Pharmacokinetics: Receptor Theory Part 1

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.