Pharmacodynamics Lecture Sep 17

Question 1

What is the study of pharmacology?

What is the study of pharmacodynamics?

Pharmacokinetics?

Answer 1

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.

Question 2

How does a drug produce an effect?

Answer 2

It interacts with a receptor on or within a cell. It acts to increase or decrease cell function–it does not confer new function.

Question 3

What is an agonist?

Answer 3

a drug that activates molecular, biochemical, and physiological events associated with the interaction

Question 4

What are the two main functions of receptors?

Answer 4

1. recognition of the ligand/drug - confers specificity
2. Signal transduction - the message has to be transmitted to the cell to elicit an effect

Question 5

What imparts selectivity of drug binding?

What confers specificity of drug action?

Answer 5

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

Question 6

True or false: most drugs bind their receptors covalently.

Answer 6

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.

Question 7

What are most receptors composed of?

Answer 7

The majority are proteins (including enzymes, ion channels, structural, and regulatory)

Some are nucleic acids, but not many

Question 8

In general terms, what are the 3 ways a receptor can propogate its signal?

Answer 8

1. Alter receptor function
2. Generates a second messenger (like cAMP)
3. Impacts gene trasncription

Question 9

Give an example of a receptor that propogates its signal through second messengers.

Answer 9

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

Question 10

How do ion channels work?

Answer 10

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

Question 11

Explain how a receptor can act as an enzyme.

Answer 11

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)

Question 12

Explain how receptors can regulate nuclear transcription.

Answer 12

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.

Question 13

What are 5 important attributes of receptor-mediated processes?

Answer 13

1. THey are highly compartmentalized (receptors are expressed only in certain tissues)
2. They are self-limiting on relatively short time scales (this is extremely important otherwise they wouldn’t make for very good signalling pathways)
3. THey are often organized into opposing systems (one end will turn on a cascade and the other will turn it off)
4. They provide opportunities for signal amplification (this is characteristic of GPCR - they snowball the effect)
5. They operate through a relatively small number of 2nd messenger systems (many receptors will operate through the same signalling pathway, often simultaneously)

Question 14

Some drugs don’t interact with receptors. WHat are some examples of things they react with?

Answer 14

• interact with small molecules
• produc physicochemical effects (move water around, alter pH, etc)
• target rapidly dividing cells

Question 15

Why are drug drug interactions so common?

Answer 15

DD interactions are common because a large number of receptors may operate through a small number of secondary messenger systems

Question 16

What are some of the ways cell cycle-specific drugs will be tosic to cells that are cycling?

Answer 16

1. Can be structural analogs of endogensou compounds (like 5-fluouracil or methotrexate) that act by interfering with DNA/RNA synthesis
2. THey can bind to DNA causing strand breaks (like the ABx bleomycin)
3. Others target the cellular machinery needed for cell division (like tubulin)

Question 17

How can cell cycle-nonspecific drugs be toxic to cells?

What cells are they toxic to?

Answer 17

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

Question 18

What does occupany theory state?

Answer 18

The effect of a drug is proportional to the receptor occupandy AND the interactions between receptor and ligand are monovalent

Question 19

What is the Kd?

What is the ED50?

How are they related?

Answer 19

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

Question 20

How does one determine the Kd experimentally?

Answer 20

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.

Question 21

What is the affinity of a drug?

How is it characterized mathematically?

Answer 21

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.

Question 22

WHat is a drug’s potency?

How is it determined based on a dose response plot?

Answer 22

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

Question 23

What does efficacy/intrinsic activity deal with?

what term describes the efficacy?

Answer 23

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)

Question 24

What is the difference between a full agonist and a partial agonist?

Which has greater efficacy?

Answer 24

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.

Question 25

Can a partial agonist ever have an alpha value of 1?

Answer 25

No - it will always have partial efficacy, no matter how much drug you give. It will never reach maximal response

Question 26

What is a pure antagonist?

Answer 26

It has affinity for the receptor It inhibits the action of an agonist HAS NO EFFICACY (alpha = 0)

Question 27

Describe competitive antagonism. WHat happens to the dose respnse curve? How about the maximal response?

Answer 27

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

Question 28

Explain non-competitive antagonism. What happens to the dose response curve? What happens to apparent affinity? Maximal response?

Answer 28

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)

Question 29

What is physiological antagonism?

Answer 29

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

Question 30

What will a partial agonist do in the presence of a full agonist?

Answer 30

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

Question 31

Why does partial agonism go against occupancy theory?

Answer 31

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.

Question 32

What is inverse agonism?

Answer 32

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.

Question 33

In general terms, what is two-state theory?

Answer 33

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.

Question 34

Explain the idea of spare receptors.

Answer 34

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.

Question 35

Explain a quantal dose effect.

Answer 35

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.

Question 36

What is a cumulative frequency curve? What information does it give us and how is that information different from a dose response curve?

Answer 36

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.

Question 37

Someone who is hyperreactive will respond to what kind of dose? Someone who is hyporeactive will respond to what kind of dose?

Answer 37

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.

Question 38

What is tolerance? Why is tachyphylaxis?

Answer 38

Tolerance is a form of hyporeactivity induced by repeated administration. Tachyphylaxis is a form of hyporeactivity induced rapidly after only a few doses.

Question 39

What is the therapeutic index? How is it calculated? What does a low TI mean for safety?

Answer 39

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.

Question 40

What is the certain safety factor?

Answer 40

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

Question 41

What often gives rise fo side effects? How can they be managed?

Answer 41

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.