Dose response curves, drug receptor theory, agonists and antagonists

What is the relationship between drug dose and response

What is a dose response

Drug effect is proportional to the amount of the drug binding to the receptors. Can be plotted on a quantitative dose-response curve, quantitative concentration-effect curve or cumulative quantal dose-response curve.

What is efficacy

Size or strength of a response produced by a particular agonist in a particular tissue.

What is Emax?

Measure of efficacy, maximum response produced by a particular agonist in a particular tissue.

What is a spare receptor?

Full agonist can cause a maximum response when occupying only a fraction of the total receptor population.

What is intrinsic efficacy?

The ability of the drug to induce a response from the activation of a single receptor.

What is potency

Measure of the dose that is required to produce a defined response.

What is ED50?

Dose of the drug that produces 50% of the maximal response

What is EC50?

concentration of a drug that produces 50% of the maximal response.

What is the difference between efficacy and potency

What is drug receptor theory

1. A binding site on the receptor

2. Binding: Majority of drug binding is via weak chemical bonds, hence continuous association/dissociation of the drug from the receptor complex.

3. The drug/receptor complex

4. Signal transduction = binding of the drug results in a biological response.

What is a drug receptor complex

The receptor is bound to the receptor site of the drug

What is classical drug receptor theory

Classical drug receptor theory:

• Affinity: strength of the drug binding to the receptor.

• Efficacy: Ability of drug-receptor complex to produce a response.

• Mass action equation Kd (Equilibrium dissociation constant) = [L][R]/[LR] change to [L] ([RT] - [LR])/[LR]

• RT (total receptor conc) = [R] + [LR]

• Simplified: [LR] = [L][RT] / [L] + Kd

What is affinity

• Strength of the binding of the drug to the receptor.

• Dependent on structure of drug and receptor, = to 1/Kd.

• Concentration of the drug required to occupy 50% of the receptor population.

• Small Kd = greater affinity.

What is selectivity

Drug binds to more than one receptor, higher affinity for one receptor over another.

What does being on target mean?

Binded to receptor you want to bind to

What does off target mean?

Binded to receptor you don't want to bind to.

What is intrinsic activity

• The maximal response to an agonist is expressed as a fraction of the maximal response for the entire system.

• A full agonist has intrinsic activity of 1. Antagonist has intrinsic activity of 0. Partial agonist has intrinsic activity between 0-1.

What is intrinsic efficacy

The ability of the drug to induce a response from the activation of a single receptor.

What is conformational induction and conformational selection

Induction is lock and key of activities of receptor and selection is when only certain receptors are active that the drug can bind to and cause change.

What is the 2 state model

Drugs have an affinity to receptors either in their inactive or active form.
Receptors shift between their active and inactive form, when no ligand is present, the equilibrium lies to the left with few receptors in the active form.

What is a partial agonist

Lower affinity for active receptor than the agonist, lower affinity for the inactive receptor than the antagonist. Lower efficacy than full agonist, even at high concentration. A partial agonist can compete with the endogenous ligand to reduce the opening of the channel and have a net antagonist action.
If disease is cause by lack of opening of the receptor, a partial agonist can cause the channel to open more frequently, having a net agonist effect.

What do endogenous ligands do?

Endogenous ligands bind to the receptor and keeps them open (neurotransmitter) maximally and frequently.

What is an inverse agonist

Has affinity. Efficacy is lower than basal levels. High affinity for inactive receptor, so equilibrium shifts to the left.

What is the difference between an agonist, partial agonist, antagonist and inverse agonist

• Agonist = Affinity for active receptor

• Partial agonist = Lower affinity for active receptor than the agonist, lower affinity for the inactive receptor than the antagonist.

• Inverse agonist = Affinity for the inactive receptor.

What are the types of antagonist

Reversible competitive, irreversible competitive, non-competitive antagonist.

What is a reversible competitive antagonist

Binds to same site as agonist and they compete. Binds then comes off, when off agonist can produce effect, surmountable (increasing conc of agonist will overcome effect of antagonist).

What is an irreverisble competitive antagonist

Binds to same site as agonist and they compete. Binds and stays, not surmountable.

What is a non-competitive anatgonist

Binds to another site, agonist can't bind at same time so not surmountable.

How does an antagonist act on a ligand gated ion channel

What is the Schild's plot?

log (dose response - 1) \= log (conc agonist) - log KB (equilibrium constant of antagonist). Linear line \= reversible competitive antagonist.
pA2 \= -log of molar conc of antagonist that makes it necessary to double the conc of the agonist to induce the original effect, measure of affinity.