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Pharmacology > Pharmacodynamics I > Flashcards

Pharmacodynamics I Flashcards

1
Q

How do drugs produce their effects?

A
  • most, but not all, drugs produce their effects by interacting with receptors
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2
Q

What does it mean that receptor response to drugs are graded?

A

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

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3
Q

Biologic effects of drugs can be therapeutic or toxic, depends on:

A
  • the specific drug,
  • the clinical dose
  • its relative affinity for respective receptors mediating therapeutic vs toxic effects (i.e. the concept of drug “selectivity” )
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4
Q

What Differentiates Binding Sites from Receptors ?

A

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

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

Receptors represent only the first step in the transfer of drug information to the system ( D + R then downstream Response).

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5
Q

What does a drug’s name tell us?

A

Drug Nomenclature: A drug is referred to by a name that reflects its most prominent site of action or clinical effect (e.g. SSRI, antidepressant), although it will likely interact with many other receptors within the same dose range used therapeutically. 

However, its the “label” we attach to a drug often determines how a drug may be used or misused.

*Drug interactions with one or more receptor subtypes are determined by the drug’s chemical and structural properties that dictate its respective receptor affinities, NOT by the name given to it by humans..

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6
Q

What are the chemical forces that contribute to drug binding?

A
  1. Electrostatic
  2. Hydrogen Bonding
  3. Van de Waal’s Forces (at closer distances)
  4. Hydrophobic Forces (between lipophilic components)
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7
Q

Are drug binding interactions reversible or irreversible?

A

MOST DRUG BINDING INTERACTIONS ARE REVERSIBLE

MOST Drug Binding Interactions DO NOT Form a Covalent Bond.

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8
Q

How common is drug displacement as a mechanism of receptor occupation?

A

ALL DRUGS INTERACT ONLY WITH UNOCCUPIED (FREE) RECEPTORS

Drug “Displacement” generally does not occur in drug receptor interactions.

(Have association and dissociation from that receptor; consequence is you don’t get drug displacement (no outgoing group… on/off only and competition by another drug potentially)

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9
Q

What kind of receptors do drugs interact with?

A

ALL DRUGS INTERACT ONLY WITH UNOCCUPIED (FREE) RECEPTORS

Drug “Displacement” generally does not occur in drug receptor interactions.

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10
Q

What is the fractional occupancy equation and what does it dictate?

A

The Binding of Drugs to Receptors is Dictated by the Fractional Occupancy Equation:

Fractional Oc = 1/(1+KD/D)

Drug affinity=KD
Drug concentration=D

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11
Q

What factors are the fractional occupancy dependent on?

What is it independent of?

A

DEPENDENT on Drug affinity and drug concentration

INDEPENDENT of receptor number (density)

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12
Q

How will variant allele that increases the transcription of x receptors affect the fractional occupancy of drug xy that binds to receptor x?

A

WILL NOT AFFECT;

functional occupancy is INDEPENDENT of receptor number (density)

DEPENDENT on Drug affinity and drug concentration

ONLY on drug affinity or drug concentration (doesnt matter if 10 or 1000 receptors); only these 2 factors det. percent of receptors occupied

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13
Q

How is the rate of formation of DR complex with time related to the breakdown of DR complex with time?

A

At equilibrium the rate of formation of DR complex with time is equal to the rate of breakdown of DR complex w time

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14
Q

What do the following equations represent?

d[DR]/dt = k1 [D][R]

-d[DR]/dt = k2[DR]

A

Formation of DR complex with time d[DR]/dt = k1 [D][R]

Rate of breakdown of DR complex with time
-d[DR]/dt = k2[DR]

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15
Q

What does the KD value reflect?

A

KD value for a given drug reflects the propensity of a drug to bind to that receptor; this propensity to interact with the receptor (form [DR]) is referred to as the drugs affinity for the receptor and it is typically expressed by the KD value for a given receptor.

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16
Q

If a drug has a high affinity for a receptor, will [DR] be high or low? What will the KD value be?

A

KD value for a given drug reflects the propensity of a drug to bind to that receptor; this propensity to interact with the receptor (form [DR]) is referred to as the drugs affinity for the receptor and it is typically expressed by the KD value for a given receptor.

SO, if a drug has a high affinity for a receptor, [DR] will be large. If [DR] is large, KD must be small

KD= [D][R]/[DR]

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17
Q

For any drug, how are the KD value and affinity related?

A

inversely related

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18
Q

What value tells me the concentration of a drug that will occupy 50% of a receptor population?

A

KD in the fractional occupancy equation

1/(1+KD/[D])

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19
Q

How can you determine the fraction of any receptor population that will be occupied by ANY concentration of any drug?

A

Receptor Fractional Occupancy Equation

1/(1+KD/[D])

For any drug the FRACTION of a receptor population that it will occupy will depend ONLY on its affinity and concentration (dose)

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20
Q

How is fraction of receptors occupied by any drug related to the number of receptors present in a tissue?

