Module 7*

Question 1

Define ligand

Answer 1

a molecule that binds to another (usually larger) molecule.

Question 2

Define pharmacodynamics

Answer 2

Pharmacodynamics is the study of what the drug does to the body.

Question 3

In pharmacodynamics, what do we study?

Answer 3

the biochemical and physiological effects of drugs and the mechanisms by which drugs produce effects

Question 4

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

Answer 4

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 5

In pharmacodynamics, increasing the drug dose does what?

Answer 5

increases the response to the drug

Question 6

What do we look at to evaluate the pharmacodynamics of drugs?

Answer 6

(semi-log) dose-response curves

Question 7

What are dose-response curves?

Answer 7

dose-response curves are monotonic, which means that the response increases as the dose increases.
Importantly, dose-response curves are NOT linear. For this reason we usually look at the dose response curve as a semi-logarithmic plot.

Question 8

Define efficacy

Answer 8

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

Question 9

What does maximal efficacy represent?

Answer 9

the maximum effect that a drug is capable of achieving.

(It is read off the dose-response curve by looking at the max. 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.

Question 11

What does it mean to titrate the dose of a drug?

Answer 11

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 12

Define potency

Answer 12

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

Question 13

In order to compare potency, the drugs must what?

Answer 13

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 pressure.

Question 14

True or False: A more potent drug will require a smaller dose to achieve the desired effect than a less potent drug.

Answer 14

True

Question 15

How is potency determined?

Answer 15

• Potency is determined by comparing the dose required to produce the half maximal response. This is called the ED50.
• Drugs with a lower ED50 are said to be more potent than drugs with a high ED50.

Question 16

Most drugs act on what?

Answer 16

cellular macromolecules (receptors, enzymes, ion channels, transport proteins)

Question 17

The majority of drug targets act on what?

Answer 17

receptors

Question 18

Typical drug action involves the binding of the drug molecule to the macromolecule target. The complex is then able to produce what?

Answer 18

A biological effect

Question 19

Drugs typically mimic what?

Answer 19

an endogenous compound in the body

For example, norepinephrine binds to receptors in the heart and increases heart rate. There are drugs that mimic the action of norepinephrine by binding to the same type of receptor.

Question 20

Define endogenous

Answer 20

growing or originating from within an organism.

Question 21

Do all drugs act on cellular targets?

Answer 21

No! Although most drugs do act on cellular targets, there are a few that do not.

• The best example of drugs that don’t act on cellular targets are 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 22

List the four most important types of drug receptors

Answer 22

1) Ligand gated ion channels
2) G-protein coupled receptors
3) Enzyme linked receptors
4) Intracellular receptors

Question 23

Define receptor

Answer 23

• A receptor is a protein that a drug binds to and produces a measurable response.
• The majority of receptors are proteins that are able to translate extracellular signals into biological responses.

Question 24

Many neurotransmitters bind to which type of receptor?

Answer 24

ligand gated ion channels

Question 25

What is a really important example of a ligand gated ion channel?

Answer 25

GABA receptor

• 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.
• 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 26

Describe ligand gated ion channels

Answer 26

• 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.

Question 27

Approximately 50% of currently marketed drugs mediate their effects by binding to which type of receptor?

Answer 27

GPCRs

Question 28

List the three components of GPCRs

Answer 28

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

Question 29

Describe how GPCRs work?

Answer 29

• 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.

Question 30

Endogenous neurotransmitters such as norepinephrine, serotonin and histamine mediate their effects by binding to what?

Answer 30

GPCRs

Question 31

Describe enzyme linked receptors

Answer 31

• 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).

Question 32

What is an example of an enzyme linked receptor?

Answer 32

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 33

Define phosphorylation

Answer 33

In biology, phosphorylation is the transfer of phosphate molecules to a protein.

Question 34

Define translocation

Answer 34

the movement of something from one place to another

Question 35

Which receptors reside completely inside the cell and are also called transcription factors?

Answer 35

Intracellular receptors

Question 36

How do ligands access intracellular receptors?

Answer 36

They must be able to cross the cell membrane either by diffusion (being lipophilic) or via a drug transport protein.

Question 37

Describe Intracellular receptors

Answer 37

• Ligands must cross the cell membrane
• 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.

Question 38

Endogenous examples of ligands that bind to intracellular receptors include what?

Answer 38

estrogen and testosterone

Question 39

What is an important characteristic of a drug?

Answer 39

sensitivity

Question 40

A classical view of drug-receptor selectivity is the lock and key hypothesis. Describe the lock and key hypothesis

Answer 40

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