3 - Drug-Receptor Interactions and Pharmacodynamics

Drug Receptor Overview

1. Drug receptors can either be

or

. (LP p25)

2. What ways can drug effects come about? (LP p25)

Bind to specific
to inhibit, suppress or stimulate catalytic action
Bind to
and inhibit gene transcription
Bind to membrane
and open ion channels

3. A ligand is anything that binds to a receptor. List some examples of ligands. (LP p25)
Neurotransmitter (epinephrine)
Endogenous chemicals (histamine)

Enzyme substrate

4. A change in the receptor leads to a

5. What is an example of a drug that does not use a receptor for its action? (LP p25)

6. What is pharmacodynamics? (LP p25)

How the
the effect of the drug is.

of these drugs effect how big or

Chemistry of Receptors and Ligands

7. How do receptors bind with its ligands? (LP p26)

bonds, most commonly electrostactic and hydrogen bonds

interactions involving van der Waals forces

8. What determines how strong a bond will be? (LP p26)

The
between the

as they interact

9. What determines how selective the receptor is for its ligand? (LP p26)
The
of the bond

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10. Describe the lock and key model. (LP p26)

The key is the
The lock is the
They have to fit just right to unlock the door

11. What is the induced-fit model of drug-receptor interaction? (LP p26)

Receptor
its structure and shape in order to bind to the ligand
Conformational change
the receptor

Major Receptor Families

12. Are most drugs hydrophobic or hydrophilic?

13. What are the four types of major receptor families? (LP p27-28)
Ligand-gated ion channels

receptors
Enzyme-linked receptors

receptors

Ligand-gated Ion Channels

14. Complete the following table. (LP p26-27)
Family

Description
Channels that regulate
___________ flow across the cell
membrane
_________________ of ligand may
open or close the channel
Rapid response

15. -aminobutyric acid (GABA) is an important

Example
Nicotinic receptors
GABA

neurotransmitter. (LP p27)

16. Which class of drugs enhances the action of GABA?

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G protein-Coupled Receptors
17. What is the structure of G protein-coupled receptors? (LP p27)
A single peptide with 7
with a portion that sticks out into the
extracellular space for the ligand to bind to

18. The G protein is made up of what 3 subunits? (LP p27)

subunit
(beta) subunit
(gamma) subunit
19. What can the subunit bind to? (LP p27)
(guanosine diphosphate) or

(guanosine triphosphate)

20. Complete the following table about G protein-coupled receptors (LP p26-27)
Family

Description
Ligand binds to the ______________________ portion of
the receptor
Receptor undergoes a conformational change which
activates the G protein
GTP replaces _________________ on the unit
unit undergoes conformational change and dissociates
from subunit
and can activate enzymes
Signal is perpetuated by second messengers
G protein self-hydrolyzes GTP back to GDP which resets
moleculeto the ________________________ form

21. What is the most common second messenger? (LP p27)

22. Adenylyl cyclase turns ATP into

. (LP p27)

23. Give an example of a G protein-coupled receptor that uses adenylyl cyclase?

24. List two other second messengers that are generated from the activation of phospholipase C? (LP p27)

Inositol-1,4,5-triphosphate

25. Guanylyl cyclase converts GTP to

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. (LP p27)

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Enzyme-Linked Receptors
26. What is the duration of response for enzyme-linked receptors? (LP p28)
Several
to a few

27. List some examples of enzyme-linked receptors? (LP p28)

kinase
Insulin
Growth factors
28. A kinase is an enzyme that phosphorylates a specific

Intracellular Receptors
29. For intracellular receptors the ligand has to be hydrophilic or hydrophobic?

30. What are some examples of intracellular receptors? (LP p28)

-

Cortisol
Estrogen
Testosterone

31. What happens to the activated ligand-receptor complex? (LP p28)

Migrates to the
Binds to specific DNA sequences
Regulates
expression

Characteristics of Receptors
32. How many ligand-receptor complexes does it take to activate more than one messenger?

33. Only a small

of receptors are needed to be activated in order to achieve

cellular effects. (LP p29)

34. What are the receptors not being activated called?

35. -adrenergic receptors in the heart have what percentage of spare receptors? (LP p29)

36. What are the mechanisms that cells have built to protect themselves from the effects of overstimulation? (LP
p29)

receptors become desensitized to the action of the ligand

Down-regulation membrane-bound receptors undergo endocytosis

receptors require a rest period before they can be activated again

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Quick Review 1
1. Do most receptors bind to their ligands reversibly, or irreversibly? (LP p26)
2. To which family of receptors do the following ligands bind? (LP p27-28)
Ligand
Nicotine

Family of Receptor

Estrogen
Insulin
Histamine
Lidocaine
GABA
Cortisol
Testosterone

3. Which subunit of G proteins binds GTP? (LP p27)

4. What kind of reaction is catalyzed by tyrosine kinase? (LP p28)

Kinases catalyze the transfer of
from ATP to a substrate (phosphorylation)
In the case of a tyrosine kinase, the substrate is the amino acid tyrosine.