A

the fraction of receptors occupied by any drug will be independent of the
number of receptors present in a tissue.

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21
Q

Note that the fraction of receptors occupied by any drug will be independent of the
number of receptors present in a tissue.

However, the TOTAL NUMBER of receptors occupied by a drug depends on what?

A

1) fraction of the receptor population occupied

2) the number of receptors in a given tissue (Bmax)

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22
Q

What determines the magnitude of a drug response?

A

some function (i.e. alpha) of the total number of receptors occupied

Response = alpha (fractional occupancy) (receptor number)

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23
Q

Is the relationship between drug concentration and receptor occupation for any drug linear or non-linear?

A

non -linear

its not a linear increase; you get a graded effect

plugging these values into that equation..

24
Q

if the KD for a drug is 5nM, then a 5nM concentration of the drug could be
expressed as 1KD unit of concentration, 10nM would be…

A

2KD units

25
Q

What is the concept of Drug Selectivity ?

A
  • the ability of a drug to “target” one receptor versus others at any given clinical dose range

Since most drugs have comparable affinity for a number of receptors, the selectivity of a drug refers to its ability to interact with one type of receptor versus other receptors.

26
Q

What is drug selectivity dependent on?

A

will be dependent on the relative affinities of a drug for various receptors (i.e. comparative KDs for various receptors).

27
Q

For any drug, how will selectivity change as drug dose is increased?

A

selectivity will decrease as drug dose is increased

(Remember- all drugs can interact with any receptor at high enough doses and
it takes at least 3 log units of concentration to occupy 1-91% of receptors )

as you increase dose then get uptake block and activate other receptors; we can’t occupy the site we want without binding other receptors too- contributes to the major side effects

28
Q

What is the “selectivity window” of a drug dependent upon?

A

The “selectivity window” of a drug is dependent on the drug dose or concentration range employed. It can be difficult to obtain this range in vivo where numerous other factors are operative (e.g. drug distribution, metabolism, tissue receptor heterogeneity, etc.).

29
Q

What do graded dose response curves show?

What effect will increasing dose have on the effect?

A

The Relationship Between Drug DOSE, Receptor Occupation and the magnitude of the RESPONSE

The Dose‐Response Relationship: This is the correspondence between the amount of a drug and the magnitude of the effect produced.

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

30
Q

The Dose‐Response Relationship: This is the correspondence between the amount of a drug and the magnitude of the effect produced.

What is the initial step in producing any effect?

A

The initial step in producing any effect is the binding (i.e. interaction) of a drug with a receptor.

31
Q

The Simple Occupancy Theory predicts that there is a one to one relationship between receptor occupation and response. It holds:

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 only when all receptors are occupied.

Expansion of simple occupancy theory to account for
experimental findings that could not be explained by the original theory became the Modified Occupancy Theory. Explain.

A

1) The response of a drug was some positive function of receptor occupancy (i.e., not
necessarily linearly proportional to the percent of receptors occupied).
2. Maximum effects could be produced by an agonist occupying only a small proportion of
receptors.
3. Different drugs may have varying capacities to initiate a response.

These findings resulted in the concepts of Drug Efficacy and Potency

32
Q

What does potency refer to?

A

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

33
Q

What does potency depend on?

A

Drug Potency depends in part on:

  • its affinity for the receptor (KD) and
  • the efficiency with which the receptor activation is coupled to response
34
Q

Define maximal efficacy/Intrinsic activity.

At what point is this value found on a the curve?

A

the maximal response produced by the drug


(used synonymously with the term Intrinsic Activity)

this can be determined directly
from the graded dose‐response curve and is the limit (or plateau) of the dose‐response
curve on the response axis

35
Q

Describe and explain the values for full agonists, partial agonists, antagonists (neutral) and inverse agonists (negative antagonists)

A

Full agonists would have an intrinsic activity = 1

Partial agonists would have an
intrinsic activity less than 1

Neutral Antagonists that bind but produce no biologic effect
would have an intrinsic activity of 0.

Negative Antagonists (Inverse Agonists) reduce the
response produced by constitutively active receptors (active in the absence of agonist)
and have a negative intrinsic activity ( less than 0)
36
Q

What is a negative antagonist? What does it do?

A

neg. ant. bind and induce conformational change that can lower activity
- an antagonist that can reduce the constitutive activity of receptors

37
Q

What would a graph for two drugs that have the same potency but different maximal efficacy look like?

A

Slide 24

(refers to the concentration or dose of a drug necessary to produce 50% of that drug’s
maximal response and is expressed as an ED50 value.

38
Q

What would a graph look like of two drugs with different potencies but the same maximal efficacies?

A

Graph B slide 24

similar potency but diff maximal efficacy
both can alleviate pain to same extent (same maximal efficacy) diff is that morphine can do so at a lower dose, so morphine is more potent but the maximal efficacies are the same

39
Q

Compare lines a/b/c on graph 25.

