Module 7: Dose-Response Relationships

Question 1

Define pharmacodynamics:

Answer 1

Pharmacodynamics is the study of what the drug does to the body
- In pharmacodynamics we study the biochemical and physiological effects of drugs and the mechanisms by which drugs produce effects.

Question 2

In therapeutics it is important to combine…

Answer 2

… knowledge of pharmacokinetics and pharmacodynamics in order to provide optimal pharmacotherapy.

Question 3

Increasing the dose of a drug results in increased…

Answer 3

… plasma concentrations

Question 4

Increasing the dose of a drug in pharmacodynamics, increases the…

Answer 4

… response of the drug.

Question 5

Does-response curves are monotonic, meaning…

Answer 5

… the response increases as the dose increases

Question 6

Are dose response curves linear?

Answer 6

No

- Semi-logarithmic plot

Question 7

What are the (3) phases of the semi-logarithmic dose-response curves?

Answer 7

Phase 1 – Doses are too low to elicit a clinically relevant response.

Phase 2 - The response is graded and nearly linear.

Phase 3 – Larger doses do not lead to greater response. Larger doses may cause toxicity.

Question 8

What is drug efficacy?

Answer 8

Is a measure of how effective a drug is at a given dose.

Question 9

What does maximal drug efficacy represent?

- How is it read?

Answer 9

Maximal efficacy represents the maximum effect that a drug is capable of achieving
- Maximal efficacy is read off the dose response curve by looking at the maximum height

Question 10

Do we always choose the drug with the highest efficacy to treat patients?

Answer 10

NO! We choose the drug and dose that are therapeutically effective with the fewest side effects

Health care professionals often titrate the dose of a drug.
- This means they start with a low dose of the drug and slowly increase the dose while monitoring the patient’s response.

Question 11

What is potency?

Answer 11

Potency refers to the amount of drug required to elicit a pharmacological response

Question 12

In order to compare potency…

Answer 12

… the drugs must produce the same therapeutic effect

- For example, you can’t compare the potency of a medication used for pain relief with one that lowers blood pressur

Question 13

T/F

- A more potent drug will require a smaller dose to achieve the desired effect than a less potent drug.

Answer 13

True

Question 14

How is potency determined?

Answer 14

Potency is determined by comparing the dose required to produce the half maximal response
- This is called the ED50.

Question 15

T/F

- Drugs with a lower ED50 are said to be more potent than drugs with a high ED50

Answer 15

True

Question 16

What do most drugs act on?

Answer 16

Macromolecules

- Ex. Receptors, enzymes, etc.

Question 17

What are the majority of drug targets?

Answer 17

Receptors

- But drugs also act on enzymes, ion channels, and transport proteins

Question 18

Do all drugs act on cellular targets?

- Examples

Answer 18

No
- Most drugs do act on cellular targets but there are a few that do not

Ex. Antacids

• Antacids are drugs that neutralize stomach acid to provide symptomatic relief from some gastrointestinal disorders.
• Antacids are simply bases that neutralize stomach acid, therefore they do not bind to any cellular target.

Question 19

What is a receptor?

Answer 19

A receptor is a protein that a drug binds to and produces a measurable response.

Question 20

What can majority of receptors do?

Answer 20

The majority of receptors are proteins that are able to translate extracellular signals into biological responses.

Question 21

Ligand gated ion channels:

• Movement/function?
• Channels?
• Control?
• What binds?
• GABA?
• GABA results in?
• Benzodiazepine
• Activation of GABA results in?
• Response time?

Answer 21

• The movement of ions into or out of a cell can cause instantaneous changes in function.
• As ions are unable to directly cross the cell membrane they utilize specialized channels.
• Ligands (i.e. drugs or endogenous molecules) control the opening and closing of ion channels.
• Many neurotransmitters bind to these types of receptors - The GABA receptor is an important example of a ligand gated ion channel.
• When GABA (a neurotransmitter) binds to the GABA receptor, it causes the opening of a channel that allows the ion chloride to flow into the cell.
• Drugs that are part of the benzodiazepine class are also able to bind to the GABA receptor and allow chloride to enter the cell. We’ll see benzodiazepines in Module 14!
• Activation of the GABA receptor causes sedation and muscle relaxation mediated by the increased intracellular chloride.
• Responses to these receptors are very rapid having a duration of milliseconds.

Question 22

G-protein coupled receptors (GPCRs):

• Components
• What causes activation?
• What activates the effector?
• Response time?
• Mediator?

Answer 22

Approximately 50% of currently marketed drugs mediate their effects through actions on GPCRs.

GPCRs have three components:

1) A seven transmembrane spanning protein receptor.
2) A G-protein which has three subunits.
3) An effector molecule (i.e. an enzyme).

• Binding of a ligand to a GPCR causes activation of the G-protein.
• The G-protein then dissociates from the receptor and activates the effector.
• Activation of GPCRs result in a response that lasts from seconds to minutes in duration.
• Endogenous neurotransmitters such as norepinephrine, serotonin and histamine mediate their effects by binding to GPCRs.

Question 23

Enzyme linked receptors:

• Location?
• Activation?
• Response time?
• Example?

Answer 23

• Enzyme linked receptors span the cell membrane with the ligand binding domain on the outside of the cell and the enzyme’s catalytic site on the inside.
• Binding of a ligand on the outside of the cell activates the enzyme on the inside of the cell.
• Responses to enzyme linked receptors occur very rapidly (seconds).

An example of an enzyme linked receptor is the insulin receptor.

• Binding of insulin to the insulin receptor causes enzyme mediated phosphorylation and activation of an intracellular effector.
• The phosphorylated effector causes an increased translocation of glucose transporters to the cell membrane.
• The net effect of insulin binding to its receptor is increased cellular glucose uptake and utilization.

Question 24

Intracellular receptors:

• Location?
• Access?
• Binding results in?
• What is stimulated?
• Time?
• Soluble?

Answer 24

• These receptors reside completely inside the cell and are also called transcription factors.
• In order to access these receptors, ligands must be able to cross the cell membrane either by diffusion or via a drug transport protein.
• Binding of the ligand causes translocation of this complex to the nucleus and binding to DNA.
• When the ligand/receptor complex binds to DNA, transcription of messenger RNA is stimulated.
• Protein synthesis occurs hours or days later.
  •- Ligands to these receptors are typically highly lipid soluble. Endogenous examples include the steroid hormones testosterone and estrogen.

Question 25

What is an important characteristic of drugs?

- What is the classical view?

Answer 25

Selectivity

- Lock and key hypothesis

Question 26

What is the lock and key hypothesis?

Answer 26

The lock can be thought of as the receptor

The lock requires a key with a specific size and unique shape to open it.
- The drug can be thought of as the key

If it has the right shape and size, it can open the lock.

Question 27

T/F

Drugs that are selective will bind to only one receptor and therefore will be less likely to produce side effects.

Answer 27

True

Note that even if drugs bind to only one receptor, they still may have side effects

Why?

• The target for therapy may be in the brain but the receptor may be located in the brain and in the intestine
• Therefore side effects in the intestine may occur.