Pharmacology: drug- receptor interactions: agonists & antagonists

At equilibrium, what will happen to the drug?

It will occupy a number of receptors AR

What is drug receptor interaction represented by

Ka

What measure is preferred over therapeutic index

Margin of safety

How to calculate therapeutic index

Maximum tolerated dose / minimum effective dose

How do pharmacokinetic antagonists work

Reduce the free concentration of the substance being antagonised (at its target) - done by reducing drug absorption or by accelerating renal or hepatic elimination

Drug that acts as a functional/ physiological antagonist

Salbumatol

Dose-response curves in the presence of an antagonist are useful because

Tell us if the antagonist is competitive and if competitive, they provide receptor classification.

What does the value of Ka really show

the concentration of agonist drug that at equilibrium occupies 50% of the receptors.

Effect of a drug is proportional to

the concentration of the drug at its site of action

Ka in equations shows

the dissociation constant of the drug A

All or one response

the drug either does or does not produce the effect

Relationship between affinity constant and Ka

the higher the value of the affinity constant, the lower the value of Ka Makes sense because the stronger the binding, the less the dissociation. High Ka = low affinity (bc lots of dissociation)

What about drugs varies significantly

the margin of safety

the magnitude of the shift is given by what equation

the schild equation

Pharmacokinetics

the way the body deals with the drug

Pharmacodynamics

the way the drug affects the body

Partial agonists vs full agonists

partial agonists are *less potent* than full agonists. & have *less intrinsic activity* & have *lower efficacy*

ED50

"median effective dose" dose which elicits a response in 50% of the sample

LD50

"median lethal dose" dose which is lethal in 50% of the sample.

Difference between competitive and non competitive antagonism (at same receptor)

*Competitive* > overlapping binding sites > binding= mutually exclusive > can be reversible or irreversible. *Non-competitive* > distinct binding sites (e.g channel blocker)

What is the EC50

*effective concentration* concentration of a drug that gives half maximal response concentration producing a response 50% of the maximum

How does salbutamol act as a functional/ physiological antagonist?

- acts as an agonist on beta-2 adrenoreceptors in bronchiolar smooth muscle- *smooth muscle relaxant* - but antagonises the bronchoconstrictor action of endogenous leukotrienes by acting on leukotriene C4 receptors

2 events that occur when an agonist binds to a receptor

1) *agonist- receptor interaction* (drug receptor interaction) 2) *agonist induced response* (drug induced response)

2 ways in which antagonism works:

1) does not involve receptor through which agonist acts 2) acts on the same receptor as the agonist

Reasons why the concentration of drug at receptors will never be accurate

1) enzyme degradation (of drug) 2) binding of drug to tissue components 3) problems related to diffusion of drug to action site

Mass of paracetamol enough for severe liver damage

10-15g

Maximum therapeutic dose of paracetamol

4g/day

Example of indirect antagonism

Ca2+ channel blockers will prevent smooth muscle contraction elicited by various agonists through which the agonist produces an effect

What kind of equilibrium would prove a drug is a partial agonist

Equilibrium that favours AR with only a few receptors occupied in the activated state

How does the dose response curve change with competitive antagonists

The curve shifts to the right in a parallel fashion with increasing concentrations of competitive antagonist

What can you not determine from conc-response/ conc-occupancy curves?

agonist affinity for the respective receptors cannot be determined.

Can the effect of the antagonist be overcome in competitive antagonism?

Yes if the antagonist binds reversibly, its effect can be overcome by increasing the conc of agonist so it competes more effectively for the binding sites.

What kind of response is an agonist induced response

a graded response

What is this shift of the dose response curve expressed as

a ratio (r) - dose ratio the dose ratio is defined as the factor by which the agonist concentration must be increased in the presence of antagonist to restore response to that given by agonist alone.

What does agonist binding do to receptors

activates them

Example of functional/ physiological antagonism

adrenaline and histamine have opposite effects on bronchial smooth muscle. adrenaline- relaxes it histamine- constricts it.

Ka is the reciprocal of the

affinity constant

How does functional/ physiological antagonism work

agonist and antagonist have opposite effects, but act on diff receptors. effect of agonist is reduced due to action of antagonist on another receptor (on which it itself is an agonist)

How does competitive antagonism work?

antagonist binds to receptor- prevents binding of agonist.

How is indirect (non competitive) antagonism achieved?

antagonist blocks one of the steps in the signal transduction process initiated by receptor activation.

4 types of antagonism where there is no binding to receptor

chemical functional/ physiological indirect (non competitive pharmacokinetic

How do chemical antagonists work

combine with the drug (in plasma or gut lumen) to produce an insoluble & inactive complex.

Antagonism can happen at the same receptor as the agonist. This occurs in two ways:

competitive non competitive

How can an agonist-induced response be plotted

conc-effect/ dose-response curve

A conc-response curve looks similar to a

conc-occupancy curve

What does the extent of the shift depend on (basis of schild equation)

concentration of antagonist antagonist affinity for receptor (Kb)

B

concentration of antagonist producing the shift

Ka

dissociation equilibrium constant for the binding of a drug to a receptor

Kb

dissociation equilibrium constant for the binding of the antagonist.

Agonist

drug (or endogenous chemical) that binds to a receptor and activates the cell's response

High Ka and resultant low affinity will result in fewer

drug receptor complexes

Antagonist

drug that reduces or inhibits the action of the agonist.

Antagonist

drug that reduces the action of an agonist; endogenous ligand or a drug

Partial agonist

drugs (even when acting on the same receptors) may not give the maximum tissue response in any concentration.

Key words in drug-induced response

efficacy

Why is receptor subtype classification being based on competitive antagonism useful?

for therapeutics

Is drug-receptor interaction reversible or irreversible

freely reversible

Types of agonist

full agonist partial agonist

Partial agonists occupy the receptors in what way

in two states- resting state and activated state (R & R* respectively)

How might drugs be administered

intravenously intra/transdermal intramuscular sublingual inhalation oral/stomach oral/intestine

When a muscle is exposed to a concentration of histamine [A], you must allow...

it to reach equilibrium

What does "less potent" mean

less able to elicit a response from the receptors to which they bind

Schild equation

links the extent of the shift (r) by the antagonist affinity for the receptor (Kb) r - 1 = [B] / Kb

Link between potency of drug and concentration

low potency drug will require a greater concentration to have its effect vs a high potency drug which will require a small conc to have its effect

Full agonist

maximum response produced- corresponds to max response that the tissue can give.

Is the increase in effect of drug infinite?

no as you increase the concentration of the drug, the bigger the effect up to maximum effect further increases of dose then produce no further increase in effect.

Does therapeutic index have a use

not in practical use

Key words in drug-receptor interaction

occupancy affinity

What has been done to prevent paracetamol overdose

pack size reduced to 16 tablets (8g)

Example of chemical antagonist

protamine sulfate neutralises the action of heparin.

What area is competitive antagonism useful in

receptor subtype classification

What is a graded response

response increases with the amount of energy supplied as opposed to the reaction bought about by the all or none law

Efficacy

the ability of a drug, after binding to a receptor to activate transduction mechanisms that lead to a response.

Role of salbutamol

treats an asthma attack

Examples of indirect antagonism

tyramine releases noradrenaline at a nerve ending propanolol blocks noradrenaline receptors

Different partial agonists acting on the same receptoe

usually have similar maximum responses.

Can partial agonists also be seen as competitive antagonists

yes- bc partial agonists occupy receptors preventing full agonists from binding so partial agonists competitively agonise the action of a full agonist they do this while producing a small effect of their own