Pharmacokinetics: Receptor Theory Part 1

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Questions and Answers

What is the term for the situation where the presence of a ligand decreases further ligand binding?

Negative cooperativity (correct)

Reversible binding

Equilibrium dissociation

Positive cooperativity

What is the name of the model that describes the binding of chemicals to metal surfaces, which is also applied to drug receptor interactions?

Clark's equation

Langmuir Adsorption Isotherm (correct)

Law of equilibrium

Mass action law

What is the ratio of k-1/k+1 in the drug receptor interaction, and what does it represent?

Affinity constant, representing the strength of binding

Efficacy, representing the response to the drug

Equilibrium dissociation constant (Kd), representing the amount of drug bound to the receptor (correct)

Rate of association, representing the energy change of binding

What is the concentration of ligand required to occupy 50% of receptors at equilibrium, and what does it represent?

Kd, representing the affinity of the drug for the receptor Signup and view all the answers

What can be used to estimate the Kd of a drug, and what does it represent?

EC50, representing the affinity of the drug for the receptor Signup and view all the answers

Who is credited with coining the term 'receptor' in 1900?

Ehrlich Signup and view all the answers

What is the main advantage of expressing the dosage on a semi-logarithmic scale in agonist concentration-response relationships?

It allows a wide range of doses to be shown concisely and the maximum response to be more easily observed Signup and view all the answers

What is the term for the change in state of the drug target upon binding of the drug?

Efficacy Signup and view all the answers

What is the term for a drug that produces a submaximal response of the system, occupying a relatively low proportion of receptors?

Partial agonist Signup and view all the answers

What is the term for the phenomenon where the presence of ligand enhances further ligand binding?

Positive cooperativity Signup and view all the answers

What is the main difference between the EC50 and kd of a drug?

EC50 is the concentration of agonist at which 50% maximal response occurs, while kd is the concentration of agonist at which 50% receptor binding occurs. Signup and view all the answers

What is the significance of the rate of association (k+1) in the drug-receptor interaction?

It is the rate at which the drug binds to the receptor, driven by energy changes that make it energetically favorable. Signup and view all the answers

What is the relationship between the affinity of a drug for its receptor and the equilibrium dissociation constant (Kd)?

The affinity of a drug for its receptor is inversely proportional to the Kd. Signup and view all the answers

What is the significance of the Langmuir Adsorption Isotherm in pharmacology?

It is a model that describes the binding of chemicals to metal surfaces, and is also applicable to drug receptor interactions. Signup and view all the answers

What is the effect of negative cooperativity on ligand binding?

It decreases the binding of ligand to the receptor. Signup and view all the answers

Study Notes

Receptor Theory and Pharmacokinetics

The concept of receptors originated with John Langley in 1887, and the term "receptor" was coined by Ehrlich in 1900.
Clark proposed the occupation theory in 1926, which allowed for the prediction of the relationship between drug concentration and response.

Agonism and Antagonism

An agonist is a ligand that binds to its receptor and elicits an observable response (can be endogenous or exogenous).
An antagonist is a ligand that does not produce a response itself but interferes with the response to an agonist.

Agonist Concentration-Response Relationships

Drugs acting on a specific target in a physiological system exhibit a graded response with an increase in drug concentration (or dose).
The dose/concentration curve describes the relationship between drug doses (in vivo) or concentrations (in vitro) and pharmacologic effect.

Caveats to In Vivo Experiments

In vivo, it is assumed that the drug dosage used provides a known concentration of drug at the target receptor, but this is not always true.
In vitro experiments, where tissues are incubated in media mimicking true physiology, can accurately link concentration to drug activity.

Potency

The location of the curve on the graph denotes the potency of the drug.
Potency is the concentration of the drug needed to produce a defined response or effect.
EC50 is the concentration of agonist producing half of the maximal response to the same agonist.

Efficacy

Potency and maximal response of a drug depend on different molecular properties.
Maximal response is dependent on the drug's efficacy.
Efficacy is the change in state of the drug target upon binding of the drug.

Intrinsic Activity

The maximal response of the drug being studied may or may not equal the system's maximal response, which is called intrinsic activity.
Full agonists produce the maximal response of the system and have an intrinsic activity of 1.
Partial agonists produce a submaximal response of the system and have an intrinsic activity greater than 0.

Cooperativity of Drug-Target Interactions

Many ligands interact with their receptors to form trimolecular complexes.
Ligand binding to a receptor and the ensuing biological response can be influenced by other receptors or the presence of ligand on the receptor.
If the presence of ligand enhances further ligand binding, there is positive cooperativity.
If the presence of ligand decreases further ligand binding, there is negative cooperativity.

Langmuir Adsorption Isotherm

The Langmuir Adsorption Isotherm is a simple model of ligand binding that describes the binding of chemicals to metal surfaces.
The amount of chemical bound to the surface is the product of the concentration of drug, rate of binding, and fraction of surface left for binding.
The amount of drug diffusing away is the product of the amount already bound and the rate of dissociation.

Applying the Langmuir Adsorption Isotherm to Drug Receptor Interactions

Drug receptor interactions are generally reversible and obey the law of mass action.
The rate of association of the drug with the target is driven by energy changes, making it energetically favorable for the drug to bind.
The drug also has a rate of dissociation from the receptor, which describes the energy change when the molecule diffuses away from the receptor.

Equilibrium Dissociation Constant (Kd)

The ratio of k-1/k+1 determines the amount of drug bound to the receptor at any one time and becomes a measure of how well the drug binds to the receptor.
Kd is the concentration of ligand [D] required to occupy 50% of receptors at equilibrium.
The smaller the Kd, the higher the affinity of the drug for its receptors.

Clark's Equation

Derivation of Langmuir's isotherm gives: E = Emax D / (D + Kd).
When the concentration of drug equals Kd, the drug occupies 50% of the receptor population.
The magnitude of Kd is inversely proportional to the affinity of the drug for the receptor.

Affinity

Consider two drugs, one with a Kd of 10^-9 M and another with a Kd of 10^-7 M.
The first drug occupies 50% of receptors at a concentration 1/100 of that required by the second drug.
The drug with a Kd of 10^-9 M has a higher affinity for the receptor than the drug with a Kd of 10^-7 M.

Predicting the Binding Curve

Using the equation E = Emax D / (D + Kd), the fraction of sites bound can be calculated for any concentration of drug.
EC50 of partial agonists can be used to estimate Kd.
Low EC50 indicates high affinity of binding.

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Test your understanding of Pharmacokinetics with this quiz on Receptor Theory Part 1. Learn about the concept of receptors, agonism, and antagonism, and how they relate to drug concentrations and responses.