Pharmacology Dynamics Flashcards
What is the generic name of tylenol
-acetaminophen or paracetamol
What are some examples of cellular responses to receptor activation
-there can be changes in the ion content of cells directly or inderectly
-reduce signalling by excitable cells
-promote secretion of hormones
-alter contractile activity
-stimulate synthesis of proteins
How do most drugs work?
-most drugs bind to a regulatory proteins
->regulatory proteins are those such as ion channels, receptors, enzymes and transporters
What is meant by the term binding?
-it is when a small molecule joins with a protein target to form a complex
Do drugs bind to where an endogenous ligand would bind?
-yes
What does the term ligand mean?
-term used to refer to any small molecule
->ligand can also be a drug, it just needs to bind to a target
Is cell physiology altered when a drug binds to a protein?Why?
-yes
->because the function or behaviour of the regulatory protein is altered
What is the Lock and Key model
-only a specific shape fits into the protein and activates it
What is a positive allosteric modulator
-it doesn’t bind directly to a receptor the agonist binds to
->binds to another site
-but when an agonist comes along, it enhances the effect of the agonist
What is a negative allosteric modulator
-it doesn’t bind directly to a receptor the agonist binds to
->it binds to another site
->but when an agonist comes along, it reduces the effect of the agonist
What is an agonist
-a ligand that binds to a receptor protein and active the receptor
->almost all endogenous ligands are agonistd
Are majority of the drugs antagonists?
Yes
What is nifedipine
-L type Ca2+ channel antagonist
What is Bay-K 8644
-binds to the same side as nifedipine but enhances the CA2+ flux following depolirization
What is lidocaine
-use dependent blocker of voltage activated sodium channels
How do we predict a size of a response of a tissue to a ligand
-the fraction of receptors bound by a ligand
->more of the receptors that are occupied the more effect
What determines the fraction of receptors bound by a ligand
-the concentration of the ligand in the proximity of the receptors in interest
What determines the tightness of binding between a ligand and a receptor
-the higher the number and quality of complimentary interactions, the more tightly the drug binds
-shape(steric hindrance), lipophilic/hydrophilic incompatibility or charge clashes can reduce binding tightness
What shape can you use to describe the binding of ligands to receptors
-a hyperbole shape
What does binding affinity mean for a graph showing the ligand concentration and the number of receptors bound
-if the graph is more to the right, then that means it has a less of an affinity for a receptor at the same concentration compared to another ligand or drug
What is meant by the term affinity
-we are talking about how tightly a drug binds
What is the numerical value used to define affinity at which 50% of the ligand is bound to the target
-it is referred to as Kd
What does a Kd allow for
-it allows for a quantitative comparisons to be made between binding of different drugs
What is selectivity
-a drug shows selectivity for a target when it binds with higher affinity
What is the equation for a hyperbola that relates ligand binding to concentration
-the Hill-Langmuir equation
-it is b/bmax
->b is concentration fo target proteins bound by ligand
->b max is maximum possible binding(total concentration of target proteins)
What is a ligand binding study generate
-it generates a binding curve
->Kd is used to look at 50% of the targets that are bound
What is a concentration-effect curve
-it is an EC50 curve
->concentration of a ligand that gives 50% of maximum effect
What is a log dose response curve
-an in vivo study generates a log dose response curve
->ED 50 is a dose of ligand that generates 50% of the maximum response
What is a Quantal Dose response curve? Give an example
-demonstrates response in a group of patients where the effect either does or does not occur
->for example, a loss of consciousness to a general anaesthetic
Is a quantal dose response curve normally distributed
-no
->that is why you need to use a log axis to normalise it
Do vast majority of ligands bind reversibly to proteins?
-yes
->so there is an equilibrium set up between bound and unbound proteins existing
->ligand associates(going onto target) and dissociation(coming off the target) from the protein
->only bound drug has an effect on protein behaviour
-the consequences of a drug remains
What is the relationship between Kd and association
-the lower the Kd, the more tightly it binds
->associates more often and remains bound for a longer time
What is the k on
-the association rate constant
->it doesn’t change for a particular ligand or drug interacting with a receptor
How is association rate calculated
-kon x [substrate] x [receptor]
-the association rate decreases because the receptor concentration decreases as the complex forms
What does a higher kon value mean
-a larger kon value is more likely to bind to a receptor than a drug with a lower kon
-it is like a magnet
-higher kon means more likely association
->more likely associations means faster association rate
What is the koff
-the dissociation rate constant
How is the dissociation rate calculated
-koff x [complex between ligand and receptor]
-as the complex falls apart, the rate goes down
->it is an exponential decay curve with a half life
What does a high koff mean
-the one with the higher k off will remain bound for a shorter time and have a faster dissociation rate
-the one with the lower koff will remain bound for longer and slower dissociation rate
Describe the relationship between Kd, koff and kon
-high drug binding affinity occurs when you have a small koff and or a large kon
-Kd=koff/kon
At equilibrium, are dissociation and association occurring together?
-yes
->eventually they will be the same rates
What does a very small koff mean for the drug amount in plasma
-drugs with a very small koff has a very high binding affinity
->drug concentrations in plasma after dose can be extremely low
What does a high koff mean for the association rate
-the association rate is slow and it can take a long time to reach equilibrium
-max drug binding may occur long after max drug concentration in plasma is reached
->drug can remain bound to targets long after it has mostly disappeared from the plasma(so the effect of the drug continues)
What does a very large kon have for the drug concentration in plasma
-have very high binding affinities and and drug concentration in the plasma can be very low after a therapeutic dose
What is a drug with a high kon likely to do after disscoiating
-drug is more likely to re-associate than to diffuse away in the plasma
What does rebinding do for the concentration of drugs in the vicinity of the targets
-the localized drug concentration could be ten-fold higher than it is in the plasma as a result
Are most irreversible drugs enzyme inhibitors
-yes
How do irreversible drugs work
-often an initial reversible interaction, followed by convalent bonding
->the protein is permanently inactive
What are examples of irreversible drugs
-aspirin
-omeprazole
-tranylcypromine
What is agonist efficacy
-effectiveness of an agonist in activating a single receptor
What happens to tissue response with an agonist who has increased efficacy
-as agonist efficacy is increased, the tissue response becomes greater
What is a full agonist
-causes the tissue to give the maximum response that it could provide
What happens as you increase the efficacy of the agonist
-as you increase the efficacy, you need to occupy less receptors to achieve the same tissue response
Can partial agonist act as an antagonist
-yes
->if an endogenous agonist has too much of an effect on a tissue response, a partial agonist can come in and compete for those receptors
->it can then cause less of a response
-note used as an agonist, a partial one cannon over-stimulate the tissue
-used as antagonist even at a high dose, we cannot over inhibit the tissue
-a partial agonist can lead to increased patient safety
What is drug potency
-semi-quantitative term
-a comparative term
-refers to the relative dose of a drug to achieve a particular magnitude of a response
Do you get potency from a binding curve
-no from a dose response curve or a concentration effect curve
How is potency of antagonist change with binding affinity
-potency of antagonist increases as binding affinity increases
How is potency of agonist changing with binding affinity and efficacy
-potency of agonist increases with binding affinity and efficacy
