This viva is relevant to the objectives of Section C(v) of the 2017 CICM Primary Syllabus, which asks the exam candidate to "describe affinity and dissociation constants".
What are the rate constants of drug and receptor binding?
- kon and koff are rate constants for association and dissociation:
- The population of drug molecules and receptor molecules combine at a certain rate kon, and then separate again at another (possibly different) rate koff.
- When the system is allowed to rest for an infinitely long time these reactions will run to an equilibrium, where there will be a constant concentration of free drug, unbound receptor and drug/receptor complexes.
- In this equilibrium state, kon = koff.
- Units used to describe rate constants are usually are units of [D] multiplied by the units of [R] over time, i.e. it is usually expressed in moles per second
(Lower case "k" is used to denote rate constants such as kon and koff, whereas uppercase K is used for equilibrium constants (such as Kd). To be precise, kon and koff are actually not the official terms - the IUPAC would prefer you to use k+1 for the association reaction and k-1 for the dissociation of drug from receptor)
What is the dissociation constant?
- Kd is the dissociation constant. This is the constant which describes the drug / receptor interactions at equilibrium.
- The units for Kd are mol/L , i.e. units of concentration.
What is the association constant?
- It is the opposite of Kd; i.e. when a drug has a low Kd it has a high Ka(i.e. it binds avidly to the receptor).
- The colloquial term "affinity" is often used interchangeably with Ka; however affinity as a chemical definition is actually something slightly different.
What is meant by "affinity", with regards to drug-receptor interactions?
- Affinity is usually used to describe how avidly a drug binds to its receptor.
- This concept is borrowed from chemical physics and physical chemistry, where affinity is defined as the quantifiable representation of the tendency of dissimilar chemical species to form chemical compounds.
What are the determinants of affinity?
- The major factors which affect affinity and dissociation constant are
- Presence of a catalyst.
- The presence of a catalyst affects the activation energy for the reaction (Ea)
- In general, the rate of any reaction is determined by the Arrhenius equation, in which most factors are fixed constants (eg. the universal gas constant).