Pharm - #8

Question 1

most, but not all, drugs produce their effects by interacting with what?

Biological response to drugs are graded. EXPLAIN

Answer 1

Receptors

2. increasing dose increases the response (up to some maximal point).

– biologic effects of drugs can be therapeutic or toxic,
depends on: the drug, the dose and its receptor “selectivity”

Question 2

Drug Nomenclature: Drugs are referred to by a name that reflects what?

Answer 2

their most prominent site of action or clinical effect

– Most drugs will likely interact with many other receptors within a given clinical dose range used therapeutically. (not just at target site, but other sites as well)

**Drug interactions with one or more receptor subtypes are determined by the drug’s chemical and structural properties, not by the name given to it by humans.

(ex: beta blocker also has high affinity for seratonin receptors)

Question 3

What are the following:

1. Electrostatic (+ and -)
2. Hydrogen Bonding (dipolar interactions)
3. Van de Waal’s Forces (at closer distances)  overlapping electron clouds
4. Hydrophobic Forces (between lipophilic components)

Answer 3

The Chemical Forces that Contribute to Drug Binding

Question 4

MOST DRUG BINDING INTERACTIONS ARE ____.

Most Drug Binding Interactions DO NOT Form a____Bond.

IMPORTANT:all drugs interact only with unoccupied free receptors

Answer 4

1. REVERSIBLE
2. Covalent
3. Drug “displacement” generally does NOT occur in drug receptor interactions
   - Reversible interaction between drug & receptor should be viewed as a dynamic equilibrium process. Thus the drug is either on or off the receptor at any point in time.

Question 5

______ - can bind a substance (e.g. drug) but are not themselves capable of initiating a subsequent response, whereas

______ – can bind a substance and are capable of initiating a subsequent response.

Answer 5

Binding Sites

Receptors

-Receptors represent only the first step in the transfer of drug information to the system ( D + R Response

Question 6

What happens after receptor amplification?

Answer 6

Signal Amplification

• single drug interaction leads to amplification

Gives rise to concepts of efficacy, potency, and spare receptors (reserve capacity)

Question 7

II. What is the Relationship between Drug Concentration and Receptor Occupation ?

For any receptor population, the percent occupied (“fractional occupancy”) is dependent only on the drug’s what? (2)

Answer 7

To initiate a response, drugs need to occupy receptors

1. Affinity and
2. Concentration (or dose)
   - Drug Binding to Receptors is a Dynamic Equilibrium Process
   - the term k2/k1 (or koff/kon ) is the equilibrium dissociation constant (aka, the drug affinity constant) which is denoted by the term KD .

Question 8

What does the KD value represent?

2. *Drug Affinity and KD values are ______ related

What ELSE does the Kd constant represent?

Answer 8

1. The KD value (i.e. affinity constant) of a drug represents a measure of the propensity of a drug to bind to a given receptor (a.k.a.,… its affinity
2. Inversely
3. The Affinity Constant (i.e., the KD) of a drug also represents the concentration of that drug required to occupy 50% of a receptor population.

Question 9

The Binding of Drugs to Receptors is Dictated by the what equation?

Answer 9

Simple Fractional Occupancy Equation

Fractional Occ = 1/ [ 1+ Kd/[D]}

Question 10

receptor fractional occupancy is dependent only on what 2 things?

Answer 10

1. Drug affinity

2. Drug concentration

Question 11

total number of receptors occupied by a drug will depend on what 2 factors?

What type of plot will result from the plotting of concentration vs. receptor occupation (where drug conc. is in units Kd)

Answer 11

1. The fraction of the receptor population occupied
2. the number of receptors in a given tissue (Bmax)
3. LINEAR PLOT
   - For example: If the KD of a drug is 1nM, then a conc. of 1nM would be a conc. of 1 KD unit, 2nM would be 2 KD units, etc. If another drug’s KD were 1uM, then it would take a conc. of 1uM to be at a 1KD conc for that drug, 2uM to be at 2 KD units of conc., etc.

Question 12

At its KD concentration, a drug will occupy ____of its receptor population

What happens once we approach Kd? Once we exceed?

Answer 12

1. 50%

-First we see a linear increase, then at the drug’s Kd a drug will occupy 50% of
receptor

-as we approach Kd and exceed we tail off and get a SMALL increase

**Increasing dose will increase receptor occupation in a NON-LINEAR fashion over most of the dose range.

-As the concentration of drug increases, the fraction of receptors occupied by the drug will increase from 1-91% over approximately 3 orders of magnitude (3 log units of drug conc.) about its Kd value, as shown in the figure

Question 13

The magnitude of a drug response will be some function of what?

Answer 13

Total number of receptors occupied
( fractional occupancy * receptor density)

-RESPONSE = ƒ [(Fractional Occupancy) (Receptor Density)]

= ƒ [ Total # Receptors Occupied]

Question 14

Drug Selectivity – will be dependent on the relative _____ of a drug
for various receptors.

2. selectivity will ____ as drug dose is increased

Answer 14

affinities

-(i.e. comparative KD values for various receptors).

