Pharmacodynamics Lecture Sep 17 Flashcards
What is the study of pharmacology?
What is the study of pharmacodynamics?
Pharmacokinetics?
study of drugs that interact wiht living systems through chemical processes
Pharmacodynamics is how the drugs affect the body.
Pharmacokinetics is how the body affects the drugs.
How does a drug produce an effect?
It interacts with a receptor on or within a cell. It acts to increase or decrease cell function–it does not confer new function.
What is an agonist?
a drug that activates molecular, biochemical, and physiological events associated with the interaction
What are the two main functions of receptors?
- recognition of the ligand/drug - confers specificity
- Signal transduction - the message has to be transmitted to the cell to elicit an effect
What imparts selectivity of drug binding?
What confers specificity of drug action?
Receptor recognition of a drug imparts selectivity of drug binding–a drug will only bind one or a small number of receptor types
The tissue localizaiton of different receptor types imparts specificity of drug action - the drug exerts a distinctive influence on the body because the receptors are located in distinctive organs/systems
True or false: most drugs bind their receptors covalently.
False
If a drug binds to its receptor permanently, it essentially takes the receptor out of circulation because the bond is pretty much permanent. THe body would have to synthesize more receptor sin order to rescue the response.
SOme drugs actualy do this, but most bind noncovalently through H bonding, ionic interactions, etc. THey still need to fit appropriately into the active site, however.
What are most receptors composed of?
The majority are proteins (including enzymes, ion channels, structural, and regulatory)
Some are nucleic acids, but not many
In general terms, what are the 3 ways a receptor can propogate its signal?
- Alter receptor function
- Generates a second messenger (like cAMP)
- Impacts gene trasncription
Give an example of a receptor that propogates its signal through second messengers.
G protein-coupled receptor signalling
A durg binds to the G protein
Subunits separate and have their own characteristic puposes, such as increases or decreases cAMP, initiating calcium release, etc.
About half of the drugs we use today act through this mechanism
How do ion channels work?
You get a ligand/drug binding to the channel
this causes a conformational change and the channel opens
ions will flow through the channels down the electrochemical gradient
this could cause the depolarization of the membrane or the ion itself will be the secondary messenger
Explain how a receptor can act as an enzyme.
Many receptors possess enzymatic activity.
Very commonly, the ligand will bind receptor
receptors will dimerize
After the dimerization, the receptor can become an enzyme to catalyze reactions
these reacions are often phosphorylations (such as for the tyrosine kinase receptors) or dephosphorylation (like the tyrosine phosphatase receptors)
Explain how receptors can regulate nuclear transcription.
Many steroid hormones operate through this mechanism.
You have a receptor typically located in the cyotplasm or in the nucleus bound to chaperone (like a heat shock protein)
WHen the drug/ligand binds the receptor, the chaperone is inactivated and falls off.
This allows the receptor to interact with a hormone response element on the DNA
The receptor bound to the DNA will then recruit transcription machinery to alter gene expression
**note: these drugs are often moderatly lipophylic because they need to be able to travel across cell membranes easily.
What are 5 important attributes of receptor-mediated processes?
- THey are highly compartmentalized (receptors are expressed only in certain tissues)
- They are self-limiting on relatively short time scales (this is extremely important otherwise they wouldn’t make for very good signalling pathways)
- THey are often organized into opposing systems (one end will turn on a cascade and the other will turn it off)
- They provide opportunities for signal amplification (this is characteristic of GPCR - they snowball the effect)
- They operate through a relatively small number of 2nd messenger systems (many receptors will operate through the same signalling pathway, often simultaneously)
Some drugs don’t interact with receptors. WHat are some examples of things they react with?
- interact with small molecules
- produc physicochemical effects (move water around, alter pH, etc)
- target rapidly dividing cells
Why are drug drug interactions so common?
DD interactions are common because a large number of receptors may operate through a small number of secondary messenger systems
What are some of the ways cell cycle-specific drugs will be tosic to cells that are cycling?
- Can be structural analogs of endogensou compounds (like 5-fluouracil or methotrexate) that act by interfering with DNA/RNA synthesis
- THey can bind to DNA causing strand breaks (like the ABx bleomycin)
- Others target the cellular machinery needed for cell division (like tubulin)
How can cell cycle-nonspecific drugs be toxic to cells?
What cells are they toxic to?
They are toxic to both cells that are cycling and cells that are resting (in G0)
Many damage and/or bind to DNA to interfere wiht normal celll function
Examples include alkylating agents and some antibiotics
What does occupany theory state?
The effect of a drug is proportional to the receptor occupandy AND the interactions between receptor and ligand are monovalent
What is the Kd?
What is the ED50?
How are they related?
The Kd is the dissociation constant
The EC50 is the concentration of a drug that produces a 50% response
THe Kd = EC50 under occupancy theory
How does one determine the Kd experimentally?
Since the Kd is equal to the EC50, you can give a drug at various dosages and calculate effect. THen plot response (effect) by the dose.
To make it easier to interpret, we always log transport the dosages so that logDose is on the x axis. The dose that confers the 50% respnse is the EC50, which is equal to the Kd.
What is the affinity of a drug?
How is it characterized mathematically?
A drug’s affinity is its ability to form a complex with the receptor.
Mathematically it is characterized as 1/Kd (the inverse of the Kd).
So the higher the dissociation constant, the lower the affinity of the drug, which makes intuitive sense.
THe greater the affinity the lower the drug concentration required to produce an effect.
WHat is a drug’s potency?
How is it determined based on a dose response plot?
A drug’s potency is the relative position of the dose-reponse curve. A potent drug will be further to the left because it takes less of a drug to exhibit an effect
Contrary to what many expect, potency does NOT have anything to do with maximal effect - it has to do with the Kd
What does efficacy/intrinsic activity deal with?
what term describes the efficacy?
