Week 1: Pharmacodynamics I

Question 1

What is pharmacodynamics?

Answer 1

What the drug does to the body

Drugs interact with specific receptors to cause a response:

Drug (epinephrine) + Receptor (adren. receptor) <=> Drug/Receptor => Response

Question 2

What type of biochemical interaction is similar to pharmacodynamics? What is the principal equation for pharmacodynamics?

Answer 2

The Michelis-Menten principal of enzyme kinetics is similar to the drug-receptor principle of pharmacodynamics.

Question 3

What is the constant that dictates the drug/receptor interaction in pharmacodynamics, and what constant is it similar to?

Answer 3

K_d, or the dissociation constant, and it is similar to K_m for enzymes

Question 4

As you add more of a drug to a pharmacodynamic equation, what happens?

Answer 4

The response increases via

D + R(eceptor) <=> DR => Response

As the equation shifts to the right

Question 5

What was Paul Erlich responsible for in pharmacodynamic chemistry?

Answer 5

The lock-and-key concept of drug/receptor interactions

Question 6

What was John Langley’s key discovery regarding pharmacodynamics?

Answer 6

He found that nicotine activated skeletal muscle tissue, generating the concept of a receptive substance.

Question 7

By what mechanisms do drugs combine with protein binding sites?

Answer 7

Drugs combine via precise physiochemical and steric interactions between chemical groups on the drug and chemical groups on the protein.

Question 8

Where does binding energy for the drug/receptor complex come from?

Answer 8

Bonds and interactions (pHHILES or “files) including:

Lipophilic

Hydrophilic

Ionic

Steric

Hydrogen bonds

Electronic effects

pK effects (acidity values)

Question 9

Can you have multiple types of binding in a drug/receptor interaction? If so, explain.

Answer 9

Yes–drugs are long molecules, often with several key interaction sites. Pictured is a drug that uses both lipophilic and ionic bonding properties to fit into a given receptor.

Question 10

Why do receptors exist? What are some examples of things that interact with them?

Answer 10

Receptors that drugs interact with don’t exist BECAUSE of the drugs–rather, they exist due to the need for interactions of different body elements with endogenous ligands.

Opiate receptors are activated by endorphins and enkephalins produced by the body, and can also be stimulated by morphine, an exogenously produced substance (made from poppies!)

Question 11

What are the five assumptions of drug-receptor interactions?

Answer 11

1) The binding of a drug to the receptor causes an event that leads to a response
2) The response to the drug is graded–i.e. dose-dependent (creates an exponential curve where E_max is analagous to V_max)
3) The drug-receptor interaction follows mass-action relationships
4) For a given drug, the response is directly proportional to the bound vs unbound ((DR)/(R_T)) receptor sites
5) The number of drug molecules is much greater than the number of receptors available

Question 12

What are the two ways in which conformational changes occur in receptors?

Answer 12

Drugs either:

1) Cause a conformational change in the receptor

or

2) Bind to a preferred conformation of the receptor, as receptor conformations are continually in flux

Question 13

How do mass-action relationships work?

Answer 13

More of a drug causes the reaction to shift to the right in:

D + R <=> DR => Response

This is reversible when there is one D/R interaction, but is not always reversible when there are multiple drug interactions that lead to a response.

Question 14

What is the equilibrium dissociation constant for a drug/receptor interaction?

Answer 14

K_d = [D] * [R]

[DR]

Question 15

How does the proportionality of bound and unbound receptors compare to the response curve? What is the term for a drug “taking up space” by interacting with a receptor?

Answer 15

(DR)/(R_T) ∝ E/E_max

(∝ means “is proportional to”)

A drug interacting with a receptor, when bound, is called an “occupant”

Question 16

How does the number of available drug molecules binding to receptors impact the amount of “free drug” available?

Answer 16

Because there are SO many more drug molecules than receptors, [R] goes down as drug molecules begin to bind, forming [DR]. However, [D] does NOT decrease significantly!

Question 17

What is fractional occupancy? What does it depend on?

Answer 17

Fractional occupancy is the ratio of occupied vs free receptors:

[DR]/[R_T] = [D]/K_D+[D]

The fraction of receptors occupied depends ONLY on the concentration of the drug and it’s K_D value

Question 18

What are the effects of a given drug dependent on, and what is the relationship between this effect and a dose of a given drug?

Answer 18

The biological response, or effect, e is proportional to the fractional occupancy ([DR]/[R_T]) and the maxiumum response, E_max is proportional to R_T via:

e/E_max = [D]/K_D+[D]

Question 19

What kind of curve is created by plotting the response versus drug concentration from the e/E_max equation? How is it graphed or expressed?

Answer 19

A hyperbolic curve, which is expressed as a percent rather than as a fraction

Question 20

What are the common unitary prefixes relevant to pharmacodynamics?

Answer 20

milli = 10^-3

micro = 10^-6

nano = 10^-9

pico = 10^-12

Question 21

On a -log curve of drug concentrations, what point is most commonly used as a comparison between two drugs plotted on the same curve?

Answer 21

The halfway point (50% occupancy), also known as EC₅₀

Question 22

What are the three terms that relate to the ability of a drug to bind to it’s receptor? What axis is this conveyed on in a graph?

Answer 22

Potency

Affinity

K_D

EC₅₀ (50% of maximally effective conc. for an individual)

ED₅₀ (same as EC₅₀ but with “dose” for a population)

These are all conveyed on the x-axis, shifts left when it is more potent (less required to generate a response)

Question 23

What are the three terms that indicate the ability of a drug to produce a response? What axis do these terms convey a response on?

Answer 23

Efficacy

Power

Intrinsic activity

These aspects of drug effectiveness determine where the drug “tops out” asymptotically on the y-axis–not all drugs have the same efficacy! Those that have lower asymptotes are not as effective.

Question 24

How do agonists work?

Answer 24

Agonists activate receptors and create a response

Question 25

What are the steps that lead to activation of a response?

Answer 25

OLDER concept: Binding -> Conformational change -> Activation

NEWER concept: Conformational change -> Binding -> Activation

Question 26

Can receptors be activated without a drug? Can drugs bind and not activate a receptor?

Answer 26

Yes! If the conformation changes independently without a drug bound, it can still cause an effect. Conversely, a drug can bind and NOT cause an effect if the conformational state of the receptor is not correct.

Question 27

What is it called when effects of receptor activation occur even when an agonist is not present?

Answer 27

Constitutive activity

Question 28

What is the relative percent of active vs inactive receptors in the body?

Answer 28

R* (active conformation) = ~ 1%

R (inactive conformation) = ~99%

Question 29

Describe the pharmacodynamics of a full agonist

Answer 29

Full agonist drugs have a high affinity for R* (K_D = 1 nM) and a low affinity for R (K_D = 1mM), so the drug will preferentially bind to R* and cause the response

Question 30

Describe the pharmacodynamics of a partial agonist

Answer 30

Partial agonist drugs have a high affinity for R* (KD = 1 nM) and a modest affinity for R (KD = 10 nM), so the drug will bind to BOTH the R* and R states and cause a decreased response