3. decrease
   - - as conc. increases, likely to interact with sites that interact with SIDE EFFECTS

Question 15

DRUG SELECTIVITY:

Remember- all drugs can interact with any receptor at_____

&

it takes at least____ log units of concentration to occupy 1-91% of receptors

The “selectivity window” of a drug is dependent on the what?

Answer 15

1. high enough doses
2. 3 log units to occupy 1-91% of receptors
3. drug dose or concentration range employed.
   - It can be difficult to obtain this range in vivo where numerous factors are operative (drug distribution, metabolism, tissue receptor heterogeneity)

Question 16

_____;this is the correspondence between the amount of drug and the magnitude of the effect;

Answer 16

Dose Response Relationship

-increasing the dose, increases the effect in a graded manner.

Question 17

What is the simple occupancy theory?

Answer 17

1:1 relationship between occupation & response

-It’s simple……..
but doesn’t represent the dose-response relationship in most biologic systems

1. The magnitude of the pharmacological effect is linearly proportional to the NUMBER of receptors occupied by the drug
2. the maximum response Is obtained when all receptors are occupied

Question 18

What did the modified occupancy theory give rise to? What was it an expansion of?

Answer 18

gave rise to:

1. Potency
2. maximal efficacy

An expansion of the original theory to account for experimental findigns

The response of a drug was some positive function of receptor occupancy (i.e. not necessarily linearly proportional to the percent of receptors occupied

Maximum effects could be produced by an agonist occupying only a small proportion of receptors

Different drugs may have varying capacities to initiate a response

Question 19

Potency refers to what?

What does it depend on (2)?

Answer 19

• refers to the concentration or dose of drug needed to produce 50% of that drugs maximal response (EC50 or ED50 value)

1. Affinity for the receptor
2. Efficiency with which the receptor activation is coupled to response

Question 20

______: the maximal response produced by the drug.Used synonymously with?

What is the intrinsic activity of the following:

1. Full agonists
2. Partial Agonists
3. Antagonists(neutral)
4. Inverse agonists (negative antagonists)

Why are antagonists considered “neutral”?

Answer 20

Maximal efficacy

Intrinsic Activity
-This can be determined directly from the graded dose –response curve and is the limit of the dose response curve on the response axis

1. Full agonists I = 0
2. Partial Agonists IA

Question 21

A negative antagonist (or inverse agonist) can do what?

Answer 21

Reduce the constitutive activity of receptors

Question 22

Remember: Biological Activity CANNOT Be Determined From what?

Answer 22

Fractional Occupancy

example of 3 graphs:
Shown below, 3 drugs have equal affinity for a receptor, yielding equivalent fractional occupancy with dose, despite having different biological activities
= different response

could be antagonist, full agonist,
partial agonist

Question 23

Dose response curves demonstrate the concepts of _____ and ____

Describe the example of Morphine & Petazocine

Answer 23

Efficacy & Potency

-Efficacy and Potency are Independent Properties of a Drug

1. different POTENCY
2. same degree of pain relief efficacy (but different MAXIMUM efficacy)

ex:Morphine is more potent so need a lower dose
but both achieve the same pain relief efficacy

Increase dose = increase degree of pain relief up to some max response

Pentazocine also has some response, but will never achieve the same degree of pain relief
as with Meparidine  both drugs equipotent, but DIFFERENT MAXIMAL EFFICACY

Question 24

True or false:The Clinical Effectiveness of a Drug Depends on it’s Maximal Efficacy (Emax) not Potency (ED50)

Answer 24

TRUE!

reference the example fo the graph
- max efficacy is the limit of the graph

• ED50 is the same for morphine & petnamazocine for example

Question 25

# Define: Systems in which maximal response is achieved by doses of agonists that occupy only a SMALL percentage (or fraction ) of receptors True or False: This means only some receptors are functional, and others are not

Answer 25

are considered to have “spare receptors” (aka, “receptor reserve” - FALSE: This doesn’t mean that only some receptors are functional and others are not (i.e. “spare”). All receptors are considered to be EQUALLY functional, but its NOT required that ALL receptors be occupied to achieve a maximal response - generally because amplification is so robust

Question 26

What can help identify evidence of SPARE receptors?

Answer 26

identified from the “steepness” or dose-range required to achieve Emax in a D-R curve NOTE that a larger dose range is required for noradrenaline to elicit a maximal response in Tissue 1 compared to Tissue 2 THEREFORE: tissue 2 has MORE spare receptors LARGER RESERVE = smaller occupancy

Question 27

What does the following help us identify:it takes 3 log units of concentration for a drug to occupy 91% of any receptor population yet a maximal response occurs over a more narrow dose range (

Answer 27

Spare Receptors

Question 28

EXPERIMENTAL DETERMINATION OF SPARE RECEPTORS: How does one achieve Sequential increase in ED50 and EC50 with no change in Emax ? How can Emax be changed in Experimental Determination of spare receptors? (example)

Answer 28

Reduce the DENSITY (aka Fractional Occupancy) As you reduce receptor density = shift to right, increase in ED50 2. Reduce the number of Spare Receptors ex: if # receptors needed for Emax = 20, and you decrease to

Question 29

What is "surmountable" antagonist? What are the 3 effects they produce to the graph of agonist dose vs. percent of maximum? Does E max change? Can they be overcome?