A

a is more potent than b and c

a and b have equal efficacies

b and c are equipotent but b is more efficacious than c

a is more potent and more efficacious than c

40
Q

In regards to efficacy vs potency, which is more clinically effective?

A

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

41
Q

Describe the concept of spare receptors.

A

Systems in which maximal response is achieved by doses of agonists that occupy only a small percentage (or fraction ) of receptors are considered to have “spare receptors” (aka, “receptor reserve”)

All receptors are considered to be equally functional, but its not required for all receptors to be occupied to achieve a maximal response.

Receptor reserve, “spare receptors” is most likely a function of the degree of response amplification following any given drug receptor interaction.

42
Q

How can you evaluate spare receptors from D-R curves?

A

(can sometimes be identified from the “steepness” or dose-range required to achieve Emax in a D-R curve)

D-R Curves for the same receptor mediated response in two different tissues: A larger dose range is required for noradrenaline to elicit a maximal response in Tissue 1 compared to Tissue 2

Slide 28

43
Q

Draw how the curves will shift under the following conditions:

A:
Total number receptors: 100
# Needed for Emax= 20
Frac. Occup. = 20

B
Total number receptors: 40
# Needed for Emax= 20
Frac. Occup. = 50

C
Total number receptors: 20
# Needed for Emax= 20
Frac. Occup. = 100

Total number receptors: 10
# Needed for Emax= 20
Frac. Occup. = 100

Total number receptors: 5
# Needed for Emax= 20
Frac. Occup. = 100

A

Slide 29

hallmark of system w spare receptors;when reduce receptor density you see shift in right (increase in EC50) in dose response curve; then when you exceed reserve capacity from 20 to 10 you don’t have enough receptors, and Emax reduces.

44
Q

Show on dose response graph how DR curve, ED50, and Emax are affected in the presence of agonist alone; antagonist, and agonist plus competitive antagonist.

What effect do agonists have on:

1) DR curve
2) ED50
3) Emax

A

Slide 32

1) Shift to the right in DR Curve, 2) Increase in ED50, 3) No change in Emax

Since an antagonist will “bind” but not elicit a response, higher concentration of agonist are required to occupy the same number of receptors to produce an equivalent response to that observed at lower concentrations in the absence of antagonist. Competitive antagonists will change the ED50 of the agonist for the receptor rather than reduce the maximal response (Emax).

45
Q

Show on a dose response graph the effect of agonist alone, the effect of antagonist, and agonist plus irreversible antagonist.

How are Emax and ED50 affected?

A

Non-Competitive Antagonists - Decrease in Emax but No Change in ED50

Slide 33

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 (this process could be
reversible or irreversible). Consequently, 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.
However, the remaining receptors would exhibit the same affinity (KD) for the drug and thus the
ED50 would not be altered.

46
Q

Describe the effect of partial agonists when they are administered alongside full agonists.

A

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 are administered together.

47
Q

Draw a graph that compares partial agonist to full agonist on a graph comparing partial agonist on x axis to percentage of maximal binding.

A

Slide 34

48
Q

Discuss the following non-pharmalogical means to antagonize drug effects:

Chemical antagonism

A

via chemical inactivation of a drug

49
Q

Discuss the following non-pharmalogical means to antagonize drug effects:

Physiologic antagonism

A

the use of opposing pathways to antagonize the effects of a drug

(e.g. antgonism of bronchioconstrictor actions of histamine via epinephrine activation of beta-adrenergic receptors)

These effects are less specific and less easy to control than the
effects of a receptor specific antagonist.

50
Q

Discuss the following non-pharmalogical means to antagonize drug effects:

Biologic antagonism

A

one drug may affect the metabolism or pharmacokinetics of another drug (e.g. via inhibition or induction of common P450 isozymes)

51
Q

What is does the quantal dose response curve show?

A

the Relationship between Drug DOSE and a SPECIFIED EFFECT produced in a Patient or Animal Population

52
Q

What graph can be used to obtain the median effective dose (ED50)?

A

This is the dose at which 50% of individuals will exhibit a specified effect.

Can be used to obtain an index of the selectivity of a drug’s actions by comparing its
ED50 for different specified effects.

quantal dose response curve

53
Q

How is therapeutic index determined?

A

It is the ratio of the TD50 or LD50 to the ED50 determined from
quantal dose response curves.

54
Q

What is the therapeutic window?

A

the dosage range between the minimum effective therapeutic dose (or conc.) and the minimum toxic dose (or conc.). This is a more clinically relevant index of safety.

55
Q

In a system with spare receptors, if you reduce receptor density how does the dose response curve change? How does potency change? How does Emax change?

What about when you exceed reserve capacity?

A

hallmark of system w spare receptors;when reduce receptor density you see shift in right (increase in EC50) in dose response curve; then when you exceed reserve capacity from 20 to 10 you don’t have enough receptors, and Emax reduces.

Pharmacology (13 decks)

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