.

Question 22

Log Dose Response Curve Characteristics:

_______ – the beginning of the curve – dose of agonist at which a response begins May relate to the affinity of the agonist for the receptor.

_______ – rate of rise of the response on the steep portion of the curve, Log of EC50 also relates to affinity

_______ _______ – the top of the curve, represents E Max for that particular agonist

Answer 22

Log Dose Response Curve Characteristics:

Threshold – the beginning of the curve – dose of agonist at which a response begins May relate to the affinity of the agonist for the receptor.

Slope – rate of rise of the response on the steep portion of the curve, Log of EC50 also relates to affinity

Maximal Asymptote – the top of the curve, represents E Max for that particular agonist

Question 23

Receptor Occupancy - Intensity of response is proportional to the fraction of the receptors _______.

Effect =

Answer 23

Receptor Occupancy - Intensity of response is proportional to the fraction of the receptors occupied.

Effect = (Emax)[D]/ [D] + KD

where KD = EC 50

See figure 11, pg.9

Question 24

Intrinsic Activity: Ability to _______ the receptor once bound. Relates to structure and influences efficacy
and potency. Greater intrinsic activity = _______ efficacy. Drugs with best intrinsic activity reach Emax.

Answer 24

Intrinsic Activity: Ability to stimulate the receptor once bound. Relates to structure and influences efficacy
and potency. Greater intrinsic activity = greater efficacy. Drugs with best intrinsic activity reach Emax.

Question 25

_______ Receptors - Not all receptors need to be occupied to achieve Emax. Less efficacious agonists may need
to occupy more receptors than highly efficacious agonists.

Answer 25

Spare Receptors - Not all receptors need to be occupied to achieve Emax. Less efficacious agonists may need
to occupy more receptors than highly efficacious agonists.

Question 26

_______ Receptors - Outside of the target tissue(s), may mediate other effects of the drug “side effects”

Answer 26

Secondary Receptors - Outside of the target tissue(s), may mediate other effects of the drug “side effects”

Question 27

Receptor Regulation - A cell can up or down regulate a population of receptors by changing the total _______ of
receptors or their _______. Homeostasis.

eg: denervation hypersensitivity

eg: desensitization - can occur with down regulation of the
receptor or with fatigue or depletion of the intracellular or tissue mechanisms

Answer 27

Receptor Regulation - A cell can up or down regulate a population of receptors by changing the total number of
receptors or their sensitivity. Homeostasis.

eg: denervation hypersensitivity

eg: desensitization - can occur with down regulation of the
receptor or with fatigue or depletion of the intracellular or tissue mechanisms

Question 28

See figure 12 pg 10

Answer 28

See figure 12 pg 10

Question 29

Agonist Drugs -These bind to the receptor and produce a pharmacologic effect.

Two important events:

1. _______ to receptor
2. _______ receptor after binding

Answer 29

Agonist Drugs -These bind to the receptor and produce a pharmacologic effect.

Two important events:

1. Bind to receptor
2. Activate receptor after binding

Question 30

See equation pg. 10 & figure 13 on pg. 11

Answer 30

See equation pg. 10 & figures 13 & 14 on pg. 11

Question 31

Same Emax means _______ intrinsic activity, different Emax = _______ intrinsic activity.

Answer 31

Same Emax means same intrinsic activity, different Emax = different intrinsic activity. See figures 15 & 16 on pg. 12.

Question 32

Higher affinity = _______ shift on the curve. See figure 17 on pg. 13

Answer 32

Higher affinity = left shift on the curve.

Question 33

_______ is the ability of the drug to activate the effector portion of the receptor once the drug is bound to the receptor

Depends upon: the structure of the drug

Answer 33

Efficacy is the ability of the drug to activate the effector portion of the receptor once the drug is bound to the receptor

Depends upon: the structure of the drug

Question 34

_______ relates to the amount of drug that is needed for an effect.

Depends upon:

1. The biologic system
   a. receptor density
   b. efficiency of the stimulus-response mechanisms of the tissue
2. Interaction of the drug with the receptor
   a. affinity
   b. efficacy

Answer 34

Potency relates to the amount of drug that is needed for an effect.

Depends upon:

1. The biologic system
   a. receptor density
   b. efficiency of the stimulus-response mechanisms of the tissue
2. Interaction of the drug with the receptor
   a. affinity
   b. efficacy

See figure 18.

Question 35

_______ can block the binding of agonists and prevent the pharmacologic response.

Answer 35

Antagonists can block the binding of agonists and prevent the pharmacologic response.

See figure 19.

Question 36

With _______ Antagonists, the Antagonist effect can be overcome by increasing the dose of the agonist.

See figure 20, pg. 15

Answer 36

With Competitive Antagonists, the Antagonist effect can be overcome by increasing the dose of the agonist.

See figures 20 & 21, pg. 15

Question 37

_______ Antagonists - can’t be overcome by increasing doses of agonist. Receptors remain occupied by antagonist and not enough DR interactions occur to achieve Emax.

Binding of antagonist to receptor is a strong bond - such as a _______ bond and is not easily reversed.

eg: proton pump inhibitors

The inhibitor can either change the Effector or the Binding site.

2 types:

A) Changes the effector, & does _______ change binding of drug to the ligand site. Or Antagonist _______ the effector site. Even if the ligand binds to the receptor it cannot initiate the effect.

B) Changes the _______ site for the Agonist by directly binding to it or by attaching to a different portion of the receptor and altering the Agonist binding site.
Inhibitor interferes with agonist binding.

In noncompetitive inhibition, the agonist and antagonist are _______ competing for the same site. Increasing the dose of agonist will _______ shift the equilibrium to the right since most of the complexes are irreversible.

See figure 22.

Answer 37

Noncompetitive Antagonists - can’t be overcome by increasing doses of agonist. Receptors remain occupied by antagonist and not enough DR interactions occur to achieve Emax.

Binding of antagonist to receptor is a strong bond - such as a covalent bond and is not easily reversed.

eg: proton pump inhibitors

The inhibitor can either change the Effector or the Binding site.

2 types:

A) Changes the effector, does not change binding of drug to the ligand site. Or Antagonist blocks the effector site. Even if the ligand binds to the receptor it cannot initiate the effect.

B) Changes the binding site for the Agonist by directly binding to it or by attaching to a different portion of the receptor and altering the Agonist binding site.
Inhibitor interferes with agonist binding.

In noncompetitive inhibition, the agonist and antagonist are not competing for the same site. Increasing the dose of agonist will not shift the equilibrium to the right since most of the complexes are irreversible.

See figure 22. & equations for competitive and noncompetitive inhibition.