When we’re talking about maximal response, we refer to the efficacy (or intrinsic activity–they’re synonymous)
The efficacy is described by the alpha term. The alpha will range from 0 (no effect) to 1 (full efficacy)
What is the difference between a full agonist and a partial agonist?
Which has greater efficacy?
A full agonist exerts a maximal response and has full efficacy with alpha = 1
A partial agonist is more common - it produces less than maximal response and has partial efficacy with alpha greater than 0 and less than 1.
Can a partial agonist ever have an alpha value of 1?
No - it will always have partial efficacy, no matter how much drug you give. It will never reach maximal response
What is a pure antagonist?
It has affinity for the receptor
It inhibits the action of an agonist
HAS NO EFFICACY (alpha = 0)
Describe competitive antagonism.
WHat happens to the dose respnse curve?
How about the maximal response?
Competitive antagonism occurs when an antagonist competes against an agonist for a receptor in a REVERSIBLE fashion
The dose response shifts to the RIGHT because it will take more of the agonist to produce the same effect as without the antagonist
The slope of the dose reponse curve does NOT change
The maximal response can still be produced if more agonist is given-it just takes more
Explain non-competitive antagonism.
What happens to the dose response curve?
What happens to apparent affinity? Maximal response?
This occurs when the antagonist binds to the receptor covalently = permanently.
It’s irreversible and the apparent number of receptors decreases
The maximal response is therefore reduced because no matter how much agonist you add, the repsonse will not be rescued
Because of this, the slope of the dose-response curve decreases
The apparent affinity changes little if at all (because the receptors that are not bound to the antagonist will still bind the drug with the same affinity)
What is physiological antagonism?
This is distinct from the type of antagonism–it involves interactions among regulatory pathways mediated by DIFFERENT receptors
So a drug that impacts on pathway is used to antagonize an effect caused by a different pathway
What will a partial agonist do in the presence of a full agonist?
The partial agonist will often act as an antagonist.
If given in increasing concentrations, the partial agonist will swamp out the full agonist at the receptor. Since the partial agonist has less efficacy than the full agonist, it will thus act to antagonize the full effect of the drug
Why does partial agonism go against occupancy theory?
because occupany states that the response is proportional to the amount of receptor occupied
But in partial agonism, the maximum response is never reached no matter how much receptor is occupied because that’s the limited step–it’s limited by something else such as a second messenger.
What is inverse agonism?
This also doesn’t jive with occupancy theory.
It’s the idea that for a system that always have some level of constitutive activation, if you give an inverse agonist, you will actually get a DECREASE in response.
You can add in an normal agonist, which will increase the activation if you can swamp out the inverse agonist.
To further this point, if you give a pure antagonist to this type of system, activation will not respond to either an inverse agonist or a normal agonist.
In general terms, what is two-state theory?
THe receptor actually exists as 2 different forms: the active form and the inactive form.
THe level of active receptor around at baseline is responsible for the constitutive or basal effect of the receptor (you don’t even need a drug/ligand to be bound)
An agonist will stabilize the ACTIVE receptor form and cause an increase in response from the constitutive baseline.
An inverse agonist will stabilize the INACTIVE receptor form, resulting in a decrease from the constitutive basal effect.
A pure antagonist will block the activity of both the agonist and the inverse agonist, so you get a level of activation that is near the constitutive effect.
Explain the idea of spare receptors.
This is when a very small dose ilicits a full response from the system.
You max out a second messenger - not the receptor.
In this case, the EC50 is no longer equal to the Kd because the Kd is the value for half occupancy and the EC50 is the value for half the response–there’s now a disengage between the two.
Explain a quantal dose effect.
This is an all or nothing kind of thing that looks at population response.
It cares more about the median effective dose (ED50), which is the dose that produces effect in 50% of the population
This CANNOT be used to determine the Kd or maximal efficacy because it’s a yes no thing - it’s not about the level of response, just whether there was one.
What is a cumulative frequency curve?
What information does it give us and how is that information different from a dose response curve?
A cumulative frequency is a summation of the number of people who experience a quantal dose effect at a given dose.
Although it will look similar to a dose response curve, it gives different information.
The mediate dose produccing a responsein 50% of the population (the ED50) will be in this curve, while the EC50 was in the dosage repsonse curve.
You also cannot tell the maximal efficacy of a drug through this curve. You can get some idea of potency because potency deals with the relative position of the curve.
Someone who is hyperreactive will respond to what kind of dose?
Someone who is hyporeactive will respond to what kind of dose?
Hyperreactive if they response to a dose that is much much less than the ED50.
Hyporeactive if they response only to a dose that is much much greater than the ED50.
What is tolerance?
Why is tachyphylaxis?
Tolerance is a form of hyporeactivity induced by repeated administration.
Tachyphylaxis is a form of hyporeactivity induced rapidly after only a few doses.
What is the therapeutic index?
How is it calculated?
What does a low TI mean for safety?
It’s a measure of relative safety
It is the ratio of the LD50 to the ED50
(dose needed to kill half the patients)/(dose needed to illicit a repsonse in half of the patients)
You want this number to be high. The higher the TI the safer the drug.
What is the certain safety factor?
The CSF is a more conservative measure of relative safety.
It’s the ratio of the LD1 to the ED99
IN other words, its qual to
(dose required to kill 1% of patients)/(dose required to illicit response in 99% of the patients)
This is much harder to calculate than the TI
What often gives rise fo side effects?
How can they be managed?
Side effects often arise from the drug acting on addition receptors in other pathways (usually as partial agonist or antagonists)
This can be managed by dosing appropriately. If given at a lower dose, the drug will work only at the receptor for which is has the lowest Kd.
