2-Pharmacodynamics Flashcards
What is pharmacodynamics?
term used to describe the effects of a drug on the body
What is affinity?
the number of bound receptors is directly proportional to the concentration of the drug
Give me an equation for affinity for affinity
[LR] is the number of occupied receptors at the concentration of a drug (ligand) [L]
Ro is the maximum concentration of receptors available
Kd is equilibrium concentration constant
What exactly is Kd?
the concentration of ligand at which 50% of the available receptors are occupied, inversely proportional to infinity
True or False: a small Kd means a large affinity
True.
Small affinity= large Kd
Large affinity= small Kd
Graphically, is a drug with a higher affinity for a receptor to the left or right of a drug that has lesser affinity to it’s receptor?
To the left.
The Kd is smaller.
(drug A has a higher affinity for it’s R than B)
What is the relation between the body’s response to a drug and the concentration of receptors?
the body’s response is porpotional to the concentration of receptors that are bound by the drug
What are Graded Dose-Relationships?
What is the drugs Potency(EC50)?
the concentration at which the drug elicits 50% of its maximal response
This enables doctors to determine how much of a drug you need to achieve a certain effect
What is the relationship between potency and EC50?
Potency is inversely proportional to EC50.
The higher the EC50, the less potent of a drug, or vice versa.
Is determined in part by affinity for the receptor
What is Efficacy(Emax)?
Maximal response produced by the drug.
This enables doctors to decide what the drug does and if it’s appropriate for a given therapy
Should you choose a drug based off efficacy or potency?
Efficacy
You want the drug that has the maximum efficacy for the job you want it to do, and then you can look at the potency to see how much drug you need to produce that effect.
Which drug is more potent? A or B?
Drug A more potent than B b/c its EC50 is at a lower concentration
Which drug has a higher efficacy? A or B?
TRICK QUESTION
Drugs A and B have the same efficacy b/c both elicit the same maximal response
What are Quantal dose response curves?
plots the fraction of the population that responds to a given dose of a drug as a function of the drug dose used to find median effective dose (ED50), median toxic dose (TD50), and medial lethal dose (LD50)
What is the ED50?
the dose that effectively treats 50% of the population
What is the TD50?
that dose of drug that causes a toxic response on 50% of the population
What is the TI?
the therapeutic index, or margin of safety
What is the TI equation?
TI=TD50/ED50
Is a larger or a smaller TI safer?
Larger TI
Remember, TI=TD50/ED50
Larger TI=safer drug, that dose that kills and the dose that treats are further apart
Small TI=dangerous drug, the dose that is toxic is very close to the dose that treats
If drug A has an ED50 of 150 mg, and drug B has an ED50 of 10mg, how much less potent is drug A than B?
15x less potent than B
What is the LD50?
the dose required to kill half the members of a tested population after a specified test duration
Generally, what are the 2 states that a drug receptor can be in?
Active and passive state
How are drugs named according to the state of the receptor?
If upon binding the drug favors the active conformation, it’s an agonist.
If the drug prevents agonist-induce activation, its an antagonist
In which state does a partial agonist stabilize the receptor?
It stabilizes the receptor equally in the inactive and active conformations, with no specific preference for either form.
Does a partial agonist produce the same full effect of a regular agonist?
No. it’s always less because it stabilizes the receptor in the inactive form as well as the active form
Why are partial agonists sometimes called “partial antagonists?”
Since partial agonist and full agonist bind to the same receptors, a partial agonist can reduce the response caused by a full agonist
It’s like you want to get people to go out to lunch to Subway. There are a group of people who really want to go to subway (the full agonists) and some are indifferent to Subway or Burger King (partial agonists). If you get a group of 10 people who are full agonists for Subway, 10 people will be going to Subway. However, if you get 6 people who are full agonists and 4 that are indifferent to Subway or Burger King, you’ll probably only end up getting 8 to go to Subway. Youll get a better turnout (response) if you only have the full agonists (those who want to go to subway) than with people who are indifferent (the partial agonists). Sorry if this confuses you. I tried!
Why is Pindolol a partial agonist?
