Pharmacodynamics: agonists and antagonists

What is a receptor?

Protein target (which may be on membrane surface/inside the cell)

with which a naturally occurring chemical mediator (hormone, paracrine mediator, neurotransmitter)

binds specifically to initiate a cellular response

Chemical mediators fall into 2 classes:

1. Molecules too large/hydrophillic to cross the cell membrane → rely on surface receptors

2. Molecules small enough/hydrophobic pass through the membrane and directly activate intracellular proteins

For the effects of the chemical mediator to be apparent, receptors require:

Linkage to a signal transduction process

Chemical mediator on binding causes

A shape change

which stabilises the active form of the receptor

enhances interaction with signal transduction mechanism

2 stages of interaction

Binding and activation

What does an agonist do?

Mimics action of chemical mediator

bind in such a way that they cause a shape change

What does a receptor (competitive) antagonist do?

Binding of chemical mediator/agonist is blocked

no shape change triggered, blocks binding site

therefore agonist/chemical mediator cannot get in

list the 5 factors that affect size of response to a receptor agonist

1. Concentration of drug in vicinity of receptor at a given time

2. Affinity of drug

3. Intrinsic efficacy

4. Nature of receptor-response coupling

5. Total number of receptors present

What type of reaction is an agonist involved in?

Reversible reaction

What does the fraction of the total number of receptors available which are occupied depend on?

agonist concentration

Strength of bonds formed (affinity)

what is K_A?

drug equilibrium constant

when does K_A become equal to the concentration of the agonist?

when ½ the receptors are occupied

what effect does K_A have on affinity of agonist for receptors?

increased K_A = decreased affinity of agonist for receptor

How does affinity relate to strength of bonds?

high affinity = strong bonds

Low affinity = weak bonds

how does K_A relate to occupancy of agonist?

smaller K_A reaches higher level of occupancy than larger

what is EC₅₀?

The effective concentration needed to produce 50% of the maximum response possible on stimulation of that receptor population

how does EC₅₀ affect potency?

small EC₅₀ = high potency, good affinity

What is potency?

the dose of a drug required to produce a given response

More potent = lower dose needed

what is intrinsic efficacy?

the ability of an agonist on binding to a receptor to activate a change in the shape or folding of the receptor

Measured as a percentage 0-100%

what is a full agonist, and what is its intrinsic efficacy?

produces a large response - maximum response of which the tissue of capable on activation of all that population of receptors

Intrinsic efficacy = 1

what is a partial agonist and what is its intrinsic efficacy value?

produces a smaller response, even at very high concentrations

Intrinsic efficacy <1

what are the 2 types of competitive antagonists?

competitive reversible

Competitive irreversible

what is the function of competitive antagonists?

compete with chemical mediator/agonist drugs for the same binding site on receptor

But without initiating a cellular response

Reduce probability that receptor will be occupied by the chemical mediator/agonist

what is the IE of a competitive antagonist?

0

what type of drug has an intrinsic efficacy of 0?

competitive antagonists

How are competitive agonists classified?

by how long they remain associated with receptor

how do competitive antagonists work?

associate but can then disassociate again

so effects can be overcome by adding more agonist, as this increases chance that receptor will be occupied by agonist instead

how is the effect of a reversible antagonist overcome?

by adding more agonist

how do irreversible antagonists work?

often involve covalent bonds, effect of agonist cannot be reversed unless new receptor proteins are made

Associate and remain associated with receptor indefinitely

what effect does adding an agonist have on an irreversible antagonist?

receptors are permenantly blocked so increasing agonist concentration will have no effect on receptors since they will remain blocked

what is the action of a non-competitive antagonist?

affects the action of the agonist at some point in the chain leading to response

but does not compete with agonist for same site on receptors themselves

What may be involved in a non-competitive antagonist response?

binding to an allosteric site on an unoccupied receptor

to cause conformational change

which opposes agonist binding and/or initiation of signal transduction

Or can involve interference with a component of the signal transduction pathway from the receptor binding site

what is a physiological antagonist?

opposite effect to the agonist, but achieves its result by acting on separate cells/tissues or on different population of receptors on the same cell

what is a pharmacokinetic antagonist?

when one drug decreases concentration of another drug by interfering with its absorption/distribution/metabolism/excretion

How does a competitive reversible antagonist effect the log concentration response curve of an agonist?

agonist EC₅₀ appears to be larger in presence of the competitive reversible antagonist

RIGHTWARD parallel shift without reduction in maximum response

what is affinity?

tendency of a drug to bind

Strength of attraction between agonist and receptor

What is signal transduction mechanism?

nature of receptor-response coupling