Pharmacodynamics and Pharmacokinetics Lecture

Flashcards covering key vocabulary, physiological constants, and graphical plots used in pharmacodynamics to quantify ligand-receptor interactions and affinity.

Endogenous mediator

Soluble substances, including proteins (cytokines), peptides (Annexin-A1), gases ($H_{2}S$), and Specialized Pro-resolving Mediators (SPMs), that control the inflammatory response within the body.

Pharmacodynamics

The branch of pharmacology studying the effect of chemical molecules (natural or synthetic) on living beings by targeting membrane receptors, enzymes, etc., using biochemistry, physiology, and electrophysiology.

Affinity

The strength of the non-covalent physicochemical interaction and recognition capacity between a ligand and a receptor; it is calculated as the inverse of the dissociation constant ($1/K_{D}$).

Selectivity

The property where a ligand has a preference for one receptor over another, which is also influenced by the ligand concentration.

Agonist

The result of binding between a ligand and a receptor that generates a biological response similar to that of an endogenous mediator.

Antagonist

An interaction where a ligand binds to a receptor but does not trigger a biological response, effectively blocking the effect of the endogenous mediator.

Inverse agonist

A drug that competes with a mediator for receptor binding and mediates a biological response opposite to that of an agonist.

Mass action law

A law describing a dynamic equilibrium between free and associated forms of ligand and receptor where at equilibrium: $[L] imes [R] imes k_{1} = [LR] imes k_{-1}$.

$K_{D}$ (Equilibrium dissociation constant)

The quantity of ligands required to occupy $50\%$ of receptors at equilibrium, extractable as $([L] imes [R]) / [LR] = k_{-1}/k_{1}$.

Occupancy theory (Clark, 1926)

The theory stating that the biological response is proportional to the percentage of occupied receptors, reaching a maximal response when $100\%$ of receptors are occupied.

$\alpha$ (Intrinsic activity factor)

A proportionality factor defined by Ariens (1954) describing a ligand's ability to stimulate tissues: full agonist ($\alpha = 1$), partial agonist (0 < \alpha < 1), antagonist ($\alpha = 0$), and inverse agonist (\alpha < 0).

Receptor reserve

The concept that a maximal response can be achieved with only a low proportion ($2-20\%$) of receptors occupied, leaving free receptors available.

$$EC_{50}$$

The effective concentration of an agonist needed to obtain $50\%$ of the maximal effect in an in vitro functional study.

$$pD_{2}$$

The negative logarithm of $EC_{50}$ ($pD_{2} = -\log_{10} (EC_{50})$); a higher $pD_{2}$ indicates higher potency/affinity.

Competitive antagonism

The binding of an antagonist to the agonist binding site, which shifts the dose-response curve to the right without changing the maximal effect.

Non-competitive antagonism

The binding of an antagonist to a receptor site distinct from the agonist site, resulting in a decrease of the maximal effect of the agonist.

$$pA_{2}$$

The negative logarithm of the molar concentration of an antagonist that causes a two-fold shift in the agonist concentration-response curve; used to measure antagonist potency.

Specific binding

Binding characterized by high affinity and saturability, occurring when a ligand directly binds to its intended receptor.

Non-specific binding

Binding to sites other than the specific receptor, characterized by low affinity and a non-saturable nature.

$$B_{max}$$

A parameter determined in binding studies representing the maximal number of receptors available in a tissue, cell, or membrane preparation.

Scatchard plot

A graphical method for determining $K_{D}$ and $B_{max}$ using the linear equation: $\frac{B}{F} = -\frac{1}{K_{D}} \times B + \frac{B_{max}}{K_{D}}$, where B is Bound and F is Free ligand.

Hill number ($n$)

The slope of a Hill plot ($\log_{10} (B/(B_{max}-B))$ vs $\log_{10} [L^*]$) where $n=1$ indicates no cooperativity and n>1 indicates positive cooperativity.

$$IC_{50}$$

Half maximal inhibitory concentration; the concentration of an unlabeled ligand that inhibits $50\%$ of the radioligand binding.

$K_{i}$ (Inhibition constant)

A corrected value determined in competition binding studies as $K_{i} = IC_{50} / (1 + ([L^*] / K_{D}))$ that characterizes ligand affinity regardless of radioligand concentration.