Intro to Drug Action (tbc)

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What is a receptor? What are their characteristics?

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

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

What are the four structural classifications of receptors?

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

What is a drug target?

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.

Define a ligand

A substance that is bound to a protein Signup and view all the answers

What is affinity?

Tendency of a ligand to bind to its receptor Signup and view all the answers

What is a drug?

any single synthetic or natural substance of known structure used in the treatment, prevention or diagnosis of disease. Signup and view all the answers

What is an agonist?

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 Signup and view all the answers

What is efficacy in terms of drug action?

Efficacy is the tendency for an agonist to activate the receptor state resulting in a biological response. Signup and view all the answers

What is affinity in terms of drug action?

Affinity is the strength of association between ligand and receptor (binding) Signup and view all the answers

What is an antagonist?

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. Signup and view all the answers

What is selectivity?

Selectivity is the ability of a drug to distinguish between different molecular targets within the body Signup and view all the answers

What is the relationship between association and dissociation at equilibrium?

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

What is the Hill Langmuir equation?

It models the relationship between ligand concentration and receptor occupancy. pAR=[A]/(KA+[A]) Signup and view all the answers

What is KA? What is the relationship between KA and affinity of ligand for the receptor?

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. Signup and view all the answers

What is pR?

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) Signup and view all the answers

What is pAR?

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

What is the relationship between agonist binding and receptor activation?

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. Signup and view all the answers

What is IC50?

Half maximal inhibitory concentration is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. Signup and view all the answers

What is the two state model in receptor theory?

In order to achieve a tissue response:- <ol> <li>The ligand (A) and free receptor (R) combine to form a ligand receptor complex (AR)- a process which is governed by affinity.</li> <li>The next process in which the ligand receptor complex becomes activated to form an activated receptor is governed by efficacy.</li> </ol> The two states of the ligand receptor complex and the activated receptor are the basis of the two state model. Signup and view all the answers

What is drug potency?

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. Signup and view all the answers

What are the factors that drug potency is dependant on?

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

Give an example of a relationship between potency and selectivity. Also describe why one drug would be preferred over another in that case.

In order to treat asthma to the effect of bronchodilation, we could potentially use:- <ol> <li>Adrenaline- binds to and activates all adrenoreceptors- provides a full sympathetic physiological response with unwanted effects.</li> <li>Isoprenaline- binds to activates beta 1 and beta 2 adrenoreceptors- provides bronchodilation but also causes tachycardia.</li> <li>Salbutamol- Binds to and activates only beta 2 adrenoreceptor causing bronchodilation.</li> </ol> Salbutamol also has a lower potency than isoprenaline but we use it because it doesn't cause unnecessary side effects. Signup and view all the answers

What is a partial agonist?

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. Signup and view all the answers

What is the difference between full and partial agonist in the mechanisms?

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. Signup and view all the answers

How do partial agonists such as pindolol act on beta 1 adrenoreceptors?

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. Signup and view all the answers

How do beta blockers like pindolol work on beta 2 adrenoreceptors?

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

What is the difference between Beta 1 and beta 2 adrenergic receptors?

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. Signup and view all the answers

What is the mechanism of reversible competitive antagonism?

<ol> <li>The antagonist competes with the agonist for the same binding site on the receptor.</li> <li>The interaction between the antagonist and the receptor is reversible.</li> <li>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).</li> <li>The antagonist's function is surmountable over a large range of concentrations.</li> </ol> Signup and view all the answers

What is the mechanism of non-competitive antagonism?

<ol> <li>The antagonist acts by combining with a separate inhibitory site on the receptor.</li> <li>Thus, agonist and antagonist molecules can be bound to the receptor at the same time.</li> <li>The receptor can become active only when the agonist site alone is occupied.</li> <li>The antagonist action can be reversible or irreversible.</li> </ol> Signup and view all the answers

What is irreversible competitive antagonism?

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. Signup and view all the answers

What are some forms of antagonism not involving the receptor?

<ol> <li>Chemical antagonism</li> <li>Physiological antagonism</li> <li>Pharmacokinetic antagonism</li> </ol> Signup and view all the answers

What is chemical 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). Signup and view all the answers

What is physiological antagonism?

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). Signup and view all the answers

What is pharmacokinetic antagonism?

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). Signup and view all the answers