Pharmacology L1: Pharmacodynamics Flashcards
What is pharmacology?
Study of how drugs work
What is an agonist?
a substance that promotes a receptor-mediated biological response, often by competing with another substance at the same receptor.
On the molecular level, agonists bind to ________.
receptors
What is a receptor?
a molecular structure or site on the surface or interior (In surface of cell or inside the cell) of a cell that binds with substances such as hormones, antigens, drugs, or neurotransmitters with specificity.
Many different types of molecules can serve as receptors and can include ___, ___, ____ and ____ in DNA, etc
enzymes; membrane proteins; nucleic acids
Many drugs inhibit _______, such as in a patient (ACE inhibitors), in microbes which infect us (penicillin), and in cancer cells (5- FU).
specific key enzymes
_____ that are receptors may be structural, involved in transport, contain ion pores or coupled to proteins downstream.
Cellular proteins
Some drugs bind, with their receptor, to the _____ itself.
DNA
What does the receptor diversity and timelines look like?
What are the 4 types of ____?
- Ligand ion channel
- G-Protein-Coupled Receptors (GPCRs)
- Kinase-linked Receptors
- Nuclear receptors
What are Ligand ion channel receptors?
millisecond response time
When it binds Ach, it changes confirmation –> allows the inward movement of Na+ ions down the concentration gradient (no energy needed- driven by Na+ ions levels)
- Eg. voluntary movement of muscles
What is G-Protein-Coupled Receptors (GPCRs)?
is multi-step and takes seconds G proteins
- Intra-cellular Receptor
- Receptor can binds an agonist or drug (from outside) –> changes confirmation
- Translatory effect –> externally –> signal that G protein can read Benefits
- Seconds (still quite quick)
- No nicotonic receptors = amplification
- Multi step cascade = binding of single drug/agonist = multiplication/amplification effect
What are Kinase-linked receptors?
The phosphorylated active receptor is now recognized by multiple relay proteins, such as Grb2.
What is nuclear receptors?
Receptors may also be present within the cells and on the DNA itself, leading to long-term changes due to protein synthesis
- Receptors are present in DNA itself
- Hormones are lipophilic =can cross the membrane
- Once they cross the bilayer –> associate with internal receptors = combination can travel to the DNA itself = evoke changes in transcription and translation
- Hormones can evoke change –> impact genetic expression
The binding of an agonist to its receptor(s) has ________ leading to ______, and binding is mostly _____… Factors such as ____. ____. ______, etc. are crucial for such binding to occur.
structural specificity; affinity (attraction); reversible; charge; shape; hydrophobic/hydrophillic regions
What is drug specificity?
Shape/physicochemical properties of the drug
Shape/physicochemical properties of target molecule
What is the enzyme (lock and key concept)?
Enzyme = lock and key concept (restricted) = hand going into a glove (more accommodation of the structure of agonist and the structure of receptor= give and take aspects while still preserving the specificity)
Agonist interactions with receptors are _______-dependent
concentration
Determines the extent of interaction
Agonists and Receptors usually ______ interact, and the amount of AR formed at any given time is directly links to agonist and receptor concentrations.
reversibly
Drug concentration can be controlled more______, and so drug concentration determines how many activated receptors you might have at any given time.
easily
What does drug concentration determine?
how many activated receptors you might have at any given time.
Some agonists are better able to get effects (____) compared to others, and this impacts the _____’ ability to generate a response.
efficacy; receptors
What are binding curves?
affinity (potency) and efficacy (effectiveness)
What are EC50?
Effective Concentration for 50% response (EC50) is a classic pharmacological measurement that can tell us a great deal about how potent (powerful- How much is needed? ) an agonist might be.
At a relatively low concentration of agonist, what happens?
A low concentration of agonist binds to its receptors, causing physiological changes in the targeted cell.
Dynamic and reversible
At a relatively high concentration of agonist, what happens?
At high concentration of agonist, almost all of the receptors will be occupied at any given time, leading to a greater physiological effect.
Dynamic and reversible
Increase likelihood that agonist will bind to receptor
What is the relative potency of two agonist?
Same maximal response in the same tissue
Depends on occupancy and activity relative affinities relative efficacies Compare EC50 values
Drug X is more potent than Drug Y
What is the Relative efficacy of two agonists?
Different maximal response in the same tissue
Different relative efficacies
Compare fractional responses
Drug Y has 50% efficacy of Drug X
Binding the receptor is a key ______ interaction…But, it isn’t enough…the drug or agonist must also have _____ activity, the ability of a drug to induce changes in receptor structure leading to alterations in cellular activity. This is why not all drugs stimulate their receptors to the ____ extent, even if they are binding to the same site(s)…they may have different intrinsic activities.
pharmacodynamic; intrinsic; same
Drug A and Drug B have comparable EC50 values, but different magnitudes of effects, what does that look like?
Which drug has the greatest affinity for the receptors?
Drug A (best affinity = best response/cause an effect)
How many times greater is the affinity of Drug B compared to Drug C?
Drug B is 5 times more powerful than Drug C
How effective are these drugs compared to each other?
What can be said about the potency of Drugs A, B and C?
EC50= same in all 3 drugs (where curve switches direction) = same potency
Which is more efficacious, Drug B or Drug C?
B = bigger on T axis
Do you think it is likely that you could achieve Drug A’s effect with a high enough concentration of Drug C? Why?
No . Why?
- Binding is not good
- Activation of secondary messengers is not good
Receptor antagonists bind to _____ and do not cause a response themselves …instead they prevent or alter the binding of _____.
receptors; agonist
What is the competitive antagonist?
The high-affinity competitive antagonist binds to the receptor, but does not activate the effectors.
Notice that it binds to the same area on the receptor as the agonist did earlier.
No concentration-response curve is possible, as there is no response!
The _____-affinity competitive _____ binds to the receptor, but does not activate the effectors. Notice that it binds to the same area on the receptor as the agonist did earlier. No concentration-response curve is possible, as there is no response!
high; antagonist
What is the competitive antagonist and agonist?
the competitive antagonist physically blocks the sites, reducing the ability of the agonist to bind and cause a response.
This leads to a reduction in the effect of the agonist at each concentration.
What happens at a At a higher concentration of agonist?
At high concentration of agonist, almost all of the receptors will be occupied at any given time, leading to a greater physiological effect.
This means that concentration is crucial, and this principle only works if the binding is reversible.
The odds of the antagonist binding to the receptor become virtually zero as there is so much agonist present.
What is the irreversible competitive antagonism?
…in which some of the receptors become permanently bound to receptors, at the same site as where the agonist binds.
When the agonist is applied, the maximum number of receptors available is less than 100% as some of them are permanently occupied by the antagonist
Lose % of receptors = efficacy drops
What are positive allosteric modulators?
positive allosteric modulators. (Enhances Affects structure Modulates)
By binding to a different site on the receptor complex, they actually increase the affinity of the agonist for its own receptor, making the response even greater.
What is Receptor Internalisation (recycling or down-regulation)?
Receptor expression can be very dynamic.
What is Receptor desensitization?
An uncoupling with the second messenger system b-Arrestin binding renders the receptor unable to respond to agonist as GP binding site is blocked.
In addition, downstream second messengers may be depleted and this may also lead to reduction of signal and reduced physical changes.
What is a Classic example of how receptor desensitization/down-regulation is important clinically?
Morphine (opiate) is used to treat cancer patients (and others) to relieve chronic pain.