It’s a partial agonist for beta-adrenergic cells of the heart.
partially inhibits the beta1 receptors (competes with epinephrine, which is the normal agonist)
Burprenorphrine is a partial agonist for which receptors?
high affinity for mu-opioid receptors
used to stop relapse of opioid addiction
What are full agonists?
Drugs that stabilize the receptor in the active conformation
What is the main mechanism of competitive antagonists?
it binds directly to the active site and prevents the agonists from binding
What does competitive antagonists do to the potency of an agonist?
Reduces it.
It will shift the EC50 to the right, thus lowering the potency
What does competitive antagonists do to the efficacy of an agonist?
NOTHING
The effects in the human will be the same as the competitive antagonist can be overcome with saturation of agonist.
In the graph, it’s like drug A was the “before exposure to competitive antagonist” and B was “after exposure.” The EC50 shifted right, thus reducing the potency, but the efficacy was unchanged.
What is an example of a drug that is a competitive antagonist that binds to the active site of HMG-CoA?
Pravastatin
Where does a noncompetitive antagonist bind?
either the active site or an allosteric site.
What is significant of the strength of binding of a noncompetitive antagonist?
It’s irreversible
the receptor cannot be activated and cannot be washed out with agonist
What is an example of a noncompetitive antagonist to COX? It’s mechanism?
Aspirin
Aspirin irreversibly acetylates cyclo-oxygenase which is needed to make thromboxane A2 in platelets which is needed for platelet aggregation
What is the mechanism of action of a chemical antagonist?
It inactivates the agonist by modifying or sequestering it to make it unavailable
What does a chemical antagonist not use that other antagonists use?
A receptor!
It just goes in there and kicks the agonist drug in the face
What is an example of a chemical antagonist that is basic and binds to the acidic heparin and forms a complex?
Protamine
Think -amine means basic
What is the mechanism of action of a physiological antagonist?
It activates or blocks a receptor that mediates a response physiologically opposite to that of the agonist
What is an example of a mechanism to treat the symptoms of hyperthyroidism without affecting the thyroid hormone receptors or thyroid hormone at all?
Using beta-adrenergic antagonists binds and counteracts the tachycardic effect of endogenous thyroid hormone, even though thyroid hormone does not use beta-adrenergic receptors to cause tachycardia.
What is an inverse agonist?
it binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist
What is the concept of “spare receptors?”
it is a concept that allows for maximal response to occur when there is not 100% receptor occupancy by the agonist
Again, what is the difference between EC50 and Kd?
**EC50 ** is the concentration that a drug elicits 50% of its max response
Kd is the concentration where 50% of the available receptors are bound
In the concept of the spare receptors, is the EC50 more or less than the Kd?
Less
50% of the response from the drug (EC50) is less than 50% if the total # of receptors that are bound (Kd)
essentially, the # of receptors to physiological response is not always a 1:1 ratio. There can be < 50% of the receptors bound but there is already 50% of the response from the drug.
What are 2 molecular mechanisms behind the spare receptor concept?
- Receptor could remain activated after the agonist departs allowing one agonist molecule to activate several receptors
- Cell signaling pathways could allow for amplification, or a relatively small signal and activation of only a few receptors could cause a maximal response
Do you need more or less of a noncompetitive antagonist for the desired effects when talking about spare receptors?
More
The antagonist will bind to the spare receptors and inhibit them, but that won’t matter because the agonist won’t bind to those receptors to elicit it’s response (it’s like it’s being wasted).
You need a higher dose of a noncompetitive antagonist to bind to the receptors that elicit the physiological response.
When talking about spare receptors, at low concentrations of the noncompetitive antagonist, what happens to the potency and efficacy?
Potency decreases because it’s proportional to the amount of receptors that must be occupied to produce 50% response (which has now been decreased even though it’s binding to spare receptors)
Efficacy is unchanged because there are receptors there to elicit the same amount of physiological response.
When talking about spare receptors, at high concentrations of the noncompetitive antagonist, what happens to the potency and efficacy?
Both efficacy and potency decrease because both the spare receptors and the receptors needed for the response to the agonist are blocked by the antagonist.