Answer 29

COMPETITIVE ANTAGONISM (“SURMOUNTABLE”) 1) Shift to the right in DR Curve, 2) Increase in ED50, 3) No change in Emax -Increase antagonism by increasing DOSE or concentration of AGONIST will maintain E max originally had for that agonist HIGHER CONCENTRATION required to compete with antagonist in order to occupy the same number of receptors to produce a response equal to that observed in the absence of antagonist.

Question 30

What is an "insurmountable" antagonist? How do they affect the following: 1. Emax 2. ED50 Can they be overcome?

Answer 30

Non – competitive = insurmountable = NO SPARE RECEPTORS (reduced density) Non – competitive antagonists bind to the receptor and result in a change in the receptor that effectively removes it from the sites available to interact with the drug. (reversible or irreversible). 1. DECREASE Emax 2. No change in ED50 - The remaining receptors would exhibit the same affinity (Kd) for the drug and thus the ED50 would not be altered. If there is no receptor reserve, there would be a decrease in the maximal response (Emax) due to the loss of available receptors to be activated.

Question 31

WHat is the effect of administering a Partial Agonist? Why?

Answer 31

ANTAGONISM - will diminish activation of full agonist -will give LESS of a response (1 + 0/5 is actually 0.5 not 1.5) Since partial agonists can bind to the full complement of a receptor population but CANNOT produce the maximal response of full agonists, THEY CAN REDUCE THE MAXIMAL RESPONSE OF FULL AGONISTS WHEN BOTH DRUGS ADMINISTERED TOGETHER (cannot produce the maximal response of full agonists)

Question 32

Non Pharmacological Means to Antagonize Drug Effects State the following: 1. the use of opposing pathways to antagonize the effects of a drug 2. via chemical inactivation of a drug (example) 3. - one drug may affect the metabolism or pharmacokinetics of another drug

Answer 32

1. Physiologic Antagonism 2. Chemical Antagonism Ex: protamine (+ charge) inactivates heparin (-) Less specific, and less easy to control that the effects of a receptor specific antagonist 3.Biologic Antagonism

Question 33

What is the QUANTAL Dose response curve? Where is it obtained?

Answer 33

- the relationship between drug dose and a specified effect in a population of individuals 2. This is obtained from the cumulative frequency distribution of doses of drug that produce a specified (i.e. quantal) effect in a patient or animal population.

Question 34

What are 3 things the Quantal Dose Response Curve can be used to obtain?

Answer 34

1. Can be used to obtain median effective dose ED50. Dose at which 50% of people will exhibit a specified effect 2. Used to obtain INDEX of SELECTIVITY of a drugs actions by comparing its ED50 for different specified effects 4. Used to determine THERAPEUTIC INDEX representing some estimate of safety of a drug. It is the ratio of TD50 or LD 50 to the ED50 determined from quantal dose response curves

Question 35

How is the Quantal Dose Curve obtained? 1st? 2nd? 3rd? 4th & final?

Answer 35

1. First: specify your endpoint effect (or multiple endpoints) that can be answered in digital fashion; Yes or No ! (sedation, decongestation, anxiety) 2. Give a low dose of drug and determine the number of individuals that exhibit the effect (they do or they don’t – there’s no grading on a curve here, its PASS or FAIL) 3. Give a higher dose of drug and again determine the number of individuals (percent of population) that exhibit the effect 4. Continue this strategy of increasing the dose until you obtain the effect in all individuals in the population – then ADD it all up and plot !

Question 36

ED50 is always less than what in the quantal dose resposne curve?

Answer 36

LD50! As you increase dose, what percentage of pop. responds with specified endpoint to given dose

Question 37

What 3 things are determined by Quantal Dose Response Curve?

Answer 37

1. median effective Dose (ED50) 2. Index of SELECTIVITY of a drugs action - by comparing its ED50 for different specified effects 3. An ESTIMATE of the degree of SAFETY for a Drug for a Specified Effect (i. e. the Therapeutic Index TD50/ED50 or LD50 /ED50

Question 38

What is a more clinically relevant index of safety other than quantal dose curve? Ex?

Answer 38

Therapeutic Window – a more clinically relevant index of safety **This is the Dosage Range between the minimum effective therapeutic dose and the minimum toxic dose (e.g. 8mg/L – 18mg/L theophylline) EX: theophylline has a narrow therapeutic window!!! *Want ED50 and LD50 to be as FAR as possible from one another = less toxicity and safer

Question 39

Drugs can have the same therapeutic INDEX, but a small therapeutic window. True or false? Which is better to assess drug safety?(therapeutic index or therapeutic window)

Answer 39

TRUE - do not prescribe these drugs Take Home: Drug safety can be better assessed from the Therapeutic Window than from the Therapeutic Index