Intro to Drug Action (tbc)

Receptor is a class of cellular macromolecules that are concerned specifically and directly with chemical signalling.

1. They are finite; thus they should be saturable under high concentrations
2. They should display stereoselectivity i.e. recognise only one of the naturally occurring isomers of a ligand. (R/S or D/L)

1)Ligand gated ion-channel receptors 2) G protein-coupled receptors 3) Kinase linked receptors 4) Nuclear receptors

It is a class of cellular macromolecules that drugs can bind to and mediate chemical signalling. These include receptors, ion channels, enzymes and transport proteins.

A substance that is bound to a protein

Tendency of a ligand to bind to its receptor

any single synthetic or natural substance of known structure used in the treatment, prevention or diagnosis of disease.

An agonist is a drug in which the ligand binds to a receptor to produce a cellular response - Temporarily activate receptors by producing a conformational change - Possess affinity and efficacy

Efficacy is the tendency for an agonist to activate the receptor state resulting in a biological response.

Affinity is the strength of association between ligand and receptor (binding)

An antagonist is a drug that reduces, or blocks, the actions of an agonist by binding to the same receptor – do not activate them. It possesses affinity but not efficacy.

Selectivity is the ability of a drug to distinguish between different molecular targets within the body

At equilibrium, the rate of ligand and receptor complex being formed is equal to the rate of them dissociating.

It models the relationship between ligand concentration and receptor occupancy.

pAR=[A]/(KA+[A])

KA is the dissociation equilibrium constant and it is equal to the concentration of ligand required to occupy 50% of the receptors.

Simply put, when [A]=KA, pAR=0.5

The lower the KA, the greater the affinity of the ligand for the receptor.

pR is the proportion of free receptors. pR is equal to [R]/[Rt]. It is the concentration of free receptors in a solution. Rt is total receptors (free and occupied)

pAR is the proportion of occupied receptors (ligand and receptor complex) in a solution. pAR is equal to [AR]/[Rt]

Some agonists only need to occupy a small proportion of receptors to give the maximal response. It is because 1 agonist molecule can set off a signalling cascade that is progressively amplified within the cell (receptors have evolved to be efficient in gating cellular and tissue responses.

Half maximal inhibitory concentration is a measure of the potency of a substance in inhibiting a specific biological or biochemical function.

In order to achieve a tissue response:-

1. The ligand (A) and free receptor (R) combine to form a ligand receptor complex (AR)- a process which is governed by affinity.
2. The next process in which the ligand receptor complex becomes activated to form an activated receptor is governed by efficacy.

The two states of the ligand receptor complex and the activated receptor are the basis of the two state model.

Drug potency is an expression of the activity of a drug in terms of the concentration or amount needed to produce a defined effect such as EC50 for agonists.

Drug potency depends on both the receptor (in terms of affinity and efficacy) and tissue (receptor numbers, drug accessibility) parameters.

In order to treat asthma to the effect of bronchodilation, we could potentially use:-

1. Adrenaline- binds to and activates all adrenoreceptors- provides a full sympathetic physiological response with unwanted effects.
2. Isoprenaline- binds to activates beta 1 and beta 2 adrenoreceptors- provides bronchodilation but also causes tachycardia.
3. Salbutamol- Binds to and activates only beta 2 adrenoreceptor causing bronchodilation.

Salbutamol also has a lower potency than isoprenaline but we use it because it doesn't cause unnecessary side effects.

An agonist that in a given tissue cannot elicit a large enough effect (even when applied at high concentrations with 100% receptor occupancy) as another agonist acting through the same receptors in the same tissue.

Partial agonist has a sub-maximal response to a full agonist even at 100% receptor occupancy and high concentrations. Both agonist and partial agonist have same affinity but the full agonist has a higher efficacy.

A partial agonist such as pindolol occupies the beta 1 adrenoreceptors and prevents the adrenaline from binding with them and providing an effect. This allows it to reduce heart rate and blood pressure. The partial agonist acts as an antagonist in the presence of a full agonist like adrenaline.

Beta blockers like pindolol bind to beta 2 receptors and block the effect of adrenaline/noradrenaline and thereby causes vasodilation in smooth muscles

β1-Adrenergic receptors predominate in the heart and in the cerebral cortex, whereas β2-adrenergic receptors predominate in the lung and cerebellum. β-Adrenoceptors regulate many aspects of airway function, including airway smooth muscle tone, mast cell mediator release, and plasma exudation.

1. The antagonist competes with the agonist for the same binding site on the receptor.
2. The interaction between the antagonist and the receptor is reversible.
3. The agonist concentration-response curve is 'shifted to the right' without a change in maximal response or change in slope (i.e. the shape of the concentration response curve remains unchanged).
4. The antagonist's function is surmountable over a large range of concentrations.

1. The antagonist acts by combining with a separate inhibitory site on the receptor.
2. Thus, agonist and antagonist molecules can be bound to the receptor at the same time.
3. The receptor can become active only when the agonist site alone is occupied.
4. The antagonist action can be reversible or irreversible.

In this type of antagonism, the maximal response percentage is reduced. The antagonist action of an irreversible competitive antagonist is insurmountable over a range of agonist concentrations therefore it reduces the level of response potential.

1. Chemical antagonism
2. Physiological antagonism
3. Pharmacokinetic antagonism

The antagonist combines in solution directly with the chemical being antagonised (e.g. chelating agents used to treat lead poisoning bind to heavy metals and form a less toxic chelate).

Two agonists that produce opposing physiological actions and cancel each other out. Each drug acts through its own receptors (e.g. adrenaline relaxes bronchial smooth muscle reducing the bronchoconstriction of histamine).

The antagonist reduces the concentration of the active drug at its site of action (e.g. phenobarbitone increases hepatic metabolism of the anticoagulant drug warfarin).