5. What do second messengers (inositol-1,4,5-trisphosphate and diacylglycerol) do? (LP p27-28)

Regulate intracellular
Transfer signals from hormones, neurotransmitters and drugs

6. What type of channel will regulate the flow of ions across the cell membrane? (LP p27)

7. List three ways that G protein-linked receptors amplify signal duration and intensity? (LP p29)
A single ligand-receptor complex can interact with many
Activated G proteins persist
than the original ligand-receptor complex
Second messengers can exert their effects longer than the original G protein

8. What is the name of the process where cells endocytose receptors in order to protect themselves from
overstimulation? (LP p29)
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Dose-Response Relationships
1. What are the two types of dose-response relationships? (LP p30-33)

dose-response

dose-response

2. What does graded dose-response mean? (LP p30)

More drug, more

and

slope

3. What important properties can be determined from the graded dose-response curve? (LP p30)

4. What is potency? (LP p30)

How much of a

5. How is potency determined? (LP p30)

By the amount of drug required to achieve

is needed to give an effect of a given

of the maximum effect of the drug

6. What does EC50 stand for? (LP p30)

The effective concentration to give

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7. Because the range of doses may span several orders of magnitude, the graded dose-response curve is plotted
on a logarithmic or linear scale? (LP p30)

8. What is efficacy? (LP p30)

The ability of the drug to illicit a

when it interacts with a receptor

9. What factors does efficacy depend on? (LP p30)

How
drug-receptor complexes are formed
How
drug-receptor complexes elicit a
response

10. Instead of comparing the EC50 as with potency, what are we comparing with efficacy? (LP p30)
Maximum
(Emax)

11. What is Kd? (LP p31)

that determines how much affinity the ligand has for its receptor

12. What does a high Kd mean? (LP p31)

interaction between drug and receptor and
affinity

13. What does it mean when [DR]/[Rt] =1?

Total number of drug-receptor complexes is
to the total number of
(all the receptors are bound to the drug and gives you a maximum effect)

14. What is an agonist? (LP p31)

A substance that binds to a receptor and elicits a
effects of an endogenous ligand)
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(for drugs it mimics the

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15. What is an antagonist? (LP p32)

Any substance that
or diminishes the
drugs it reduces the action of another drug or endogenous ligand)

response (for

16. Competitive antagonist will bind to the

endogenous ligand. (LP p32)

of the receptor as the

17. Where do noncompetitive antagonists bind? (LP p32)

Receptor at another site called

18. Describe what a functional antagonist is? (LP p32)

Drugs action
Doesnt use the same

site

the action of the agonist

19. Give an example of a drug that can work as a functional antagonist? (LP p32)

20. How do you overcome the antagonism?

Increase the amount of

21. What effect does a competitive antagonist have on potency and efficacy?
Reduced
but not

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22. What effect does a non-competitive antagonist have on potency and efficacy?
Reduce
but not

23. Km (Michaelis constant) is the

of substrate required to get reaction velocity to

.

24. What is Km equivalent to?

25. How do Lineweaver-Burk plots demonstrate competitive vs. non-competitive antagonists (inhibitors)?

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26. A partial agonist has a

than a full agonist? (LP p32)

27. Aripiprazole is a partial agonist at what receptors? (LP p32)

Quantal Dose-Response
28. Quantal means

or

29. Does quantal dose-response deal with individual response or big population response? (LP p33)

30. Describe what a therapeutic index is? (LP p33)

Ratio of the
dose to the

dose

31. What percentage of the toxic effect and therapeutic effect in a population are we concerned with for our
calculations? (LP p33)

32. Write the therapeutic index equation? (LP p33)

Therapeutic index =

33. What does therapeutic index measure? (LP p33)

Drugs
(Higher the therapeutic index, the more safe the drug is)

34. List some examples of drugs with a small therapeutic index? (LP p33)

Lithium
Digoxin
Phenobarbital

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Quick Review 2
1. What is EC50? (LP p30)
EC50 is the concentration of drug that produces an effect that is

2. Drugs A and B are both antihypertensive drugs. Drug A has an EC50 of 180mg, while Drug B has an EC50 of
100mg. Which drug is more potent?
(The lower the EC50 indicates a more potent drug)

3. Complete the following table:

Competitive
Antagonists

Non-competitive
Antagonists

Will higher doses of the agonist overcome the inhibition?

Does the antagonist bind the receptor at the same site as the
agonist?
What effect does the antagonist have on the efficacy of the
agonist?
What effect does the antagonist have on potency of the
agonist?

4.

Label the following plots as either competitive or non-competitive inhibition:

A=
B=

A=
B=

5. What is the formula for Therapeutic Index? (LP p33)

Therapeutic Index =
(or LD50 / ED50)

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6. Drugs that oppose the action of the agonist but do not use the same receptor are called what? (LP p32)

7. Drugs that bind to the allosteric site are called what? (LP p32)

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End Session Quiz

1. Put the following steps of G protein signaling in chronological order. (LP p27)
subunit of GS protein dissociates and activates adenylyl cyclase
Unoccupied receptor does not interact with GS protein
GTP on the subunit is hydrolyzed to GDP and adenylyl cyclase is deactivated
Occupied receptor changes shape and interacts with GS, which releases GDP and binds GTP

2. Why is cortisol able to bind to intracellular receptors?

3. Define potency and efficacy. (LP p30)

4. Drugs X and Y are both antihypertensive drugs capable of lowering the systolic blood pressure 20mm Hg.
Drug X has an EC50 of 50mg, while Drug Y has an EC50 of 100mg.
How much would you expect a 50 mg dose of Drug X to lower a patients systolic blood pressure?

Which drug is more potent?

Drug Z is capable of lowering the systolic blood pressure 25 mm Hg. Compared to Drug X, does Drug Z
have greater potency, greater efficacy, or both?

5. What is the difference between a competitive antagonist and a noncompetitive antagonist? (LP p32)

6. Does a non-competitive antagonist affect the potency of the agonist, the efficacy, or both?

7. Label points A and B:

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8. Would you expect a very safe drug to have a low therapeutic index or a high therapeutic index? (LP p33)

9. List four drugs with a low therapeutic index. (LP p33)

10. How does a partial agonist work in comparison to a full agonist? (LP p32-33)

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