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intro to pharmacology > Drug affinity and efficacy > Flashcards

Drug affinity and efficacy Flashcards

1
Q

Define drug affinity (1)

A

Drug affinity refers to the strength/ability of a drug to bind to its target

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2
Q

What is affinity dependent on? (2)

A

The chemical interactions between the drug and target (bonding)
Complementary steric match (shape and size)

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3
Q

How does most drug-target binding occur? (2)

A

Non-covalent bonding, comprising Van Der Waals, H-bond, and electrostatic interactions

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4
Q

What is a ligand? (1)

A

A substance that is able to bind to and form a complex with a biomolecule.

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5
Q

How does drug-target interaction take place? (4)

A

Drugs are ligands that work by specifically interacting with a molecular target in order to cause/block a biological response

Ligand shape is complementary to binding site

Irreversible interaction takes place (rare), after the initial drug-target interaction has occurred - covalent bond

Reversible complex (not rare) is formed via non-covalent interactions:
- ionic / electrostatic
- hydrogen bonds
- van der Waals interactions

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6
Q

Describe Van der Waals interaction (4)

A

Random asymmetric distribution of the electron clouds in molecules results in the formation of temporary dipoles.

This can induce formation of dipoles in neighboring atoms and cause attractive forces when atoms are an appropriate distance apart i.e. the van Der Waals contact distance

They are weak forces and there is only a narrow distance range within which atom can interact and attract each other

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7
Q

What are Van Der Waals interaction? (2)

A

Van Der Waals interactions are the sum of the attractive or repulsive forces between neighbouring atoms/molecules, excluding ionic, covalent or H-bond interactions

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8
Q

Describe hydrogen bonding (4)

A

Hydrogen bonds are formed between one of the three highly electronegative atoms (F, O, N) and a hydrogen that is covalently bonded to one of the three highly electronegative atoms (F, O, N)
Electrons move towards the electronegative O, N or F atom
This results in a separation of charge
The partially +ve charged H atom interacts with the slightly -ve charged O/N/F atom

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9
Q

Define the law of mass action (1)

A

The rate of a reaction is proportional to the product of the concentration of the reactants

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10
Q

How is drug affinity measured? (2)

A

Concentration of drug required to occupy 50% of the drug target at equilibrium - law of mass action

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11
Q

What is Kd (equilibrium dissociation constant)? (1)

A

The concentration of the drug that is required to occupy 50% of the receptors

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12
Q

How is the equilibrium dissociation constant estimated? (3)

A

Can be estimated from different types of experiment:
- saturation binding assays
- kinetic binding/dissociation assay
- competition binding assays.

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13
Q

What is drug selectivity? (3)

A

The concentration-dependent preference of a drug for one target over others and is dependent upon differential drug-target affinity
As drug concentrations increase, selectivity decreases

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14
Q

What is saturation binding? (3)

A

Eventually, as you add more and more ligand, all the sites will be occupied- saturation

On a saturation binding curve, we are able to work out the maximal binding (Bmax) and, therefore, the conc of ligand required to reach half this value (Kd).

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15
Q

What is the problem with using saturation binding to measure affinity? (2)

A

Need to have radio-labelled ligand and you need lots of it

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16
Q

What is kinetic experiments? (2)

A

Kinetic experiments relate to measuring over time courses

Need to know rate of association and dissociation of drug with receptor and concentration of drug

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17
Q

What is competition binding? (3)

A

A low number of receptors are radio-labelled
Compete radio-ligand off by increasing concentration of competitor
Once competitor reaches its own Kd, and occupies half of receptors, it should have removed 50% of radio-ligand which gives Kd of competition ligand

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18
Q

What can drugs do to a biological response? (3)

A

Activate/enhance
Inhibit/attenuate
Drug binding changes the rate or magnitude of an intrinsic biological response.

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19
Q

How do small molecule drugs usually bind to their target? (2)

A

Either the orthosteric or an allosteric binding site.

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19
Q

What is an orthosteric binding site? (2)

A

Mimic the effects of the endogenous ligand (agonists)
Block the binding of the endogenous ligand (antagonists, enzyme inhibitors)

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20
Q

What are inverse agonist? (1)

A

Reduce basal/constitutive activity

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21
Q

What is a full agonist? (1)

A

Increase basal/constitutive activity

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22
Q

What is an antagonist? (1)

A

No effect on basal/constitutive activity

23
Q

What are allosteric sites? (2)

A

Allosteric sites are separate from the endogenous active site / orthosteric site
Allosteric ligands affect the protein conformation and the orthosteric site

24
Q

What can allosteric ligands do? (2)

A

Attenuate the effects of an endogenous agonist (negative allosteric modulators NAMs)
Potentiate/enhance the effects of an endogenous agonist (positive allosteric modulators PAMs)

