Module 7: Dose-Response Relationships Flashcards
Define pharmacodynamics:
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.
In therapeutics it is important to combine…
… knowledge of pharmacokinetics and pharmacodynamics in order to provide optimal pharmacotherapy.
Increasing the dose of a drug results in increased…
… plasma concentrations
Increasing the dose of a drug in pharmacodynamics, increases the…
… response of the drug.
Does-response curves are monotonic, meaning…
… the response increases as the dose increases
Are dose response curves linear?
No
- Semi-logarithmic plot
What are the (3) phases of the semi-logarithmic dose-response curves?
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.
What is drug efficacy?
Is a measure of how effective a drug is at a given dose.
What does maximal drug efficacy represent?
- How is it read?
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
Do we always choose the drug with the highest efficacy to treat patients?
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.
What is potency?
Potency refers to the amount of drug required to elicit a pharmacological response
In order to compare potency…
… 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
T/F
- A more potent drug will require a smaller dose to achieve the desired effect than a less potent drug.
True
How is potency determined?
Potency is determined by comparing the dose required to produce the half maximal response
- This is called the ED50.
T/F
- Drugs with a lower ED50 are said to be more potent than drugs with a high ED50
True
What do most drugs act on?
Macromolecules
- Ex. Receptors, enzymes, etc.
What are the majority of drug targets?
Receptors
- But drugs also act on enzymes, ion channels, and transport proteins
Do all drugs act on cellular targets?
- Examples
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.
What is a receptor?
A receptor is a protein that a drug binds to and produces a measurable response.
What can majority of receptors do?
The majority of receptors are proteins that are able to translate extracellular signals into biological responses.
Ligand gated ion channels:
- Movement/function?
- Channels?
- Control?
- What binds?
- GABA?
- GABA results in?
- Benzodiazepine
- Activation of GABA results in?
- Response time?
- 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.
G-protein coupled receptors (GPCRs):
- Components
- What causes activation?
- What activates the effector?
- Response time?
- Mediator?
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.
Enzyme linked receptors:
- Location?
- Activation?
- Response time?
- Example?
- 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.
Intracellular receptors:
- Location?
- Access?
- Binding results in?
- What is stimulated?
- Time?
- Soluble?
- 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.
What is an important characteristic of drugs?
- What is the classical view?
Selectivity
- Lock and key hypothesis
What is the lock and key hypothesis?
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.
T/F
Drugs that are selective will bind to only one receptor and therefore will be less likely to produce side effects.
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.
