Guide to pharmacology

The information is not intended to be an exhaustive list, but to provide assistance to those researchers who are new to this field of research.

Definitions of commonly used pharmacological terms

Agonist:
A drug capable of binding and activating a receptor, leading to a pharmacological response that may mimic that of a naturally occurring substance. Can be classified as full, partial or inverse.

• Full agonist - Capable of eliciting a maximal response as it displays full efficacy at that receptor.
• Partial agonist - Binds to and activates a receptor but is only able to elicit partial efficacy at that receptor. A maximal effect cannot be produced, even when the concentration is increased. When full and partial agonists are present the partial agonist may act as a competitive antagonist.
• Inverse agonist - Produces an effect that is pharmacologically opposite to an agonist, yet acts at the same receptor. The receptor must elicit intrinsic or basal activity in the absence of a ligand and the addition of an inverse agonist will decrease the activity below the basal level. A receptor that possesses basal activity is the GABA_A receptor; agonists have a sedative effect whilst inverse agonists have an anxiogenic effect.

 
Antagonist:
Does not produce a biological response on binding to a receptor but instead blocks or reduces the effect of an agonist. It may be competitive or non-competitive.

• Competitive antagonism - Drug binds selectively to a receptor without causing activation but in such a way to prevent binding of the agonist. The antagonism may be reversible; the effect can be overcome by increasing the concentration of the agonist, which will lead to a shift in the equilibrium.
• Non-competitive antagonism - A non-competitive antagonist may affect the reaction by binding to the active site of the receptor or to an allosteric site, therefore not competing with the agonist. The magnitude of the maximal response is reduced, regardless of the amount of agonist present.

 
Allosteric modulator:
A drug that binds to a receptor at a site distinct from the active site. A conformational change is induced in the receptor, altering the affinity of the receptor for the endogenous ligand.

• Positive allosteric modulators - Increase the affinity of the receptor for the endogenous ligand.
• Negative allosteric modulators - Decrease the affinity of the receptor for the endogenous ligand.

 
B_max:
Maximum amount of drug which can bind specifically to receptors in a membrane preparation. If one drug molecule binds to each receptor it acts as an indication of the concentration of receptors in the tissue.
 
Cheng-Prusoff equation:
Used to determine the K_i value from an IC₅₀ value.

Concentration response curve:
An example concentration response curve in a typical in vitro preparation. Curve A represents a full agonist (EC₅₀ = 3 x 10^-8 M) whilst curve B is a partial agonist acting on the same receptor.

Desensitization - A loss of responsiveness which may be due to the continued presence of an agonist at a receptor or repeated presentation of the agonist.
 
EC₅₀ - The molar concentration of an agonist that produces a 50% response of the maximum possible response for that agonist. Figures may also be stated as other percentages of the maximum response EC₂₀ and EC₈₀ representing a 20% and 80% response respectively.
 
ED₅₀ - Dose of drug that produces 50% of its maximum response or effect. Can be a term used in vitro or in vivo (although it is more common in vivo).
 
Efficacy - Used to describe agonist responses in relation to receptor occupation. High efficacy agonists can produce a maximal response whilst occupying a relatively low proportion of receptors. Low efficacy agonists are unable to cause receptor activation to the same degree and a maximal response may not be achieved even at full occupation of the entire receptor population. Low efficacy agonists are often termed partial agonist.
 
Ex vivo - Experimentation using tissue in an artificial environment outside the living organism. An example may include short-term (up to 24 hour) culture of tissue, following its removal from the organism.
 
Half-life (t½) - An important pharmacokinetic measurement. The metabolic half-life of a drug in vivo is the time taken for its concentration in plasma to decline to half its original level. t½ refers to the duration of action of a drug and depends upon how quickly the drug is eliminated from the plasma.
Clearance and distribution of a drug from the plasma are important parameters for half-life determination.

IC₅₀ - Molar concentration of an agonist or antagonist that causes 50% of the maximum possible inhibition. Figures may also be stated as other percentages of the inhibition.

In vitro - Studies carried out using components of an organism that have been isolated from their usual biological surroundings. The analysis is usually carried out in test-tubes or culture dishes.
 
In vivo - Experimentation using the whole living organism. Normal physiology will be involved in any response.

K_A - Equilibrium dissociation constant for an agonist; the concentration at which 50% of receptors would be occupied at equilibrium.
 
K_B - The equilibrium dissociation constant for a competitive antagonist; the concentration at which 50% of the receptors would be occupied at equilibrium.
 
K_d - The dissociation constant. Concentration of a drug which at equilibrium occupies 50% of receptors.
 
K_i - Inhibition constant for a drug where 50% of receptors will be occupied. Provides an absolute value and does not differ between experiments. Calculated from the IC₅₀ value using the Cheng-Prusoff equation.

Non-specific binding:
Proportion of radioligand that is not displaced by other competitive ligands that are specific for a particular receptor. It can be due to:

• Binding to other receptors or proteins
• Partitioning into lipids

pA₂ - Logarithmic measure of antagonist potency. It is the negative log of the molar concentration of an antagonist that would produce a 2-fold shift in the concentration response curve for an agonist.
 
pD₂ - Negative logarithm of the EC₅₀ or IC₅₀ value.
 
pEC₅₀ - Negative logarithm of the EC₅₀ value.
 
pIC₅₀ - Negative logarithm of the IC₅₀ value.
 
pK_A - Negative logarithmic measure of the potency of an antagonist.
 
pK_B - Negative logarithm of K_B value. For a competitive antagonist the pK_B theoretically equals the pA₂ value.
 
pK_d - Negative logarithm of the K_d value.
 
pK_i - Negative logarithm of the K_i value.
 
Potency:
Measure of the effective concentration of a drug. It is a vague term and it is advisable to further categorise the measurement:

• Agonists – EC₅₀, IC₅₀ or pD₂
• Antagonists – pA₂, K_B or pK_B

Occupancy - The proportion of receptors to which a drug is bound.

[D] = Drug concentration
K = Dissociation constant