25
Q

What is drug efficacy? (1)

A

Describes what a drug can do its target

26
Q

What is intrinsic efficacy? (1)

A

It is the inherent property of an agonist drug that enables it to alter the conformation of molecular drug target, initiating a cellular response

27
Q

Which type of drugs have no intrinsic efficacy? (1)

A

Antagonist drugs

28
Q

What are antagonist drugs? (1)

A

They can bind to the target since they have affinity, but they do not affect the conformational state of the target

Can act as blockers for agonist drugs by blocking the target - prevents effects

29
Q

How can efficacy be measured? (2)

A

Using a concentration-response relationship

30
Q

Define Emax (1)

A

Maximal response of an agonist in a system

31
Q

What is agonist potency (EC50)? (1)

A

The drug concentration that yields 50% of its EMAX

32
Q

What is intrinsic activity (α)? (1)

A

The maximal response of a drug as a fraction of the maximal response of a full agonist in the same system

33
Q

What is the value of intrinsic activity when full agonists produce the maximal known response of the system? (1)

A

α=1

34
Q

What is the value of intrinsic activity when antagonists produce no response? (1)

A

α=0

35
Q

What is the value of intrinsic activity when partial agonists produce a maximal response below full agonists? (1)

A

α>0<1

36
Q

What does a typical log concentration-response curve for an agonist drug look like and response with agonist in the presence of a competitive antagonist? (2)

A

https://www.google.com/url?sa=i&url=https%3A%2F%2Fderangedphysiology.com%2Fmain%2Fcicm-primary-exam%2Frequired-reading%2Fpharmacodynamics%2FChapter%2520418%2Fcompetitive-and-non-competitive-antagonists&psig=AOvVaw3n8_1TrZ2OjSc99X56yuof&ust=1708025380605000&source=images&cd=vfe&opi=89978449&ved=0CBMQjRxqFwoTCJCHr8LIq4QDFQAAAAAdAAAAABAQ

37
Q

What is the advantage of plotting agonist concentration-response relationships as the logarithm (base 10) of concentration versus response. (2)

A

Clumping of data points does not occur when the concentration range is large
The graph becomes S-shaped with a well defined linear central portion.

38
Q

What is agonist potency? (1)

A

A measure of the concentration of agonist needed to elicit a given effect.

39
Q

What is a full agonist? (1)

A

Full agonist elicit a maximum response from the system even when only a small fraction of the receptor population is occupied

40
Q

What is a partial agonist? (1)

A

Partial agonists cannot induce a maximum response even when all receptors are occupied.

41
Q

A partial agonist is not able to evoke a maximum response so how is the intrinsic activity measured? (1)

A

Partial agonist is not able to evoke a maximum response, so the intrinsic activity of a partial agonist is the ratio of the maximum response obtained with the partial agonist to the maximum response produced by the full agonist.

42
Q

What can agonist concentration–response relationships be used for? (2)

A

Agonist concentration–response relationships can be used to determine and compare antagonist affinity, antagonist potency, as well as types of antagonism

43
Q

What are surmountable antagonists (2)

A

Reduce apparent agonist potency but not agonist max effect

44
Q

What are insurmountable antagonists? (2)

A

Insurmountable antagonists reduce the maximum effect of an agonist, with or without effects on apparent agonist potency.

45
Q

What is Schild analysis (1)

A

Concentration-response relationships can be used to estimate the affinity of a competitive antagonist (Schild analysis)

46
Q

What does the term potency mean? (2)

A

Common expression used in pharmacology to compare the activity of a drug - however, it is an imprecise term that should always be further defined

47
Q

What is pA2? (1)

A

Concentration of antagonist that requires a 2-fold increase in agonist concentration to regain original response level

48
Q

How does pA2 link with Kb? (1)

A

pA2 is approximately the –Log Kb

49
Q

What is competitive antagonism? (2)

A

Antagonist competes with agonist for same receptor site
Can be surmountable or insurmountable

50
Q

What is insurmountable competitive antagonism and when is it observed? (2)

A

Increasing the agonist concentration will not restore the maximum response; hence the block cannot be totally reversed by the agonist.

This type of competitive antagonism is observed when the antagonist has a very high affinity (little tendency to dissociate) for the receptor or it forms a covalent bond with the receptor and will not dissociate from it

51
Q

What is non-competitive antagonism? (2)

A

Antagonist binding to a different site on the receptor than the agonist
Non-competitive antagonists often induce a conformational change in the structure of the receptor molecule that reduces the affinity of the receptor for the agonist or prevents the agonist from occupying its binding site

52
Q
A
52
Q

What is functional antagonism? (1)

A

In this form of antagonism the two drugs act on entirely different receptors to elicit opposing effects

52
Q
A

intro to pharmacology (5 decks)

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